corporate overview - · pdf filecorporate overview ... validated risk factor for coronary...
TRANSCRIPT
Corporate Overview
September 2011
Alnylam Forward Looking Statements
This presentation contains forward-looking statements. There are a number of important factors that could cause actual results to differ materially from the results anticipated by these forward-looking statements. These important factors include those that we discuss in our most recent quarterly report on Form 10-Q under the caption “Risk Factors.” If one or more of these factors materialize, or if any underlying assumptions prove incorrect, our actual results, performance or achievements may vary materially from any future results, performance or achievements expressed or implied by these forward-looking statements.
2
RNA Interference (RNAi) A New Class of Innovative Medicines
RNAi Therapeutics Harness natural pathway
» Catalytic mechanism
» Mediated by small interfering RNAs or “siRNAs”
Treat disease with therapeutic gene silencing » Any gene in genome
– Creates unique opportunities for innovative medicines
3
RNAi Therapeutics The Time is Now: 3 Reasons
2. Growing human experience: safety and predictable PK >500 Subjects/patients enrolled overall
Systemic delivery in human trials » > 60 Patients dosed
» >200 Doses administered
» >12 Months of dosing
RNAi therapeutics generally well tolerated
Pharmacologically relevant human tissue levels achieved
1. Delivery breakthroughs
enable clinical translation
3. Human RNAi proof of mechanism established
Patient A Pre-treatment
Patient B Post-treatment
Patient A Post-treatment
Untreated control colorectal cancer
Untreated control hepatocellular cancer
Untreated control normal liver
27.9%
29.2%
1.4%
0.6%
0.3%
0.1%
Rea
ds
/To
tal R
ea
ds
% Specific
cleavage
Evidence
of RNAi
NO
YES
YES
NO
NO
NO
5’ Location along mRNA 3’
4
0.0
0.2
0.4
0.6
0.8
1.0
1.2
TT
R m
RN
A L
eve
ls
(Re
lative
to
Con
trol)
0.03 0.1 0.3
siRNA
(MC3-LNP)
mg/kg
Control
Pre-Clinical Animal Studies
...ATAGGAGAGATGAGCTTCCTACACAGCACACAAACAAATG ...
AGATGAGCTTCCT... CAGCACACAAACA...
cleavage site
plot location vs. no of reeds
p<0.0001
Alnylam 5x15TM
Focused Product Development Pipeline for Innovative Medicines
RNAi for genetically defined disease
as core strategy
5 Products by 2015 in advanced
clinical development
Product characteristics
Genetically defined target/disease
Existing Alnylam delivery platform
Early biomarkers in Phase I
Clear and rapid development and
commercial paths
5
ALN-RSV
ALN-VSP
ALN-HTT
Core Programs
1. ALN-TTR
2. ALN-PCS
3. ALN-HPN
4. ALN-APC
5. TBA
Partner
Programs
Discovery Development Phase I Phase II Phase III
TTR-Mediated Amyloidosis
Severe Hypercholesterolemia
Hemophilia
Refractory Anemia
Program 5 (TBA)
Respiratory
Syncytial Virus
Liver Cancers
Huntington’s
Disease
Alnylam Development Pipeline
6
Partner Programs Alnylam 5x15 Programs
ALN-RSV01
ALN-TTR01
ALN-TTR02
ALN-VSP
ALN-PCS
ALN-HTT
ALN-APC
ALN-HPN
Transthyretin (TTR)-Mediated Amyloidosis (ATTR) Program Unmet Need and Product Opportunity
RNAi to treat genetic disease ATTR is significant orphan disease
» ~50,000 patients worldwide
Clinical pathology » Onset ~40 to >60 yr
» Two predominant forms – Familial amyloidotic polyneuropathy (FAP)
– Familial amyloidotic cardiomyopathy (FAC)
» Peripheral sensorimotor neuropathy, autonomic
neuropathy, and/or cardiomyopathy
» Fatal within 5-15 years
Liver transplant current standard of care » <3,000 Patients eligible
7
TTR Target and ALN-TTR Program
Mutant TTR is genetic cause of ATTR >100 Defined mutations; Autosomal dominant
Misfolds and forms amyloid deposits in
nerves and heart
Wild-type TTR also accumulates in
amyloid plaques » Limits benefits of liver transplantation
Additional validation in mouse genetic models
8
Gly6Ser
Leu12Pro
Val20Ile
Pro24Ser
Val28Met
Phe33Cys
Phe33Ile
Phe33Leu
Phe33Val
Lys35Asn
Asp38Ala
Glu42Asp
Glu42Gly
Ala45Asp
Ala45Ser
Ala45Thr
Thr49Ala
Thr49Pro
Glu51Gly
Gly53Glu
Leu55Arg
Leu55Pro
Leu55Gln
Thr59Lys
Glu61Lys
Ile68Leu
Lys70Asn
Ile73Val
Ser77Phe
Ser77Thy
Glu89Gln
Glu89Lys
Ala97Gly
Ala97Ser
Pro102Arg
Ile107Val
Leu111Met
Tyr114Cys
Tyr114His
Ala120Ser
Pro125Ser
Ala91Ser Thr118Met
Asp18Glu
Asp18Gly
Ala25Ser
Ala25Thr
Arg34Thr
Ala36Pro
Trp41Leu
Gly47Ala
Gly47Arg
Gly47Glu
Gly47Val
Ser50Arg
Glu54Gln
Glu54Gly
Leu58Arg
Leu58His
Thr60Ala
Phe64Leu
Phe64Ser
Tyr69His
Tyr69Ile
Val71Ala
Asp74His
Ile84Asn
Ile84Ser
His90Asn
Gln92Lys
Gly101Ser
Arg104Cys
Arg104His
Ala109Thr
Ala109Val
Ala109Ser
Ser112Ile
Tyr116Ser
Thr119Met
Val122Ala
Val122Ile Val122 (-) Cys10Arg
Ser23Asn Phe44Ser
Ser52Pro
Val30Ala
Val30Gly
Val30Leu
Val30 Met
5’ UTR
3’ UTR
ALN-TTR in clinical development Targets mutant and wild-type TTR
In vivo efficacy established in multiple
pre-clinical animal models
Phase I with ALN-TTR01
IND for ALN-TTR02 in H2 ’11
ALN-TTR Therapeutic Efficacy V30M TTR Transgenic Model
ALN-TTR01 treatment results in TTR amyloid regression Treatment paradigm in animals with existing amyloid plaques
>90% Regression of existing V30M hTTR deposits in peripheral tissues
Similar animal model data in prevention paradigm
9
ALN-TTR01
Control siRNA
0
10
20
30
40
50
60
70
Sciatic
nerve
Dorsal root
ganglion
Esophagus Colon Stomach
Re
lati
ve
TT
R T
iss
ue
Le
ve
ls
Control siRNA ALN-TTR01
Dorsal Root Ganglion
100%
98.8%
98.5%
97%
98.8%
Int’l Amyloidosis Symp., April 2010
ALN-TTR01 Phase I Study Study Design
Randomized, placebo-controlled, single-dose escalation study
~36 Patients with ATTR
» Conducted in Portugal, Sweden, UK and France
Primary objective
» Safety and tolerability
Secondary objectives
» Characterize pharmacokinetics
» Assess preliminary pharmacodynamic activity
– Serum TTR levels
Treatment regimen
» Single ALN-TTR01 i.v. infusion
» Dose levels: 0.01-1.0 mg/kg
Status
» Initiated Q3 ’10; actively enrolling
» Expect to report human POC data in Q4’11
– International Symposium on FAP, November 20-22, 2011
10
2nd Generation ALN-TTR Program ALN-TTR02
ALN-TTR02 shows >10-fold
improved in vivo efficacy in animal
models ALN-TTR02 uses 2nd generation
MC3 LNP formulation
Single i.v. infusion; Serum TTR
levels post-dosing
Potent, dose-dependent, and
durable TTR silencing
On track to file IND in H2 ’11
11
Se
rum
TT
R C
on
ce
ntr
ati
on
(%
Co
ntr
ol P
re-d
os
e)
Time (days)
0
20
40
60
80
100
120
0 5 10 15 20 25 30
ALN-TTR01
(1.0 mg/kg)
ALN-TTR02
(0.1 mg/kg)
Control
siRNA
Dose
Oligo Ther Soc., Sep 2011
Severe Hypercholesterolemia Program Unmet Need and Product Opportunity
RNAi to treat severe hypercholesterolemia
Elevated LDLc (“bad” cholesterol) is
validated risk factor for coronary artery
disease and MI
» Current target level <70 mg/dL
Significant unmet medical need
» >500,000 Patients with severe
hypercholesterolemia
– LDLc >200 mg/dL
– Inadequately managed by statins and other drugs
– Includes statin intolerant patients
– At risk for early MI, recurrent MI, death
» Multiple genetically defined patient subgroups
with increasing delineation
– Defines novel strategies for innovative medicines
12
PCSK9 Target and ALN-PCS Program
13
PCSK9 function well defined PCSK9 (proprotein convertase subtilisin/kexin type 9)
expressed predominantly in liver
Both intracellular and extracellular PCSK9 regulate LDL
receptor (LDLr) levels on hepatocytes » Increased PCSK9 decreases LDLr levels, elevating
plasma LDLc
Extracellular PCSK9 can be measured in plasma
PCSK9 genetically defined disease target
N. Engl. J. Med. (2006) 354:1264-1272; Am. J. Hum. Genet. (2006) 79: 514-523
Fre
qu
en
cy (
%)
Loss of Function
PSCK9 Mutation Plasma LDL Cholesterol
(mg/dL)
0
10
20
30
50 100 150 200 250 300
Loss of Function
PCSK9 Mutation
(N=85)
0
10
20
30
Wild-type PCSK9
(N=3278) 50th Percentile
0
4
8
12
No Yes
Co
ron
ary
Heart
Dis
ease (
%)
ALN-PCS in clinical development Targets both intracellular and
extracellular PCSK9
In vivo efficacy established in multiple
pre-clinical animal models
CTA filed July 2011
Liver LDL
PCSK9
LDLr
LDL
Peripheral cells
VLDL Rem
VLDL Rem
PCSK9
PCSK9
LDLr
LDLr
LDLc
LDLc
ALN-PCS Pre-Clinical Efficacy Phenocopies Human Genetics
ALN-PCS demonstrates potent efficacy after single dose Rapid and dose-dependent reduction in PCSK9 protein
PCSK9 silencing results in >50% reduction in LDLc
Durable efficacy lasting >30 days
No decrease in HDL levels
PCSK9 Conference: From Gene to Therapeutic, Mar 2010
14
siRNA
Dose
0
100
200
300
400
500
600
700
800
0 1 2 3 4 5
Weeks
LD
Lc
, m
g/d
L
0 1 2 3 4 5
0
10
20
30
40
50
60
70
80
90
100
PC
SK
9 p
rote
in, n
g/m
L
Weeks
control (1.00 mg/kg)
0.03 mg/kg
0.10 mg/kg
0.30 mg/kg
1.00 mg/kg
siRNA
Dose
ALN-PCS Phase I Study
Study Design
Randomized, placebo-controlled, single-dose escalation study
~32 healthy volunteer subjects with elevated baseline LDLc (>116mg/dL)
» Conducted in UK
Primary objective
» Safety and tolerability
Secondary objectives
» Characterization of pharmacokinetics
» Assess preliminary pharmacodynamic activity
– Plasma PCSK9 protein and LDLc levels
Treatment regimen
» Dose levels: 0.015 to 0.25 mg/kg
Status
» Filed CTA, July 2011
– Phase I trial to be initiated upon clearance
» Expect to report human POC data in Q4’11
15
Hemophilia Program Unmet Need and Product Opportunity
RNAi to treat hemophilia
Hemophilias are recessive X-linked monogenic
bleeding disorders
» Hemophilia A defined by loss of function mutations
in Factor VIII
– >40,000 Patients in EU/US
» Hemophilia B defined by loss of function mutations
in Factor IX
– ~9,500 Patients in EU/US
Hemophilia A “inhibitor” patients define segment
of highest unmet need and cost*
» ~1/3 Patients with severe hemophilia A
» >6 Bleeds/patient/year
» >5 in-hospital days/patient/year
» >$300,000/patient/year
» Very poor quality of life
Only available therapies: rFVIIa (NovoSevenTM)
and FEIBA
» Short half-life, requiring frequent dosing
» Not optimally effective
16
*Gringeri et al., Blood 2003
Protein C Target and ALN-APC Program
17
Protein C (PC) is genetically defined target Activated Protein C (APC) defines key
natural anticoagulant pathway » Inactivates factors Va and VIIIa
» Attenuates thrombin generation
Heterozygous PC deficiency associated
with increased thrombin generation
Expressed in liver; circulates in plasma
ALN-APC in R2D siRNA optimization
In vivo efficacy in pre-clinical animal
models
IND Filing 2013
APC Resistance (i.e., Factor VLeiden)
Co-inheritance associated with milder
bleeding in hemophilia patients
Kurnik et al., Hematologica, 2007
No
Co-Inheritance
With
Co-Inheritance
First bleed age
(range)
0.9
(0.1– 4.0)
1.5
(0.5 – 7.1)
Annual bleeding
frequency (range)
6.0
(0 – 30)
1.8
(0 – 7)
Intrinsic system
FIXa
FVIIa FVII
FVIIIa
Extrinsic system
FVa FV
FX
FXa
Fibrinogen Fibrin
Thrombin
Hemophilia B
Hemophilia A
Prothrombin
APC PC
FIX
FVIII
Blood
clot
ALN-APC Pre-clinical Efficacy Robust and Durable Silencing After Single Dose
ALN-APC demonstrates potent efficacy after single dose Dose-dependent silencing with ED50 ~0.02 mg/kg
Rapid and durable efficacy after single injection
Significant reduction in Protein C plasma levels
Duration of effect on
Protein C mRNA
Time (days)
Pro
tein
C m
RN
A (
% C
on
tro
l P
re-d
ose
)
0
20
40
60
80
100
120
140
0 4 8 12 16
ALN-APC
(0.3mg/kg)
Control siRNA
(0.3mg/kg)
18
Reduction in
Protein C protein levels
Purified human
protein C (ng)
ALN-APC Control
siRNA
150
100
75
50
35
25
20
PC (41 KD) aPC (35 KD)
light
chain (21 KD)
100
200
500
0
20
40
60
80
100
1.0 1.0 0.3 0.1 0.03 0.01 0.003
Control
siRNA
(mg/kg)
ALN-APC (mg/kg)
Pro
tein
C m
RN
A (
% C
on
tro
l)
Dose-Dependent Silencing
of Protein C mRNA
ED50 ~ 0.02 mg/kg
siRNA
Dose Oligo Ther Soc., Sep 2011
Refractory Anemia Program Unmet Need and Product Opportunity
RNAi to treat refractory anemia Anemia of chronic disease (ACD)
across multiple populations
» End-stage renal disease (ESRD)
» Cancer
» Chronic inflammatory disorders
Significant unmet need; e.g., ESRD
» Resistant to high doses of EPO and
i.v. iron and poor QOL
Significant unmet need; e.g., Cancer
» Anemia in multiple myeloma and MDS
Additional genetic causes
» E.g., Iron-refractory iron deficiency
anemia (IRIDA)
19
Hepcidin Pathway and ALN-HPN Program
20
Hepcidin pathway is genetically defined Hepcidin is central regulator of iron
homeostasis » Down-regulates ferroportin
─ Reduces iron uptake by enterocytes
─ Reduces mobilization by macrophages
Validated in human genetics » Mutations in hepcidin and hepcidin pathway
Expressed in liver, circulates in plasma
ALN-HPN in R2D siRNA optimization for multiple
hepcidin pathway targets
In vivo efficacy in pre-clinical animal
models
IND Filing 2012
Genetic defects in hepcidin pathway lead to anemia
Gut
Liver
Hepcidin Elevated
hepcidin
levels
Inhibition of
dietary iron
uptake
Reduced iron delivery to
marrow results in ACD
Inhibition of
iron
release from
cellular
stores
IL6
Infection, LPS
High serum iron
Other (e.g., uremia)
Macrophage
Wild type
control
TMPRSS6 -/-
patient
Hb (g/dL) 14-18 7.9-9.4
Serum Fe (mg/dL) 92-184 12-18
Transferrin
saturation (%) 15-45 3.3-4.8
Altamura et al., Biochem J, 2010
Alnylam 5x15TM
Programs Definable Clinical Paths with Phase I POC
21
Unmet
Need
Phase I Serum
Biomarkers
Early
Development
Advanced
Development
ALN-TTR Significant morbidity
and mortality 45-60 yrs
of age with neuropathy
and cardiomyopathy
• TTR
• Vitamin A
• Retinol binding
protein
Dose/regimen for
>50% TTR
reduction
FAP: Improvement
in neuropathy
score (NIS-LL)
ALN-PCS Significant morbidity
and mortality
associated with LDLc
>200 mg/dL
• PCSK9
• LDLc
Dose/regimen for
>50% LDLc
reduction
LDLc reduction in
genetically defined
high risk population
ALN-HPN Poor QOL and need for
blood transfusions, very
high EPO and i.v. iron
doses
• Hepcidin
• Iron
• Hb
• Transferrin
saturation
Dose/regimen for
serum hepcidin
reduction and
increase in Hb
>1 g/dL increase in
Hb in refractory
anemia patients
ALN-APC Significant bleeding,
hospitalizations, and
costs associated with
severe hemophilias,
including “Inhibitor” pts
• Protein C
• Thrombin
generation
• Thrombo-
elastography
Dose/regimen to
normalize thrombin
generation
Reduced #bleeds
over 6-12 mo
period
Partner Programs
Respiratory Syncytial Virus
Significant unmet medical need
» >125,000 Pediatric hosp./yr in US
» >170,000 Adult hosp./yr in US
No effective therapies to treat RSV
Liver Cancer Prevalent solid tumor and common
site of metastatic disease » ~700,000/yr Incidence of HCC
worldwide
» ~500,000/yr Patients with liver mets
22
Huntington’s Disease Significant inherited
neurodegenerative disease » Caused by mutations in huntingtin gene
» 30,000 US patients; 150,000 with 50% risk
22
ALN-RSV01 Targets key viral gene blocking
replication
Phase IIb RSV-infected lung
transplant patient study ongoing » Received regulatory approval to
perform interim analysis ─ Increase enrollment up to 120
patients
» Data in 2012
50-50 US Partnership with Cubist
Partnered with Kyowa in Asia
ALN-VSP Targets two distinct genes involved in
cancer pathways » KSP for proliferation; VEGF for angiogenesis
Phase I liver cancer study completed » Results reported at ASCO 2011
─ ALN-VSP generally well-tolerated
─ 41 Patients; ranging from 0.1 - 1.5mg/kg
─ Recommended Phase II dose is 1.0
mg/kg q2w
─ 5 Patients on extension study
» Demonstrated both clinical activity and RNAi
POM
─ 64% Disease control at Phase II dose
─ 1 PR in endometrial cancer patient
─ RNAi demonstrated in biopsy samples
Partner prior to Phase II
ALN-HTT Targets huntingtin gene
Pre-clinical development » IND candidate 2012
Drug-Device collaboration with
CHDI and Medtronic » Alnylam/Medtronic 50/50 in U.S
» 50% funding from CHDI
RNAi Technologies and New Ventures
RNAi pathway
cartoon
RNAi
Bioprocessing/
Biologics
Other Non-Coding RNAs (e.g., RNAa) Vaccines
Genomics
microRNA Therapeutics
23
Stem Cells
Regulus Therapeutics Leading microRNA Therapeutics Company
Co-Founded by Alnylam and Isis
Focused on microRNA therapeutics
Key IP for microRNA therapeutics field
Lead programs Anti-miR122 for HCV infection
Anti-miR21 for heart failure/fibrosis/cancer
Anti-miR33 for hypercholesterolemia
Two partnerships with GSK Immuno-inflammatory collaboration
HCV collaboration
Partnership with sanofi-aventis 4 microRNA targets, including lead
fibrosis program targeting microRNA-21
24
>700 microRNAs in human genome Regulate expression of
> 1/3 of all human genes
Regulate entire gene networks and
biological pathways
Defines whole new frontier for
pharmaceutical research
Alnylam Biotherapeutics Enabling Innovations in the Manufacture of Biologics
Transformative for biologics manufacturing
RNAi enables production of proteins and Mabs
» Powerful and established cell biology tool applied at
scale
– Transient genetic manipulation
– Target multiple pathways specifically and rapidly
Leverage Alnylam position in RNAi
» IP estate and expertise
» Delivery technology and collaborations
Demand for improved production technology
» Integrate from early to late stage production
Formed 2 collaborations with biotech/pharma
» ~$2M of revenue in 2010
Additional collaborations expected in 2011
25
Need for Innovations
in Manufacturing Growing pipeline of biologics
» Opportunity to increase
yield and quality
New technologies needed
Financials and Goals
26
Financial Summary
2011 Q2 Financial Results Cash ~$316M
» ~$7.50 per share
GAAP Revenues ~$21M » Roche, Takeda, Cubist, and other licenses
GAAP Operating Expenses ~$34M » Includes non-cash stock-based compensation charges of ~$4M
Shares Outstanding ~43M
2011 Guidance Year-end Cash >$250M
27
Alnylam Goals Pipeline Goals 2011-2012
28
Additional Corporate Goals 2011 Additional partnerships
Year-end cash >$250M
ALN-TTR01 2012
Q4 ’11
ALN-TTR02 H1 ’12 H2 ’11
ALN-PCS H2 ’11 H1 ’11
ALN-HPN 2012
Program 5 Q4 ’11
ALN-VSP Partner/2012 / Q2 ’11
ALN-APC Q3 ’11
ALN-RSV01 2012
ALN-HTT 2012
R2D
Phase II
Start
Phase I
Human POC IND
Phase II
Data
Aln
yla
m 5
x1
5
Pro
gra
ms
P
art
ne
r P
rog
ram
s
2013
Thank You
www.Alnylam.com
29