targeting neuroinflammation: the common thread in … · biomarkers n = 620 • aged 55-79 •...
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Targeting Neuroinflammation: The Common Thread in Neurodegenerative Disease Progression
200 Clarendon Street, 17th Floor
Boston, MA 02116
www.aztherapies.com
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Innovative Approach and Compelling Opportunity
Robust IP Estate with More Than 100 Patents and Applications
Late Stage Lead Program – Fully Enrolled
ALZT-OP1 in Early Stage Alzheimer’s Disease;Completion Expected Q1 2021
Experienced Leadership Team
Growing Pipeline with Near-term Clinical Milestones
Multiple Programs Targeting Neuroinflammation to Address Neurodegeneration
Novel Approach
Targeting Neuroinflammation by Multimodal Mechanisms as a Key Driver of Neurodegeneration
3
Experienced Leadership Team
David R. Elmaleh, PhD
Founder, Chairman, and CEO
Karen Reeves, MD
President and CMO
Jay Mohr
COO and CBO
Head of Commercial Development
Rudolph E. Tanzi, PhD
Chairman, Scientific Advisory Board
Brian Bartlett
Chief Financial & Accounting Officer
Philip Ashton-Rickardt, PhD
Senior Vice President, Immunology
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Program Discovery Pre-clinical Phase 1 Phase 2 Phase 3 Expected Milestones
ALZT-OP1Early Alzheimer’s Disease
COGNITE Phase 3 trial fully enrolled, data readout in earlyQ1 2021
AZT-101ALS – Phase 2a Ready
Initiation in 1H 2020(IND Approved)
AZT-101Ischemic Stroke – Phase 2 Ready
Initiation 1H 2021
AZT-211 (Next-Gen)Neurodegenerative Diseases
IND expected 2H 2020
Universal Donor
CAR-Treg ProgramNeurodegenerative Diseases
Pre-clinical proof-of-concept in 1H 2020
Microbiome ProgramAlzheimer’s Disease
Observational study to initiate in 1H 2020
Robust Pipeline with Phase 3 Trial and Multiple Follow-on Opportunities
COGNITE Phase 3 Trial
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The Resilient Brain: Inflammation is Associated with Decreased Cognitive Function
Source: Perez-Nievas et al. Dissecting phenotypic traits linked to human resilience to Alzheimer’s pathology, Brain 2013; Isabel Barroeta-Espar et al. Distinct cytokine profiles in human brains resilient to Alzheimer’s pathology. Neurobiol Dis. 2019.
Neuroinflammation is potentially a key predictor of neurodegenerative disease and progression
Aβ Plaques Activated Microglia NeuronsActivated AstrocytesTau Tangles
ResilientNo Alzheimer’s
SymptomaticAlzheimer’s
Inflammation
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ALZT-OP1: A Multimodal CombinationApproach to Treat Complex Progression of AD
✓ A novel, inhalable cromolyn with a low dose formulated oral ibuprofen
✓ Re-engineered physical delivery to cross the blood brain barrier
✓ Well characterized safety profile
✓ Ongoing COGNITE Phase 3 clinical trial fully enrolled with trial completion in Q1 2021
✓ 505(b)2 pathway conducted under FDA Special Protocol Assessment (SPA)
✓ Speed-to-market strategy
17.1 mg capsule for daily inhalation via dry powder inhaler
Targets neuroinflammation and neurotoxic peptides
Shifts microglia into neuroprotective, phagocytic state
Inhibits pro-inflammatory cytokine production; oligomerization of Aβ peptides; and mast cell degranulation
Cromolyn
10 mg tablet for oral administration
Targets neuroinflammation as a COX1/COX2 non-specific NSAID
May boost cromolyn efficacy by promoting microglial recruitment to Aβ plaques
Ibuprofen
Oral Tablet
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Anti-amyloid Aggregation: Cromolyn inhibits amyloid fibrillization and increases amyloid clearance
Anti-inflammatory: Cromolyn induces a
protective, phagocytic state in
microglia versus neuroinflammation
Cromolyn: Dual Mechanisms to Reduce Neuronal Death in Alzheimer’s Disease
Source: Zhang, C et al. Cromolyn Reduces Levels of the Alzheimer’s Disease-Associated Amyloid ß-Protein by Promoting Microglial Phagocytosis. Scientific Reports, January 2018. Hori. Journal of Biological Chemistry, 2015.
Aβ oligomers form, plaques accumulate, trap in
synapses; Tau tangles form
Neuronal degeneration& death
Alzheimer’s disease progression and dementia
Microglial activation and aggravated
neuroinflammation
Amyloid protein precursor (APP) cleavage and Aβ
(40 – 42) peptides released
% o
f Iba
1 P
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ve P
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Col
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izin
g w
ith A
myl
oid
Dep
osits
Alz
he
ime
r’s
Pro
gre
ssio
n
Role of ALZT-OP1 Treatment
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Pro-inflammatory Microglia Damage Neurons and Synapses
Source: “Alzheimer’s in a Dish; Park et al., Nature Neurosci. (2018); Hoozemans et al (2011) CNS & Neurol Disorders–Drug Targets, 10: 57-67; Heneka et al (2005) Brain 128, 1442-1453.
Neurotoxic Microglia (M1) Attack Neurons
“Beyond the amyloid approach, an alternate line of thought based on the role of mast cells and microglia is neuroinflammation and the potential targeting of these cells for the treatment of AD represents a paradigm shift in therapeutic strategies.” - GlobalData Dec 2018
Microglia in Brain During AD Progression
Multi-modal approach aligns with current views on neuroinflammation as a leading
cause of neurodegenerative disease and progressive brain damage
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ALZT-OP1: Improving Memory Capabilities in Preclinical Model of AD
Source: Data on file, Mass General Hospital.
Morris Maze Memory Test
0
1
2
3
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Mock-trt tg ALZT-OP1a trt tg WT controlNon-treated Control(APP/PS1 Mice Without Drug
Treatment)
Treatment Group(APP/PS1 Mice With
ALZT-OP1 Treatment)
Healthy Control (Wild Type Mice
Without Drug Treatment)
# Ti
me
s R
eac
hin
g Ta
rget
Lo
cati
on
p = 0.03Transgenic APP/PS1 mice (4-month-old) or same-age healthy
controls (wild type mice) were treated weekly with I.P. injections
for 6 months, trained on the Morris Maze Memory Test for 7
days, and then tested on day 8 for their ability to recall their training
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Cromolyn Anti-inflammatory Effect Validated in Multiple Recent Publications
2019
2018
2017
2016
2015
Independent AZTherapies
2015
2019
2019
2018
2019
2016
2019
2016
2016
2017
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ALZT-OP1: Phase 1 Studies Confirmed Crossed the Blood-Brain-Barrier
• AZT-002 Phase 1a study1:
– Cromolyn (17.1 mg) and ibuprofen (10 mg) pharmacokinetics in healthy volunteers – cromolyn and ibuprofen reached desired concentrations in plasma and CSF, the latter indicating blood brain barrier crossing
• AZT-004 Phase 1b study2:
– Cromolyn (17.1 mg) and ibuprofen (10 mg) pharmacokinetics in healthy volunteers and AD patients – cromolyn and ibuprofen reached desired concentrations in plasma and CSF, the latter indicating blood brain barrier crossing
1 Brazier, et al: Pharmacokinetics of Cromolyn and Ibuprofen in Healthy Volunteers; Clin Drug Investig (2017).2 Data on file, AZTherapies, Inc.
Study Patients Cmax Tmax
Cro
mo
lyn
AZT-002(4 Hour CSF)
Healthy Adults 0.24 ng/mL 3.7 hours
AZT-004(8 Hour CSF)
Healthy Adults 0.4 ng/mL 3.6 hours
AD Patients 1.4 ng/mL 3.8 hours
Ibu
pro
fen
AZT-002(4 Hour CSF)
Healthy Adults 3.9 ng/mL 2.6 hours
AZT-004(8 Hour CSF)
Healthy Adults 4.1 ng/mL 3.0 hours
AD Patients 6.0 ng/mL 4.0 hours
ALZT-OP1 Pharmacokinetics (CSF)
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Primary Endpoint: Mean change from baseline in Clinical
Dementia Rating-Sum of Boxes (CDR-
SB) at week 72, comparing
combination treatment to monotherapy
cromolyn and monotherapy ibuprofen
Conducted under Special Protocol
Assessment (SPA)
Exploratory Biomarkers
Study Completion:Anticipated Trial Completion
in Q1 2021
ALZT-OP1: COGNITE Phase 3 Trial –Fully Enrolled
Randomization
Eligibility Criteria &
Assessments
Week 4
Safety &
Compliance
Check
Week 48
CDR-SB
MMSE
Safety
Day 1
Initial Drug
Dispense
Week 12
CDR-SB
MMSE
Safety
Week 24
CDR-SB
MMSE
Safety
Week 72
CDR-SB
MMSE
Safety
Biomarkers
n = 620
• Aged 55-79
• Confirmed early AD
• Aß-42 180-690 pg/mL
• Global CDR 0.5
• Memory Box ≥ 0.5
• WMS LMII
• CDR-SB
• MMSE
Ibuprofen
Placebo
Cromolyn
ALZT-OP1
While there are four-arms in the trial design, ~50% of the patients are receiving cromolyn
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AZT-101 Demonstrates Significant Potential in ALS
Source: Granucci. Cromolyn sodium delays disease onset and is neuroprotective in the SOD1G93A Mouse Model of amyotrophic lateral sclerosis. Scientific Reports. 2019; Note: Study performed on 149 male and female age- and litter-matched transgenic (Tg) SOD1G93A and wild-type (Wt) SOD1G93A mice.
Key Results Provide Evidence ofAZT-101 Activity in SOD1 ALS Model
Delayed disease onset and progression
Reduced motor deficits in the Paw Grip Endurance (PaGE) task
Spared lumbar spinal cord motor neurons & preserved neuro-muscular-junction integrity
Reduced pro-inflammatory cytokine levels in the spinal cord and plasma
Significant effect on motor symptoms as measured by age at paresis onset
**** p<0.0001
Onset of Paresis
Neuro-muscular-Junction Denervation
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Universal Donor CAR-Treg: Immense Potential in Treating Neurodegeneration
Source: AZTherapies Data; Appel. Neurol Neuroimmunol Neuroinflamm. 2018; scFv: Single-chain Variable Fragment.
Concentration (nM)
Fronto-temporal Dementia
(FTD)
Alzheimer’s Disease
Multiple Sclerosis
(MS)
ALS
Progressive Supranuclear
Palsy (PSP)
Parkinson’sDisease
Pre-clinical
Validation
Identify scFv`
Glia-binding scFv
Signaling &Co-stimulation
Domains CD28CD3zGlia
CAR Technology Increases Treg Localization to CNS, Enhancing Anti-Inflammation Effects and Limiting Off-
Target Suppression, Compared to Autologous Treg Infusions
Assess Efficacy`Validate Construct`
Identified seven unique human scFv and assessed
binding via ELISA
All CAR constructs are stably expressed on
surface of Tcells
In vitro and in vivo validation of CAR-Tregconstructs is ongoing
ALS Progression Slowed During Autologous Treg
Infusions in P1 Trial
Clinical Rationale`
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IP Portfolio: Select Examples
1 Listed pending applications are in the public domain, with additional pending applications that have yet to be disclosed.
Alzheimer’s Disease (ALZT-OP1, AZT-101)
TBD
Method of Use: Cromolyn + Ibuprofen for Treating AD; Exp: 2030
Formulation: Cromolyn +/- Ibuprofen Formulations; Exp: 2034
Composition of Matter: AZT-211 Exp: 2030
Method of Use: Cromolyn +/- Ibuprofen (IP, IV, SubQ) for Treating AD; Exp: 2030
Method of Use: Cromolyn + Cholinesterase Inhibitor/Select Aβ Antibody for Treating AD; Exp: 2033
Composition of Matter: CAR-Tregs for Treating Neurodegenerative Disease;Exp: ~2039
Method of Use: Cromolyn for Treating ALS; Exp: ~2037
Granted
Pending1
Key examples demonstrate the robust portfolio with IP protection well beyond 2030; additional patent applications not yet in the public domain further extending our exclusivity timeline
Non-Exhaustive IP Examples
Additional Programs (NCE, ALS, CAR-Treg)
Formulation: Cromolyn Formulations;Exp: 2034
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ALZT-OP1 WW Revenue Forecast
Note: Based on a detailed forecast of the US. A scale up factor was used to estimate ROW revenues.Source: Health Advances model.
U.S. + ROW Revenue Forecast2030 WW Revenue $4.5 B
$0.9$1.3
$1.8$2.0
$2.3 $2.4 $2.5 $2.7$0.6
$0.9
$1.2
$1.4
$1.5$1.6
$1.7$1.8
$0.0
$0.5
$1.5
$2.2
$3.0
$3.4
$3.8 $4.0
$4.3
$4.5
$0.0
$0.5
$1.0
$1.5
$2.0
$2.5
$3.0
$3.5
$4.0
$4.5
2021 2022 2023 2024 2025 2026 2027 2028 2029 2030
Reve
nu
es
(U
SD
B)
Rest-of-World Revenue
U.S. Revenue
Based on the strength of the product profile shared
with physicians and payers, ALZT-OP1 can expect to
generate WW peak revenues of ~$4.5B
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2020
Upcoming Milestones
✓ Submit IND for AZT-101 in ALS(IND Approved)
❏ Initiate and Complete Phase 2a Trial in ALS Patients
❏ Conduct Preclinical Proof-of-Concept with CAR-Treg Platform
❏ Submit IND for AZT-211
❏ Perform Scale-up Manufacturing of ALZT-OP1
❏ Initiate Microbiome Observational Study
❏ Continue Corporate Financings
2021
❏ Complete Phase 3 ALZT-OP1 Early AD Trial in Q1 2021
❏ Submit NDA and Gain FDA Approval in Early AD for ALZT-OP1
❏ Complete Commercial Preparation and Readiness for ALZT-OP1 in Early AD
❏ Initiate and Complete AZT-101 Phase 2 Stroke Trial
❏ Initiate Phase 1 Trial for AZT-211
❏ Submit First IND for CAR-Treg
❏ Complete Microbiome Observational Study
❏ Continue Corporate Financings
2020 – 2021
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CosineIBS CapitalInvestors
Strong Institutional and Investor Support
Institutional Partners
Wooshin
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Board of Directors and Advisory Boards
Board of Directors
Business Advisory Board
Scientific Advisory Board
David R. Elmaleh, PhD, Chair CEO, AZTherapies, Inc.
George D. Behrakis Investor/Former Biopharma Executive
Peter Conti, MD, PhD Prof. of Radiology, USC
Keith Greenfield The Dover Group
Gillian Sandler Cosine Capital, LLC
David Taft IBS Capital, LLC
Ronald Tompkins, MD, ScD Prof. of Surgery, Harvard
Rudolph E. Tanzi, PhD, Chair Prof. of Neurology, Harvard
Adam Boxer, MD, PhD Prof. of Neurology, UCSF
Martin R. Farlow, MD Prof. of Neurology, Indiana University
Seth P. Finkelstein, MD Assoc. Prof./Neurologist, Mass General
Bradley T. Hyman, MD Prof. of Neurology, MGH Inst of Neurodegenerative Disease Center
Keith A. Johnson, MD Prof. of Radiology/Neurology, Harvard
Scott E. Kasner, MD Chief Vascular Neurology, UPenn
Vijay K. Kuchroo, DVM, PhD Prof. of Neurology, Harvard
Megan Levings, PhD Prof., Department of Surgery, University of British Columbia
Ziv Neeman, PhD Director of Diagnostic Imaging Institute, Technion Medical School
Eran Segal, PhD Prof. of Computer Science, Weizmann Institute of Science
Sangram S. Sisodia, PhD Prof. of Neurobiology, University of Chicago
Shahin Tabatabaei, MD Assoc Prof. Urology, Mass General
Steven L. Wagner, PhD Assoc Prof. of Neurosciences, UCSD
Michael Porter, Chair Prof., Harvard Business School
Isabelle Bajeux-Besnainou Prof. of Finance, McGill
William S. Belichick New England Patriots
Noah Gottdiener Chair/CEO, Duff and Phelps
David H.P. King Co-founder and Managing Partner Peak Capital Holdings
Thierry Porté Managing Director, JC Flowers
Thank You
200 Clarendon Street, 17th Floor
Boston, MA 02116
www.aztherapies.com
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