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Corporate Summary for Investors amp PartnersAugust 2017
2Executive Summary
P2 clinical-stage firm pooling dominant IP position in therapeutic uses of inhaled AND small molecule carbon monoxide Orphan Drug designation for IPF received
CO rationale supported by bull $227 million in ongoing NIH funding to scientific co-founder (Augustine Choi MD) to complete three P2
trials in iCO IPF ARDS PAH first two of these completed and positive
bull Over 50 preclinical studies and 12 investigator sponsored clinical trials completed to date
Acquisition of Alfama Inc (Lisbon Portugal) the dominant CO-releasing molecule (ldquoCORMrdquo) company completed May 2017 euro15 million of investment in CORM portfolio to date
Alfama acquisition involves $2 million commitment by Alfamarsquos largest shareholder (Portugal Ventures) to invest in Proterris Series A round
Lead clinical programs focused on acute indications (iCO for DGF in renal transplant recipients and CORM for acute liver failure) with chronic indications (eg IPF) available for partnering
Also pursuing CORM-focused spin-outs in oncology GI and neuroscience indications
Compared to NO proposition of Ikaria CO indicationcommercial potential far greater and CO far LESS toxic at therapeutic doses
Given data amp progress to date Proterris represents Ikaria-like value-creation opportunity for investors and partners bull March 2015 Mallinckrodt acquisition of Ikaria for $23 billion
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
3Proterrisrsquo Value Proposition
$23 million in NIH funding to Dr Choi to fund three first-in-human iCO clinical trials for IPF ARDS amp PAH
~euro15 million invested in Alfama(CORM company acquired by Proterris)
Positive results from completed NIH-funded P12a IPF amp ARDS trials
Globally dominant IP position in therapeutic uses of both gaseous amp CORM forms of CO
IPF Orphan Drug Designation received DGF Orphan Drug Designation submitted amp pending
Broad platform generating multiple ldquoshots-on-goalrdquo
Extensive pre-clinical validation of therapeutic CO potential in variety of transplant pulmonary vascular amp neuronal injury models
Extensive KOL support
4
bull
bull
bull
bull
bull
bull
bull
bull
bull
bull
bull
bull
bull
bull
Jeff Wager MD Chairman amp CEO
5
Matthew Bennett Director Served as CEO of CIOX Health Before that was
EVP Global Medical Operations amp Chief Legal Officer for Ikaria Inc also functioning as
CFO amp Head of Corporate Development Negotiated $23 billion sale of Ikaria to
Mallinckrodt Prior to Ikaria was EVP Chief Administrative amp Chief Legal Officer at
VIASYS Healthcare Inc (NYSE VAS) responsible for growth mergers and
acquisitions
Peter Hutt Director Chief Counsel of the FDA from 1971-1975 co-author of the
casebook used to teach food and drug law throughout the country Author of Medical
Devices Act external counsel to Ikaria Serves on boards of Moderna Seres and
American Sterilizer served on Boards of CV Therapeutics Momenta Pervasis IDEC
Parexel among many others Advisory board member to Polaris formerly New Leaf
Venture Partners Has participated in the drafting of most major FDA legislation
considered by Congress during the past 40 years served on several NIH advisory
committees and is a Legal Counsel to the American College of Toxicology and the
Society for Risk Analysis
Proterris Board Top-Tier Public Company
Ex-Ikaria amp Regulatory Leadership
Dr J Donald deBethizy Director Donald served as president and CEO of
Santaris Pharma AS until September 2014 and led the acquisition by Roche He
served as executive chairman of Contera Pharma ApS until its sale to Bukwang
Pharma in November 2014 Donald was co-founder and CEO of Targacept Inc listed
on NASDAQ Has served on the boards of Newron Pharma SpA arGEN-X NV
Rigontec GmbH and Serendex Pharma AS amongst others
6Key Proterris Co-Founders amp Shareholders
Augustine M K Choi MD Dean Weill Cornell Medical College World-renowned pulmonologist gt25 years of CO research inventor of core Proterris patents
David Pinsky MD Chief of Cardiovascular Medicine at the University of Michigan Scientific Director of the U-M Cardiovascular Center key inventor of Columbia CO patent covering DGF indication licensed to Proterris
Apeiron Partners LLC life science spin-out and advisory boutique headed by Proterris CEO Jeff Wager has closed transactionsfirms worth $15 billion since 2000
12th Man Technologies Inc former Advanced Technologies Respiratory Team of CareFusion gt 25 patentsapplications covering inhaled gaseous drug delivery extensive inhaled NO amp CO delivery experience
Columbia University Beth Israel Deconess Medical Center U of Pittsburgh Yale Johns Hopkins
Former shareholders of Alfama Inc
7
IND
Product Pipeline
iCO for IPF
2017 2018 2019 2020 2021 2022 2023
P2 Prep P2A P2B Prep NDA
2024 2025 2026
P3
iCO for DGF P2B3 Prep P2B3 NDAP3
iCO for AKI
iCO for RF
TBD
TBD
CO-RMs
for ALFNASHIND-enabling Preclin P1 TBD
8COrsquos Mechanism Of Action
In Indications Of Interest To Proterris
Confers potent anti-oxidant effects
Confers potent anti-inflammatory effects
Confers potent anti-apoptosis effects
Confers potent anti-proliferative effects
Confers cellular homeostasis and quiescence
9COrsquos General Mechanism Of Action in vivo
Vol 9 p728-743 (September 2010)
Vasoactive response
CO
Guanylyl cyclase
Potassium channels
NO by NOS
Activation
Induction
Repression
Redox control
CO
Mitochdrial ROS
NADPH oxidase
Cellular bioenergenix
Modulation of inflammation
CO
Pro-inflammatory
Genes (TNF iNOS)
Anti-inflammatory
Genes (IL10)
Cytoprotection
CO
PPARy and HIFla
Apoptosis
Mitochondrial biogenesis
Proliferation
CO gas
CO-RMs
10ALFAMA Has A Unique Collection
Of CO-RMs
gt850 molecules
Each will differ in
- Trigger for CO release
- CO release kinetics
- Pharmacokinetics
- Biodistribution
- Bioavailability
Many are
- easily modifiable
- simple to synthesize
- Inexpensive to produce
Alfamarsquos patent applications cover both the concept (use) and some new chemical
entities (substance of matter)
General scheme of Alfamarsquos pharmaceutical CO-RMs
11NIH-Funded Clinical Trials Granted to Dr Choi
(Proterris Co-Founder) Validates iCO Rx Opportunity
Idiopathic Pulmonary Fibrosis (IPF) bull ldquoA Phase 2 Trial of Carbon Monoxide for the Treatment of Idiopathic
Pulmonary Fibrosisrdquo (NIH U01HL105371)
bull Total Grant $621M
bull 58 patient study completed positive read-out May 2015
Adult Respiratory Distress Syndrome (ARDS)bull ldquoPhase 12 Study of Inhaled Carbon Monoxide for the Treatment of
Sepsis-Induced Adult Lung Injuryrdquo (NIH P01 HL108801)
bull Jul 2011 ndash Mar 2017
bull Total Grant $14M
Pulmonary Arterial Hypertension (PAH)bull ldquoHeme Oxygenase-1Carbon Monoxide in Lung Vascular Injuryrdquo
(NIH R01 HL060234)
bull March 2013 - June 2018
bull IND filed Mar 2017
bull Total Grant $25M
12Low-dose Inhaled CO is
SafeWell-Tolerated in Multiple Clinical Trials
No iCO-related SAEs in NIH-funded IPF P2 study run by Dr Choi after 12 wksof 2xwk dosing
Multiple smallshort dosing trials in healthy volunteers and subjects with a variety of conditions have supported the safety of inhaled CO in the 100-400 ppm range to achieve a [COHb] in 4-10 range bull COPD
bull (Kerstjens et al Eur Respir J 2007 30 1131ndash1137)
bull Healthy subjects with exercisebull (Med Sci Sports Exerc 2012 Nov44(11)2118-24)
bull Healthy subjects exposed to 500 ppm for 1 hour then challenged with LPS bull (Am J Respir Crit Care Med Vol 171 pp 354ndash360 2005)
bull Colon-surgery patients at risk for paralytic Ileusbull (ClinicalTrialsgov identifier NCT01050712)
bull Retinal Blood flow studies in healthy volunteersbull (Invest OphthalmolVis Sci 2005464275ndash4280)
Inhaled CO use in pulmonary function labs for assessment of lung diffusion capacity has long been standard and safe
13Clinical Development Strategy
Significantly leverages extensive (~$23 million) of NIH funding to de-risk early stage clinical development risk
All indications being pursued are Orphan-qualifying
Balances smaller market size near-term acute indications (DGF acute liver failure) with chronic multi-$B indications (eg IPF NASH renal fibrosis others)
Significant DGF labeling-claim expansion opportunity following approval slow-graft function (SGF) acute kidney injury (AKI) delay of ESRD-associated dialysis renal fibrosis
CORM development offers life-cycle management with ivorally bioavailable next-gen CO therapeutics
14
bull Over half of the 13K US cadaveric
kidney transplants per year lead to
delayedslow graft function (DGFSGF)
bull DGF significantly increases risk of
acute and chronic rejection episodes
bull An iCo treatment for DGF would allow a
larger proportion of allografts from
donors after cardiac death (DCD) and
extended criteria donors (ECD) which
currently have a higher DGF and IRI risk
bull DGF increases post-surgical costs by
$4K+ increases post-transplant hospital
stay (usually 5-10 days) by up to 75
bull Over five years post-transplant DGF
patients had significantly higher time on
dialysis transplant rejection and mortality
bull An effective therapy for DGF would
significantly increase viable donor
organ pool and increase utilization of
those from extended criteria donors (many
currently unusable and are discarded)
bull There are ~13K cadaveric donor kidney transplants per year in US ~15K per year in
Canada and ~14K per year in the EU ndash incidence of DGF precludes larger numbers
bull By reducing ECD DGF iCO would shorten transplant wait times reduce
morbiditymortality on dialysis reduce effective cost of successful transplants
bull iCO for DGF could reach $300M+ annual revenues with less than one-third transplant
penetration for hospital treatment and one-third of those moving on to home treatment
Opportunity in Delayed Graft Function (DGF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwvalueinhealthjournalcomarticleS1098-3015(14)01756-2pdf [2] httpwwwncbinlmnihgovpubmed23538345
15
bull Idiopathic Pulmonary Fibrosis
progressive deterioration of lung
function and near-universal mortality
within five years from onset
bull No known cause no cure
bull Mean survival time only 38 years
bull Two recently approved medications only
moderately slow progression with
significant adverse effects seen in trials
bull Most of pipeline targets one mechanism
bull Recently approved medications Ofev
(nintendanib BI) and Esbriet (pirfenidone
Roche) priced at nearly $100Kyear
bull The only fully effective treatment a double-
lung transplant costs ~$800K end-to-end
bull CO for IPF offers
bull Synergy with OfevEsbriet
bull Improved disease progression
bull Lower all-in cost per year
bull Easier dosing schedule
(3xweek vs twice daily)
bull Prevalence of IPF is gt120K in US gt20K in Canada gt150K in Europe 20K in Japan
bull Clinicians estimate 70 of IPF patients are early-enough in disease progression to see
meaningful clinical improvement from stoppingslowing fibrosis expansion
bull Even at half or less Ofev pricing $2B annual revenues could be reached with only
30 patient penetration in only the three markets listed above
Opportunity in Idiopathic Pulmonary
Fibrosis (IPF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwaafporgafp20121001p631html [2] httpwwwniddknihgovhealth-informationhealth-statisticsPageskidney-disease-statistics-united-statesaspx [3] httpjasnasnjournalsorgcontent16113365fullpdf
16
RENAL PROGRAMS
17Increasing Use of Kidneys at Risk for DGF
17
Adult solitary primary kidney transplants
Source UNOSOPTN data as of April 29 2011
Note ECD kidneys are reluctantly utilized due to higher incidences and prevalence of DGF SGF AR CR etc
+ 14
+ 296
18iCO for Delayed Graft Function in
Renal Transplant Patients
Growing unmet need ~50K renal transplantsyear in both the US and EU ~10K ROW
No approved drugs
Recent transplant advances make therapies to prevent rejection and late or non-function more criticalbull Allowinguarr transplantation of organs from extended criteria and cardiac death donors
bull Allowinguarrtransplant of organs with longer warm and cold ischemia times
In several animal models inhaled CO dramatically darrs frequency and duration of delayed graft function (DGF)bull Multiple predictive animal models of CO administration demonstrated acute ischemia reperfusion injury
recovery and chronic allograft rejection (CAN) preventionmitigation
CO therapy at time of transplant feasible add-on to existing Rxbull short intra- or perioperative courses of Rx
Substantial benefit to patients payers and hospitalsbull Prevents or shortens need for dialysis biopsies ICU days etc
bull Allows earlier hospital discharge
Substantial label-expansion potential for acute and longer-term bull Chronic allograft nephropathy (CAN)
bull Acute kidney injury (AKI)
bull Renal fibrosis
19Inhaled CO
Pig Allo-transplantation Model
Warm and cold ischemia
bull 60 minutes of warm ischemia aortic cross-clamping
bull 24 hours cold storage in UW
Allo-transplantation after bilateral nephrectomy
CO delivered through ventilator for one hour starting at
incision (3mgkg with 40 FiO2)
Tacrolimus immunosuppression
Hanto et al AJT 2010
20Intraoperative Inhaled CO
Accelerates Renal Recovery from IRI
BUN Cr
Hanto et al AJT 2010
CoHb Levels
21Inhaled CO Improves
Histology and Reduces Apoptosis
Hanto et al AJT 2010
22Inhaled CO Increases
Proliferation and Reduces Inflammation
Hanto et al AJT 2010
Phospho-
histone 3
Tissue
Factor
23Inhaled CO Induces Changes
in Tissue Gene Expression
HSP 90Retinol binding
protein 4
MCP-1Osteopontin
Hanto et al AJT 2010
QT-PCR Confirmation
24Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Lewis to Brown Norway orthotopic kidney transplant
model following bilateral nephrectomy
Brief FK (05mgkg day 0-6)
Continuous CO exposure in CO chamber (20 ppm) days
60-150
Other exposure regimens
bull Continuous exposures days 0-30 30-60 or 0-90
bull 1hr daily CO (250 ppm) days 0-90
Nakao et al Am J Physiology 2009
25Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Nakao et al Am J Physiology 2009
Graft function CAN by histology Expression of
fibrosis genes
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
2Executive Summary
P2 clinical-stage firm pooling dominant IP position in therapeutic uses of inhaled AND small molecule carbon monoxide Orphan Drug designation for IPF received
CO rationale supported by bull $227 million in ongoing NIH funding to scientific co-founder (Augustine Choi MD) to complete three P2
trials in iCO IPF ARDS PAH first two of these completed and positive
bull Over 50 preclinical studies and 12 investigator sponsored clinical trials completed to date
Acquisition of Alfama Inc (Lisbon Portugal) the dominant CO-releasing molecule (ldquoCORMrdquo) company completed May 2017 euro15 million of investment in CORM portfolio to date
Alfama acquisition involves $2 million commitment by Alfamarsquos largest shareholder (Portugal Ventures) to invest in Proterris Series A round
Lead clinical programs focused on acute indications (iCO for DGF in renal transplant recipients and CORM for acute liver failure) with chronic indications (eg IPF) available for partnering
Also pursuing CORM-focused spin-outs in oncology GI and neuroscience indications
Compared to NO proposition of Ikaria CO indicationcommercial potential far greater and CO far LESS toxic at therapeutic doses
Given data amp progress to date Proterris represents Ikaria-like value-creation opportunity for investors and partners bull March 2015 Mallinckrodt acquisition of Ikaria for $23 billion
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
3Proterrisrsquo Value Proposition
$23 million in NIH funding to Dr Choi to fund three first-in-human iCO clinical trials for IPF ARDS amp PAH
~euro15 million invested in Alfama(CORM company acquired by Proterris)
Positive results from completed NIH-funded P12a IPF amp ARDS trials
Globally dominant IP position in therapeutic uses of both gaseous amp CORM forms of CO
IPF Orphan Drug Designation received DGF Orphan Drug Designation submitted amp pending
Broad platform generating multiple ldquoshots-on-goalrdquo
Extensive pre-clinical validation of therapeutic CO potential in variety of transplant pulmonary vascular amp neuronal injury models
Extensive KOL support
4
bull
bull
bull
bull
bull
bull
bull
bull
bull
bull
bull
bull
bull
bull
Jeff Wager MD Chairman amp CEO
5
Matthew Bennett Director Served as CEO of CIOX Health Before that was
EVP Global Medical Operations amp Chief Legal Officer for Ikaria Inc also functioning as
CFO amp Head of Corporate Development Negotiated $23 billion sale of Ikaria to
Mallinckrodt Prior to Ikaria was EVP Chief Administrative amp Chief Legal Officer at
VIASYS Healthcare Inc (NYSE VAS) responsible for growth mergers and
acquisitions
Peter Hutt Director Chief Counsel of the FDA from 1971-1975 co-author of the
casebook used to teach food and drug law throughout the country Author of Medical
Devices Act external counsel to Ikaria Serves on boards of Moderna Seres and
American Sterilizer served on Boards of CV Therapeutics Momenta Pervasis IDEC
Parexel among many others Advisory board member to Polaris formerly New Leaf
Venture Partners Has participated in the drafting of most major FDA legislation
considered by Congress during the past 40 years served on several NIH advisory
committees and is a Legal Counsel to the American College of Toxicology and the
Society for Risk Analysis
Proterris Board Top-Tier Public Company
Ex-Ikaria amp Regulatory Leadership
Dr J Donald deBethizy Director Donald served as president and CEO of
Santaris Pharma AS until September 2014 and led the acquisition by Roche He
served as executive chairman of Contera Pharma ApS until its sale to Bukwang
Pharma in November 2014 Donald was co-founder and CEO of Targacept Inc listed
on NASDAQ Has served on the boards of Newron Pharma SpA arGEN-X NV
Rigontec GmbH and Serendex Pharma AS amongst others
6Key Proterris Co-Founders amp Shareholders
Augustine M K Choi MD Dean Weill Cornell Medical College World-renowned pulmonologist gt25 years of CO research inventor of core Proterris patents
David Pinsky MD Chief of Cardiovascular Medicine at the University of Michigan Scientific Director of the U-M Cardiovascular Center key inventor of Columbia CO patent covering DGF indication licensed to Proterris
Apeiron Partners LLC life science spin-out and advisory boutique headed by Proterris CEO Jeff Wager has closed transactionsfirms worth $15 billion since 2000
12th Man Technologies Inc former Advanced Technologies Respiratory Team of CareFusion gt 25 patentsapplications covering inhaled gaseous drug delivery extensive inhaled NO amp CO delivery experience
Columbia University Beth Israel Deconess Medical Center U of Pittsburgh Yale Johns Hopkins
Former shareholders of Alfama Inc
7
IND
Product Pipeline
iCO for IPF
2017 2018 2019 2020 2021 2022 2023
P2 Prep P2A P2B Prep NDA
2024 2025 2026
P3
iCO for DGF P2B3 Prep P2B3 NDAP3
iCO for AKI
iCO for RF
TBD
TBD
CO-RMs
for ALFNASHIND-enabling Preclin P1 TBD
8COrsquos Mechanism Of Action
In Indications Of Interest To Proterris
Confers potent anti-oxidant effects
Confers potent anti-inflammatory effects
Confers potent anti-apoptosis effects
Confers potent anti-proliferative effects
Confers cellular homeostasis and quiescence
9COrsquos General Mechanism Of Action in vivo
Vol 9 p728-743 (September 2010)
Vasoactive response
CO
Guanylyl cyclase
Potassium channels
NO by NOS
Activation
Induction
Repression
Redox control
CO
Mitochdrial ROS
NADPH oxidase
Cellular bioenergenix
Modulation of inflammation
CO
Pro-inflammatory
Genes (TNF iNOS)
Anti-inflammatory
Genes (IL10)
Cytoprotection
CO
PPARy and HIFla
Apoptosis
Mitochondrial biogenesis
Proliferation
CO gas
CO-RMs
10ALFAMA Has A Unique Collection
Of CO-RMs
gt850 molecules
Each will differ in
- Trigger for CO release
- CO release kinetics
- Pharmacokinetics
- Biodistribution
- Bioavailability
Many are
- easily modifiable
- simple to synthesize
- Inexpensive to produce
Alfamarsquos patent applications cover both the concept (use) and some new chemical
entities (substance of matter)
General scheme of Alfamarsquos pharmaceutical CO-RMs
11NIH-Funded Clinical Trials Granted to Dr Choi
(Proterris Co-Founder) Validates iCO Rx Opportunity
Idiopathic Pulmonary Fibrosis (IPF) bull ldquoA Phase 2 Trial of Carbon Monoxide for the Treatment of Idiopathic
Pulmonary Fibrosisrdquo (NIH U01HL105371)
bull Total Grant $621M
bull 58 patient study completed positive read-out May 2015
Adult Respiratory Distress Syndrome (ARDS)bull ldquoPhase 12 Study of Inhaled Carbon Monoxide for the Treatment of
Sepsis-Induced Adult Lung Injuryrdquo (NIH P01 HL108801)
bull Jul 2011 ndash Mar 2017
bull Total Grant $14M
Pulmonary Arterial Hypertension (PAH)bull ldquoHeme Oxygenase-1Carbon Monoxide in Lung Vascular Injuryrdquo
(NIH R01 HL060234)
bull March 2013 - June 2018
bull IND filed Mar 2017
bull Total Grant $25M
12Low-dose Inhaled CO is
SafeWell-Tolerated in Multiple Clinical Trials
No iCO-related SAEs in NIH-funded IPF P2 study run by Dr Choi after 12 wksof 2xwk dosing
Multiple smallshort dosing trials in healthy volunteers and subjects with a variety of conditions have supported the safety of inhaled CO in the 100-400 ppm range to achieve a [COHb] in 4-10 range bull COPD
bull (Kerstjens et al Eur Respir J 2007 30 1131ndash1137)
bull Healthy subjects with exercisebull (Med Sci Sports Exerc 2012 Nov44(11)2118-24)
bull Healthy subjects exposed to 500 ppm for 1 hour then challenged with LPS bull (Am J Respir Crit Care Med Vol 171 pp 354ndash360 2005)
bull Colon-surgery patients at risk for paralytic Ileusbull (ClinicalTrialsgov identifier NCT01050712)
bull Retinal Blood flow studies in healthy volunteersbull (Invest OphthalmolVis Sci 2005464275ndash4280)
Inhaled CO use in pulmonary function labs for assessment of lung diffusion capacity has long been standard and safe
13Clinical Development Strategy
Significantly leverages extensive (~$23 million) of NIH funding to de-risk early stage clinical development risk
All indications being pursued are Orphan-qualifying
Balances smaller market size near-term acute indications (DGF acute liver failure) with chronic multi-$B indications (eg IPF NASH renal fibrosis others)
Significant DGF labeling-claim expansion opportunity following approval slow-graft function (SGF) acute kidney injury (AKI) delay of ESRD-associated dialysis renal fibrosis
CORM development offers life-cycle management with ivorally bioavailable next-gen CO therapeutics
14
bull Over half of the 13K US cadaveric
kidney transplants per year lead to
delayedslow graft function (DGFSGF)
bull DGF significantly increases risk of
acute and chronic rejection episodes
bull An iCo treatment for DGF would allow a
larger proportion of allografts from
donors after cardiac death (DCD) and
extended criteria donors (ECD) which
currently have a higher DGF and IRI risk
bull DGF increases post-surgical costs by
$4K+ increases post-transplant hospital
stay (usually 5-10 days) by up to 75
bull Over five years post-transplant DGF
patients had significantly higher time on
dialysis transplant rejection and mortality
bull An effective therapy for DGF would
significantly increase viable donor
organ pool and increase utilization of
those from extended criteria donors (many
currently unusable and are discarded)
bull There are ~13K cadaveric donor kidney transplants per year in US ~15K per year in
Canada and ~14K per year in the EU ndash incidence of DGF precludes larger numbers
bull By reducing ECD DGF iCO would shorten transplant wait times reduce
morbiditymortality on dialysis reduce effective cost of successful transplants
bull iCO for DGF could reach $300M+ annual revenues with less than one-third transplant
penetration for hospital treatment and one-third of those moving on to home treatment
Opportunity in Delayed Graft Function (DGF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwvalueinhealthjournalcomarticleS1098-3015(14)01756-2pdf [2] httpwwwncbinlmnihgovpubmed23538345
15
bull Idiopathic Pulmonary Fibrosis
progressive deterioration of lung
function and near-universal mortality
within five years from onset
bull No known cause no cure
bull Mean survival time only 38 years
bull Two recently approved medications only
moderately slow progression with
significant adverse effects seen in trials
bull Most of pipeline targets one mechanism
bull Recently approved medications Ofev
(nintendanib BI) and Esbriet (pirfenidone
Roche) priced at nearly $100Kyear
bull The only fully effective treatment a double-
lung transplant costs ~$800K end-to-end
bull CO for IPF offers
bull Synergy with OfevEsbriet
bull Improved disease progression
bull Lower all-in cost per year
bull Easier dosing schedule
(3xweek vs twice daily)
bull Prevalence of IPF is gt120K in US gt20K in Canada gt150K in Europe 20K in Japan
bull Clinicians estimate 70 of IPF patients are early-enough in disease progression to see
meaningful clinical improvement from stoppingslowing fibrosis expansion
bull Even at half or less Ofev pricing $2B annual revenues could be reached with only
30 patient penetration in only the three markets listed above
Opportunity in Idiopathic Pulmonary
Fibrosis (IPF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwaafporgafp20121001p631html [2] httpwwwniddknihgovhealth-informationhealth-statisticsPageskidney-disease-statistics-united-statesaspx [3] httpjasnasnjournalsorgcontent16113365fullpdf
16
RENAL PROGRAMS
17Increasing Use of Kidneys at Risk for DGF
17
Adult solitary primary kidney transplants
Source UNOSOPTN data as of April 29 2011
Note ECD kidneys are reluctantly utilized due to higher incidences and prevalence of DGF SGF AR CR etc
+ 14
+ 296
18iCO for Delayed Graft Function in
Renal Transplant Patients
Growing unmet need ~50K renal transplantsyear in both the US and EU ~10K ROW
No approved drugs
Recent transplant advances make therapies to prevent rejection and late or non-function more criticalbull Allowinguarr transplantation of organs from extended criteria and cardiac death donors
bull Allowinguarrtransplant of organs with longer warm and cold ischemia times
In several animal models inhaled CO dramatically darrs frequency and duration of delayed graft function (DGF)bull Multiple predictive animal models of CO administration demonstrated acute ischemia reperfusion injury
recovery and chronic allograft rejection (CAN) preventionmitigation
CO therapy at time of transplant feasible add-on to existing Rxbull short intra- or perioperative courses of Rx
Substantial benefit to patients payers and hospitalsbull Prevents or shortens need for dialysis biopsies ICU days etc
bull Allows earlier hospital discharge
Substantial label-expansion potential for acute and longer-term bull Chronic allograft nephropathy (CAN)
bull Acute kidney injury (AKI)
bull Renal fibrosis
19Inhaled CO
Pig Allo-transplantation Model
Warm and cold ischemia
bull 60 minutes of warm ischemia aortic cross-clamping
bull 24 hours cold storage in UW
Allo-transplantation after bilateral nephrectomy
CO delivered through ventilator for one hour starting at
incision (3mgkg with 40 FiO2)
Tacrolimus immunosuppression
Hanto et al AJT 2010
20Intraoperative Inhaled CO
Accelerates Renal Recovery from IRI
BUN Cr
Hanto et al AJT 2010
CoHb Levels
21Inhaled CO Improves
Histology and Reduces Apoptosis
Hanto et al AJT 2010
22Inhaled CO Increases
Proliferation and Reduces Inflammation
Hanto et al AJT 2010
Phospho-
histone 3
Tissue
Factor
23Inhaled CO Induces Changes
in Tissue Gene Expression
HSP 90Retinol binding
protein 4
MCP-1Osteopontin
Hanto et al AJT 2010
QT-PCR Confirmation
24Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Lewis to Brown Norway orthotopic kidney transplant
model following bilateral nephrectomy
Brief FK (05mgkg day 0-6)
Continuous CO exposure in CO chamber (20 ppm) days
60-150
Other exposure regimens
bull Continuous exposures days 0-30 30-60 or 0-90
bull 1hr daily CO (250 ppm) days 0-90
Nakao et al Am J Physiology 2009
25Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Nakao et al Am J Physiology 2009
Graft function CAN by histology Expression of
fibrosis genes
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
3Proterrisrsquo Value Proposition
$23 million in NIH funding to Dr Choi to fund three first-in-human iCO clinical trials for IPF ARDS amp PAH
~euro15 million invested in Alfama(CORM company acquired by Proterris)
Positive results from completed NIH-funded P12a IPF amp ARDS trials
Globally dominant IP position in therapeutic uses of both gaseous amp CORM forms of CO
IPF Orphan Drug Designation received DGF Orphan Drug Designation submitted amp pending
Broad platform generating multiple ldquoshots-on-goalrdquo
Extensive pre-clinical validation of therapeutic CO potential in variety of transplant pulmonary vascular amp neuronal injury models
Extensive KOL support
4
bull
bull
bull
bull
bull
bull
bull
bull
bull
bull
bull
bull
bull
bull
Jeff Wager MD Chairman amp CEO
5
Matthew Bennett Director Served as CEO of CIOX Health Before that was
EVP Global Medical Operations amp Chief Legal Officer for Ikaria Inc also functioning as
CFO amp Head of Corporate Development Negotiated $23 billion sale of Ikaria to
Mallinckrodt Prior to Ikaria was EVP Chief Administrative amp Chief Legal Officer at
VIASYS Healthcare Inc (NYSE VAS) responsible for growth mergers and
acquisitions
Peter Hutt Director Chief Counsel of the FDA from 1971-1975 co-author of the
casebook used to teach food and drug law throughout the country Author of Medical
Devices Act external counsel to Ikaria Serves on boards of Moderna Seres and
American Sterilizer served on Boards of CV Therapeutics Momenta Pervasis IDEC
Parexel among many others Advisory board member to Polaris formerly New Leaf
Venture Partners Has participated in the drafting of most major FDA legislation
considered by Congress during the past 40 years served on several NIH advisory
committees and is a Legal Counsel to the American College of Toxicology and the
Society for Risk Analysis
Proterris Board Top-Tier Public Company
Ex-Ikaria amp Regulatory Leadership
Dr J Donald deBethizy Director Donald served as president and CEO of
Santaris Pharma AS until September 2014 and led the acquisition by Roche He
served as executive chairman of Contera Pharma ApS until its sale to Bukwang
Pharma in November 2014 Donald was co-founder and CEO of Targacept Inc listed
on NASDAQ Has served on the boards of Newron Pharma SpA arGEN-X NV
Rigontec GmbH and Serendex Pharma AS amongst others
6Key Proterris Co-Founders amp Shareholders
Augustine M K Choi MD Dean Weill Cornell Medical College World-renowned pulmonologist gt25 years of CO research inventor of core Proterris patents
David Pinsky MD Chief of Cardiovascular Medicine at the University of Michigan Scientific Director of the U-M Cardiovascular Center key inventor of Columbia CO patent covering DGF indication licensed to Proterris
Apeiron Partners LLC life science spin-out and advisory boutique headed by Proterris CEO Jeff Wager has closed transactionsfirms worth $15 billion since 2000
12th Man Technologies Inc former Advanced Technologies Respiratory Team of CareFusion gt 25 patentsapplications covering inhaled gaseous drug delivery extensive inhaled NO amp CO delivery experience
Columbia University Beth Israel Deconess Medical Center U of Pittsburgh Yale Johns Hopkins
Former shareholders of Alfama Inc
7
IND
Product Pipeline
iCO for IPF
2017 2018 2019 2020 2021 2022 2023
P2 Prep P2A P2B Prep NDA
2024 2025 2026
P3
iCO for DGF P2B3 Prep P2B3 NDAP3
iCO for AKI
iCO for RF
TBD
TBD
CO-RMs
for ALFNASHIND-enabling Preclin P1 TBD
8COrsquos Mechanism Of Action
In Indications Of Interest To Proterris
Confers potent anti-oxidant effects
Confers potent anti-inflammatory effects
Confers potent anti-apoptosis effects
Confers potent anti-proliferative effects
Confers cellular homeostasis and quiescence
9COrsquos General Mechanism Of Action in vivo
Vol 9 p728-743 (September 2010)
Vasoactive response
CO
Guanylyl cyclase
Potassium channels
NO by NOS
Activation
Induction
Repression
Redox control
CO
Mitochdrial ROS
NADPH oxidase
Cellular bioenergenix
Modulation of inflammation
CO
Pro-inflammatory
Genes (TNF iNOS)
Anti-inflammatory
Genes (IL10)
Cytoprotection
CO
PPARy and HIFla
Apoptosis
Mitochondrial biogenesis
Proliferation
CO gas
CO-RMs
10ALFAMA Has A Unique Collection
Of CO-RMs
gt850 molecules
Each will differ in
- Trigger for CO release
- CO release kinetics
- Pharmacokinetics
- Biodistribution
- Bioavailability
Many are
- easily modifiable
- simple to synthesize
- Inexpensive to produce
Alfamarsquos patent applications cover both the concept (use) and some new chemical
entities (substance of matter)
General scheme of Alfamarsquos pharmaceutical CO-RMs
11NIH-Funded Clinical Trials Granted to Dr Choi
(Proterris Co-Founder) Validates iCO Rx Opportunity
Idiopathic Pulmonary Fibrosis (IPF) bull ldquoA Phase 2 Trial of Carbon Monoxide for the Treatment of Idiopathic
Pulmonary Fibrosisrdquo (NIH U01HL105371)
bull Total Grant $621M
bull 58 patient study completed positive read-out May 2015
Adult Respiratory Distress Syndrome (ARDS)bull ldquoPhase 12 Study of Inhaled Carbon Monoxide for the Treatment of
Sepsis-Induced Adult Lung Injuryrdquo (NIH P01 HL108801)
bull Jul 2011 ndash Mar 2017
bull Total Grant $14M
Pulmonary Arterial Hypertension (PAH)bull ldquoHeme Oxygenase-1Carbon Monoxide in Lung Vascular Injuryrdquo
(NIH R01 HL060234)
bull March 2013 - June 2018
bull IND filed Mar 2017
bull Total Grant $25M
12Low-dose Inhaled CO is
SafeWell-Tolerated in Multiple Clinical Trials
No iCO-related SAEs in NIH-funded IPF P2 study run by Dr Choi after 12 wksof 2xwk dosing
Multiple smallshort dosing trials in healthy volunteers and subjects with a variety of conditions have supported the safety of inhaled CO in the 100-400 ppm range to achieve a [COHb] in 4-10 range bull COPD
bull (Kerstjens et al Eur Respir J 2007 30 1131ndash1137)
bull Healthy subjects with exercisebull (Med Sci Sports Exerc 2012 Nov44(11)2118-24)
bull Healthy subjects exposed to 500 ppm for 1 hour then challenged with LPS bull (Am J Respir Crit Care Med Vol 171 pp 354ndash360 2005)
bull Colon-surgery patients at risk for paralytic Ileusbull (ClinicalTrialsgov identifier NCT01050712)
bull Retinal Blood flow studies in healthy volunteersbull (Invest OphthalmolVis Sci 2005464275ndash4280)
Inhaled CO use in pulmonary function labs for assessment of lung diffusion capacity has long been standard and safe
13Clinical Development Strategy
Significantly leverages extensive (~$23 million) of NIH funding to de-risk early stage clinical development risk
All indications being pursued are Orphan-qualifying
Balances smaller market size near-term acute indications (DGF acute liver failure) with chronic multi-$B indications (eg IPF NASH renal fibrosis others)
Significant DGF labeling-claim expansion opportunity following approval slow-graft function (SGF) acute kidney injury (AKI) delay of ESRD-associated dialysis renal fibrosis
CORM development offers life-cycle management with ivorally bioavailable next-gen CO therapeutics
14
bull Over half of the 13K US cadaveric
kidney transplants per year lead to
delayedslow graft function (DGFSGF)
bull DGF significantly increases risk of
acute and chronic rejection episodes
bull An iCo treatment for DGF would allow a
larger proportion of allografts from
donors after cardiac death (DCD) and
extended criteria donors (ECD) which
currently have a higher DGF and IRI risk
bull DGF increases post-surgical costs by
$4K+ increases post-transplant hospital
stay (usually 5-10 days) by up to 75
bull Over five years post-transplant DGF
patients had significantly higher time on
dialysis transplant rejection and mortality
bull An effective therapy for DGF would
significantly increase viable donor
organ pool and increase utilization of
those from extended criteria donors (many
currently unusable and are discarded)
bull There are ~13K cadaveric donor kidney transplants per year in US ~15K per year in
Canada and ~14K per year in the EU ndash incidence of DGF precludes larger numbers
bull By reducing ECD DGF iCO would shorten transplant wait times reduce
morbiditymortality on dialysis reduce effective cost of successful transplants
bull iCO for DGF could reach $300M+ annual revenues with less than one-third transplant
penetration for hospital treatment and one-third of those moving on to home treatment
Opportunity in Delayed Graft Function (DGF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwvalueinhealthjournalcomarticleS1098-3015(14)01756-2pdf [2] httpwwwncbinlmnihgovpubmed23538345
15
bull Idiopathic Pulmonary Fibrosis
progressive deterioration of lung
function and near-universal mortality
within five years from onset
bull No known cause no cure
bull Mean survival time only 38 years
bull Two recently approved medications only
moderately slow progression with
significant adverse effects seen in trials
bull Most of pipeline targets one mechanism
bull Recently approved medications Ofev
(nintendanib BI) and Esbriet (pirfenidone
Roche) priced at nearly $100Kyear
bull The only fully effective treatment a double-
lung transplant costs ~$800K end-to-end
bull CO for IPF offers
bull Synergy with OfevEsbriet
bull Improved disease progression
bull Lower all-in cost per year
bull Easier dosing schedule
(3xweek vs twice daily)
bull Prevalence of IPF is gt120K in US gt20K in Canada gt150K in Europe 20K in Japan
bull Clinicians estimate 70 of IPF patients are early-enough in disease progression to see
meaningful clinical improvement from stoppingslowing fibrosis expansion
bull Even at half or less Ofev pricing $2B annual revenues could be reached with only
30 patient penetration in only the three markets listed above
Opportunity in Idiopathic Pulmonary
Fibrosis (IPF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwaafporgafp20121001p631html [2] httpwwwniddknihgovhealth-informationhealth-statisticsPageskidney-disease-statistics-united-statesaspx [3] httpjasnasnjournalsorgcontent16113365fullpdf
16
RENAL PROGRAMS
17Increasing Use of Kidneys at Risk for DGF
17
Adult solitary primary kidney transplants
Source UNOSOPTN data as of April 29 2011
Note ECD kidneys are reluctantly utilized due to higher incidences and prevalence of DGF SGF AR CR etc
+ 14
+ 296
18iCO for Delayed Graft Function in
Renal Transplant Patients
Growing unmet need ~50K renal transplantsyear in both the US and EU ~10K ROW
No approved drugs
Recent transplant advances make therapies to prevent rejection and late or non-function more criticalbull Allowinguarr transplantation of organs from extended criteria and cardiac death donors
bull Allowinguarrtransplant of organs with longer warm and cold ischemia times
In several animal models inhaled CO dramatically darrs frequency and duration of delayed graft function (DGF)bull Multiple predictive animal models of CO administration demonstrated acute ischemia reperfusion injury
recovery and chronic allograft rejection (CAN) preventionmitigation
CO therapy at time of transplant feasible add-on to existing Rxbull short intra- or perioperative courses of Rx
Substantial benefit to patients payers and hospitalsbull Prevents or shortens need for dialysis biopsies ICU days etc
bull Allows earlier hospital discharge
Substantial label-expansion potential for acute and longer-term bull Chronic allograft nephropathy (CAN)
bull Acute kidney injury (AKI)
bull Renal fibrosis
19Inhaled CO
Pig Allo-transplantation Model
Warm and cold ischemia
bull 60 minutes of warm ischemia aortic cross-clamping
bull 24 hours cold storage in UW
Allo-transplantation after bilateral nephrectomy
CO delivered through ventilator for one hour starting at
incision (3mgkg with 40 FiO2)
Tacrolimus immunosuppression
Hanto et al AJT 2010
20Intraoperative Inhaled CO
Accelerates Renal Recovery from IRI
BUN Cr
Hanto et al AJT 2010
CoHb Levels
21Inhaled CO Improves
Histology and Reduces Apoptosis
Hanto et al AJT 2010
22Inhaled CO Increases
Proliferation and Reduces Inflammation
Hanto et al AJT 2010
Phospho-
histone 3
Tissue
Factor
23Inhaled CO Induces Changes
in Tissue Gene Expression
HSP 90Retinol binding
protein 4
MCP-1Osteopontin
Hanto et al AJT 2010
QT-PCR Confirmation
24Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Lewis to Brown Norway orthotopic kidney transplant
model following bilateral nephrectomy
Brief FK (05mgkg day 0-6)
Continuous CO exposure in CO chamber (20 ppm) days
60-150
Other exposure regimens
bull Continuous exposures days 0-30 30-60 or 0-90
bull 1hr daily CO (250 ppm) days 0-90
Nakao et al Am J Physiology 2009
25Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Nakao et al Am J Physiology 2009
Graft function CAN by histology Expression of
fibrosis genes
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
4
bull
bull
bull
bull
bull
bull
bull
bull
bull
bull
bull
bull
bull
bull
Jeff Wager MD Chairman amp CEO
5
Matthew Bennett Director Served as CEO of CIOX Health Before that was
EVP Global Medical Operations amp Chief Legal Officer for Ikaria Inc also functioning as
CFO amp Head of Corporate Development Negotiated $23 billion sale of Ikaria to
Mallinckrodt Prior to Ikaria was EVP Chief Administrative amp Chief Legal Officer at
VIASYS Healthcare Inc (NYSE VAS) responsible for growth mergers and
acquisitions
Peter Hutt Director Chief Counsel of the FDA from 1971-1975 co-author of the
casebook used to teach food and drug law throughout the country Author of Medical
Devices Act external counsel to Ikaria Serves on boards of Moderna Seres and
American Sterilizer served on Boards of CV Therapeutics Momenta Pervasis IDEC
Parexel among many others Advisory board member to Polaris formerly New Leaf
Venture Partners Has participated in the drafting of most major FDA legislation
considered by Congress during the past 40 years served on several NIH advisory
committees and is a Legal Counsel to the American College of Toxicology and the
Society for Risk Analysis
Proterris Board Top-Tier Public Company
Ex-Ikaria amp Regulatory Leadership
Dr J Donald deBethizy Director Donald served as president and CEO of
Santaris Pharma AS until September 2014 and led the acquisition by Roche He
served as executive chairman of Contera Pharma ApS until its sale to Bukwang
Pharma in November 2014 Donald was co-founder and CEO of Targacept Inc listed
on NASDAQ Has served on the boards of Newron Pharma SpA arGEN-X NV
Rigontec GmbH and Serendex Pharma AS amongst others
6Key Proterris Co-Founders amp Shareholders
Augustine M K Choi MD Dean Weill Cornell Medical College World-renowned pulmonologist gt25 years of CO research inventor of core Proterris patents
David Pinsky MD Chief of Cardiovascular Medicine at the University of Michigan Scientific Director of the U-M Cardiovascular Center key inventor of Columbia CO patent covering DGF indication licensed to Proterris
Apeiron Partners LLC life science spin-out and advisory boutique headed by Proterris CEO Jeff Wager has closed transactionsfirms worth $15 billion since 2000
12th Man Technologies Inc former Advanced Technologies Respiratory Team of CareFusion gt 25 patentsapplications covering inhaled gaseous drug delivery extensive inhaled NO amp CO delivery experience
Columbia University Beth Israel Deconess Medical Center U of Pittsburgh Yale Johns Hopkins
Former shareholders of Alfama Inc
7
IND
Product Pipeline
iCO for IPF
2017 2018 2019 2020 2021 2022 2023
P2 Prep P2A P2B Prep NDA
2024 2025 2026
P3
iCO for DGF P2B3 Prep P2B3 NDAP3
iCO for AKI
iCO for RF
TBD
TBD
CO-RMs
for ALFNASHIND-enabling Preclin P1 TBD
8COrsquos Mechanism Of Action
In Indications Of Interest To Proterris
Confers potent anti-oxidant effects
Confers potent anti-inflammatory effects
Confers potent anti-apoptosis effects
Confers potent anti-proliferative effects
Confers cellular homeostasis and quiescence
9COrsquos General Mechanism Of Action in vivo
Vol 9 p728-743 (September 2010)
Vasoactive response
CO
Guanylyl cyclase
Potassium channels
NO by NOS
Activation
Induction
Repression
Redox control
CO
Mitochdrial ROS
NADPH oxidase
Cellular bioenergenix
Modulation of inflammation
CO
Pro-inflammatory
Genes (TNF iNOS)
Anti-inflammatory
Genes (IL10)
Cytoprotection
CO
PPARy and HIFla
Apoptosis
Mitochondrial biogenesis
Proliferation
CO gas
CO-RMs
10ALFAMA Has A Unique Collection
Of CO-RMs
gt850 molecules
Each will differ in
- Trigger for CO release
- CO release kinetics
- Pharmacokinetics
- Biodistribution
- Bioavailability
Many are
- easily modifiable
- simple to synthesize
- Inexpensive to produce
Alfamarsquos patent applications cover both the concept (use) and some new chemical
entities (substance of matter)
General scheme of Alfamarsquos pharmaceutical CO-RMs
11NIH-Funded Clinical Trials Granted to Dr Choi
(Proterris Co-Founder) Validates iCO Rx Opportunity
Idiopathic Pulmonary Fibrosis (IPF) bull ldquoA Phase 2 Trial of Carbon Monoxide for the Treatment of Idiopathic
Pulmonary Fibrosisrdquo (NIH U01HL105371)
bull Total Grant $621M
bull 58 patient study completed positive read-out May 2015
Adult Respiratory Distress Syndrome (ARDS)bull ldquoPhase 12 Study of Inhaled Carbon Monoxide for the Treatment of
Sepsis-Induced Adult Lung Injuryrdquo (NIH P01 HL108801)
bull Jul 2011 ndash Mar 2017
bull Total Grant $14M
Pulmonary Arterial Hypertension (PAH)bull ldquoHeme Oxygenase-1Carbon Monoxide in Lung Vascular Injuryrdquo
(NIH R01 HL060234)
bull March 2013 - June 2018
bull IND filed Mar 2017
bull Total Grant $25M
12Low-dose Inhaled CO is
SafeWell-Tolerated in Multiple Clinical Trials
No iCO-related SAEs in NIH-funded IPF P2 study run by Dr Choi after 12 wksof 2xwk dosing
Multiple smallshort dosing trials in healthy volunteers and subjects with a variety of conditions have supported the safety of inhaled CO in the 100-400 ppm range to achieve a [COHb] in 4-10 range bull COPD
bull (Kerstjens et al Eur Respir J 2007 30 1131ndash1137)
bull Healthy subjects with exercisebull (Med Sci Sports Exerc 2012 Nov44(11)2118-24)
bull Healthy subjects exposed to 500 ppm for 1 hour then challenged with LPS bull (Am J Respir Crit Care Med Vol 171 pp 354ndash360 2005)
bull Colon-surgery patients at risk for paralytic Ileusbull (ClinicalTrialsgov identifier NCT01050712)
bull Retinal Blood flow studies in healthy volunteersbull (Invest OphthalmolVis Sci 2005464275ndash4280)
Inhaled CO use in pulmonary function labs for assessment of lung diffusion capacity has long been standard and safe
13Clinical Development Strategy
Significantly leverages extensive (~$23 million) of NIH funding to de-risk early stage clinical development risk
All indications being pursued are Orphan-qualifying
Balances smaller market size near-term acute indications (DGF acute liver failure) with chronic multi-$B indications (eg IPF NASH renal fibrosis others)
Significant DGF labeling-claim expansion opportunity following approval slow-graft function (SGF) acute kidney injury (AKI) delay of ESRD-associated dialysis renal fibrosis
CORM development offers life-cycle management with ivorally bioavailable next-gen CO therapeutics
14
bull Over half of the 13K US cadaveric
kidney transplants per year lead to
delayedslow graft function (DGFSGF)
bull DGF significantly increases risk of
acute and chronic rejection episodes
bull An iCo treatment for DGF would allow a
larger proportion of allografts from
donors after cardiac death (DCD) and
extended criteria donors (ECD) which
currently have a higher DGF and IRI risk
bull DGF increases post-surgical costs by
$4K+ increases post-transplant hospital
stay (usually 5-10 days) by up to 75
bull Over five years post-transplant DGF
patients had significantly higher time on
dialysis transplant rejection and mortality
bull An effective therapy for DGF would
significantly increase viable donor
organ pool and increase utilization of
those from extended criteria donors (many
currently unusable and are discarded)
bull There are ~13K cadaveric donor kidney transplants per year in US ~15K per year in
Canada and ~14K per year in the EU ndash incidence of DGF precludes larger numbers
bull By reducing ECD DGF iCO would shorten transplant wait times reduce
morbiditymortality on dialysis reduce effective cost of successful transplants
bull iCO for DGF could reach $300M+ annual revenues with less than one-third transplant
penetration for hospital treatment and one-third of those moving on to home treatment
Opportunity in Delayed Graft Function (DGF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwvalueinhealthjournalcomarticleS1098-3015(14)01756-2pdf [2] httpwwwncbinlmnihgovpubmed23538345
15
bull Idiopathic Pulmonary Fibrosis
progressive deterioration of lung
function and near-universal mortality
within five years from onset
bull No known cause no cure
bull Mean survival time only 38 years
bull Two recently approved medications only
moderately slow progression with
significant adverse effects seen in trials
bull Most of pipeline targets one mechanism
bull Recently approved medications Ofev
(nintendanib BI) and Esbriet (pirfenidone
Roche) priced at nearly $100Kyear
bull The only fully effective treatment a double-
lung transplant costs ~$800K end-to-end
bull CO for IPF offers
bull Synergy with OfevEsbriet
bull Improved disease progression
bull Lower all-in cost per year
bull Easier dosing schedule
(3xweek vs twice daily)
bull Prevalence of IPF is gt120K in US gt20K in Canada gt150K in Europe 20K in Japan
bull Clinicians estimate 70 of IPF patients are early-enough in disease progression to see
meaningful clinical improvement from stoppingslowing fibrosis expansion
bull Even at half or less Ofev pricing $2B annual revenues could be reached with only
30 patient penetration in only the three markets listed above
Opportunity in Idiopathic Pulmonary
Fibrosis (IPF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwaafporgafp20121001p631html [2] httpwwwniddknihgovhealth-informationhealth-statisticsPageskidney-disease-statistics-united-statesaspx [3] httpjasnasnjournalsorgcontent16113365fullpdf
16
RENAL PROGRAMS
17Increasing Use of Kidneys at Risk for DGF
17
Adult solitary primary kidney transplants
Source UNOSOPTN data as of April 29 2011
Note ECD kidneys are reluctantly utilized due to higher incidences and prevalence of DGF SGF AR CR etc
+ 14
+ 296
18iCO for Delayed Graft Function in
Renal Transplant Patients
Growing unmet need ~50K renal transplantsyear in both the US and EU ~10K ROW
No approved drugs
Recent transplant advances make therapies to prevent rejection and late or non-function more criticalbull Allowinguarr transplantation of organs from extended criteria and cardiac death donors
bull Allowinguarrtransplant of organs with longer warm and cold ischemia times
In several animal models inhaled CO dramatically darrs frequency and duration of delayed graft function (DGF)bull Multiple predictive animal models of CO administration demonstrated acute ischemia reperfusion injury
recovery and chronic allograft rejection (CAN) preventionmitigation
CO therapy at time of transplant feasible add-on to existing Rxbull short intra- or perioperative courses of Rx
Substantial benefit to patients payers and hospitalsbull Prevents or shortens need for dialysis biopsies ICU days etc
bull Allows earlier hospital discharge
Substantial label-expansion potential for acute and longer-term bull Chronic allograft nephropathy (CAN)
bull Acute kidney injury (AKI)
bull Renal fibrosis
19Inhaled CO
Pig Allo-transplantation Model
Warm and cold ischemia
bull 60 minutes of warm ischemia aortic cross-clamping
bull 24 hours cold storage in UW
Allo-transplantation after bilateral nephrectomy
CO delivered through ventilator for one hour starting at
incision (3mgkg with 40 FiO2)
Tacrolimus immunosuppression
Hanto et al AJT 2010
20Intraoperative Inhaled CO
Accelerates Renal Recovery from IRI
BUN Cr
Hanto et al AJT 2010
CoHb Levels
21Inhaled CO Improves
Histology and Reduces Apoptosis
Hanto et al AJT 2010
22Inhaled CO Increases
Proliferation and Reduces Inflammation
Hanto et al AJT 2010
Phospho-
histone 3
Tissue
Factor
23Inhaled CO Induces Changes
in Tissue Gene Expression
HSP 90Retinol binding
protein 4
MCP-1Osteopontin
Hanto et al AJT 2010
QT-PCR Confirmation
24Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Lewis to Brown Norway orthotopic kidney transplant
model following bilateral nephrectomy
Brief FK (05mgkg day 0-6)
Continuous CO exposure in CO chamber (20 ppm) days
60-150
Other exposure regimens
bull Continuous exposures days 0-30 30-60 or 0-90
bull 1hr daily CO (250 ppm) days 0-90
Nakao et al Am J Physiology 2009
25Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Nakao et al Am J Physiology 2009
Graft function CAN by histology Expression of
fibrosis genes
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
5
Matthew Bennett Director Served as CEO of CIOX Health Before that was
EVP Global Medical Operations amp Chief Legal Officer for Ikaria Inc also functioning as
CFO amp Head of Corporate Development Negotiated $23 billion sale of Ikaria to
Mallinckrodt Prior to Ikaria was EVP Chief Administrative amp Chief Legal Officer at
VIASYS Healthcare Inc (NYSE VAS) responsible for growth mergers and
acquisitions
Peter Hutt Director Chief Counsel of the FDA from 1971-1975 co-author of the
casebook used to teach food and drug law throughout the country Author of Medical
Devices Act external counsel to Ikaria Serves on boards of Moderna Seres and
American Sterilizer served on Boards of CV Therapeutics Momenta Pervasis IDEC
Parexel among many others Advisory board member to Polaris formerly New Leaf
Venture Partners Has participated in the drafting of most major FDA legislation
considered by Congress during the past 40 years served on several NIH advisory
committees and is a Legal Counsel to the American College of Toxicology and the
Society for Risk Analysis
Proterris Board Top-Tier Public Company
Ex-Ikaria amp Regulatory Leadership
Dr J Donald deBethizy Director Donald served as president and CEO of
Santaris Pharma AS until September 2014 and led the acquisition by Roche He
served as executive chairman of Contera Pharma ApS until its sale to Bukwang
Pharma in November 2014 Donald was co-founder and CEO of Targacept Inc listed
on NASDAQ Has served on the boards of Newron Pharma SpA arGEN-X NV
Rigontec GmbH and Serendex Pharma AS amongst others
6Key Proterris Co-Founders amp Shareholders
Augustine M K Choi MD Dean Weill Cornell Medical College World-renowned pulmonologist gt25 years of CO research inventor of core Proterris patents
David Pinsky MD Chief of Cardiovascular Medicine at the University of Michigan Scientific Director of the U-M Cardiovascular Center key inventor of Columbia CO patent covering DGF indication licensed to Proterris
Apeiron Partners LLC life science spin-out and advisory boutique headed by Proterris CEO Jeff Wager has closed transactionsfirms worth $15 billion since 2000
12th Man Technologies Inc former Advanced Technologies Respiratory Team of CareFusion gt 25 patentsapplications covering inhaled gaseous drug delivery extensive inhaled NO amp CO delivery experience
Columbia University Beth Israel Deconess Medical Center U of Pittsburgh Yale Johns Hopkins
Former shareholders of Alfama Inc
7
IND
Product Pipeline
iCO for IPF
2017 2018 2019 2020 2021 2022 2023
P2 Prep P2A P2B Prep NDA
2024 2025 2026
P3
iCO for DGF P2B3 Prep P2B3 NDAP3
iCO for AKI
iCO for RF
TBD
TBD
CO-RMs
for ALFNASHIND-enabling Preclin P1 TBD
8COrsquos Mechanism Of Action
In Indications Of Interest To Proterris
Confers potent anti-oxidant effects
Confers potent anti-inflammatory effects
Confers potent anti-apoptosis effects
Confers potent anti-proliferative effects
Confers cellular homeostasis and quiescence
9COrsquos General Mechanism Of Action in vivo
Vol 9 p728-743 (September 2010)
Vasoactive response
CO
Guanylyl cyclase
Potassium channels
NO by NOS
Activation
Induction
Repression
Redox control
CO
Mitochdrial ROS
NADPH oxidase
Cellular bioenergenix
Modulation of inflammation
CO
Pro-inflammatory
Genes (TNF iNOS)
Anti-inflammatory
Genes (IL10)
Cytoprotection
CO
PPARy and HIFla
Apoptosis
Mitochondrial biogenesis
Proliferation
CO gas
CO-RMs
10ALFAMA Has A Unique Collection
Of CO-RMs
gt850 molecules
Each will differ in
- Trigger for CO release
- CO release kinetics
- Pharmacokinetics
- Biodistribution
- Bioavailability
Many are
- easily modifiable
- simple to synthesize
- Inexpensive to produce
Alfamarsquos patent applications cover both the concept (use) and some new chemical
entities (substance of matter)
General scheme of Alfamarsquos pharmaceutical CO-RMs
11NIH-Funded Clinical Trials Granted to Dr Choi
(Proterris Co-Founder) Validates iCO Rx Opportunity
Idiopathic Pulmonary Fibrosis (IPF) bull ldquoA Phase 2 Trial of Carbon Monoxide for the Treatment of Idiopathic
Pulmonary Fibrosisrdquo (NIH U01HL105371)
bull Total Grant $621M
bull 58 patient study completed positive read-out May 2015
Adult Respiratory Distress Syndrome (ARDS)bull ldquoPhase 12 Study of Inhaled Carbon Monoxide for the Treatment of
Sepsis-Induced Adult Lung Injuryrdquo (NIH P01 HL108801)
bull Jul 2011 ndash Mar 2017
bull Total Grant $14M
Pulmonary Arterial Hypertension (PAH)bull ldquoHeme Oxygenase-1Carbon Monoxide in Lung Vascular Injuryrdquo
(NIH R01 HL060234)
bull March 2013 - June 2018
bull IND filed Mar 2017
bull Total Grant $25M
12Low-dose Inhaled CO is
SafeWell-Tolerated in Multiple Clinical Trials
No iCO-related SAEs in NIH-funded IPF P2 study run by Dr Choi after 12 wksof 2xwk dosing
Multiple smallshort dosing trials in healthy volunteers and subjects with a variety of conditions have supported the safety of inhaled CO in the 100-400 ppm range to achieve a [COHb] in 4-10 range bull COPD
bull (Kerstjens et al Eur Respir J 2007 30 1131ndash1137)
bull Healthy subjects with exercisebull (Med Sci Sports Exerc 2012 Nov44(11)2118-24)
bull Healthy subjects exposed to 500 ppm for 1 hour then challenged with LPS bull (Am J Respir Crit Care Med Vol 171 pp 354ndash360 2005)
bull Colon-surgery patients at risk for paralytic Ileusbull (ClinicalTrialsgov identifier NCT01050712)
bull Retinal Blood flow studies in healthy volunteersbull (Invest OphthalmolVis Sci 2005464275ndash4280)
Inhaled CO use in pulmonary function labs for assessment of lung diffusion capacity has long been standard and safe
13Clinical Development Strategy
Significantly leverages extensive (~$23 million) of NIH funding to de-risk early stage clinical development risk
All indications being pursued are Orphan-qualifying
Balances smaller market size near-term acute indications (DGF acute liver failure) with chronic multi-$B indications (eg IPF NASH renal fibrosis others)
Significant DGF labeling-claim expansion opportunity following approval slow-graft function (SGF) acute kidney injury (AKI) delay of ESRD-associated dialysis renal fibrosis
CORM development offers life-cycle management with ivorally bioavailable next-gen CO therapeutics
14
bull Over half of the 13K US cadaveric
kidney transplants per year lead to
delayedslow graft function (DGFSGF)
bull DGF significantly increases risk of
acute and chronic rejection episodes
bull An iCo treatment for DGF would allow a
larger proportion of allografts from
donors after cardiac death (DCD) and
extended criteria donors (ECD) which
currently have a higher DGF and IRI risk
bull DGF increases post-surgical costs by
$4K+ increases post-transplant hospital
stay (usually 5-10 days) by up to 75
bull Over five years post-transplant DGF
patients had significantly higher time on
dialysis transplant rejection and mortality
bull An effective therapy for DGF would
significantly increase viable donor
organ pool and increase utilization of
those from extended criteria donors (many
currently unusable and are discarded)
bull There are ~13K cadaveric donor kidney transplants per year in US ~15K per year in
Canada and ~14K per year in the EU ndash incidence of DGF precludes larger numbers
bull By reducing ECD DGF iCO would shorten transplant wait times reduce
morbiditymortality on dialysis reduce effective cost of successful transplants
bull iCO for DGF could reach $300M+ annual revenues with less than one-third transplant
penetration for hospital treatment and one-third of those moving on to home treatment
Opportunity in Delayed Graft Function (DGF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwvalueinhealthjournalcomarticleS1098-3015(14)01756-2pdf [2] httpwwwncbinlmnihgovpubmed23538345
15
bull Idiopathic Pulmonary Fibrosis
progressive deterioration of lung
function and near-universal mortality
within five years from onset
bull No known cause no cure
bull Mean survival time only 38 years
bull Two recently approved medications only
moderately slow progression with
significant adverse effects seen in trials
bull Most of pipeline targets one mechanism
bull Recently approved medications Ofev
(nintendanib BI) and Esbriet (pirfenidone
Roche) priced at nearly $100Kyear
bull The only fully effective treatment a double-
lung transplant costs ~$800K end-to-end
bull CO for IPF offers
bull Synergy with OfevEsbriet
bull Improved disease progression
bull Lower all-in cost per year
bull Easier dosing schedule
(3xweek vs twice daily)
bull Prevalence of IPF is gt120K in US gt20K in Canada gt150K in Europe 20K in Japan
bull Clinicians estimate 70 of IPF patients are early-enough in disease progression to see
meaningful clinical improvement from stoppingslowing fibrosis expansion
bull Even at half or less Ofev pricing $2B annual revenues could be reached with only
30 patient penetration in only the three markets listed above
Opportunity in Idiopathic Pulmonary
Fibrosis (IPF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwaafporgafp20121001p631html [2] httpwwwniddknihgovhealth-informationhealth-statisticsPageskidney-disease-statistics-united-statesaspx [3] httpjasnasnjournalsorgcontent16113365fullpdf
16
RENAL PROGRAMS
17Increasing Use of Kidneys at Risk for DGF
17
Adult solitary primary kidney transplants
Source UNOSOPTN data as of April 29 2011
Note ECD kidneys are reluctantly utilized due to higher incidences and prevalence of DGF SGF AR CR etc
+ 14
+ 296
18iCO for Delayed Graft Function in
Renal Transplant Patients
Growing unmet need ~50K renal transplantsyear in both the US and EU ~10K ROW
No approved drugs
Recent transplant advances make therapies to prevent rejection and late or non-function more criticalbull Allowinguarr transplantation of organs from extended criteria and cardiac death donors
bull Allowinguarrtransplant of organs with longer warm and cold ischemia times
In several animal models inhaled CO dramatically darrs frequency and duration of delayed graft function (DGF)bull Multiple predictive animal models of CO administration demonstrated acute ischemia reperfusion injury
recovery and chronic allograft rejection (CAN) preventionmitigation
CO therapy at time of transplant feasible add-on to existing Rxbull short intra- or perioperative courses of Rx
Substantial benefit to patients payers and hospitalsbull Prevents or shortens need for dialysis biopsies ICU days etc
bull Allows earlier hospital discharge
Substantial label-expansion potential for acute and longer-term bull Chronic allograft nephropathy (CAN)
bull Acute kidney injury (AKI)
bull Renal fibrosis
19Inhaled CO
Pig Allo-transplantation Model
Warm and cold ischemia
bull 60 minutes of warm ischemia aortic cross-clamping
bull 24 hours cold storage in UW
Allo-transplantation after bilateral nephrectomy
CO delivered through ventilator for one hour starting at
incision (3mgkg with 40 FiO2)
Tacrolimus immunosuppression
Hanto et al AJT 2010
20Intraoperative Inhaled CO
Accelerates Renal Recovery from IRI
BUN Cr
Hanto et al AJT 2010
CoHb Levels
21Inhaled CO Improves
Histology and Reduces Apoptosis
Hanto et al AJT 2010
22Inhaled CO Increases
Proliferation and Reduces Inflammation
Hanto et al AJT 2010
Phospho-
histone 3
Tissue
Factor
23Inhaled CO Induces Changes
in Tissue Gene Expression
HSP 90Retinol binding
protein 4
MCP-1Osteopontin
Hanto et al AJT 2010
QT-PCR Confirmation
24Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Lewis to Brown Norway orthotopic kidney transplant
model following bilateral nephrectomy
Brief FK (05mgkg day 0-6)
Continuous CO exposure in CO chamber (20 ppm) days
60-150
Other exposure regimens
bull Continuous exposures days 0-30 30-60 or 0-90
bull 1hr daily CO (250 ppm) days 0-90
Nakao et al Am J Physiology 2009
25Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Nakao et al Am J Physiology 2009
Graft function CAN by histology Expression of
fibrosis genes
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
6Key Proterris Co-Founders amp Shareholders
Augustine M K Choi MD Dean Weill Cornell Medical College World-renowned pulmonologist gt25 years of CO research inventor of core Proterris patents
David Pinsky MD Chief of Cardiovascular Medicine at the University of Michigan Scientific Director of the U-M Cardiovascular Center key inventor of Columbia CO patent covering DGF indication licensed to Proterris
Apeiron Partners LLC life science spin-out and advisory boutique headed by Proterris CEO Jeff Wager has closed transactionsfirms worth $15 billion since 2000
12th Man Technologies Inc former Advanced Technologies Respiratory Team of CareFusion gt 25 patentsapplications covering inhaled gaseous drug delivery extensive inhaled NO amp CO delivery experience
Columbia University Beth Israel Deconess Medical Center U of Pittsburgh Yale Johns Hopkins
Former shareholders of Alfama Inc
7
IND
Product Pipeline
iCO for IPF
2017 2018 2019 2020 2021 2022 2023
P2 Prep P2A P2B Prep NDA
2024 2025 2026
P3
iCO for DGF P2B3 Prep P2B3 NDAP3
iCO for AKI
iCO for RF
TBD
TBD
CO-RMs
for ALFNASHIND-enabling Preclin P1 TBD
8COrsquos Mechanism Of Action
In Indications Of Interest To Proterris
Confers potent anti-oxidant effects
Confers potent anti-inflammatory effects
Confers potent anti-apoptosis effects
Confers potent anti-proliferative effects
Confers cellular homeostasis and quiescence
9COrsquos General Mechanism Of Action in vivo
Vol 9 p728-743 (September 2010)
Vasoactive response
CO
Guanylyl cyclase
Potassium channels
NO by NOS
Activation
Induction
Repression
Redox control
CO
Mitochdrial ROS
NADPH oxidase
Cellular bioenergenix
Modulation of inflammation
CO
Pro-inflammatory
Genes (TNF iNOS)
Anti-inflammatory
Genes (IL10)
Cytoprotection
CO
PPARy and HIFla
Apoptosis
Mitochondrial biogenesis
Proliferation
CO gas
CO-RMs
10ALFAMA Has A Unique Collection
Of CO-RMs
gt850 molecules
Each will differ in
- Trigger for CO release
- CO release kinetics
- Pharmacokinetics
- Biodistribution
- Bioavailability
Many are
- easily modifiable
- simple to synthesize
- Inexpensive to produce
Alfamarsquos patent applications cover both the concept (use) and some new chemical
entities (substance of matter)
General scheme of Alfamarsquos pharmaceutical CO-RMs
11NIH-Funded Clinical Trials Granted to Dr Choi
(Proterris Co-Founder) Validates iCO Rx Opportunity
Idiopathic Pulmonary Fibrosis (IPF) bull ldquoA Phase 2 Trial of Carbon Monoxide for the Treatment of Idiopathic
Pulmonary Fibrosisrdquo (NIH U01HL105371)
bull Total Grant $621M
bull 58 patient study completed positive read-out May 2015
Adult Respiratory Distress Syndrome (ARDS)bull ldquoPhase 12 Study of Inhaled Carbon Monoxide for the Treatment of
Sepsis-Induced Adult Lung Injuryrdquo (NIH P01 HL108801)
bull Jul 2011 ndash Mar 2017
bull Total Grant $14M
Pulmonary Arterial Hypertension (PAH)bull ldquoHeme Oxygenase-1Carbon Monoxide in Lung Vascular Injuryrdquo
(NIH R01 HL060234)
bull March 2013 - June 2018
bull IND filed Mar 2017
bull Total Grant $25M
12Low-dose Inhaled CO is
SafeWell-Tolerated in Multiple Clinical Trials
No iCO-related SAEs in NIH-funded IPF P2 study run by Dr Choi after 12 wksof 2xwk dosing
Multiple smallshort dosing trials in healthy volunteers and subjects with a variety of conditions have supported the safety of inhaled CO in the 100-400 ppm range to achieve a [COHb] in 4-10 range bull COPD
bull (Kerstjens et al Eur Respir J 2007 30 1131ndash1137)
bull Healthy subjects with exercisebull (Med Sci Sports Exerc 2012 Nov44(11)2118-24)
bull Healthy subjects exposed to 500 ppm for 1 hour then challenged with LPS bull (Am J Respir Crit Care Med Vol 171 pp 354ndash360 2005)
bull Colon-surgery patients at risk for paralytic Ileusbull (ClinicalTrialsgov identifier NCT01050712)
bull Retinal Blood flow studies in healthy volunteersbull (Invest OphthalmolVis Sci 2005464275ndash4280)
Inhaled CO use in pulmonary function labs for assessment of lung diffusion capacity has long been standard and safe
13Clinical Development Strategy
Significantly leverages extensive (~$23 million) of NIH funding to de-risk early stage clinical development risk
All indications being pursued are Orphan-qualifying
Balances smaller market size near-term acute indications (DGF acute liver failure) with chronic multi-$B indications (eg IPF NASH renal fibrosis others)
Significant DGF labeling-claim expansion opportunity following approval slow-graft function (SGF) acute kidney injury (AKI) delay of ESRD-associated dialysis renal fibrosis
CORM development offers life-cycle management with ivorally bioavailable next-gen CO therapeutics
14
bull Over half of the 13K US cadaveric
kidney transplants per year lead to
delayedslow graft function (DGFSGF)
bull DGF significantly increases risk of
acute and chronic rejection episodes
bull An iCo treatment for DGF would allow a
larger proportion of allografts from
donors after cardiac death (DCD) and
extended criteria donors (ECD) which
currently have a higher DGF and IRI risk
bull DGF increases post-surgical costs by
$4K+ increases post-transplant hospital
stay (usually 5-10 days) by up to 75
bull Over five years post-transplant DGF
patients had significantly higher time on
dialysis transplant rejection and mortality
bull An effective therapy for DGF would
significantly increase viable donor
organ pool and increase utilization of
those from extended criteria donors (many
currently unusable and are discarded)
bull There are ~13K cadaveric donor kidney transplants per year in US ~15K per year in
Canada and ~14K per year in the EU ndash incidence of DGF precludes larger numbers
bull By reducing ECD DGF iCO would shorten transplant wait times reduce
morbiditymortality on dialysis reduce effective cost of successful transplants
bull iCO for DGF could reach $300M+ annual revenues with less than one-third transplant
penetration for hospital treatment and one-third of those moving on to home treatment
Opportunity in Delayed Graft Function (DGF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwvalueinhealthjournalcomarticleS1098-3015(14)01756-2pdf [2] httpwwwncbinlmnihgovpubmed23538345
15
bull Idiopathic Pulmonary Fibrosis
progressive deterioration of lung
function and near-universal mortality
within five years from onset
bull No known cause no cure
bull Mean survival time only 38 years
bull Two recently approved medications only
moderately slow progression with
significant adverse effects seen in trials
bull Most of pipeline targets one mechanism
bull Recently approved medications Ofev
(nintendanib BI) and Esbriet (pirfenidone
Roche) priced at nearly $100Kyear
bull The only fully effective treatment a double-
lung transplant costs ~$800K end-to-end
bull CO for IPF offers
bull Synergy with OfevEsbriet
bull Improved disease progression
bull Lower all-in cost per year
bull Easier dosing schedule
(3xweek vs twice daily)
bull Prevalence of IPF is gt120K in US gt20K in Canada gt150K in Europe 20K in Japan
bull Clinicians estimate 70 of IPF patients are early-enough in disease progression to see
meaningful clinical improvement from stoppingslowing fibrosis expansion
bull Even at half or less Ofev pricing $2B annual revenues could be reached with only
30 patient penetration in only the three markets listed above
Opportunity in Idiopathic Pulmonary
Fibrosis (IPF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwaafporgafp20121001p631html [2] httpwwwniddknihgovhealth-informationhealth-statisticsPageskidney-disease-statistics-united-statesaspx [3] httpjasnasnjournalsorgcontent16113365fullpdf
16
RENAL PROGRAMS
17Increasing Use of Kidneys at Risk for DGF
17
Adult solitary primary kidney transplants
Source UNOSOPTN data as of April 29 2011
Note ECD kidneys are reluctantly utilized due to higher incidences and prevalence of DGF SGF AR CR etc
+ 14
+ 296
18iCO for Delayed Graft Function in
Renal Transplant Patients
Growing unmet need ~50K renal transplantsyear in both the US and EU ~10K ROW
No approved drugs
Recent transplant advances make therapies to prevent rejection and late or non-function more criticalbull Allowinguarr transplantation of organs from extended criteria and cardiac death donors
bull Allowinguarrtransplant of organs with longer warm and cold ischemia times
In several animal models inhaled CO dramatically darrs frequency and duration of delayed graft function (DGF)bull Multiple predictive animal models of CO administration demonstrated acute ischemia reperfusion injury
recovery and chronic allograft rejection (CAN) preventionmitigation
CO therapy at time of transplant feasible add-on to existing Rxbull short intra- or perioperative courses of Rx
Substantial benefit to patients payers and hospitalsbull Prevents or shortens need for dialysis biopsies ICU days etc
bull Allows earlier hospital discharge
Substantial label-expansion potential for acute and longer-term bull Chronic allograft nephropathy (CAN)
bull Acute kidney injury (AKI)
bull Renal fibrosis
19Inhaled CO
Pig Allo-transplantation Model
Warm and cold ischemia
bull 60 minutes of warm ischemia aortic cross-clamping
bull 24 hours cold storage in UW
Allo-transplantation after bilateral nephrectomy
CO delivered through ventilator for one hour starting at
incision (3mgkg with 40 FiO2)
Tacrolimus immunosuppression
Hanto et al AJT 2010
20Intraoperative Inhaled CO
Accelerates Renal Recovery from IRI
BUN Cr
Hanto et al AJT 2010
CoHb Levels
21Inhaled CO Improves
Histology and Reduces Apoptosis
Hanto et al AJT 2010
22Inhaled CO Increases
Proliferation and Reduces Inflammation
Hanto et al AJT 2010
Phospho-
histone 3
Tissue
Factor
23Inhaled CO Induces Changes
in Tissue Gene Expression
HSP 90Retinol binding
protein 4
MCP-1Osteopontin
Hanto et al AJT 2010
QT-PCR Confirmation
24Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Lewis to Brown Norway orthotopic kidney transplant
model following bilateral nephrectomy
Brief FK (05mgkg day 0-6)
Continuous CO exposure in CO chamber (20 ppm) days
60-150
Other exposure regimens
bull Continuous exposures days 0-30 30-60 or 0-90
bull 1hr daily CO (250 ppm) days 0-90
Nakao et al Am J Physiology 2009
25Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Nakao et al Am J Physiology 2009
Graft function CAN by histology Expression of
fibrosis genes
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
7
IND
Product Pipeline
iCO for IPF
2017 2018 2019 2020 2021 2022 2023
P2 Prep P2A P2B Prep NDA
2024 2025 2026
P3
iCO for DGF P2B3 Prep P2B3 NDAP3
iCO for AKI
iCO for RF
TBD
TBD
CO-RMs
for ALFNASHIND-enabling Preclin P1 TBD
8COrsquos Mechanism Of Action
In Indications Of Interest To Proterris
Confers potent anti-oxidant effects
Confers potent anti-inflammatory effects
Confers potent anti-apoptosis effects
Confers potent anti-proliferative effects
Confers cellular homeostasis and quiescence
9COrsquos General Mechanism Of Action in vivo
Vol 9 p728-743 (September 2010)
Vasoactive response
CO
Guanylyl cyclase
Potassium channels
NO by NOS
Activation
Induction
Repression
Redox control
CO
Mitochdrial ROS
NADPH oxidase
Cellular bioenergenix
Modulation of inflammation
CO
Pro-inflammatory
Genes (TNF iNOS)
Anti-inflammatory
Genes (IL10)
Cytoprotection
CO
PPARy and HIFla
Apoptosis
Mitochondrial biogenesis
Proliferation
CO gas
CO-RMs
10ALFAMA Has A Unique Collection
Of CO-RMs
gt850 molecules
Each will differ in
- Trigger for CO release
- CO release kinetics
- Pharmacokinetics
- Biodistribution
- Bioavailability
Many are
- easily modifiable
- simple to synthesize
- Inexpensive to produce
Alfamarsquos patent applications cover both the concept (use) and some new chemical
entities (substance of matter)
General scheme of Alfamarsquos pharmaceutical CO-RMs
11NIH-Funded Clinical Trials Granted to Dr Choi
(Proterris Co-Founder) Validates iCO Rx Opportunity
Idiopathic Pulmonary Fibrosis (IPF) bull ldquoA Phase 2 Trial of Carbon Monoxide for the Treatment of Idiopathic
Pulmonary Fibrosisrdquo (NIH U01HL105371)
bull Total Grant $621M
bull 58 patient study completed positive read-out May 2015
Adult Respiratory Distress Syndrome (ARDS)bull ldquoPhase 12 Study of Inhaled Carbon Monoxide for the Treatment of
Sepsis-Induced Adult Lung Injuryrdquo (NIH P01 HL108801)
bull Jul 2011 ndash Mar 2017
bull Total Grant $14M
Pulmonary Arterial Hypertension (PAH)bull ldquoHeme Oxygenase-1Carbon Monoxide in Lung Vascular Injuryrdquo
(NIH R01 HL060234)
bull March 2013 - June 2018
bull IND filed Mar 2017
bull Total Grant $25M
12Low-dose Inhaled CO is
SafeWell-Tolerated in Multiple Clinical Trials
No iCO-related SAEs in NIH-funded IPF P2 study run by Dr Choi after 12 wksof 2xwk dosing
Multiple smallshort dosing trials in healthy volunteers and subjects with a variety of conditions have supported the safety of inhaled CO in the 100-400 ppm range to achieve a [COHb] in 4-10 range bull COPD
bull (Kerstjens et al Eur Respir J 2007 30 1131ndash1137)
bull Healthy subjects with exercisebull (Med Sci Sports Exerc 2012 Nov44(11)2118-24)
bull Healthy subjects exposed to 500 ppm for 1 hour then challenged with LPS bull (Am J Respir Crit Care Med Vol 171 pp 354ndash360 2005)
bull Colon-surgery patients at risk for paralytic Ileusbull (ClinicalTrialsgov identifier NCT01050712)
bull Retinal Blood flow studies in healthy volunteersbull (Invest OphthalmolVis Sci 2005464275ndash4280)
Inhaled CO use in pulmonary function labs for assessment of lung diffusion capacity has long been standard and safe
13Clinical Development Strategy
Significantly leverages extensive (~$23 million) of NIH funding to de-risk early stage clinical development risk
All indications being pursued are Orphan-qualifying
Balances smaller market size near-term acute indications (DGF acute liver failure) with chronic multi-$B indications (eg IPF NASH renal fibrosis others)
Significant DGF labeling-claim expansion opportunity following approval slow-graft function (SGF) acute kidney injury (AKI) delay of ESRD-associated dialysis renal fibrosis
CORM development offers life-cycle management with ivorally bioavailable next-gen CO therapeutics
14
bull Over half of the 13K US cadaveric
kidney transplants per year lead to
delayedslow graft function (DGFSGF)
bull DGF significantly increases risk of
acute and chronic rejection episodes
bull An iCo treatment for DGF would allow a
larger proportion of allografts from
donors after cardiac death (DCD) and
extended criteria donors (ECD) which
currently have a higher DGF and IRI risk
bull DGF increases post-surgical costs by
$4K+ increases post-transplant hospital
stay (usually 5-10 days) by up to 75
bull Over five years post-transplant DGF
patients had significantly higher time on
dialysis transplant rejection and mortality
bull An effective therapy for DGF would
significantly increase viable donor
organ pool and increase utilization of
those from extended criteria donors (many
currently unusable and are discarded)
bull There are ~13K cadaveric donor kidney transplants per year in US ~15K per year in
Canada and ~14K per year in the EU ndash incidence of DGF precludes larger numbers
bull By reducing ECD DGF iCO would shorten transplant wait times reduce
morbiditymortality on dialysis reduce effective cost of successful transplants
bull iCO for DGF could reach $300M+ annual revenues with less than one-third transplant
penetration for hospital treatment and one-third of those moving on to home treatment
Opportunity in Delayed Graft Function (DGF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwvalueinhealthjournalcomarticleS1098-3015(14)01756-2pdf [2] httpwwwncbinlmnihgovpubmed23538345
15
bull Idiopathic Pulmonary Fibrosis
progressive deterioration of lung
function and near-universal mortality
within five years from onset
bull No known cause no cure
bull Mean survival time only 38 years
bull Two recently approved medications only
moderately slow progression with
significant adverse effects seen in trials
bull Most of pipeline targets one mechanism
bull Recently approved medications Ofev
(nintendanib BI) and Esbriet (pirfenidone
Roche) priced at nearly $100Kyear
bull The only fully effective treatment a double-
lung transplant costs ~$800K end-to-end
bull CO for IPF offers
bull Synergy with OfevEsbriet
bull Improved disease progression
bull Lower all-in cost per year
bull Easier dosing schedule
(3xweek vs twice daily)
bull Prevalence of IPF is gt120K in US gt20K in Canada gt150K in Europe 20K in Japan
bull Clinicians estimate 70 of IPF patients are early-enough in disease progression to see
meaningful clinical improvement from stoppingslowing fibrosis expansion
bull Even at half or less Ofev pricing $2B annual revenues could be reached with only
30 patient penetration in only the three markets listed above
Opportunity in Idiopathic Pulmonary
Fibrosis (IPF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwaafporgafp20121001p631html [2] httpwwwniddknihgovhealth-informationhealth-statisticsPageskidney-disease-statistics-united-statesaspx [3] httpjasnasnjournalsorgcontent16113365fullpdf
16
RENAL PROGRAMS
17Increasing Use of Kidneys at Risk for DGF
17
Adult solitary primary kidney transplants
Source UNOSOPTN data as of April 29 2011
Note ECD kidneys are reluctantly utilized due to higher incidences and prevalence of DGF SGF AR CR etc
+ 14
+ 296
18iCO for Delayed Graft Function in
Renal Transplant Patients
Growing unmet need ~50K renal transplantsyear in both the US and EU ~10K ROW
No approved drugs
Recent transplant advances make therapies to prevent rejection and late or non-function more criticalbull Allowinguarr transplantation of organs from extended criteria and cardiac death donors
bull Allowinguarrtransplant of organs with longer warm and cold ischemia times
In several animal models inhaled CO dramatically darrs frequency and duration of delayed graft function (DGF)bull Multiple predictive animal models of CO administration demonstrated acute ischemia reperfusion injury
recovery and chronic allograft rejection (CAN) preventionmitigation
CO therapy at time of transplant feasible add-on to existing Rxbull short intra- or perioperative courses of Rx
Substantial benefit to patients payers and hospitalsbull Prevents or shortens need for dialysis biopsies ICU days etc
bull Allows earlier hospital discharge
Substantial label-expansion potential for acute and longer-term bull Chronic allograft nephropathy (CAN)
bull Acute kidney injury (AKI)
bull Renal fibrosis
19Inhaled CO
Pig Allo-transplantation Model
Warm and cold ischemia
bull 60 minutes of warm ischemia aortic cross-clamping
bull 24 hours cold storage in UW
Allo-transplantation after bilateral nephrectomy
CO delivered through ventilator for one hour starting at
incision (3mgkg with 40 FiO2)
Tacrolimus immunosuppression
Hanto et al AJT 2010
20Intraoperative Inhaled CO
Accelerates Renal Recovery from IRI
BUN Cr
Hanto et al AJT 2010
CoHb Levels
21Inhaled CO Improves
Histology and Reduces Apoptosis
Hanto et al AJT 2010
22Inhaled CO Increases
Proliferation and Reduces Inflammation
Hanto et al AJT 2010
Phospho-
histone 3
Tissue
Factor
23Inhaled CO Induces Changes
in Tissue Gene Expression
HSP 90Retinol binding
protein 4
MCP-1Osteopontin
Hanto et al AJT 2010
QT-PCR Confirmation
24Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Lewis to Brown Norway orthotopic kidney transplant
model following bilateral nephrectomy
Brief FK (05mgkg day 0-6)
Continuous CO exposure in CO chamber (20 ppm) days
60-150
Other exposure regimens
bull Continuous exposures days 0-30 30-60 or 0-90
bull 1hr daily CO (250 ppm) days 0-90
Nakao et al Am J Physiology 2009
25Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Nakao et al Am J Physiology 2009
Graft function CAN by histology Expression of
fibrosis genes
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
8COrsquos Mechanism Of Action
In Indications Of Interest To Proterris
Confers potent anti-oxidant effects
Confers potent anti-inflammatory effects
Confers potent anti-apoptosis effects
Confers potent anti-proliferative effects
Confers cellular homeostasis and quiescence
9COrsquos General Mechanism Of Action in vivo
Vol 9 p728-743 (September 2010)
Vasoactive response
CO
Guanylyl cyclase
Potassium channels
NO by NOS
Activation
Induction
Repression
Redox control
CO
Mitochdrial ROS
NADPH oxidase
Cellular bioenergenix
Modulation of inflammation
CO
Pro-inflammatory
Genes (TNF iNOS)
Anti-inflammatory
Genes (IL10)
Cytoprotection
CO
PPARy and HIFla
Apoptosis
Mitochondrial biogenesis
Proliferation
CO gas
CO-RMs
10ALFAMA Has A Unique Collection
Of CO-RMs
gt850 molecules
Each will differ in
- Trigger for CO release
- CO release kinetics
- Pharmacokinetics
- Biodistribution
- Bioavailability
Many are
- easily modifiable
- simple to synthesize
- Inexpensive to produce
Alfamarsquos patent applications cover both the concept (use) and some new chemical
entities (substance of matter)
General scheme of Alfamarsquos pharmaceutical CO-RMs
11NIH-Funded Clinical Trials Granted to Dr Choi
(Proterris Co-Founder) Validates iCO Rx Opportunity
Idiopathic Pulmonary Fibrosis (IPF) bull ldquoA Phase 2 Trial of Carbon Monoxide for the Treatment of Idiopathic
Pulmonary Fibrosisrdquo (NIH U01HL105371)
bull Total Grant $621M
bull 58 patient study completed positive read-out May 2015
Adult Respiratory Distress Syndrome (ARDS)bull ldquoPhase 12 Study of Inhaled Carbon Monoxide for the Treatment of
Sepsis-Induced Adult Lung Injuryrdquo (NIH P01 HL108801)
bull Jul 2011 ndash Mar 2017
bull Total Grant $14M
Pulmonary Arterial Hypertension (PAH)bull ldquoHeme Oxygenase-1Carbon Monoxide in Lung Vascular Injuryrdquo
(NIH R01 HL060234)
bull March 2013 - June 2018
bull IND filed Mar 2017
bull Total Grant $25M
12Low-dose Inhaled CO is
SafeWell-Tolerated in Multiple Clinical Trials
No iCO-related SAEs in NIH-funded IPF P2 study run by Dr Choi after 12 wksof 2xwk dosing
Multiple smallshort dosing trials in healthy volunteers and subjects with a variety of conditions have supported the safety of inhaled CO in the 100-400 ppm range to achieve a [COHb] in 4-10 range bull COPD
bull (Kerstjens et al Eur Respir J 2007 30 1131ndash1137)
bull Healthy subjects with exercisebull (Med Sci Sports Exerc 2012 Nov44(11)2118-24)
bull Healthy subjects exposed to 500 ppm for 1 hour then challenged with LPS bull (Am J Respir Crit Care Med Vol 171 pp 354ndash360 2005)
bull Colon-surgery patients at risk for paralytic Ileusbull (ClinicalTrialsgov identifier NCT01050712)
bull Retinal Blood flow studies in healthy volunteersbull (Invest OphthalmolVis Sci 2005464275ndash4280)
Inhaled CO use in pulmonary function labs for assessment of lung diffusion capacity has long been standard and safe
13Clinical Development Strategy
Significantly leverages extensive (~$23 million) of NIH funding to de-risk early stage clinical development risk
All indications being pursued are Orphan-qualifying
Balances smaller market size near-term acute indications (DGF acute liver failure) with chronic multi-$B indications (eg IPF NASH renal fibrosis others)
Significant DGF labeling-claim expansion opportunity following approval slow-graft function (SGF) acute kidney injury (AKI) delay of ESRD-associated dialysis renal fibrosis
CORM development offers life-cycle management with ivorally bioavailable next-gen CO therapeutics
14
bull Over half of the 13K US cadaveric
kidney transplants per year lead to
delayedslow graft function (DGFSGF)
bull DGF significantly increases risk of
acute and chronic rejection episodes
bull An iCo treatment for DGF would allow a
larger proportion of allografts from
donors after cardiac death (DCD) and
extended criteria donors (ECD) which
currently have a higher DGF and IRI risk
bull DGF increases post-surgical costs by
$4K+ increases post-transplant hospital
stay (usually 5-10 days) by up to 75
bull Over five years post-transplant DGF
patients had significantly higher time on
dialysis transplant rejection and mortality
bull An effective therapy for DGF would
significantly increase viable donor
organ pool and increase utilization of
those from extended criteria donors (many
currently unusable and are discarded)
bull There are ~13K cadaveric donor kidney transplants per year in US ~15K per year in
Canada and ~14K per year in the EU ndash incidence of DGF precludes larger numbers
bull By reducing ECD DGF iCO would shorten transplant wait times reduce
morbiditymortality on dialysis reduce effective cost of successful transplants
bull iCO for DGF could reach $300M+ annual revenues with less than one-third transplant
penetration for hospital treatment and one-third of those moving on to home treatment
Opportunity in Delayed Graft Function (DGF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwvalueinhealthjournalcomarticleS1098-3015(14)01756-2pdf [2] httpwwwncbinlmnihgovpubmed23538345
15
bull Idiopathic Pulmonary Fibrosis
progressive deterioration of lung
function and near-universal mortality
within five years from onset
bull No known cause no cure
bull Mean survival time only 38 years
bull Two recently approved medications only
moderately slow progression with
significant adverse effects seen in trials
bull Most of pipeline targets one mechanism
bull Recently approved medications Ofev
(nintendanib BI) and Esbriet (pirfenidone
Roche) priced at nearly $100Kyear
bull The only fully effective treatment a double-
lung transplant costs ~$800K end-to-end
bull CO for IPF offers
bull Synergy with OfevEsbriet
bull Improved disease progression
bull Lower all-in cost per year
bull Easier dosing schedule
(3xweek vs twice daily)
bull Prevalence of IPF is gt120K in US gt20K in Canada gt150K in Europe 20K in Japan
bull Clinicians estimate 70 of IPF patients are early-enough in disease progression to see
meaningful clinical improvement from stoppingslowing fibrosis expansion
bull Even at half or less Ofev pricing $2B annual revenues could be reached with only
30 patient penetration in only the three markets listed above
Opportunity in Idiopathic Pulmonary
Fibrosis (IPF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwaafporgafp20121001p631html [2] httpwwwniddknihgovhealth-informationhealth-statisticsPageskidney-disease-statistics-united-statesaspx [3] httpjasnasnjournalsorgcontent16113365fullpdf
16
RENAL PROGRAMS
17Increasing Use of Kidneys at Risk for DGF
17
Adult solitary primary kidney transplants
Source UNOSOPTN data as of April 29 2011
Note ECD kidneys are reluctantly utilized due to higher incidences and prevalence of DGF SGF AR CR etc
+ 14
+ 296
18iCO for Delayed Graft Function in
Renal Transplant Patients
Growing unmet need ~50K renal transplantsyear in both the US and EU ~10K ROW
No approved drugs
Recent transplant advances make therapies to prevent rejection and late or non-function more criticalbull Allowinguarr transplantation of organs from extended criteria and cardiac death donors
bull Allowinguarrtransplant of organs with longer warm and cold ischemia times
In several animal models inhaled CO dramatically darrs frequency and duration of delayed graft function (DGF)bull Multiple predictive animal models of CO administration demonstrated acute ischemia reperfusion injury
recovery and chronic allograft rejection (CAN) preventionmitigation
CO therapy at time of transplant feasible add-on to existing Rxbull short intra- or perioperative courses of Rx
Substantial benefit to patients payers and hospitalsbull Prevents or shortens need for dialysis biopsies ICU days etc
bull Allows earlier hospital discharge
Substantial label-expansion potential for acute and longer-term bull Chronic allograft nephropathy (CAN)
bull Acute kidney injury (AKI)
bull Renal fibrosis
19Inhaled CO
Pig Allo-transplantation Model
Warm and cold ischemia
bull 60 minutes of warm ischemia aortic cross-clamping
bull 24 hours cold storage in UW
Allo-transplantation after bilateral nephrectomy
CO delivered through ventilator for one hour starting at
incision (3mgkg with 40 FiO2)
Tacrolimus immunosuppression
Hanto et al AJT 2010
20Intraoperative Inhaled CO
Accelerates Renal Recovery from IRI
BUN Cr
Hanto et al AJT 2010
CoHb Levels
21Inhaled CO Improves
Histology and Reduces Apoptosis
Hanto et al AJT 2010
22Inhaled CO Increases
Proliferation and Reduces Inflammation
Hanto et al AJT 2010
Phospho-
histone 3
Tissue
Factor
23Inhaled CO Induces Changes
in Tissue Gene Expression
HSP 90Retinol binding
protein 4
MCP-1Osteopontin
Hanto et al AJT 2010
QT-PCR Confirmation
24Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Lewis to Brown Norway orthotopic kidney transplant
model following bilateral nephrectomy
Brief FK (05mgkg day 0-6)
Continuous CO exposure in CO chamber (20 ppm) days
60-150
Other exposure regimens
bull Continuous exposures days 0-30 30-60 or 0-90
bull 1hr daily CO (250 ppm) days 0-90
Nakao et al Am J Physiology 2009
25Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Nakao et al Am J Physiology 2009
Graft function CAN by histology Expression of
fibrosis genes
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
9COrsquos General Mechanism Of Action in vivo
Vol 9 p728-743 (September 2010)
Vasoactive response
CO
Guanylyl cyclase
Potassium channels
NO by NOS
Activation
Induction
Repression
Redox control
CO
Mitochdrial ROS
NADPH oxidase
Cellular bioenergenix
Modulation of inflammation
CO
Pro-inflammatory
Genes (TNF iNOS)
Anti-inflammatory
Genes (IL10)
Cytoprotection
CO
PPARy and HIFla
Apoptosis
Mitochondrial biogenesis
Proliferation
CO gas
CO-RMs
10ALFAMA Has A Unique Collection
Of CO-RMs
gt850 molecules
Each will differ in
- Trigger for CO release
- CO release kinetics
- Pharmacokinetics
- Biodistribution
- Bioavailability
Many are
- easily modifiable
- simple to synthesize
- Inexpensive to produce
Alfamarsquos patent applications cover both the concept (use) and some new chemical
entities (substance of matter)
General scheme of Alfamarsquos pharmaceutical CO-RMs
11NIH-Funded Clinical Trials Granted to Dr Choi
(Proterris Co-Founder) Validates iCO Rx Opportunity
Idiopathic Pulmonary Fibrosis (IPF) bull ldquoA Phase 2 Trial of Carbon Monoxide for the Treatment of Idiopathic
Pulmonary Fibrosisrdquo (NIH U01HL105371)
bull Total Grant $621M
bull 58 patient study completed positive read-out May 2015
Adult Respiratory Distress Syndrome (ARDS)bull ldquoPhase 12 Study of Inhaled Carbon Monoxide for the Treatment of
Sepsis-Induced Adult Lung Injuryrdquo (NIH P01 HL108801)
bull Jul 2011 ndash Mar 2017
bull Total Grant $14M
Pulmonary Arterial Hypertension (PAH)bull ldquoHeme Oxygenase-1Carbon Monoxide in Lung Vascular Injuryrdquo
(NIH R01 HL060234)
bull March 2013 - June 2018
bull IND filed Mar 2017
bull Total Grant $25M
12Low-dose Inhaled CO is
SafeWell-Tolerated in Multiple Clinical Trials
No iCO-related SAEs in NIH-funded IPF P2 study run by Dr Choi after 12 wksof 2xwk dosing
Multiple smallshort dosing trials in healthy volunteers and subjects with a variety of conditions have supported the safety of inhaled CO in the 100-400 ppm range to achieve a [COHb] in 4-10 range bull COPD
bull (Kerstjens et al Eur Respir J 2007 30 1131ndash1137)
bull Healthy subjects with exercisebull (Med Sci Sports Exerc 2012 Nov44(11)2118-24)
bull Healthy subjects exposed to 500 ppm for 1 hour then challenged with LPS bull (Am J Respir Crit Care Med Vol 171 pp 354ndash360 2005)
bull Colon-surgery patients at risk for paralytic Ileusbull (ClinicalTrialsgov identifier NCT01050712)
bull Retinal Blood flow studies in healthy volunteersbull (Invest OphthalmolVis Sci 2005464275ndash4280)
Inhaled CO use in pulmonary function labs for assessment of lung diffusion capacity has long been standard and safe
13Clinical Development Strategy
Significantly leverages extensive (~$23 million) of NIH funding to de-risk early stage clinical development risk
All indications being pursued are Orphan-qualifying
Balances smaller market size near-term acute indications (DGF acute liver failure) with chronic multi-$B indications (eg IPF NASH renal fibrosis others)
Significant DGF labeling-claim expansion opportunity following approval slow-graft function (SGF) acute kidney injury (AKI) delay of ESRD-associated dialysis renal fibrosis
CORM development offers life-cycle management with ivorally bioavailable next-gen CO therapeutics
14
bull Over half of the 13K US cadaveric
kidney transplants per year lead to
delayedslow graft function (DGFSGF)
bull DGF significantly increases risk of
acute and chronic rejection episodes
bull An iCo treatment for DGF would allow a
larger proportion of allografts from
donors after cardiac death (DCD) and
extended criteria donors (ECD) which
currently have a higher DGF and IRI risk
bull DGF increases post-surgical costs by
$4K+ increases post-transplant hospital
stay (usually 5-10 days) by up to 75
bull Over five years post-transplant DGF
patients had significantly higher time on
dialysis transplant rejection and mortality
bull An effective therapy for DGF would
significantly increase viable donor
organ pool and increase utilization of
those from extended criteria donors (many
currently unusable and are discarded)
bull There are ~13K cadaveric donor kidney transplants per year in US ~15K per year in
Canada and ~14K per year in the EU ndash incidence of DGF precludes larger numbers
bull By reducing ECD DGF iCO would shorten transplant wait times reduce
morbiditymortality on dialysis reduce effective cost of successful transplants
bull iCO for DGF could reach $300M+ annual revenues with less than one-third transplant
penetration for hospital treatment and one-third of those moving on to home treatment
Opportunity in Delayed Graft Function (DGF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwvalueinhealthjournalcomarticleS1098-3015(14)01756-2pdf [2] httpwwwncbinlmnihgovpubmed23538345
15
bull Idiopathic Pulmonary Fibrosis
progressive deterioration of lung
function and near-universal mortality
within five years from onset
bull No known cause no cure
bull Mean survival time only 38 years
bull Two recently approved medications only
moderately slow progression with
significant adverse effects seen in trials
bull Most of pipeline targets one mechanism
bull Recently approved medications Ofev
(nintendanib BI) and Esbriet (pirfenidone
Roche) priced at nearly $100Kyear
bull The only fully effective treatment a double-
lung transplant costs ~$800K end-to-end
bull CO for IPF offers
bull Synergy with OfevEsbriet
bull Improved disease progression
bull Lower all-in cost per year
bull Easier dosing schedule
(3xweek vs twice daily)
bull Prevalence of IPF is gt120K in US gt20K in Canada gt150K in Europe 20K in Japan
bull Clinicians estimate 70 of IPF patients are early-enough in disease progression to see
meaningful clinical improvement from stoppingslowing fibrosis expansion
bull Even at half or less Ofev pricing $2B annual revenues could be reached with only
30 patient penetration in only the three markets listed above
Opportunity in Idiopathic Pulmonary
Fibrosis (IPF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwaafporgafp20121001p631html [2] httpwwwniddknihgovhealth-informationhealth-statisticsPageskidney-disease-statistics-united-statesaspx [3] httpjasnasnjournalsorgcontent16113365fullpdf
16
RENAL PROGRAMS
17Increasing Use of Kidneys at Risk for DGF
17
Adult solitary primary kidney transplants
Source UNOSOPTN data as of April 29 2011
Note ECD kidneys are reluctantly utilized due to higher incidences and prevalence of DGF SGF AR CR etc
+ 14
+ 296
18iCO for Delayed Graft Function in
Renal Transplant Patients
Growing unmet need ~50K renal transplantsyear in both the US and EU ~10K ROW
No approved drugs
Recent transplant advances make therapies to prevent rejection and late or non-function more criticalbull Allowinguarr transplantation of organs from extended criteria and cardiac death donors
bull Allowinguarrtransplant of organs with longer warm and cold ischemia times
In several animal models inhaled CO dramatically darrs frequency and duration of delayed graft function (DGF)bull Multiple predictive animal models of CO administration demonstrated acute ischemia reperfusion injury
recovery and chronic allograft rejection (CAN) preventionmitigation
CO therapy at time of transplant feasible add-on to existing Rxbull short intra- or perioperative courses of Rx
Substantial benefit to patients payers and hospitalsbull Prevents or shortens need for dialysis biopsies ICU days etc
bull Allows earlier hospital discharge
Substantial label-expansion potential for acute and longer-term bull Chronic allograft nephropathy (CAN)
bull Acute kidney injury (AKI)
bull Renal fibrosis
19Inhaled CO
Pig Allo-transplantation Model
Warm and cold ischemia
bull 60 minutes of warm ischemia aortic cross-clamping
bull 24 hours cold storage in UW
Allo-transplantation after bilateral nephrectomy
CO delivered through ventilator for one hour starting at
incision (3mgkg with 40 FiO2)
Tacrolimus immunosuppression
Hanto et al AJT 2010
20Intraoperative Inhaled CO
Accelerates Renal Recovery from IRI
BUN Cr
Hanto et al AJT 2010
CoHb Levels
21Inhaled CO Improves
Histology and Reduces Apoptosis
Hanto et al AJT 2010
22Inhaled CO Increases
Proliferation and Reduces Inflammation
Hanto et al AJT 2010
Phospho-
histone 3
Tissue
Factor
23Inhaled CO Induces Changes
in Tissue Gene Expression
HSP 90Retinol binding
protein 4
MCP-1Osteopontin
Hanto et al AJT 2010
QT-PCR Confirmation
24Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Lewis to Brown Norway orthotopic kidney transplant
model following bilateral nephrectomy
Brief FK (05mgkg day 0-6)
Continuous CO exposure in CO chamber (20 ppm) days
60-150
Other exposure regimens
bull Continuous exposures days 0-30 30-60 or 0-90
bull 1hr daily CO (250 ppm) days 0-90
Nakao et al Am J Physiology 2009
25Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Nakao et al Am J Physiology 2009
Graft function CAN by histology Expression of
fibrosis genes
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
10ALFAMA Has A Unique Collection
Of CO-RMs
gt850 molecules
Each will differ in
- Trigger for CO release
- CO release kinetics
- Pharmacokinetics
- Biodistribution
- Bioavailability
Many are
- easily modifiable
- simple to synthesize
- Inexpensive to produce
Alfamarsquos patent applications cover both the concept (use) and some new chemical
entities (substance of matter)
General scheme of Alfamarsquos pharmaceutical CO-RMs
11NIH-Funded Clinical Trials Granted to Dr Choi
(Proterris Co-Founder) Validates iCO Rx Opportunity
Idiopathic Pulmonary Fibrosis (IPF) bull ldquoA Phase 2 Trial of Carbon Monoxide for the Treatment of Idiopathic
Pulmonary Fibrosisrdquo (NIH U01HL105371)
bull Total Grant $621M
bull 58 patient study completed positive read-out May 2015
Adult Respiratory Distress Syndrome (ARDS)bull ldquoPhase 12 Study of Inhaled Carbon Monoxide for the Treatment of
Sepsis-Induced Adult Lung Injuryrdquo (NIH P01 HL108801)
bull Jul 2011 ndash Mar 2017
bull Total Grant $14M
Pulmonary Arterial Hypertension (PAH)bull ldquoHeme Oxygenase-1Carbon Monoxide in Lung Vascular Injuryrdquo
(NIH R01 HL060234)
bull March 2013 - June 2018
bull IND filed Mar 2017
bull Total Grant $25M
12Low-dose Inhaled CO is
SafeWell-Tolerated in Multiple Clinical Trials
No iCO-related SAEs in NIH-funded IPF P2 study run by Dr Choi after 12 wksof 2xwk dosing
Multiple smallshort dosing trials in healthy volunteers and subjects with a variety of conditions have supported the safety of inhaled CO in the 100-400 ppm range to achieve a [COHb] in 4-10 range bull COPD
bull (Kerstjens et al Eur Respir J 2007 30 1131ndash1137)
bull Healthy subjects with exercisebull (Med Sci Sports Exerc 2012 Nov44(11)2118-24)
bull Healthy subjects exposed to 500 ppm for 1 hour then challenged with LPS bull (Am J Respir Crit Care Med Vol 171 pp 354ndash360 2005)
bull Colon-surgery patients at risk for paralytic Ileusbull (ClinicalTrialsgov identifier NCT01050712)
bull Retinal Blood flow studies in healthy volunteersbull (Invest OphthalmolVis Sci 2005464275ndash4280)
Inhaled CO use in pulmonary function labs for assessment of lung diffusion capacity has long been standard and safe
13Clinical Development Strategy
Significantly leverages extensive (~$23 million) of NIH funding to de-risk early stage clinical development risk
All indications being pursued are Orphan-qualifying
Balances smaller market size near-term acute indications (DGF acute liver failure) with chronic multi-$B indications (eg IPF NASH renal fibrosis others)
Significant DGF labeling-claim expansion opportunity following approval slow-graft function (SGF) acute kidney injury (AKI) delay of ESRD-associated dialysis renal fibrosis
CORM development offers life-cycle management with ivorally bioavailable next-gen CO therapeutics
14
bull Over half of the 13K US cadaveric
kidney transplants per year lead to
delayedslow graft function (DGFSGF)
bull DGF significantly increases risk of
acute and chronic rejection episodes
bull An iCo treatment for DGF would allow a
larger proportion of allografts from
donors after cardiac death (DCD) and
extended criteria donors (ECD) which
currently have a higher DGF and IRI risk
bull DGF increases post-surgical costs by
$4K+ increases post-transplant hospital
stay (usually 5-10 days) by up to 75
bull Over five years post-transplant DGF
patients had significantly higher time on
dialysis transplant rejection and mortality
bull An effective therapy for DGF would
significantly increase viable donor
organ pool and increase utilization of
those from extended criteria donors (many
currently unusable and are discarded)
bull There are ~13K cadaveric donor kidney transplants per year in US ~15K per year in
Canada and ~14K per year in the EU ndash incidence of DGF precludes larger numbers
bull By reducing ECD DGF iCO would shorten transplant wait times reduce
morbiditymortality on dialysis reduce effective cost of successful transplants
bull iCO for DGF could reach $300M+ annual revenues with less than one-third transplant
penetration for hospital treatment and one-third of those moving on to home treatment
Opportunity in Delayed Graft Function (DGF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwvalueinhealthjournalcomarticleS1098-3015(14)01756-2pdf [2] httpwwwncbinlmnihgovpubmed23538345
15
bull Idiopathic Pulmonary Fibrosis
progressive deterioration of lung
function and near-universal mortality
within five years from onset
bull No known cause no cure
bull Mean survival time only 38 years
bull Two recently approved medications only
moderately slow progression with
significant adverse effects seen in trials
bull Most of pipeline targets one mechanism
bull Recently approved medications Ofev
(nintendanib BI) and Esbriet (pirfenidone
Roche) priced at nearly $100Kyear
bull The only fully effective treatment a double-
lung transplant costs ~$800K end-to-end
bull CO for IPF offers
bull Synergy with OfevEsbriet
bull Improved disease progression
bull Lower all-in cost per year
bull Easier dosing schedule
(3xweek vs twice daily)
bull Prevalence of IPF is gt120K in US gt20K in Canada gt150K in Europe 20K in Japan
bull Clinicians estimate 70 of IPF patients are early-enough in disease progression to see
meaningful clinical improvement from stoppingslowing fibrosis expansion
bull Even at half or less Ofev pricing $2B annual revenues could be reached with only
30 patient penetration in only the three markets listed above
Opportunity in Idiopathic Pulmonary
Fibrosis (IPF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwaafporgafp20121001p631html [2] httpwwwniddknihgovhealth-informationhealth-statisticsPageskidney-disease-statistics-united-statesaspx [3] httpjasnasnjournalsorgcontent16113365fullpdf
16
RENAL PROGRAMS
17Increasing Use of Kidneys at Risk for DGF
17
Adult solitary primary kidney transplants
Source UNOSOPTN data as of April 29 2011
Note ECD kidneys are reluctantly utilized due to higher incidences and prevalence of DGF SGF AR CR etc
+ 14
+ 296
18iCO for Delayed Graft Function in
Renal Transplant Patients
Growing unmet need ~50K renal transplantsyear in both the US and EU ~10K ROW
No approved drugs
Recent transplant advances make therapies to prevent rejection and late or non-function more criticalbull Allowinguarr transplantation of organs from extended criteria and cardiac death donors
bull Allowinguarrtransplant of organs with longer warm and cold ischemia times
In several animal models inhaled CO dramatically darrs frequency and duration of delayed graft function (DGF)bull Multiple predictive animal models of CO administration demonstrated acute ischemia reperfusion injury
recovery and chronic allograft rejection (CAN) preventionmitigation
CO therapy at time of transplant feasible add-on to existing Rxbull short intra- or perioperative courses of Rx
Substantial benefit to patients payers and hospitalsbull Prevents or shortens need for dialysis biopsies ICU days etc
bull Allows earlier hospital discharge
Substantial label-expansion potential for acute and longer-term bull Chronic allograft nephropathy (CAN)
bull Acute kidney injury (AKI)
bull Renal fibrosis
19Inhaled CO
Pig Allo-transplantation Model
Warm and cold ischemia
bull 60 minutes of warm ischemia aortic cross-clamping
bull 24 hours cold storage in UW
Allo-transplantation after bilateral nephrectomy
CO delivered through ventilator for one hour starting at
incision (3mgkg with 40 FiO2)
Tacrolimus immunosuppression
Hanto et al AJT 2010
20Intraoperative Inhaled CO
Accelerates Renal Recovery from IRI
BUN Cr
Hanto et al AJT 2010
CoHb Levels
21Inhaled CO Improves
Histology and Reduces Apoptosis
Hanto et al AJT 2010
22Inhaled CO Increases
Proliferation and Reduces Inflammation
Hanto et al AJT 2010
Phospho-
histone 3
Tissue
Factor
23Inhaled CO Induces Changes
in Tissue Gene Expression
HSP 90Retinol binding
protein 4
MCP-1Osteopontin
Hanto et al AJT 2010
QT-PCR Confirmation
24Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Lewis to Brown Norway orthotopic kidney transplant
model following bilateral nephrectomy
Brief FK (05mgkg day 0-6)
Continuous CO exposure in CO chamber (20 ppm) days
60-150
Other exposure regimens
bull Continuous exposures days 0-30 30-60 or 0-90
bull 1hr daily CO (250 ppm) days 0-90
Nakao et al Am J Physiology 2009
25Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Nakao et al Am J Physiology 2009
Graft function CAN by histology Expression of
fibrosis genes
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
11NIH-Funded Clinical Trials Granted to Dr Choi
(Proterris Co-Founder) Validates iCO Rx Opportunity
Idiopathic Pulmonary Fibrosis (IPF) bull ldquoA Phase 2 Trial of Carbon Monoxide for the Treatment of Idiopathic
Pulmonary Fibrosisrdquo (NIH U01HL105371)
bull Total Grant $621M
bull 58 patient study completed positive read-out May 2015
Adult Respiratory Distress Syndrome (ARDS)bull ldquoPhase 12 Study of Inhaled Carbon Monoxide for the Treatment of
Sepsis-Induced Adult Lung Injuryrdquo (NIH P01 HL108801)
bull Jul 2011 ndash Mar 2017
bull Total Grant $14M
Pulmonary Arterial Hypertension (PAH)bull ldquoHeme Oxygenase-1Carbon Monoxide in Lung Vascular Injuryrdquo
(NIH R01 HL060234)
bull March 2013 - June 2018
bull IND filed Mar 2017
bull Total Grant $25M
12Low-dose Inhaled CO is
SafeWell-Tolerated in Multiple Clinical Trials
No iCO-related SAEs in NIH-funded IPF P2 study run by Dr Choi after 12 wksof 2xwk dosing
Multiple smallshort dosing trials in healthy volunteers and subjects with a variety of conditions have supported the safety of inhaled CO in the 100-400 ppm range to achieve a [COHb] in 4-10 range bull COPD
bull (Kerstjens et al Eur Respir J 2007 30 1131ndash1137)
bull Healthy subjects with exercisebull (Med Sci Sports Exerc 2012 Nov44(11)2118-24)
bull Healthy subjects exposed to 500 ppm for 1 hour then challenged with LPS bull (Am J Respir Crit Care Med Vol 171 pp 354ndash360 2005)
bull Colon-surgery patients at risk for paralytic Ileusbull (ClinicalTrialsgov identifier NCT01050712)
bull Retinal Blood flow studies in healthy volunteersbull (Invest OphthalmolVis Sci 2005464275ndash4280)
Inhaled CO use in pulmonary function labs for assessment of lung diffusion capacity has long been standard and safe
13Clinical Development Strategy
Significantly leverages extensive (~$23 million) of NIH funding to de-risk early stage clinical development risk
All indications being pursued are Orphan-qualifying
Balances smaller market size near-term acute indications (DGF acute liver failure) with chronic multi-$B indications (eg IPF NASH renal fibrosis others)
Significant DGF labeling-claim expansion opportunity following approval slow-graft function (SGF) acute kidney injury (AKI) delay of ESRD-associated dialysis renal fibrosis
CORM development offers life-cycle management with ivorally bioavailable next-gen CO therapeutics
14
bull Over half of the 13K US cadaveric
kidney transplants per year lead to
delayedslow graft function (DGFSGF)
bull DGF significantly increases risk of
acute and chronic rejection episodes
bull An iCo treatment for DGF would allow a
larger proportion of allografts from
donors after cardiac death (DCD) and
extended criteria donors (ECD) which
currently have a higher DGF and IRI risk
bull DGF increases post-surgical costs by
$4K+ increases post-transplant hospital
stay (usually 5-10 days) by up to 75
bull Over five years post-transplant DGF
patients had significantly higher time on
dialysis transplant rejection and mortality
bull An effective therapy for DGF would
significantly increase viable donor
organ pool and increase utilization of
those from extended criteria donors (many
currently unusable and are discarded)
bull There are ~13K cadaveric donor kidney transplants per year in US ~15K per year in
Canada and ~14K per year in the EU ndash incidence of DGF precludes larger numbers
bull By reducing ECD DGF iCO would shorten transplant wait times reduce
morbiditymortality on dialysis reduce effective cost of successful transplants
bull iCO for DGF could reach $300M+ annual revenues with less than one-third transplant
penetration for hospital treatment and one-third of those moving on to home treatment
Opportunity in Delayed Graft Function (DGF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwvalueinhealthjournalcomarticleS1098-3015(14)01756-2pdf [2] httpwwwncbinlmnihgovpubmed23538345
15
bull Idiopathic Pulmonary Fibrosis
progressive deterioration of lung
function and near-universal mortality
within five years from onset
bull No known cause no cure
bull Mean survival time only 38 years
bull Two recently approved medications only
moderately slow progression with
significant adverse effects seen in trials
bull Most of pipeline targets one mechanism
bull Recently approved medications Ofev
(nintendanib BI) and Esbriet (pirfenidone
Roche) priced at nearly $100Kyear
bull The only fully effective treatment a double-
lung transplant costs ~$800K end-to-end
bull CO for IPF offers
bull Synergy with OfevEsbriet
bull Improved disease progression
bull Lower all-in cost per year
bull Easier dosing schedule
(3xweek vs twice daily)
bull Prevalence of IPF is gt120K in US gt20K in Canada gt150K in Europe 20K in Japan
bull Clinicians estimate 70 of IPF patients are early-enough in disease progression to see
meaningful clinical improvement from stoppingslowing fibrosis expansion
bull Even at half or less Ofev pricing $2B annual revenues could be reached with only
30 patient penetration in only the three markets listed above
Opportunity in Idiopathic Pulmonary
Fibrosis (IPF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwaafporgafp20121001p631html [2] httpwwwniddknihgovhealth-informationhealth-statisticsPageskidney-disease-statistics-united-statesaspx [3] httpjasnasnjournalsorgcontent16113365fullpdf
16
RENAL PROGRAMS
17Increasing Use of Kidneys at Risk for DGF
17
Adult solitary primary kidney transplants
Source UNOSOPTN data as of April 29 2011
Note ECD kidneys are reluctantly utilized due to higher incidences and prevalence of DGF SGF AR CR etc
+ 14
+ 296
18iCO for Delayed Graft Function in
Renal Transplant Patients
Growing unmet need ~50K renal transplantsyear in both the US and EU ~10K ROW
No approved drugs
Recent transplant advances make therapies to prevent rejection and late or non-function more criticalbull Allowinguarr transplantation of organs from extended criteria and cardiac death donors
bull Allowinguarrtransplant of organs with longer warm and cold ischemia times
In several animal models inhaled CO dramatically darrs frequency and duration of delayed graft function (DGF)bull Multiple predictive animal models of CO administration demonstrated acute ischemia reperfusion injury
recovery and chronic allograft rejection (CAN) preventionmitigation
CO therapy at time of transplant feasible add-on to existing Rxbull short intra- or perioperative courses of Rx
Substantial benefit to patients payers and hospitalsbull Prevents or shortens need for dialysis biopsies ICU days etc
bull Allows earlier hospital discharge
Substantial label-expansion potential for acute and longer-term bull Chronic allograft nephropathy (CAN)
bull Acute kidney injury (AKI)
bull Renal fibrosis
19Inhaled CO
Pig Allo-transplantation Model
Warm and cold ischemia
bull 60 minutes of warm ischemia aortic cross-clamping
bull 24 hours cold storage in UW
Allo-transplantation after bilateral nephrectomy
CO delivered through ventilator for one hour starting at
incision (3mgkg with 40 FiO2)
Tacrolimus immunosuppression
Hanto et al AJT 2010
20Intraoperative Inhaled CO
Accelerates Renal Recovery from IRI
BUN Cr
Hanto et al AJT 2010
CoHb Levels
21Inhaled CO Improves
Histology and Reduces Apoptosis
Hanto et al AJT 2010
22Inhaled CO Increases
Proliferation and Reduces Inflammation
Hanto et al AJT 2010
Phospho-
histone 3
Tissue
Factor
23Inhaled CO Induces Changes
in Tissue Gene Expression
HSP 90Retinol binding
protein 4
MCP-1Osteopontin
Hanto et al AJT 2010
QT-PCR Confirmation
24Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Lewis to Brown Norway orthotopic kidney transplant
model following bilateral nephrectomy
Brief FK (05mgkg day 0-6)
Continuous CO exposure in CO chamber (20 ppm) days
60-150
Other exposure regimens
bull Continuous exposures days 0-30 30-60 or 0-90
bull 1hr daily CO (250 ppm) days 0-90
Nakao et al Am J Physiology 2009
25Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Nakao et al Am J Physiology 2009
Graft function CAN by histology Expression of
fibrosis genes
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
12Low-dose Inhaled CO is
SafeWell-Tolerated in Multiple Clinical Trials
No iCO-related SAEs in NIH-funded IPF P2 study run by Dr Choi after 12 wksof 2xwk dosing
Multiple smallshort dosing trials in healthy volunteers and subjects with a variety of conditions have supported the safety of inhaled CO in the 100-400 ppm range to achieve a [COHb] in 4-10 range bull COPD
bull (Kerstjens et al Eur Respir J 2007 30 1131ndash1137)
bull Healthy subjects with exercisebull (Med Sci Sports Exerc 2012 Nov44(11)2118-24)
bull Healthy subjects exposed to 500 ppm for 1 hour then challenged with LPS bull (Am J Respir Crit Care Med Vol 171 pp 354ndash360 2005)
bull Colon-surgery patients at risk for paralytic Ileusbull (ClinicalTrialsgov identifier NCT01050712)
bull Retinal Blood flow studies in healthy volunteersbull (Invest OphthalmolVis Sci 2005464275ndash4280)
Inhaled CO use in pulmonary function labs for assessment of lung diffusion capacity has long been standard and safe
13Clinical Development Strategy
Significantly leverages extensive (~$23 million) of NIH funding to de-risk early stage clinical development risk
All indications being pursued are Orphan-qualifying
Balances smaller market size near-term acute indications (DGF acute liver failure) with chronic multi-$B indications (eg IPF NASH renal fibrosis others)
Significant DGF labeling-claim expansion opportunity following approval slow-graft function (SGF) acute kidney injury (AKI) delay of ESRD-associated dialysis renal fibrosis
CORM development offers life-cycle management with ivorally bioavailable next-gen CO therapeutics
14
bull Over half of the 13K US cadaveric
kidney transplants per year lead to
delayedslow graft function (DGFSGF)
bull DGF significantly increases risk of
acute and chronic rejection episodes
bull An iCo treatment for DGF would allow a
larger proportion of allografts from
donors after cardiac death (DCD) and
extended criteria donors (ECD) which
currently have a higher DGF and IRI risk
bull DGF increases post-surgical costs by
$4K+ increases post-transplant hospital
stay (usually 5-10 days) by up to 75
bull Over five years post-transplant DGF
patients had significantly higher time on
dialysis transplant rejection and mortality
bull An effective therapy for DGF would
significantly increase viable donor
organ pool and increase utilization of
those from extended criteria donors (many
currently unusable and are discarded)
bull There are ~13K cadaveric donor kidney transplants per year in US ~15K per year in
Canada and ~14K per year in the EU ndash incidence of DGF precludes larger numbers
bull By reducing ECD DGF iCO would shorten transplant wait times reduce
morbiditymortality on dialysis reduce effective cost of successful transplants
bull iCO for DGF could reach $300M+ annual revenues with less than one-third transplant
penetration for hospital treatment and one-third of those moving on to home treatment
Opportunity in Delayed Graft Function (DGF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwvalueinhealthjournalcomarticleS1098-3015(14)01756-2pdf [2] httpwwwncbinlmnihgovpubmed23538345
15
bull Idiopathic Pulmonary Fibrosis
progressive deterioration of lung
function and near-universal mortality
within five years from onset
bull No known cause no cure
bull Mean survival time only 38 years
bull Two recently approved medications only
moderately slow progression with
significant adverse effects seen in trials
bull Most of pipeline targets one mechanism
bull Recently approved medications Ofev
(nintendanib BI) and Esbriet (pirfenidone
Roche) priced at nearly $100Kyear
bull The only fully effective treatment a double-
lung transplant costs ~$800K end-to-end
bull CO for IPF offers
bull Synergy with OfevEsbriet
bull Improved disease progression
bull Lower all-in cost per year
bull Easier dosing schedule
(3xweek vs twice daily)
bull Prevalence of IPF is gt120K in US gt20K in Canada gt150K in Europe 20K in Japan
bull Clinicians estimate 70 of IPF patients are early-enough in disease progression to see
meaningful clinical improvement from stoppingslowing fibrosis expansion
bull Even at half or less Ofev pricing $2B annual revenues could be reached with only
30 patient penetration in only the three markets listed above
Opportunity in Idiopathic Pulmonary
Fibrosis (IPF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwaafporgafp20121001p631html [2] httpwwwniddknihgovhealth-informationhealth-statisticsPageskidney-disease-statistics-united-statesaspx [3] httpjasnasnjournalsorgcontent16113365fullpdf
16
RENAL PROGRAMS
17Increasing Use of Kidneys at Risk for DGF
17
Adult solitary primary kidney transplants
Source UNOSOPTN data as of April 29 2011
Note ECD kidneys are reluctantly utilized due to higher incidences and prevalence of DGF SGF AR CR etc
+ 14
+ 296
18iCO for Delayed Graft Function in
Renal Transplant Patients
Growing unmet need ~50K renal transplantsyear in both the US and EU ~10K ROW
No approved drugs
Recent transplant advances make therapies to prevent rejection and late or non-function more criticalbull Allowinguarr transplantation of organs from extended criteria and cardiac death donors
bull Allowinguarrtransplant of organs with longer warm and cold ischemia times
In several animal models inhaled CO dramatically darrs frequency and duration of delayed graft function (DGF)bull Multiple predictive animal models of CO administration demonstrated acute ischemia reperfusion injury
recovery and chronic allograft rejection (CAN) preventionmitigation
CO therapy at time of transplant feasible add-on to existing Rxbull short intra- or perioperative courses of Rx
Substantial benefit to patients payers and hospitalsbull Prevents or shortens need for dialysis biopsies ICU days etc
bull Allows earlier hospital discharge
Substantial label-expansion potential for acute and longer-term bull Chronic allograft nephropathy (CAN)
bull Acute kidney injury (AKI)
bull Renal fibrosis
19Inhaled CO
Pig Allo-transplantation Model
Warm and cold ischemia
bull 60 minutes of warm ischemia aortic cross-clamping
bull 24 hours cold storage in UW
Allo-transplantation after bilateral nephrectomy
CO delivered through ventilator for one hour starting at
incision (3mgkg with 40 FiO2)
Tacrolimus immunosuppression
Hanto et al AJT 2010
20Intraoperative Inhaled CO
Accelerates Renal Recovery from IRI
BUN Cr
Hanto et al AJT 2010
CoHb Levels
21Inhaled CO Improves
Histology and Reduces Apoptosis
Hanto et al AJT 2010
22Inhaled CO Increases
Proliferation and Reduces Inflammation
Hanto et al AJT 2010
Phospho-
histone 3
Tissue
Factor
23Inhaled CO Induces Changes
in Tissue Gene Expression
HSP 90Retinol binding
protein 4
MCP-1Osteopontin
Hanto et al AJT 2010
QT-PCR Confirmation
24Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Lewis to Brown Norway orthotopic kidney transplant
model following bilateral nephrectomy
Brief FK (05mgkg day 0-6)
Continuous CO exposure in CO chamber (20 ppm) days
60-150
Other exposure regimens
bull Continuous exposures days 0-30 30-60 or 0-90
bull 1hr daily CO (250 ppm) days 0-90
Nakao et al Am J Physiology 2009
25Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Nakao et al Am J Physiology 2009
Graft function CAN by histology Expression of
fibrosis genes
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
13Clinical Development Strategy
Significantly leverages extensive (~$23 million) of NIH funding to de-risk early stage clinical development risk
All indications being pursued are Orphan-qualifying
Balances smaller market size near-term acute indications (DGF acute liver failure) with chronic multi-$B indications (eg IPF NASH renal fibrosis others)
Significant DGF labeling-claim expansion opportunity following approval slow-graft function (SGF) acute kidney injury (AKI) delay of ESRD-associated dialysis renal fibrosis
CORM development offers life-cycle management with ivorally bioavailable next-gen CO therapeutics
14
bull Over half of the 13K US cadaveric
kidney transplants per year lead to
delayedslow graft function (DGFSGF)
bull DGF significantly increases risk of
acute and chronic rejection episodes
bull An iCo treatment for DGF would allow a
larger proportion of allografts from
donors after cardiac death (DCD) and
extended criteria donors (ECD) which
currently have a higher DGF and IRI risk
bull DGF increases post-surgical costs by
$4K+ increases post-transplant hospital
stay (usually 5-10 days) by up to 75
bull Over five years post-transplant DGF
patients had significantly higher time on
dialysis transplant rejection and mortality
bull An effective therapy for DGF would
significantly increase viable donor
organ pool and increase utilization of
those from extended criteria donors (many
currently unusable and are discarded)
bull There are ~13K cadaveric donor kidney transplants per year in US ~15K per year in
Canada and ~14K per year in the EU ndash incidence of DGF precludes larger numbers
bull By reducing ECD DGF iCO would shorten transplant wait times reduce
morbiditymortality on dialysis reduce effective cost of successful transplants
bull iCO for DGF could reach $300M+ annual revenues with less than one-third transplant
penetration for hospital treatment and one-third of those moving on to home treatment
Opportunity in Delayed Graft Function (DGF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwvalueinhealthjournalcomarticleS1098-3015(14)01756-2pdf [2] httpwwwncbinlmnihgovpubmed23538345
15
bull Idiopathic Pulmonary Fibrosis
progressive deterioration of lung
function and near-universal mortality
within five years from onset
bull No known cause no cure
bull Mean survival time only 38 years
bull Two recently approved medications only
moderately slow progression with
significant adverse effects seen in trials
bull Most of pipeline targets one mechanism
bull Recently approved medications Ofev
(nintendanib BI) and Esbriet (pirfenidone
Roche) priced at nearly $100Kyear
bull The only fully effective treatment a double-
lung transplant costs ~$800K end-to-end
bull CO for IPF offers
bull Synergy with OfevEsbriet
bull Improved disease progression
bull Lower all-in cost per year
bull Easier dosing schedule
(3xweek vs twice daily)
bull Prevalence of IPF is gt120K in US gt20K in Canada gt150K in Europe 20K in Japan
bull Clinicians estimate 70 of IPF patients are early-enough in disease progression to see
meaningful clinical improvement from stoppingslowing fibrosis expansion
bull Even at half or less Ofev pricing $2B annual revenues could be reached with only
30 patient penetration in only the three markets listed above
Opportunity in Idiopathic Pulmonary
Fibrosis (IPF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwaafporgafp20121001p631html [2] httpwwwniddknihgovhealth-informationhealth-statisticsPageskidney-disease-statistics-united-statesaspx [3] httpjasnasnjournalsorgcontent16113365fullpdf
16
RENAL PROGRAMS
17Increasing Use of Kidneys at Risk for DGF
17
Adult solitary primary kidney transplants
Source UNOSOPTN data as of April 29 2011
Note ECD kidneys are reluctantly utilized due to higher incidences and prevalence of DGF SGF AR CR etc
+ 14
+ 296
18iCO for Delayed Graft Function in
Renal Transplant Patients
Growing unmet need ~50K renal transplantsyear in both the US and EU ~10K ROW
No approved drugs
Recent transplant advances make therapies to prevent rejection and late or non-function more criticalbull Allowinguarr transplantation of organs from extended criteria and cardiac death donors
bull Allowinguarrtransplant of organs with longer warm and cold ischemia times
In several animal models inhaled CO dramatically darrs frequency and duration of delayed graft function (DGF)bull Multiple predictive animal models of CO administration demonstrated acute ischemia reperfusion injury
recovery and chronic allograft rejection (CAN) preventionmitigation
CO therapy at time of transplant feasible add-on to existing Rxbull short intra- or perioperative courses of Rx
Substantial benefit to patients payers and hospitalsbull Prevents or shortens need for dialysis biopsies ICU days etc
bull Allows earlier hospital discharge
Substantial label-expansion potential for acute and longer-term bull Chronic allograft nephropathy (CAN)
bull Acute kidney injury (AKI)
bull Renal fibrosis
19Inhaled CO
Pig Allo-transplantation Model
Warm and cold ischemia
bull 60 minutes of warm ischemia aortic cross-clamping
bull 24 hours cold storage in UW
Allo-transplantation after bilateral nephrectomy
CO delivered through ventilator for one hour starting at
incision (3mgkg with 40 FiO2)
Tacrolimus immunosuppression
Hanto et al AJT 2010
20Intraoperative Inhaled CO
Accelerates Renal Recovery from IRI
BUN Cr
Hanto et al AJT 2010
CoHb Levels
21Inhaled CO Improves
Histology and Reduces Apoptosis
Hanto et al AJT 2010
22Inhaled CO Increases
Proliferation and Reduces Inflammation
Hanto et al AJT 2010
Phospho-
histone 3
Tissue
Factor
23Inhaled CO Induces Changes
in Tissue Gene Expression
HSP 90Retinol binding
protein 4
MCP-1Osteopontin
Hanto et al AJT 2010
QT-PCR Confirmation
24Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Lewis to Brown Norway orthotopic kidney transplant
model following bilateral nephrectomy
Brief FK (05mgkg day 0-6)
Continuous CO exposure in CO chamber (20 ppm) days
60-150
Other exposure regimens
bull Continuous exposures days 0-30 30-60 or 0-90
bull 1hr daily CO (250 ppm) days 0-90
Nakao et al Am J Physiology 2009
25Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Nakao et al Am J Physiology 2009
Graft function CAN by histology Expression of
fibrosis genes
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
14
bull Over half of the 13K US cadaveric
kidney transplants per year lead to
delayedslow graft function (DGFSGF)
bull DGF significantly increases risk of
acute and chronic rejection episodes
bull An iCo treatment for DGF would allow a
larger proportion of allografts from
donors after cardiac death (DCD) and
extended criteria donors (ECD) which
currently have a higher DGF and IRI risk
bull DGF increases post-surgical costs by
$4K+ increases post-transplant hospital
stay (usually 5-10 days) by up to 75
bull Over five years post-transplant DGF
patients had significantly higher time on
dialysis transplant rejection and mortality
bull An effective therapy for DGF would
significantly increase viable donor
organ pool and increase utilization of
those from extended criteria donors (many
currently unusable and are discarded)
bull There are ~13K cadaveric donor kidney transplants per year in US ~15K per year in
Canada and ~14K per year in the EU ndash incidence of DGF precludes larger numbers
bull By reducing ECD DGF iCO would shorten transplant wait times reduce
morbiditymortality on dialysis reduce effective cost of successful transplants
bull iCO for DGF could reach $300M+ annual revenues with less than one-third transplant
penetration for hospital treatment and one-third of those moving on to home treatment
Opportunity in Delayed Graft Function (DGF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwvalueinhealthjournalcomarticleS1098-3015(14)01756-2pdf [2] httpwwwncbinlmnihgovpubmed23538345
15
bull Idiopathic Pulmonary Fibrosis
progressive deterioration of lung
function and near-universal mortality
within five years from onset
bull No known cause no cure
bull Mean survival time only 38 years
bull Two recently approved medications only
moderately slow progression with
significant adverse effects seen in trials
bull Most of pipeline targets one mechanism
bull Recently approved medications Ofev
(nintendanib BI) and Esbriet (pirfenidone
Roche) priced at nearly $100Kyear
bull The only fully effective treatment a double-
lung transplant costs ~$800K end-to-end
bull CO for IPF offers
bull Synergy with OfevEsbriet
bull Improved disease progression
bull Lower all-in cost per year
bull Easier dosing schedule
(3xweek vs twice daily)
bull Prevalence of IPF is gt120K in US gt20K in Canada gt150K in Europe 20K in Japan
bull Clinicians estimate 70 of IPF patients are early-enough in disease progression to see
meaningful clinical improvement from stoppingslowing fibrosis expansion
bull Even at half or less Ofev pricing $2B annual revenues could be reached with only
30 patient penetration in only the three markets listed above
Opportunity in Idiopathic Pulmonary
Fibrosis (IPF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwaafporgafp20121001p631html [2] httpwwwniddknihgovhealth-informationhealth-statisticsPageskidney-disease-statistics-united-statesaspx [3] httpjasnasnjournalsorgcontent16113365fullpdf
16
RENAL PROGRAMS
17Increasing Use of Kidneys at Risk for DGF
17
Adult solitary primary kidney transplants
Source UNOSOPTN data as of April 29 2011
Note ECD kidneys are reluctantly utilized due to higher incidences and prevalence of DGF SGF AR CR etc
+ 14
+ 296
18iCO for Delayed Graft Function in
Renal Transplant Patients
Growing unmet need ~50K renal transplantsyear in both the US and EU ~10K ROW
No approved drugs
Recent transplant advances make therapies to prevent rejection and late or non-function more criticalbull Allowinguarr transplantation of organs from extended criteria and cardiac death donors
bull Allowinguarrtransplant of organs with longer warm and cold ischemia times
In several animal models inhaled CO dramatically darrs frequency and duration of delayed graft function (DGF)bull Multiple predictive animal models of CO administration demonstrated acute ischemia reperfusion injury
recovery and chronic allograft rejection (CAN) preventionmitigation
CO therapy at time of transplant feasible add-on to existing Rxbull short intra- or perioperative courses of Rx
Substantial benefit to patients payers and hospitalsbull Prevents or shortens need for dialysis biopsies ICU days etc
bull Allows earlier hospital discharge
Substantial label-expansion potential for acute and longer-term bull Chronic allograft nephropathy (CAN)
bull Acute kidney injury (AKI)
bull Renal fibrosis
19Inhaled CO
Pig Allo-transplantation Model
Warm and cold ischemia
bull 60 minutes of warm ischemia aortic cross-clamping
bull 24 hours cold storage in UW
Allo-transplantation after bilateral nephrectomy
CO delivered through ventilator for one hour starting at
incision (3mgkg with 40 FiO2)
Tacrolimus immunosuppression
Hanto et al AJT 2010
20Intraoperative Inhaled CO
Accelerates Renal Recovery from IRI
BUN Cr
Hanto et al AJT 2010
CoHb Levels
21Inhaled CO Improves
Histology and Reduces Apoptosis
Hanto et al AJT 2010
22Inhaled CO Increases
Proliferation and Reduces Inflammation
Hanto et al AJT 2010
Phospho-
histone 3
Tissue
Factor
23Inhaled CO Induces Changes
in Tissue Gene Expression
HSP 90Retinol binding
protein 4
MCP-1Osteopontin
Hanto et al AJT 2010
QT-PCR Confirmation
24Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Lewis to Brown Norway orthotopic kidney transplant
model following bilateral nephrectomy
Brief FK (05mgkg day 0-6)
Continuous CO exposure in CO chamber (20 ppm) days
60-150
Other exposure regimens
bull Continuous exposures days 0-30 30-60 or 0-90
bull 1hr daily CO (250 ppm) days 0-90
Nakao et al Am J Physiology 2009
25Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Nakao et al Am J Physiology 2009
Graft function CAN by histology Expression of
fibrosis genes
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
15
bull Idiopathic Pulmonary Fibrosis
progressive deterioration of lung
function and near-universal mortality
within five years from onset
bull No known cause no cure
bull Mean survival time only 38 years
bull Two recently approved medications only
moderately slow progression with
significant adverse effects seen in trials
bull Most of pipeline targets one mechanism
bull Recently approved medications Ofev
(nintendanib BI) and Esbriet (pirfenidone
Roche) priced at nearly $100Kyear
bull The only fully effective treatment a double-
lung transplant costs ~$800K end-to-end
bull CO for IPF offers
bull Synergy with OfevEsbriet
bull Improved disease progression
bull Lower all-in cost per year
bull Easier dosing schedule
(3xweek vs twice daily)
bull Prevalence of IPF is gt120K in US gt20K in Canada gt150K in Europe 20K in Japan
bull Clinicians estimate 70 of IPF patients are early-enough in disease progression to see
meaningful clinical improvement from stoppingslowing fibrosis expansion
bull Even at half or less Ofev pricing $2B annual revenues could be reached with only
30 patient penetration in only the three markets listed above
Opportunity in Idiopathic Pulmonary
Fibrosis (IPF)
Unmet Medical Need Health Economic Prop
Market Potential
[1] httpwwwaafporgafp20121001p631html [2] httpwwwniddknihgovhealth-informationhealth-statisticsPageskidney-disease-statistics-united-statesaspx [3] httpjasnasnjournalsorgcontent16113365fullpdf
16
RENAL PROGRAMS
17Increasing Use of Kidneys at Risk for DGF
17
Adult solitary primary kidney transplants
Source UNOSOPTN data as of April 29 2011
Note ECD kidneys are reluctantly utilized due to higher incidences and prevalence of DGF SGF AR CR etc
+ 14
+ 296
18iCO for Delayed Graft Function in
Renal Transplant Patients
Growing unmet need ~50K renal transplantsyear in both the US and EU ~10K ROW
No approved drugs
Recent transplant advances make therapies to prevent rejection and late or non-function more criticalbull Allowinguarr transplantation of organs from extended criteria and cardiac death donors
bull Allowinguarrtransplant of organs with longer warm and cold ischemia times
In several animal models inhaled CO dramatically darrs frequency and duration of delayed graft function (DGF)bull Multiple predictive animal models of CO administration demonstrated acute ischemia reperfusion injury
recovery and chronic allograft rejection (CAN) preventionmitigation
CO therapy at time of transplant feasible add-on to existing Rxbull short intra- or perioperative courses of Rx
Substantial benefit to patients payers and hospitalsbull Prevents or shortens need for dialysis biopsies ICU days etc
bull Allows earlier hospital discharge
Substantial label-expansion potential for acute and longer-term bull Chronic allograft nephropathy (CAN)
bull Acute kidney injury (AKI)
bull Renal fibrosis
19Inhaled CO
Pig Allo-transplantation Model
Warm and cold ischemia
bull 60 minutes of warm ischemia aortic cross-clamping
bull 24 hours cold storage in UW
Allo-transplantation after bilateral nephrectomy
CO delivered through ventilator for one hour starting at
incision (3mgkg with 40 FiO2)
Tacrolimus immunosuppression
Hanto et al AJT 2010
20Intraoperative Inhaled CO
Accelerates Renal Recovery from IRI
BUN Cr
Hanto et al AJT 2010
CoHb Levels
21Inhaled CO Improves
Histology and Reduces Apoptosis
Hanto et al AJT 2010
22Inhaled CO Increases
Proliferation and Reduces Inflammation
Hanto et al AJT 2010
Phospho-
histone 3
Tissue
Factor
23Inhaled CO Induces Changes
in Tissue Gene Expression
HSP 90Retinol binding
protein 4
MCP-1Osteopontin
Hanto et al AJT 2010
QT-PCR Confirmation
24Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Lewis to Brown Norway orthotopic kidney transplant
model following bilateral nephrectomy
Brief FK (05mgkg day 0-6)
Continuous CO exposure in CO chamber (20 ppm) days
60-150
Other exposure regimens
bull Continuous exposures days 0-30 30-60 or 0-90
bull 1hr daily CO (250 ppm) days 0-90
Nakao et al Am J Physiology 2009
25Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Nakao et al Am J Physiology 2009
Graft function CAN by histology Expression of
fibrosis genes
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
16
RENAL PROGRAMS
17Increasing Use of Kidneys at Risk for DGF
17
Adult solitary primary kidney transplants
Source UNOSOPTN data as of April 29 2011
Note ECD kidneys are reluctantly utilized due to higher incidences and prevalence of DGF SGF AR CR etc
+ 14
+ 296
18iCO for Delayed Graft Function in
Renal Transplant Patients
Growing unmet need ~50K renal transplantsyear in both the US and EU ~10K ROW
No approved drugs
Recent transplant advances make therapies to prevent rejection and late or non-function more criticalbull Allowinguarr transplantation of organs from extended criteria and cardiac death donors
bull Allowinguarrtransplant of organs with longer warm and cold ischemia times
In several animal models inhaled CO dramatically darrs frequency and duration of delayed graft function (DGF)bull Multiple predictive animal models of CO administration demonstrated acute ischemia reperfusion injury
recovery and chronic allograft rejection (CAN) preventionmitigation
CO therapy at time of transplant feasible add-on to existing Rxbull short intra- or perioperative courses of Rx
Substantial benefit to patients payers and hospitalsbull Prevents or shortens need for dialysis biopsies ICU days etc
bull Allows earlier hospital discharge
Substantial label-expansion potential for acute and longer-term bull Chronic allograft nephropathy (CAN)
bull Acute kidney injury (AKI)
bull Renal fibrosis
19Inhaled CO
Pig Allo-transplantation Model
Warm and cold ischemia
bull 60 minutes of warm ischemia aortic cross-clamping
bull 24 hours cold storage in UW
Allo-transplantation after bilateral nephrectomy
CO delivered through ventilator for one hour starting at
incision (3mgkg with 40 FiO2)
Tacrolimus immunosuppression
Hanto et al AJT 2010
20Intraoperative Inhaled CO
Accelerates Renal Recovery from IRI
BUN Cr
Hanto et al AJT 2010
CoHb Levels
21Inhaled CO Improves
Histology and Reduces Apoptosis
Hanto et al AJT 2010
22Inhaled CO Increases
Proliferation and Reduces Inflammation
Hanto et al AJT 2010
Phospho-
histone 3
Tissue
Factor
23Inhaled CO Induces Changes
in Tissue Gene Expression
HSP 90Retinol binding
protein 4
MCP-1Osteopontin
Hanto et al AJT 2010
QT-PCR Confirmation
24Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Lewis to Brown Norway orthotopic kidney transplant
model following bilateral nephrectomy
Brief FK (05mgkg day 0-6)
Continuous CO exposure in CO chamber (20 ppm) days
60-150
Other exposure regimens
bull Continuous exposures days 0-30 30-60 or 0-90
bull 1hr daily CO (250 ppm) days 0-90
Nakao et al Am J Physiology 2009
25Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Nakao et al Am J Physiology 2009
Graft function CAN by histology Expression of
fibrosis genes
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
17Increasing Use of Kidneys at Risk for DGF
17
Adult solitary primary kidney transplants
Source UNOSOPTN data as of April 29 2011
Note ECD kidneys are reluctantly utilized due to higher incidences and prevalence of DGF SGF AR CR etc
+ 14
+ 296
18iCO for Delayed Graft Function in
Renal Transplant Patients
Growing unmet need ~50K renal transplantsyear in both the US and EU ~10K ROW
No approved drugs
Recent transplant advances make therapies to prevent rejection and late or non-function more criticalbull Allowinguarr transplantation of organs from extended criteria and cardiac death donors
bull Allowinguarrtransplant of organs with longer warm and cold ischemia times
In several animal models inhaled CO dramatically darrs frequency and duration of delayed graft function (DGF)bull Multiple predictive animal models of CO administration demonstrated acute ischemia reperfusion injury
recovery and chronic allograft rejection (CAN) preventionmitigation
CO therapy at time of transplant feasible add-on to existing Rxbull short intra- or perioperative courses of Rx
Substantial benefit to patients payers and hospitalsbull Prevents or shortens need for dialysis biopsies ICU days etc
bull Allows earlier hospital discharge
Substantial label-expansion potential for acute and longer-term bull Chronic allograft nephropathy (CAN)
bull Acute kidney injury (AKI)
bull Renal fibrosis
19Inhaled CO
Pig Allo-transplantation Model
Warm and cold ischemia
bull 60 minutes of warm ischemia aortic cross-clamping
bull 24 hours cold storage in UW
Allo-transplantation after bilateral nephrectomy
CO delivered through ventilator for one hour starting at
incision (3mgkg with 40 FiO2)
Tacrolimus immunosuppression
Hanto et al AJT 2010
20Intraoperative Inhaled CO
Accelerates Renal Recovery from IRI
BUN Cr
Hanto et al AJT 2010
CoHb Levels
21Inhaled CO Improves
Histology and Reduces Apoptosis
Hanto et al AJT 2010
22Inhaled CO Increases
Proliferation and Reduces Inflammation
Hanto et al AJT 2010
Phospho-
histone 3
Tissue
Factor
23Inhaled CO Induces Changes
in Tissue Gene Expression
HSP 90Retinol binding
protein 4
MCP-1Osteopontin
Hanto et al AJT 2010
QT-PCR Confirmation
24Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Lewis to Brown Norway orthotopic kidney transplant
model following bilateral nephrectomy
Brief FK (05mgkg day 0-6)
Continuous CO exposure in CO chamber (20 ppm) days
60-150
Other exposure regimens
bull Continuous exposures days 0-30 30-60 or 0-90
bull 1hr daily CO (250 ppm) days 0-90
Nakao et al Am J Physiology 2009
25Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Nakao et al Am J Physiology 2009
Graft function CAN by histology Expression of
fibrosis genes
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
18iCO for Delayed Graft Function in
Renal Transplant Patients
Growing unmet need ~50K renal transplantsyear in both the US and EU ~10K ROW
No approved drugs
Recent transplant advances make therapies to prevent rejection and late or non-function more criticalbull Allowinguarr transplantation of organs from extended criteria and cardiac death donors
bull Allowinguarrtransplant of organs with longer warm and cold ischemia times
In several animal models inhaled CO dramatically darrs frequency and duration of delayed graft function (DGF)bull Multiple predictive animal models of CO administration demonstrated acute ischemia reperfusion injury
recovery and chronic allograft rejection (CAN) preventionmitigation
CO therapy at time of transplant feasible add-on to existing Rxbull short intra- or perioperative courses of Rx
Substantial benefit to patients payers and hospitalsbull Prevents or shortens need for dialysis biopsies ICU days etc
bull Allows earlier hospital discharge
Substantial label-expansion potential for acute and longer-term bull Chronic allograft nephropathy (CAN)
bull Acute kidney injury (AKI)
bull Renal fibrosis
19Inhaled CO
Pig Allo-transplantation Model
Warm and cold ischemia
bull 60 minutes of warm ischemia aortic cross-clamping
bull 24 hours cold storage in UW
Allo-transplantation after bilateral nephrectomy
CO delivered through ventilator for one hour starting at
incision (3mgkg with 40 FiO2)
Tacrolimus immunosuppression
Hanto et al AJT 2010
20Intraoperative Inhaled CO
Accelerates Renal Recovery from IRI
BUN Cr
Hanto et al AJT 2010
CoHb Levels
21Inhaled CO Improves
Histology and Reduces Apoptosis
Hanto et al AJT 2010
22Inhaled CO Increases
Proliferation and Reduces Inflammation
Hanto et al AJT 2010
Phospho-
histone 3
Tissue
Factor
23Inhaled CO Induces Changes
in Tissue Gene Expression
HSP 90Retinol binding
protein 4
MCP-1Osteopontin
Hanto et al AJT 2010
QT-PCR Confirmation
24Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Lewis to Brown Norway orthotopic kidney transplant
model following bilateral nephrectomy
Brief FK (05mgkg day 0-6)
Continuous CO exposure in CO chamber (20 ppm) days
60-150
Other exposure regimens
bull Continuous exposures days 0-30 30-60 or 0-90
bull 1hr daily CO (250 ppm) days 0-90
Nakao et al Am J Physiology 2009
25Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Nakao et al Am J Physiology 2009
Graft function CAN by histology Expression of
fibrosis genes
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
19Inhaled CO
Pig Allo-transplantation Model
Warm and cold ischemia
bull 60 minutes of warm ischemia aortic cross-clamping
bull 24 hours cold storage in UW
Allo-transplantation after bilateral nephrectomy
CO delivered through ventilator for one hour starting at
incision (3mgkg with 40 FiO2)
Tacrolimus immunosuppression
Hanto et al AJT 2010
20Intraoperative Inhaled CO
Accelerates Renal Recovery from IRI
BUN Cr
Hanto et al AJT 2010
CoHb Levels
21Inhaled CO Improves
Histology and Reduces Apoptosis
Hanto et al AJT 2010
22Inhaled CO Increases
Proliferation and Reduces Inflammation
Hanto et al AJT 2010
Phospho-
histone 3
Tissue
Factor
23Inhaled CO Induces Changes
in Tissue Gene Expression
HSP 90Retinol binding
protein 4
MCP-1Osteopontin
Hanto et al AJT 2010
QT-PCR Confirmation
24Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Lewis to Brown Norway orthotopic kidney transplant
model following bilateral nephrectomy
Brief FK (05mgkg day 0-6)
Continuous CO exposure in CO chamber (20 ppm) days
60-150
Other exposure regimens
bull Continuous exposures days 0-30 30-60 or 0-90
bull 1hr daily CO (250 ppm) days 0-90
Nakao et al Am J Physiology 2009
25Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Nakao et al Am J Physiology 2009
Graft function CAN by histology Expression of
fibrosis genes
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
20Intraoperative Inhaled CO
Accelerates Renal Recovery from IRI
BUN Cr
Hanto et al AJT 2010
CoHb Levels
21Inhaled CO Improves
Histology and Reduces Apoptosis
Hanto et al AJT 2010
22Inhaled CO Increases
Proliferation and Reduces Inflammation
Hanto et al AJT 2010
Phospho-
histone 3
Tissue
Factor
23Inhaled CO Induces Changes
in Tissue Gene Expression
HSP 90Retinol binding
protein 4
MCP-1Osteopontin
Hanto et al AJT 2010
QT-PCR Confirmation
24Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Lewis to Brown Norway orthotopic kidney transplant
model following bilateral nephrectomy
Brief FK (05mgkg day 0-6)
Continuous CO exposure in CO chamber (20 ppm) days
60-150
Other exposure regimens
bull Continuous exposures days 0-30 30-60 or 0-90
bull 1hr daily CO (250 ppm) days 0-90
Nakao et al Am J Physiology 2009
25Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Nakao et al Am J Physiology 2009
Graft function CAN by histology Expression of
fibrosis genes
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
21Inhaled CO Improves
Histology and Reduces Apoptosis
Hanto et al AJT 2010
22Inhaled CO Increases
Proliferation and Reduces Inflammation
Hanto et al AJT 2010
Phospho-
histone 3
Tissue
Factor
23Inhaled CO Induces Changes
in Tissue Gene Expression
HSP 90Retinol binding
protein 4
MCP-1Osteopontin
Hanto et al AJT 2010
QT-PCR Confirmation
24Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Lewis to Brown Norway orthotopic kidney transplant
model following bilateral nephrectomy
Brief FK (05mgkg day 0-6)
Continuous CO exposure in CO chamber (20 ppm) days
60-150
Other exposure regimens
bull Continuous exposures days 0-30 30-60 or 0-90
bull 1hr daily CO (250 ppm) days 0-90
Nakao et al Am J Physiology 2009
25Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Nakao et al Am J Physiology 2009
Graft function CAN by histology Expression of
fibrosis genes
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
22Inhaled CO Increases
Proliferation and Reduces Inflammation
Hanto et al AJT 2010
Phospho-
histone 3
Tissue
Factor
23Inhaled CO Induces Changes
in Tissue Gene Expression
HSP 90Retinol binding
protein 4
MCP-1Osteopontin
Hanto et al AJT 2010
QT-PCR Confirmation
24Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Lewis to Brown Norway orthotopic kidney transplant
model following bilateral nephrectomy
Brief FK (05mgkg day 0-6)
Continuous CO exposure in CO chamber (20 ppm) days
60-150
Other exposure regimens
bull Continuous exposures days 0-30 30-60 or 0-90
bull 1hr daily CO (250 ppm) days 0-90
Nakao et al Am J Physiology 2009
25Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Nakao et al Am J Physiology 2009
Graft function CAN by histology Expression of
fibrosis genes
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
23Inhaled CO Induces Changes
in Tissue Gene Expression
HSP 90Retinol binding
protein 4
MCP-1Osteopontin
Hanto et al AJT 2010
QT-PCR Confirmation
24Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Lewis to Brown Norway orthotopic kidney transplant
model following bilateral nephrectomy
Brief FK (05mgkg day 0-6)
Continuous CO exposure in CO chamber (20 ppm) days
60-150
Other exposure regimens
bull Continuous exposures days 0-30 30-60 or 0-90
bull 1hr daily CO (250 ppm) days 0-90
Nakao et al Am J Physiology 2009
25Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Nakao et al Am J Physiology 2009
Graft function CAN by histology Expression of
fibrosis genes
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
24Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Lewis to Brown Norway orthotopic kidney transplant
model following bilateral nephrectomy
Brief FK (05mgkg day 0-6)
Continuous CO exposure in CO chamber (20 ppm) days
60-150
Other exposure regimens
bull Continuous exposures days 0-30 30-60 or 0-90
bull 1hr daily CO (250 ppm) days 0-90
Nakao et al Am J Physiology 2009
25Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Nakao et al Am J Physiology 2009
Graft function CAN by histology Expression of
fibrosis genes
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
25Rat Allogeneic Kidney Transplant Model
Prevention of Chronic Allograft Nephropathy
Nakao et al Am J Physiology 2009
Graft function CAN by histology Expression of
fibrosis genes
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
26DGF Pre-IND Meeting Results
Excellent meeting no obstacles towards proceeding with
P23 study
Well attended by FDA Division of Transplant and
Ophthalmology including Division Director Dr Albrecht
No further tox required for P2 or P3 studies
Endorsedencouraged (single P2b3 + single P3) vs (single
P2 + 2 P3) program design as more efficient approval path
In addition to DGF suggested SGF be considered in label
Welcomed further interactions to finalize study program
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
27DGF Therapeutic Landscape Potentially
Synergistic With iCODrug Company Phase Study Timeline MOA
I5NP
(QPI-1002)
Quark
PharmaceuticalsP3
Start Q4 2015
End Q4 2019
siRNA for reversable inhibition of p53
activitated by oxidative stress
BB3Angion Biomedica
CorpP3
Start Q1 2016
End Q1 2018
Cytokine HGF mimetic opposing TGF
beta1- Smad signaling
Eculizumab Alexion P2 Trial FailedMonoclonal antibody blocking
complement gene upregulation
OPN-305Opsona
TherapeuticsP2
Start Q4 2012
End Q2 2017
mAb blocking toll-like receptors in
inflammatory cascade
Pulsatile perfusion
preservation
Hospices Civils de
LyonP2
Start Q2 2010
End Q2 2017
Waters Medical pulsatile perfusion
machine (RM 3)
FurosemideLoma Linda
UniversityP2
Start Q3 2016
End Q3 2018Loop diuretic (water pill)
SANGUINATEProlong
PharmaceuticalsP2
Start Q3 2015
End Q3 2016Anti-vaso-constrictive
C1INH InhibitorCedars-Sinai
Medical CenterP12
Start Q3 2014
End Q2 2019
Prevention of antibody mediated
rejection (ABMR)
BelataceptBristol-Myers
SquibbP0
Start Q2 2014
End Q4 2016
Immunosuppressive regimen of
belatacept mycophenolate steroid
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
28Inhaled CO in DGF ndash Phase 2B3 Trial
Multicenter DB randomized control trial comparing inhaled CO (~250-500 ppm given intraoperatively for 1 hour prior to graft reperfusion and day 2 post-transplant) (additional doses possible to maximize therapeutic outcome)
Primary Efficacy Outcome Rapidity of onset of effective renal function in graft recipientsbull Number of dialysis days in first 30 days post-transplantbull To include futility analysis
Secondary Efficacy Variables ndash Trajectory of Improvement of Renal Function bull Delayed Graft Function (Need for dialysis in first week post transplant)bull Slow Graft function (No dialysis serum creatinine ge 3mgDl on day 5 post graft)bull Immediate Graft Function (No dialysis serum creatinine lt 3 mgDL day 5)bull Graft failure rates at 3 6 and 12 monthsbull Rate of increase in glomerular filtration rate (GFR) post engraftmentbull Rate of improvement in serum creatinine post engraftmentbull Duration of dialysis for subjects needing itbull Hospitalization rates severitybull Variety of biomarkers
Trial Design amp Size bull Dose Ranging Design enriched for subjects at high risk for DGFbull Expert consensus that reduction of DGF incidence of 20 clinically meaningfulbull Study of N= 300 11 randomization
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
29Inhaled CO in DGF ndash Late Stage Development
Phase 3 GoNo Go Decision driven by interim analysis of P23 study
bull To include futility analysis
PH 3 trial similar in design to PH 2B3
bull Powered to achieve efficacy observed in P2B3 trial
bull Identical outcome measures as P23 study
bull Longer (12 mos Vs 6 mos) follow-up post-transplant to assess duration of dialysis
graft survival outcomes
Estimated Timelines
bull P2B 20-25 Years from IND approval to Database Lock amp Efficacy Readout
bull P3 25-35 years dependent on sample size informed by P2B result
Label expansion opportunities bull Preventionmitigation of acutechronic graft failure (36 12 months)
bull Delay of dialysis need in ESRD patients
bull Preventionmitigation of renal fibrosis
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
30
IPF PROGRAM
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
31CO For Idiopathic Pulmonary Fibrosis (IPF)
Orphan drug designation of iCO for IPF received by Proterris
Critical Unmet Need median survival worse than many aggressive cancers (~3 years)
Limited effectiveness with current Rx pirfenidone amp nintedamibrecently approved but neither curative amp both have sig toxicities
Prevalence ~100000 US pts 150000 European pts
CO mechanism of action promising as therapybull Arrests or slows fibrosis in bleomycin mouse model
bull Inhibits fibroblast proliferation in both mice and humans
bull Prolongs epithelial cell death under O2 stress prevents apoptosis
bull Reduces inflammation in pulmonary inflammatory conditions
CO dose levels required for these beneficial impacts well toleratedsafe in humans
Only brief duration intermittent Rx necessary (1hr 2-3xwk)
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
32IPF-Related Pathways Addressed By CO
bull CO inhibits cell death
caused by
proapoptotic agents
in endothelial cells
bull CO exerts
vasodilatory action
bull CO exerts
potent anti-
inflammatory
effects
bull CO exerts direct
anti-fibrotic and
anti-proliferative
effects
Source Integrating mechanisms of pulmonary fibrosis Wynn TA J Exp Med 2011 Jul 4208(7) 1339-50
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
33Top-Line Summary of NIH Sponsored
iCO P2 IPF Study
58 pts enrolled 45 pts completed
Low-dose 100-200 ppm for 2 hours 2xweek x 12 weeks targeting [COHb] of 5-8 during Rx
Study endpoints bull Primary - change in serum MMP-7
bull Secondary - change in predicted FVC TLC DLCO- 6 min walk test (ldquo6MWTrdquo)- St Georgersquos Respiratory Questionnaire
Results bull Safety - 8 pts withdrawn due to SAEs all of them headache judged by
DMC not to be related to iCO but probably incorrect facemask positioning
bull PKPD - [COHb] mean ~3
bull Efficacy - other endpoints inconclusive due to low [COHb] achieved- Biomarkers iCO-associated reduction in apoptosis proteasome
and other gene expression profiles in PMBCs
Bottom Line Conclusions bull First-time iCO in chronic administration study
bull Clean safety profile
bull Study subjects underdosed (result of cautious safety-conscious approach to trial)
bull Study justifies full P2 dose-ranging study
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
34Inhaled CO in IPF
Summary of Planned P2 Program
Phase 2a Dose Rangingbull 3 x 8 patient dose escalation trial to identify optimal iCO ppm that achieves 6-8
peak [COHb] to take into Phase2b
Phase 2b bull Multicenter DB randomized PBO controlled trial comparing iCO at selected dose
3xweek) vs placebo (room air) over 12 months of treatment
bull Primary Endpoint composite of a variety of relevant clinical parameters (FVC hospitalizations mortality TLC DLCO 6MWT St Georgersquos Respiratory amp San Diego Shortness of Breath Questionnaires)
bull Secondary Endpoints bull Change in high resolution CT (HRCT)
bull Biomarkers of Fibrosis TGFβ MMP-7 PDGF Surfactant Protein D ICAM-1 VCAM-1 VEGF Periostin CTGF others
bull safety outcomes
bull Sample Sizebull 250 patients in total
Home use feasibility studybull Designed to test feasibility amp safety of single-unit dose canister administration of
iCO in a supervised home setting
bull 100 patients planned throughout North America
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
35Inhaled CO in IPF
Summary of Planned P3 Program
Two studies x 500 patients each
Global site recruitment
11 randomization of iCO to room air
Same dose as that from Phase 2b study
3x per week 12 month treatment course
Combination of hospital-based and home based patients
utilizing single-dose unit canisters
Composite primary endpoint derived from Phase 2b study
Multiple biomarker secondary endpoints
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
36CO Compares Very Favorably and Potentially
Synergistically With Currently Approved Agents
Pirfenidone Nintedamib CO
Prevention of
Vascular Injury
No No Yes
Response to
reactive oxygen
species
Not demonstrated Not demonstrated Yes
Anti-fibrosis Yes indirectly by
downregulating
activation of TGFβ
Yes indirectly by
suppressing
FGFR
Yes directly
inhibits
fibroblast
proliferation
fibroblast A-sm
Actin expression
amp collagen-1
production
Anti-apoptotic No No Yes
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
37Superior iCO Safety Tox Profile Vs
PirfenidoneNintedamib
Compound Drug Interactions12 Major SAEs (drug-placebo)12
PirfenidoneCYP1A2 Inhibitors
CYP1A2 Inducers
others
Liver enzyme elevations (37-08)
Photosensitivity reaction rash (9-1)
Gastrointestinal disorders (185-58)
Nausea (36-16)
Diarrhea (26-20)
Abdominal Pain (24-15)
Dyspepsia (19-7)
Dizziness (18-11)
NintedanibCYP3A4 Inhibitors
P-gp Inhibitors
others
Diarrhea (62-18)
Nausea (24-7)
Abdominal Pain (15-6)
Vomiting (12-3)
Liver enzyme elevations (14-3)
Headache (8-5)
Appetite Weight loss (11-5)
Hypertension (5-4)
iCo-delivered CONone(inert non-reactive)
None(Per-P2 DSMB open minutes)
[1] httpmedlibraryorglibrxmedsesbriet
[2] httpbidocsboehringer-ingelheimcomBIWebAccessViewServletserdocBase=renetntampfolderPath=Prescribing+InformationPIsOfevofevpdf
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
38Positioning iCO for IPF
COrsquos pleiotropic mechanisms of action unique amongst
therapies in development for IPF
Neither approved agents or those in development
curative for IPF
IPF median survival = 3 yrs from time of diagnosis
Pirfenidone amp nintedamib have significant sometimes
treatment-limiting toxicities many pipeline drugs likely to
have same
Safetytolerability profile of iCO very good thus far
Given above combination drug therapy will evolve to
maximize survival activity performance and quality-of-life
Excellent therapeutic opportunity for iCO
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
39
DELIVERY DEVICE
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
40Proterrisrsquo iCO Delivery Device
bull Proterris developing ventilator and spontaneous
breathing versions for DGF and IPF indications
respectively
bull Technically identical to ldquoFirst in Humanrdquo (FIH)
device developed for NIH ARDS trial with same
source gas and dosing range capabilities
bull Human amp baboon testing support device
performance as designed
bull Progress amp experience gained during
development of device for ongoing NIH-funded
ARDS program reduces costs (gt$1MM) and
significantly reduces technology risks
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
41Coburn-Forster-Kane (CFK) Equation
for COHb Formation
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
42Coburn-Forster-Kane (CFK) Equation
for COHb Formation
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
43In Vivo CO Dosing Reproducible in
Injured-Lung Baboons With Proterris Device
S pneumoniae baboon
model
200 ppm CO for 60
minutes
Similar but not exact
degree of injury
demonstrated similar
COHb formation
response
Am J Physiol Lung Cell Mol Physiol 309 L834ndashL846 2015
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
44Summary Extraordinary Opportunity
Globally dominant company in both inhaled and small molecule CO therapeutics
Significant NIH validation of CO rationale per $23 million in funding thus far and encouraging initial clinical results
Substantial KOL interest from transplant physicians amp pulmonologists
Very clean safety profile
Indications with $billion market potential
Exit by IPO or acquisition within 3 years from Series A with strong precedent for value creation per Mallinckrodt acquisition of Ikaria
bull httpwwwwsjcomarticlesmallinckrodt-to-buy-ikaria-for-2-3-billion-to-expand-into-critical-care-1425559205
45
THANK YOU
45
THANK YOU