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Alnylam Pharmaceuticals
R&D Day
December 12, 2014
Alnylam Forward Looking Statements
This presentation contains forward-looking statements, within the meaning of Section 27A
of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of
1934. 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 our ability to discover and develop novel drug candidates and
delivery approaches, successfully demonstrate the efficacy and safety of our drug
candidates, obtain, maintain and protect intellectual property, enforce our patents and
defend our patent portfolio, obtain regulatory approval for products, establish and maintain
business alliances; our dependence on third parties for access to intellectual property; and
the outcome of litigation, as well as those risks more fully discussed 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. All forwardlooking statements speak only as of the date of this presentation and, except as required
by law, we undertake no obligation to update such statements.
2
Agenda
8:00 – 9:30 a.m.
Welcome
 Cynthia Clayton
Vice President, Investor Relations and Corporate Communications
Alnylam Pipeline Growth Strategy
 John Maraganore, Ph.D.
Chief Executive Officer
Collaborating to Develop Genetic Medicines
 David Meeker, M.D.
President and CEO, Genzyme, a Sanofi company
Genetic Medicine Pipeline Highlights
 Akshay Vaishnaw, M.D., Ph.D.
Executive Vice President and Chief Medical Officer
Q&A Session
 Moderated by Barry Greene
President and Chief Operating Officer
3
Agenda
9:30 – 10:50 a.m.
Cardio-Metabolic Disease
 Daniel Rader, M.D.
Chair, Department of Genetics, Perelman School of Medicine, University
of Pennsylvania
Cardio-Metabolic Pipeline
 Rachel Meyers, Ph.D.
Vice President, Research and RNAi Lead Development
Q&A Session
 Moderated by Barry Greene
Break
4
Agenda
10:50 a.m. – 12:00 p.m.
Hepatic Infectious Disease
 Timothy Block, M.D.
President, Hepatitis B Foundation of America and its Baruch S. Blumberg
Institute, and Professor, Drexel University College of Medicine
Hepatic Infectious Disease Pipeline
 Laura Sepp-Lorenzino, Ph.D.
Vice President, Entrepreneur-in-Residence and Program Leader
Looking Ahead
 Barry Greene
Q&A Session
 Moderated by Barry Greene
Adjourn
5
John Maraganore, Ph.D.
Chief Executive Officer
Alnylam Pipeline Growth Strategy
6
RNA Interference (RNAi)
A New Class of Innovative Medicines
RNAi Therapeutics
 Harness natural pathway
» Catalytic mechanism
» Mediated by small interfering
RNA or “siRNA”
 Therapeutic gene silencing
» Any gene in genome
» Distinct mechanism of action vs.
other drug classes
» Unique opportunities for
innovative medicines
 Clinically validated platform
7
RNAi Clinically Validated
Multiple Alnylam Programs; IV and SC Delivery
Human Safety and PK
 >3500 Doses
administered
» Includes >2 years
duration
 Generally well tolerated
 Both IV and SC
Human Clinical Activity:
Patisiran and Revusiran
 >90% Knockdown of serum
TTR, disease causing protein
 Initial evidence for disease
stabilization
» Patisiran Phase 2 OLE
 Both IV and SC
Human Clinical Efficacy:
ALN-PCS02
 Up to 57% reduction of
LDL-C w/out statins
 Up to 84% knockdown of
PCSK9
 ALN-PCSsc Phase 1 started
Human Clinical Activity:
ALN-AT3
 Positive results in ongoing
Phase 1 in hemophilia
» Up to 57% knockdown of
antithrombin
 Highly potent and durable
effects with mcg/kg SC dose
Coelho et al., N Eng J Med;369:819-29 (2013); Adams, ANA, Oct. 2014; Mauer, AHA, Nov. 2014
Fitzgerald, et al., The Lancet, EOP (2013); Sorenson, ASH Dec. 2014
8
Alnylam RNAi Therapeutics Strategy
A Reproducible and Modular Path for Innovative Medicines
2. POC achieved in Phase 1
 Blood-based biomarker with
strong disease correlation
GCCCCUGGAGGG
» e.g., Serum TTR, thrombin
generation, hemolytic activity,
LDL-C, HBsAg levels
3. Definable path to approval
and market
1. Liver-expressed target gene
 Involved in disease with high
unmet need
 Validated in human genetics
 GalNAc-siRNA enables SC dosing
with wide therapeutic index




Established endpoints
Focused trial size
Large treatment effect
Collaborative approach with
physicians, regulators,
patient groups, and payers
9
Alnylam 5x15
TM
Focused Product Development Pipeline for Genetic Medicines
RNAi therapeutics as genetic medicines
 In 2011: 5 Key products in clinical
development through 2015
 Expect to exceed 2011 guidance
» 6-7 Clinical-stage products
» At least 2 in Phase 3
» 5-6 Human POCs
 15 Programs disclosed to date
» >10 Additional programs yet to be disclosed
Product characteristics
 Genetically defined target/disease
 Existing Alnylam delivery platform
 Phase 1 proof of concept
 Clear and rapid development
 Significant commercial opportunity
10
GalNAc-siRNA Conjugates
Subcutaneous RNAi Therapeutics
GalNAc3
Asialoglycoprotein Receptor (ASGPR)




Highly expressed in hepatocytes
High rate of uptake
Recycling time ~15 minutes
Conserved across species
Revusiran, ALN-AT3, ALN-PCSsc, ALN-CC5…
 siRNA conjugated to N-acetylgalactosamine
(GalNAc) ligand
 Efficient delivery to hepatocytes following
subcutaneous administration
 Wide therapeutic index
 “Enhanced stabilization chemistry” (ESC) used
with all programs after revusiran
» Significantly improved potency and durability
GalNAc-siRNA
conjugate
ASGPR
(pH>5)
Clathrin-coated pit
protein
Recycling
ASGPR
Clathrin-coated
vesicle
RISC
Endosome
mRNA
Nucleus
11
RNAi Therapeutics Profile
Emerging profile for ESC-GalNAc-siRNA conjugates
 Attractive pharmacologic properties
»
»
»
»
Subcutaneous dose administration
High potency with microgram/kg (mcg/kg) doses
Low volume per injection, <1 mL
Durability for monthly (qM) and possibly quarterly (qQ) dose frequency
 Competitive profile with RNAi mechanism
» Block synthesis of disease-causing protein
» Efficacy independent of target protein blood levels
» Clamped knockdown with low inter-individual variability
 Well tolerated and wide therapeutic index
Supports pipeline growth beyond rare disease opportunities
12
13
14
15
16
Alnylam Strategic Therapeutic Areas (STAr)
Genetic Medicines
 Genetically validated
liver targets for rare
orphan diseases
 High unmet needs in
focused markets
 SC dosing
 Alnylam direct commercial
in NA and EU
 Genzyme alliance for
ROW commercial
»
Through end-2019
Cardio-Metabolic Disease
 Genetically validated liver
targets for dyslipidemia,
NASH, type 2 diabetes,
and hypertension
 Development path in
morbid subpopulations
 Access to larger
populations thereafter
 Emerging genetics
 qM or qQ SC dosing
 Partnership opportunities
Hepatic Infectious Disease
 Liver pathogen and/or
host targets
 Sub-acute duration of
treatment (~12 mo)
 Multiple siRNAs possible,
if needed
 Defined opportunities with
very large markets
 qM or qQ SC dosing
 Partnership opportunities
17
Alnylam Strategic Therapeutic Areas (STAr)
GCCCCUGGAGGG
18
Alnylam Development Pipeline
Discovery
Development
Phase 1
Phase 2
Phase 3
GENETIC MEDICINES
Patisiran (ALN-TTR02)
TTR-Mediated Amyloidosis
Revusiran (ALN-TTRsc)
ALN-AT3
Hemophilia and Rare Bleeding Disorders
ALN-CC5
Complement-Mediated Diseases
ALN-AS1
Hepatic Porphyrias
Alpha-1 Antitrypsin Deficiency
ALN-AAT
Beta-Thalassemia/Iron-Overload Disorders
ALN-TMP
Primary Hyperoxaluria Type 1
ALN-GO1
Additional Genetic Medicine Programs
CARDIO-METABOLIC DISEASES
ALN-PCSsc
Hypercholesterolemia
Mixed Hyperlipidemia/Hypertriglyceridemia
ALN-ANG
Hypertriglyceridemia
ALN-AC3
Hypertension/Preeclampsia
ALN-AGT
Additional Cardio-Metabolic Programs
HEPATIC INFECTIOUS DISEASES
Hepatitis B Virus Infection
ALN-HBV
Hepatitis D Virus Infection
ALN-HDV
Chronic Liver Infection
ALN-PDL
Additional Hepatic Infectious Disease Programs
David Meeker, M.D.
President and Chief Executive Officer
Genzyme, a Sanofi Company
20
Dione (with her mother) Pompe disease Brazil
www.genzyme.com
|
Milestones in Genzyme History
2003 Therapies approved for Fabry
disease and MPS-I disease
2004 New global headquarters opens
in Cambridge, MA
2006 Therapy approved for Pompe
disease
1981 Genzyme founded
1983 Henri Termeer joins Genzyme
2008 Science Center opens in
Framingham, MA
1986 Genzyme IPO
1980
1990
2000
1991 Genzyme’s first product
approved for type 1 Gaucher
disease
2010
2011 Genzyme becomes
a Sanofi company
2011 David Meeker appointed CEO
1994 Second-generation enzyme
replacement therapy approved
for type 1 Gaucher disease
1996 Manufacturing plant opens in
Allston, MA
2012 Manufacturing plant opens in
Framingham, MA
2012 Oral therapy approved for MS
2013 Therapy approved for HoFH
1998 Therapy approved to facilitate
thyroid cancer treatment and
testing
2013 Two therapies approved in the
EU for relapsing remitting MS
Our Global Commitment
Headquartered
in the U.S.
with global locations
in more than 40
countries
Expanding
manufacturing
capabilities in the
U.S. and E.U.
Collaborating with patient
communities, physicians,
universities, hospitals,
charitable organizations,
companies globally
Serving
patients in
more than 100
countries
Rare Diseases & Multiple Sclerosis
Mikhail
Gaucher
disease
Shani
MS
Joan
Thyroid
Cancer
Tiger
MS
Genetic Disease
Gaucher disease type 1 (2 treatments),
Fabry disease, Pompe disease,
MPS I disease
Endocrinology
Facilitating thyroid cancer treatment
and testing
Once-daily oral therapy for relapsing
remitting MS
Infusion therapy for relapsing
remitting MS – 2 annual treatment
courses
Cardiovascular
Homozygous Familial
Hypercholesterolemia (HoFH)
LATE STAGE PIPELINE
Patisiran (with Alnylam) familial amyloid polyneuropathy
Phase 3
Revusiran (with Alnylam) familial amyloidotic
cardiomyopathy Phase 3
Acid sphingomyelinase Niemann Pick disease type B
Phase 2
About Sanofi
•
•
Global healthcare leader
•
Major biopharmacy player: 45% of revenues generated by biologics, 80%
of projects in development are biologics
•
•
•
112 industrial sites in 41 countries
Diversified offering of medicines, consumer healthcare products, vaccines,
generics, and animal health
More than 110,000 employees in 100 countries
2013 sales: ~ €33 billion
A Lifetime Commitment
“My mom was just tremendous and an
amazing role model for me. I know the
doctors told her that I was going to die
but her perseverance, dedication and
ability to work closely with Genzyme
and search around the world to develop
a treatment was amazing.”
– Brian Berman, Type 1 Gaucher disease
1983
Brian Gaucher disease type 1
1991
2001
2011
Understanding of unmet needs of patients
61% of Gaucher patients would like their treatment to be an oral formulation(1)
(1) PeopleMetrics survey in Gaucher patients (n= 238)
What improvements would you like to see in treatments for Gaucher Disease?
Taking Care of People
Ayama
(with his mother)
Pompe disease
Sol
Pompe
disease
Critical Elements
VALUE
PARTNERSHIP
COMMITMENT
Myths
• Developing drugs for Rare Diseases is easy (easier?)
• Orphan Designation allows you to price higher
• Orphan disease pricing is not sustainable
• Commercializing an orphan disease product is easy
Transformational expanded collaboration
on Rare Genetic Diseases
Akshay Vaishnaw, M.D., Ph.D.
Executive Vice President and Chief Medical Officer
Genetic Medicine Pipeline Highlights
32
33
Alnylam Development Pipeline
Discovery
Development
Phase 1
Phase 2
Phase 3
GENETIC MEDICINES
Patisiran (ALN-TTR02)
TTR-Mediated Amyloidosis
Revusiran (ALN-TTRsc)
ALN-AT3
Hemophilia and Rare Bleeding Disorders
ALN-CC5
Complement-Mediated Diseases
ALN-AS1
Hepatic Porphyrias
Alpha-1 Antitrypsin Deficiency
ALN-AAT
Beta-Thalassemia/Iron-Overload Disorders
ALN-TMP
Primary Hyperoxaluria Type 1
ALN-GO1
Additional Genetic Medicine Programs
CARDIO-METABOLIC DISEASES
ALN-PCSsc
Hypercholesterolemia
Mixed Hyperlipidemia/Hypertriglyceridemia
ALN-ANG
Hypertriglyceridemia
ALN-AC3
Hypertension/Preeclampsia
ALN-AGT
Additional Cardio-Metabolic Programs
HEPATIC INFECTIOUS DISEASES
Hepatitis B Virus Infection
ALN-HBV
Hepatitis D Virus Infection
ALN-HDV
Chronic Liver Infection
ALN-PDL
Additional Hepatic Infectious Disease Programs
Alnylam Development Pipeline
Discovery
Development
Phase 1
Phase 2
Phase 3
GENETIC MEDICINES
Patisiran (ALN-TTR02)
TTR-Mediated Amyloidosis
Revusiran (ALN-TTRsc)
ALN-AT3
Hemophilia and Rare Bleeding Disorders
ALN-CC5
Complement-Mediated Diseases
ALN-AS1
Hepatic Porphyrias
Alpha-1 Antitrypsin Deficiency
ALN-AAT
Beta-Thalassemia/Iron-Overload Disorders
ALN-TMP
Primary Hyperoxaluria Type 1
ALN-GO1
Additional Genetic Medicine Programs
ALN-PCSsc
ALN-ANG
ALN-AC3
ALN-AGT
ALN-HBV
ALN-HDV
ALN-PDL
Transthyretin-Mediated Amyloidosis (ATTR) Program
Unmet Need and Product Opportunity
RNAi to treat genetic disease

ATTR is significant orphan disease
»

Clinical pathology
»
»

~50,000 Patients worldwide
Onset ~40 to >60 yr; fatal within 5-15 years
Two predominant forms
– Familial amyloidotic polyneuropathy (FAP)
– Familial amyloidotic cardiomyopathy (FAC)
Halting disease progression remains unmet need
»
»
Liver transplantation required early
TTR stabilizers provide modest benefit
Mutant transthyretin (TTR) is genetic cause


Autosomal dominant with >100 defined mutations
Misfolds and forms amyloid deposits in nerves, heart, other
tissues
RNAi opportunity as potentially transformative therapy



Aim to halt progression, possibly achieve regression
Value proposition supported by pharmacoeconomics and
cost of disease burden
Concentrated provider base and active patient community
36
Patisiran (ALN-TTR02)
Familial Amyloidotic Polyneuropathy (FAP)
Patisiran in clinical development
 International Nonproprietary Name designation for
ALN-TTR02 = Patisiran (pa-TEE-sa-ran)
 Orphan drug status in US/EU
 Fast track designation by FDA
 Administered by IV infusion
 Positive Phase 1 results in human volunteers
» Data published in New England Journal of Medicine
 Positive multi-dose Phase 2 results in FAP patients
 Phase 2 Open-Label Extension (OLE)
study ongoing
» Includes clinical endpoints measured every 6 months
» Positive initial data reported at ANA, October 2014
» 12 month OLE readout in 2015

Phase 3 trial ongoing
» Currently 31 sites in 11 countries
» Expect APOLLO to enable NDA submission ~2017
37
Patisiran Open-Label Extension (OLE) Study
FAP patients dosed in Phase 2 trial eligible for Phase 2 OLE study
 Clinical endpoints evaluated every 6 months for up to 2 years
» Clinical endpoints same as APOLLO Phase 3 study
» Dosing at 0.30 mg/kg IV every 3 weeks
 Study objectives
» Primary: Safety and tolerability of long-term dosing with patisiran
» Secondary: Effects on neurologic impairment (mNIS+7), quality of life,
mBMI, disability, mobility, nerve fiber density in skin biopsies, and
serum TTR levels
Status
 Ongoing; enrollment completed (N=27)
 6 mo mNIS+7 patient data (N=19) and serum TTR lowering
» Presented at ANA, October 12-14, 2014
 Report data at least once annually
38
Patisiran Phase 2 OLE Preliminary Study Results
Change in mNIS+7 at 6 Months (N=19)
Neuropathy Impairment Score (mNIS+7) stable after 6 months treatment with patisiran




Mean decrease of 0.95 points observed
Compares favorably with an up to 10 point increase estimated from historical data sets
Similar result in patients with/without concurrent TTR stabilizer therapy
Well tolerated out to 1 year dosing
»
No drug-related SAEs, no significant lab findings, low incidence of mild infusion-related reactions (~15%)
125
Change from Baseline to Month 6
Each line represents individual patient
mNIS+7
Mean
Δ
Median
Δ
SEM
Total
-0.95
0.00
2.59
NIS-weakness
0.08
0.00
1.53
NIS-reflexes
-0.39
0.00
0.43
QST
-0.68
-2.00
1.82
NCS Σ5
0.11
0.00
0.15
Postural BP
-0.05
0.00
0.10
mNIS+7 (points)
100
75
50
25
0
0
1
2
3
4
5
6
Months on treatment
Historical Data Sets
Mean (SEM)
D mNIS+7 at 6 mos.
Natural History
Tafamidis Fx1A-201
Diflunisal Phase 3
8.9 ± 5.7 (linear)
10.3 ± 5.7 (non-linear)
PBO: 8.7 ± 2.0
Drug: 2.5 ± 2.9
PBO: 7.4 ± 6.9
Drug: 2.3 ± 6.0
Adams, ANA Oct. 2014
39
Phase 3 Trial of Patisiran in FAP
Study Ongoing
Randomized, double-blind, placebo-controlled, global study
 Sample size and randomization
»
»
N=200
2:1, Patisiran vs. placebo
 Key eligibility criteria
»
»
V30M and non-V30M FAP
Baseline FAP stages 1 and 2
 Treatment regimen
»
»
Patisiran 0.30 mg/kg vs. placebo IV q3w for 18 months
All completers eligible for patisiran treatment on Phase 3 OLE study
Primary Endpoint
 mNIS+71 at 18 months
Secondary Endpoints
 Norfolk QOL-DN, NIS-weakness, mBMI, timed 10-meter walk, COMPASS-31 autonomic
symptom score
Statistical Considerations
 Placebo mNIS+7 progression rate of 17.8 points/yr derived from natural history study of 283
FAP patients
 Study with 90% power to detect as little as 37.5% difference in ΔmNIS+7 between
treatment groups with 2-sided alpha=0.05
 Blinded interim analysis
1Suanprasert
et al., J Neurol Sci., 344(1-2):121-8 (2014)
40
Revusiran (ALN-TTRsc)
Familial Amyloidotic Cardiomyopathy (FAC)
Revusiran in clinical development
 International Nonproprietary Name designation
for ALN-TTRsc = Revusiran (re-VOO-si-ran)
 Subcutaneous delivery
 Completed GLP tox studies confirming wide
therapeutic index
 Positive Phase 1 study results
» Normal healthy volunteer study in UK
 Positive initial pilot Phase 2 study results
» TTR cardiac amyloidosis patients
 Phase 2 Open-Label Extension (OLE)
study initiated November 2014


» Includes clinical endpoints measured every 6 months
study ongoing
» Screening study examining prevalence of TTR mutations
in patients suspected of having cardiac amyloidosis
» Multi-center study; up to 1,000 patients
Phase 3 trial initiated
41
GalNAc-siRNA Conjugates
Subcutaneous RNAi Therapeutics
GalNAc3
Asialoglycoprotein Receptor (ASGPR)




Highly expressed in hepatocytes
High rate of uptake
Recycling time ~15 minutes
Conserved across species
Revusiran, ALN-AT3, ALN-PCSsc, ALN-CC5…
 siRNA conjugated to N-acetylgalactosamine
(GalNAc) ligand
 Efficient delivery to hepatocytes following
subcutaneous administration
 Wide therapeutic index
 “Enhanced stabilization chemistry” (ESC) used
with all programs after revusiran
» Significantly improved potency and durability
GalNAc-siRNA
conjugate
ASGPR
(pH>5)
Clathrin-coated pit
protein
Recycling
ASGPR
Clathrin-coated
vesicle
RISC
Endosome
mRNA
Nucleus
42
GalNAc-siRNA Conjugates
Wide Therapeutic Index from Non-Clinical GLP Studies
NOAEL1 4 or 7
weeks (mg/kg)
NOAEL 13 weeks
(mg/kg)
Rat
NHP
Rat
NHP
Revusiran3
30
≥300
N/A
ALN-AT33,4
1
0.3
ALN-PCSsc
≥250
ALN-CC5
ALN-AS1
NOAEL 6 mos
Rat (mg/kg)
NOAEL 9 mos
NHP (mg/kg)
Expected Human
Therapeutic
Index (TI)2
N/A
30
≥200
>80
N/A
N/A
Ongoing
Ongoing
>10
≥250
Ongoing
Ongoing
Planned
Planned
>500
≥50
≥100
Ongoing
Ongoing
Planned
Planned
>200
N/A
N/A
≥30
≥150
Planned
Planned
>500
1No
Adverse Event Level (NOAEL)
calculated as NOAEL in NHP/Expected dose in man
37 week studies
4NOAEL in hemophilia mice >100 mg/kg, qW x 7
2TI
43
Revusiran Phase 1 Study Results
Randomized, double-blind, placebo-controlled SAD and MAD study in healthy volunteers
 Rapid, dose-dependent, consistent, and durable knockdown of serum TTR with SC dosing
» Significant knockdown of serum TTR (p<0.01) up to 94% TTR knockdown; Mean knockdown up to 92.4%
 Excellent correlation of human to non-human primate TTR knockdown on mg/kg basis
» Confirmation of human translation of GalNAc-siRNA conjugate platform
» Extended durability in human vs. NHP due to attenuated nuclease environment
-20
0
20
40
60
Revusiran
dose groups
80
Placebo (n=3)
2.5 (n=3)
5.0 (n=3)
10.0 (n=3)
Relative to Baseline
% Mean TTR Knockdown
Relative to Baseline (± SEM)
% Mean TTR Knockdown
0
20
40
60
Human
NHP
80
100
100
0
Revusiran (mg/kg), qd x5; qw x5
Days
10
Revusiran
Single 10.0 mg/kg
Injection
Zimmermann, HFSA, Sep. 2013; Manoharan, TIDES, May 2014
44
20
30
Days
40
50
60
Preliminary Revusiran Phase 2 Study Results*
Open label, multi-dose study in patients with TTR cardiac amyloidosis, FAC and SSA
 N=26; 14 FAC/12 SSA
 Up to 98.2% TTR knockdown with similar effects toward WT and mutant protein
Treatment
Mean (SEM) % Serum TTR Knockdown
( Rel. to Baseline)
0
N=22
N
Individual Max
KD (%)
Mean ± SD
Max KD (%)
All
22
98.2
87.2 ± 9.1
5.0 mg/kg
19
97.7
86.4 ± 9.4
7.5 mg/kg
3
98.2
92.1 ± 5.4
1.0
0.9
N=19
20
0.8
N=3
0.7
40
0.6
60
0.4
N=15
0.3
80
0.2
N=18
Revusiran Dose Group
5.0 mg/kg
7.5 mg/kg
100
0.1
0.0
0
10
20
30
Revusiran (mg/kg), qd x5; qw x5
40
50
60
70
80
90
100
Days since first visit
* Results as of October 3, 2014; Maurer, AHA, November 2014
45
Revusiran Phase 1 and 2 Studies
Clinical Safety Summary
Total of 92 dosed with ALN-TTRsc
 Phase 1 = 66 healthy adult volunteers
 Phase 2 = 26 patients with TTR cardiac amyloidosis
Generally well tolerated
 Phase 1: 4 non drug-related discontinuations
 Phase 2: no discontinuations
 Across both studies ~25% ISRs, typically mild and associated with transient
erythema
 One possibly related drug-related serious adverse event, per below
Laboratory-related AEs
 Phase 1
» 1/66 (1.5%) with transient LFT changes (3-4 fold increase in ALT and <2 fold increase in AST)
graded mild in subject with abnormal LFTs at baseline
 Phase 2
» 4/26 (15%) with LFT changes
–
–
Transient, mild (<1.5 x ULN ALT) in 3 of 4 patients with no interruption in dosing
1 possibly related SAE for LFT changes (~4 x ULN ALT/AST), which resolved during continued dosing;
graded mild in severity
» 4/26 (15%) with transient, mild, and clinically insignificant increases in percent monocytes,
which all occurred in patients with elevated percent monocyte counts at baseline
Phase 1 data as of Nov. 18, 2014; Phase 2 data as of Oct. 3, 2014;
Both Phase 1 and Phase 2 data are from unlocked databases
and results subject to change
46
Revusiran Open-Label Extension (OLE) Study
Patients dosed in Phase 2 trial eligible for Phase 2 OLE study
 Dosing for up to 2 years
» Fixed subcutaneous dose of 500 mg; QDx5 followed by QW
 Study objectives
» Primary: Safety and tolerability of long-term dosing with revusiran
» Secondary: Effects on mortality, hospitalization, and serum TTR levels
» Additional exploratory clinical endpoints evaluated every 6 months:
Cardiac imaging (echo and MRI), amyloid burden by technetium scans
and fat pad aspirates, cardiac biomarkers (BNP, troponins), 6MWD,
NYHC, and QOL
Status
 Study initiated November 2014
 Expect to report data at least once annually, starting in 2015
47
Phase 3 Trial of Revusiran in FAC
Randomized, double-blind, placebo-controlled, global study



Study Initiated
Sample size and randomization
»
»
N=200
2:1, revusiran vs. placebo
Key eligibility criteria
»
»
»
»
Documented TTR mutation, including V122I or other
Amyloid deposits on biopsy (cardiac or non-cardiac)
History of heart failure
Evidence of cardiac involvement by echo
Treatment regimen
»
»
Revusiran 500mg q daily x5, then q weekly for 18 mos
All completers eligible for revusiran treatment on Phase 3 OLE study
Co-Primary Endpoints


Change in 6-MWD at 18 months compared to baseline
Percent reduction in serum TTR burden over 18 months

Composite CV mortality and CV hospitalization, change NYHA class, change in Kansas City
Cardiomyopathy Questionnaire (KCCQ)
Secondary Endpoints
Statistical Considerations



Design informed by natural history study of TTR cardiac amyloidosis patients, including decrease
in 6-MWD over time
»
Results expected to be presented in early ’15
Study with 90% power to detect as little as 39% difference in 18 mo change from baseline
6-MWD between treatment groups with significance level of p < 0.05
Unblinded interim analysis for futility may be conducted when ~50% of patients reach 18 mos
48
Hemophilia and Rare Bleeding Disorders Program
Unmet Need and Product Opportunity
RNAi to treat hemophilia and rare bleeding disorders (RBD)
 Hemophilias are recessive X-linked
monogenic bleeding disorders
» Hemophilia A: loss of function in Factor VIII
– >40,000 Patients in EU/US
» Hemophilia B: loss of function in Factor IX
– ~9,500 Patients in EU/US
 Segments of high unmet need remain
» E.g., “Inhibitor” patients1,2
– 2,000 Patients in major markets; up to 6,000 WW
– >15-25 Bleeds/year; >5 in-hospital days/year
– ~$300,000/year avg. cost; up to $1M/year
 Hemophilia A and B represent >$9B market
»
»
»
»
Premium pricing established
Value supported by pharmacoeconomics
Well organized patient advocacy
Significant opportunity for global expansion
1 WFH
2012 Global Survey; 2 Antunes et al., Haemophilia. 20:65-72 (2014)
49
Antithrombin and ALN-AT3 Program
Intrinsic system
Antithrombin (AT) is genetically defined
target
 AT is key natural anticoagulant
Extrinsic system
Hemophilia B
FIX
FVIIa
FX
FIXa
FVII
Hemophilia A
» Inactivates factors Xa and thrombin
» Attenuates thrombin generation
FVIII
FVIIIa
AT
AT
FXa
 Human AT deficiency associated
with increased thrombin generation
 Expressed in liver; circulates in plasma
FVa
Prothrombin
Co-inheritance of thrombophilic traits in hemophilia
FV
Thrombin
Fibrinogen
Fibrin
 Associated with milder bleeding, reduced factor
Blood clot
requirements, fewer complications
 Includes heterozygous
ALN-AT3 in clinical development
» Antithrombin deficiency
 ESC-GalNAc-siRNA for SC dosing
» Factor VLeiden
 Positive initial Phase 1 results
» Protein C deficiency
 Orphan drug status in U.S./EU (HA/HB)
» Protein S deficiency

Phase 1 MAD study in patients ongoing
Kurnik et al., Haematologica; 92:982-5 (2007); Ettingshausen et al., Thromb Haemost; 85:218-20 50
(2001); Negrier et al., Blood; 81:690-5 (1993); Shetty et al., Br J Haematol; 138:541-4 (2007)
Genetic Validation for ALN-AT3
Co-Inheritance of Type 3 VWD and AT Deficiency
Human genetic data support targeting
AT for treatment of hemophilia and
rare bleeding disorders
 Type 3 von Willebrand disease (VWD)
is severe genetic bleeding disorder
 Recently reported study of two Type 3
VWD sibs
» Sib 1: very mild clinical phenotype
found to have co-inherited
heterozygous AT deficiency
» Sib 2: severe bleeding phenotype
requiring routine von Willebrand factor
prophylaxis
Sib
1
Sib
2
Type 3 VWD
Mild
Bleeding
Severe
Bleeding
AT Levels at
57% Normal
Fischer, WFH, May 2014
51
ALN-AT3 Pre-Clinical Efficacy
Potent AT Knockdown and Normalization of Thrombin Generation
Potent AT knockdown and normalized thrombin generation in non-human primates (NHP)


Weekly SC doses for >5 months result in potent, dose-dependent, and durable AT knockdown
In NHP hemophilia “inhibitor” model, ALN-AT3 normalizes thrombin generation
1.6
40
60
80
100
-20
1.2
1.0
(Peak Thrombin)
Relative Thrombin Generation†
p<0.01
20
(Pre-dose = 1)
% Mean AT Knockdown
0
0.8
0.6
0.4
0.2
0.0
0
20
40
60
80
100
120
140
160
Pre-dose
Saline
Normal
Recovery
Recovery
1.5 mg/kg qw x 5
Recovery
0.25
0.5
Hemophilia A
0.125 mg/kg qw x 12
(Induced)
†similar
1 mg/kg q2w x 4
~80%
AT
KD
ALN-AT3 (mg/kg) qw
Day
0.5 mg/kg qw x 8
~60%
AT
KD
results obtained by ETP (p<0.01 at 0.50 mg/kg)
0.25 mg/kg qw x 12
Akinc, ISTH, July 2013
52
ALN-AT3 Pre-Clinical Efficacy
Potent AT Knockdown and Normalization of Thrombin Generation
Potent AT knockdown and normalized thrombin generation in non-human primates (NHP)


Weekly SC doses for >5 months result in potent, dose-dependent, and durable AT knockdown
In NHP hemophilia “inhibitor” model, ALN-AT3 normalizes thrombin generation
1.6
40
60
80
100
-20
1.2
1.0
(Peak Thrombin)
Relative Thrombin Generation†
p<0.01
20
(Pre-dose = 1)
% Mean AT Knockdown
0
0.8
0.6
0.4
0.2
0.0
0
20
40
60
80
100
120
140
160
Pre-dose
Saline
Normal
Recovery
Recovery
1.5 mg/kg qw x 5
Recovery
0.25
0.5
Hemophilia A
0.125 mg/kg qw x 12
(Induced)
†similar
1 mg/kg q2w x 4
~80%
AT
KD
ALN-AT3 (mg/kg) qw
Day
0.5 mg/kg qw x 8
~60%
AT
KD
results obtained by ETP (p<0.01 at 0.50 mg/kg)
0.25 mg/kg qw x 12
Akinc, ISTH, July 2013
53
ALN-AT3 Survival Benefit in Hemophilia A Mice
Results from GLP Chronic Toxicology Study
ALN-AT3 shows disease modifying effects in hemophilia A (HA) mice
 Ongoing 26 week GLP toxicology study
»
3 Study groups (N=70/group): saline, 10 mg/kg ALN-AT3, and 30 mg/kg ALN-AT3; SC, qW x 26
»
»
No adverse clinical signs, changes in body weight, hematology or lab chemistry in ALN-AT3 animals
Survival benefit noted in treated animals (p <0.0001; Log-rank, Mantel-Cox test)
 Interim results through week 25
Survival of HA Mice
% Survival
100
50
Treatment Groups
Saline
10 mg/kg ALN-AT3
30 mg/kg ALN-AT3
0
0
50
100
150
200
Days
Akinc ASH, Dec. 2014
54
ALN-AT3 Phase 1 Study
Dose-Escalation Study in Two Parts
Primary objectives
 Safety, tolerability
Secondary objectives
 AT knockdown, thrombin generation
Part A
SingleAscending
Dose (SAD)
30 mcg/kg x 1 SC

Randomized 3:1, N=4
Single-blind
Placebo-controlled
Healthy volunteers
f
15 mcg/kg qW x 3 SC
Part B
MultipleAscending
Dose (MAD)

G
45 mcg/kg qW x 3 SC
Open-label
Hemophilia A or B
N=3/cohort
Ongoing
TBD mcg/kg qW x 3 SC
55
Up to 4 additional
cohorts
ALN-AT3 Phase 1 Study Part A (SAD)*
Pharmacodynamics and Clinical Activity
AT knockdown after single dose in human volunteers
 Maximum AT knockdown relative to baseline up to 28%
 Mean maximum AT knockdown of 19% ± 4.4% (mean ± SEM)
» Placebo vs. treated, ANOVA p < 0.01
 AT knockdown durable for over 60 days
-20
Treatment Group
Mean % AT Knockdown
ALN-AT3
30 mcg/kg
Placebo
-10
0
10
20
30
40
0
10
20
30
40
50
60
70
80
Days
*Cohort 1 data as of Nov. 24, 2014; cohort 2 data as of Dec. 5, 2014
Sorensen ASH, Dec. 2014
56
ALN-AT3 Phase 1 Study Part A (SAD)*
Pharmacodynamics and Clinical Activity
Increase in thrombin generation with AT knockdown
 Significant association between AT knockdown and peak thrombin generation
 Up to 152% increase in peak thrombin generation
 Mean maximum increase of peak thrombin 138% ± 8.9% (mean ± SEM)
%Increase Peak Thrombin Generation
» Consistent with increased sensitivity for thrombin generation increase with AT knockdown
in background of normal levels of Factor VIII or IX
200
(r= 0.44, p=0.004)
150
100
50
0
-50
-100
-20
-10
0
10
20
30
40
% AT Knockdown
*Cohort 1 data as of Nov. 24, 2014; cohort 2 data as of Dec. 5, 2014
Sorensen ASH, Dec. 2014
57
ALN-AT3 Phase 1 Study Part B (MAD)*
Cohort 1 and 2 Interim Pharmacodynamics and Clinical Activity
Initial data on AT knockdown after multi-dose in hemophilia subjects
 Cohort 1 (n=3) results
»
»
»
Mean maximum AT knockdown of 27% ± 13% (mean ± SEM)
Maximum AT knockdown up to 52% in most advanced subject; nadir at day 35
Conclusions from thrombin generation measurements are pending further analysis
»
»
AT knockdown in first subject up to 57%; data from local lab reporting
Thrombin generation results pending cohort completion
 Cohort 2 (n=1) results
ALN-AT3 Treatment Group
-20
% AT Mean Knockdown
15mcg/kg
45mcg/kg
0
20
40
60
80
0
5
10
15
20
25
30
Days
*Cohort 1 data as of Nov. 24, 2014; cohort 2 data as of Dec. 5, 2014
Sorensen ASH, Dec. 2014
58
ALN-AT3 Phase 1 Study*
Safety/Tolerability; All TEAEs
Part A (SAD), Healthy Adult Volunteers
Cohort 1
N=4
1
Relationship to Study Drug
Unlikely related
Coryza
1
Not related
Headache
1
Possibly related
Panic like symptoms
1
Unlikely related
Upper Respiratory Tract Infection
1
Not related
Adverse event
Atypical chest pain
Part B (MAD), Hemophilia Subjects
Adverse event
Muscle Bleed
Venipuncture bleed
Idiopathic abdominal pain
Joint Bleed
Myalgia
Nose Bleed
Oral mucosal bleed






Cohort 1
N=3
2
2
1
1
1
1
0
Cohort 2
N=1
0
0
0
0
0
0
1
Relationship to
Study Drug
Not related
Not related
Not related
Not related
Possibly related
Not related
Not related
No serious adverse events
All adverse events mild/moderate and no discontinuations
No injection site reactions
No thromboembolic events or clinically significant D-dimer increases
Normal physical exams, vital signs, and ECG
No laboratory AEs (LFTs, CBC, coagulation parameters)
*Cohort 1 data as of Nov. 24, 2014; cohort 2 data as of Dec. 5, 2014
Sorensen ASH, Dec. 2014
59
Clinical Development Plan
ALN-AT3 for the Treatment of Hemophilia and RBD
Broad-based development plan to maximize product opportunity
Phase 1
Adult Healthy Volunteers
and Hemophilia A/B
Key Objectives
• Safety, PK, clinical activity (AT
knockdown, thrombin generation)
• Initial dose finding
Phase 2
Hemophilia A/B
± Inhibitor
Key Objectives
• Safety, PK, clinical activity (AT
knockdown, thrombin generation,
bleeding frequency)
• Extended dosing (3-6 mo)
Phase 3
Inhibitor
On-demand
(Non-Inhibitor)
Prophylaxis
(Non-Inhibitor)
RBDs
Pediatric (< 12 y.o.)
± Inhibitor
60
Complement Disease Program
Unmet Need and Program Opportunity
Complement-Mediated Diseases
 Excessive complement activity drives disease
pathophysiology in many indications
»
»
»
»
»
Paroxysmal nocturnal hemoglobinuria (PNH)
Atypical hemolytic uremic syndrome (aHUS)
Neuromyelitis optica (NMO)
Myasthenia gravis
Many others
 SolirisTM (eculizumab) is blockbuster drug
» >$1.5B in reported 2013 sales
» >$2.0B in forecasted 2014 revenue
New therapeutic options needed
 Consistent level of efficacy
 SC delivery for more tolerable treatment regimen
 Reduce access barriers to treatment
61
Complement C5 and ALN-CC5 Program
Complement C5 is genetically validated target
 Key component of terminal pathway
»
C5 cleavage releases C5a; initiates
membrane attack complex (MAC) formation
 C5 deficiency associated with minimal
complications
»
»
C3
Initiation
»
C1
C4 and C2
C3 Convertase
Factor B
C3bBb
C3a
C5 Convertase
C4bC2a
C3b
C3bBbC3b
Opsonization
C4bC2aC3b
Inflammation
Complement C5 is clinically validated target
 Eculizumab is anti-C5 Mab
 Approved in PNH and aHUS
Lectin Pathway
C3
Susceptibility to increased Neisserial
infections
Many C5 deficient mouse strains
 Majority expressed in liver; circulates in
plasma
Classical Pathway
Alternative Pathway
C5a
Terminal Pathway
C5
C5b
C5b-C9
In PNH, >80% inhibition of hemolytic activity
associated with clinical benefit1
Membrane attack complex (MAC)
 Potential advantages of synthesis inhibition
vs. protein binding approach
1Hillmen
et al., NEJM; 350:552-9 (2004)
62
ALN-CC5
Hemolysis Inhibition and Clinical Efficacy
Hemolysis inhibition to ~≤20% normal associated with clinical efficacy in PNH and aHUS
 No evidence that “>99.99%” hemolytic activity inhibition required
 Evidence of incomplete effects of eculizumab and loss of activity between IV doses
PNH
aHUS
Incomplete effects
of eculizumab
Dosing: 900 mg every 14 days
(subjects 1 & 2 required shorter interval of 12 days)
Cugno et al., J Thromb Haemost; 10.1111/jth.12615 (2014)
Serum C5 activity (%, sRBC hemolysis assay)
Serum C5 activity (%, cRBC hemolysis assay)
Hill et al., Blood;106:2559-2565 (2005)
Loss of activity between
eculizumab doses
Weeks following last eculizumab infusion
Dosing: 800 - 2000 mg
63
ALN-CC5 Pre-Clinical Efficacy
Potent C5 Knockdown and Complement Activity Inhibition
SC Administration of ALN-CC5 in non-human primates for over 7 months

Potent dose-dependent C5 knockdown up to 99.2%
»
»

Mean maximum knockdown of 98.4% ±0.7%
Expect qM dosing regimen in humans based on translation of ESC-GalNAc-siRNA conjugates
Potent inhibition of complement activity up to 96.9%; closely correlated with C5 knockdown
»
»
Mean maximum inhibition of CAP ELISA of 95.1% ±0.93%
Mean maximum inhibition of serum hemolytic activity of 88.0% ±6.1%
Serum C5
-20
%Activity or hemolysis reduction
%C5 Knockdown
(Normalized to Pre-bleed)
0
20
40
60
80
Complement Activity (q2W)
0
2xw q2w qm
CAP
Hemolysis
20
40
60
80
100
100
0
20 40 60
2xW Regimen
80
100 120 140 160 180 200 220
Days
q2W and qM Regimens
0
20
40
60
80 100 120 140 160 180 200 220
Days
q2W Regimen
Borodovsky, ASH, Dec. 2014
64
ALN-CC5 Phase 1/2 Study
Dose-Escalation Study Including Patients with PNH
Part
A
Part
Study Design

Randomized, double-blind,
placebo-controlled SAD
study in healthy volunteers
(up to N=40)
Primary Objective

Safety and tolerability of
single dose in healthy
volunteers
Secondary Objectives


PK/PD and clinical activity
C5 levels, hemolysis
suppression
Part
B
C
Study Design

Randomized, double-blind,
placebo-controlled MAD
study in healthy volunteers
(up to N=24)
Primary Objective

Safety and tolerability of
multi-dose in healthy
volunteers
Secondary Objectives

PK/PD and clinical activity
» C5 levels, hemolysis
suppression
Study Design

Open-label MAD study in
PNH patients (N=8)
Primary Objective

Safety and tolerability of
multi-dose in PNH patients
Secondary Objectives


PK/PD and clinical activity
C5 levels, hemolysis
suppression, LDH
reduction
Status
 ESC-GalNAc-siRNA for SC dosing
 CTA filed; initiate Phase 1 early ’15
 Initial data expected mid ’15
65
Clinical Development Plan
ALN-CC5 for the Treatment of Complement-Mediated Diseases
Broad-based development plan to maximize product opportunity
Phase 1/2
Adult Healthy Volunteers
and PNH patients
Key Objectives
• Safety, PK, and Clinical Activity
(C5 knockdown and complement
activity inhibition)
• Initial Dose Finding and Extended
Dosing (3-6 mo)
• LDH Reduction in PNH Patients
Phase 2
OLE PNH
Patients
Other Complement Mediated
Diseases
Phase 3
PNH
aHUS
MG
NMO
MN
Pediatric (< 12 y.o.)
66
Acute Intermittent Porphyria (AIP) Program
Unmet Need, Product Opportunity, and Program Status
AIP is autosomal dominant disorder
 Ultra-rare orphan disease
»
»
~5,000 Patients with annual attacks U.S./EU
~500 Patients with recurrent attacks U.S./EU
High unmet need and cost
 Patients present with acute or recurrent attacks
 Limited treatment options
»
»
Blood-derived hemin given centrally
No prophylactic treatment to prevent attacks
Significant opportunity to treat and prevent
porphyric attacks
 Orphan disease with substantial morbidity
 Value supported by significant burden of
disease

study ongoing
»
Prospective observational study of
patients with hepatic porphyrias
ALN-AS1 in R2D




ESC-GalNAc-siRNA for SC dosing
Proof of concept and efficacy in animal models
DC selected
CTA filing late ’14
67
Additional Genetic Medicine Programs
AAT Deficiency Associated Liver Disease




Commonest mutant allele (PiZZ) homozygosity results in liver cirrhosis
»
»
Cell injury, ER stress, and autophagy resulting in fibrosis
WW prevalence ~20,000
ALN-AAT targets alpha-1antitrypsin PiZZ allele
Efficacy in pre-clinical animal models
»
>90% Knockdown of AAT; Reduction in fibrosis; reduced incidence of liver tumors
IND mid ’15
Primary Hyperoxaluria Type 1




Loss of function mutations in liver peroxisomal alanine-glyoxylate
aminotransferase (AGT)
»
Renal damage from increased oxalate, nephrocalcinosis, and renal obstruction
ALN-GO1 targets glycolate oxidase (GO), enzyme upstream of AGT
Efficacy in pre-clinical animal models
»
~90% Knockdown of liver GO; ~80% Reduction in urinary oxalate
DC mid ’15; IND ’16
Beta-Thalassemia and Iron-Overload Disorders



Need for disease-modifying therapy to improve anemia and manage iron levels
»
>200,000 patients WW with thalassemia major; ~10,000 non-transfusion dependent patients U.S./EU
ALN-TMP targets transmembrane protease, serine 6 (TMPRSS6) for hepcidin activation
Efficacy in pre-clinical animal models showing disease-modifying effects
»
Results published in Blood
68
Genetic Medicine STAr
Next Wave Target Assessment
Large number of opportunities based on scientific, clinical, and market insights
Target ID - Liver-expressed protein
100’s Targets
“Next Wave” Triage
Internal Validation
External Validation
• Literature review
• Genetic medicine criteria
• Preliminary prioritization
• Scientific, clinical,
and regulatory review
• KOL Interactions
Scientific Review
Deprioritized Targets
Primary prescriber unmet
need assessment
(if necessary)
Commercial Review
Discarded Targets
10’s Targets
Target Validation
•
•
•
•
In vitro and in vivo data generation
Animal model / collaboration
KOL panel
Additional commercial assessment
69
Genetic Medicine STAr
Summary (1/2)
Significant opportunity for RNAi therapeutics as
transformative medicines in rare diseases
 Potential to make meaningful impact on patient’s lives
» Close connection to patients, caregivers, and providers
 Large number of genetically validated disease targets
expressed in hepatocytes
 Reproducible and modular approach for rare disease
platform
» Unmatched in industry
 Emerging profile for ESC-GalNAc-siRNA highly attractive
» Potent and durable, with very wide therapeutic index
» Durability supports qM to qQ subcutaneous dose regimens
» Best-in-class approach across industry
70
Genetic Medicine STAr
Summary (2/2)
Alnylam Genetic Medicine STAr advancing large number of programs
 Established human POC in 4 RNAi therapeutic programs
» Includes active programs (patisiran, revusiran, and ALN-AT3)
 Patisiran and revusiran in Phase 3 trials for TTR amyloidosis
» Both FAP and FAC to impact across entirety of disease spectrum






ALN-AT3 in Phase 1 trial for hemophilia and rare bleeding disorders
ALN-CC5 with filed CTA for complement-mediated diseases
ALN-AS1 with CTA on track for YE ’14 in hepatic porphyrias
ALN-AAT with IND in mid ’15 for alpha-1-antitrypsin deficiency liver disease
Many clinical data read outs in 2015 and beyond
Multiple additional pipeline programs, many undisclosed
» Expect 1-3 INDs/year
Alnylam plan to directly market and sell in NA and EU
 Pharmacoeconomics support value-based pricing model
 Genzyme partner for ROW and select 50-50 partner for certain programs in
NA/EU
» Expect >8 human POC from pipeline through end-2019
71
Pipeline Growth Strategy and Genetic Medicine STAr
Q&A
72
Daniel Rader, M.D.
Chair, Department of Genetics,
Perelman School of Medicine,
University of Pennsylvania
73
Cardiometabolic Disease: an Epidemic
Insulin resistance
Type 2 diabetes
Inflammation
Hypertension
Dyslipidemia
Fatty liver
Cardiovascular
disease
Prevalence of obesity (% adults with BMI > 30)
Body fat distribution
Visceral fat
Subcutaneous fat
Obese
Lean
National Geographic; Aug 2004
Diseases associated with obesity
Diabetes
Dyslipidemia
Hypertension
Heart disease
Stroke
Sleep apnea
Hypoventilation
Asthma
GERD
NAFLD
Gall stones
Gout
Osteoarthritis
PCOS
Infertility
Thrombophlebitis
Lymphedema
Psoriasis
Depression
Pseudotumor cerebri
Dementia
Cancer (breast,
endometrium, ovary,
prostate, colon,
esophagus, stomach,
kidney, pancreas)
Type 2 diabetes
Chan J et al. Diabetes Care 1994;17:961; Colditz G et al. Ann Intern Med 1995;122:481.
Coronary Heart Disease
Folsom et al. Arch Intern Med 2000;160:2117. The Iowa Women’s Health Study
Hospitalization Costs for Chronic
Complications of Diabetes in the US
Ophthalmic
disease
Renal
disease
Others
Neurologic
 CVD accounts
disease
for 64% of
total costs
Peripheral
vascular
disease  Total costs 12
billion US $
Cardiovascular
disease
American Diabetes Association. Economic Consequences
of Diabetes Mellitus in the US in 1997. Alexandria, VA:
American Diabetes Association, 1998:1-14.
Dyslipidemia and coronary
disease
A-I
B
TG, CE
CE
LDL
TG-rich
lipoproteins
Lp(a)
HDL
The Liver LDL Receptor regulates plasma LDL levels
For illustration purposes only
81
81
PCSK9 is a liver-derived protein that regulates LDL
uptake and is a major target for therapeutic inhibition
For illustration purposes only
82
82
Triglyceride-rich lipoproteins
are an important cause of
cardiovascular disease
B
TG
CE
LPL
CE
B
Multiple liver-derived proteins
influence triglyceride metabolism
B
TG
CE
A-V
LPL
CE
B
C-III
ANGPTL3
ANGPTL4
Non-alcoholic fatty liver disease
(NAFLD)
Adipose
Liver
Normal
Steatosis
Steatohepatitis
Fibrosis
(fatty liver)
(inflammation and
stellate cell activation)
(collagen deposition)
NASH
Cirrhosis
The Burden of NAFLD in the US
Obese
90 million
NAFLD
75 million
NASH
12.5 million
0%
10%
20%
30%
40%
AASLD guidelines 2012.
US Census Bureau.
Mortality in NAFLD
20%
18-year Mortality
17.5%
15%
10%
5%
2.7%
Causes
1. CV
2. Cancer
3. Liver
0%
NAFL
NASH
Rafiq, et al. CJH 2009; Ong, et al. J Hepatol 2008.
Pathophysiology of NAFLD and
Cardiometabolic disease
Anstee, Nature Reviews
Gastro and Hepatol 2013
The Liver is a Central Mediator of and Therapeutic
Target for Cardiometabolic Diseases
Hypertension
AngiotensinRenin system
NAFLD/NASH
Cardiovascular
Disease
TGs
FFAs
Inflammation
Gluconeogenesis
Lipid
Storage
LDL/HDL
Fructose
LDL/HDL
Clearance
Type 2
Diabetes
Insulin
Resistance
Glucotoxicity
Glucose
Nutrients
Insulin
GI Tract
Retinopathy Nephropathy Neuropathy
Pancreas
Intra-abdominal
Obesity
Rachel Meyers, Ph.D.
Vice President, Research and RNAi Lead Development
Cardio-Metabolic Pipeline
90
91
Alnylam Development Pipeline
Discovery
Development
Phase 1
Phase 2
Phase 3
GENETIC MEDICINES
Patisiran (ALN-TTR02)
TTR-Mediated Amyloidosis
Revusiran (ALN-TTRsc)
ALN-AT3
Hemophilia and Rare Bleeding Disorders
ALN-CC5
Complement-Mediated Diseases
ALN-AS1
Hepatic Porphyrias
Alpha-1 Antitrypsin Deficiency
ALN-AAT
Beta-Thalassemia/Iron-Overload Disorders
ALN-TMP
Primary Hyperoxaluria Type 1
ALN-GO1
Additional Genetic Medicine Programs
CARDIO-METABOLIC DISEASES
ALN-PCSsc
Hypercholesterolemia
Mixed Hyperlipidemia/Hypertriglyceridemia
ALN-ANG
Hypertriglyceridemia
ALN-AC3
Hypertension/Preeclampsia
ALN-AGT
Additional Cardio-Metabolic Programs
HEPATIC INFECTIOUS DISEASES
Hepatitis B Virus Infection
ALN-HBV
Hepatitis D Virus Infection
ALN-HDV
Chronic Liver Infection
ALN-PDL
Additional Hepatic Infectious Disease Programs
Alnylam Development Pipeline
Discovery
Development
Phase 1
Phase 2
Phase 3
Patisiran (ALN-TTR02)
Revusiran (ALN-TTRsc)
ALN-AT3
ALN-CC5
ALN-AS1
ALN-AAT
ALN-TMP
ALN-GO1
CARDIO-METABOLIC DISEASES
ALN-PCSsc
Hypercholesterolemia
Mixed Hyperlipidemia/Hypertriglyceridemia
ALN-ANG
Hypertriglyceridemia
ALN-AC3
Hypertension/Preeclampsia
ALN-AGT
Additional Cardio-Metabolic Programs
ALN-HBV
ALN-HDV
ALN-PDL
Alnylam RNAi Therapeutics Strategy
A Reproducible and Modular Path for Innovative Medicines
2. POC achieved in Phase 1
 Blood-based biomarker with
strong disease correlation
GCCCCUGGAGGG
» e.g., Serum TTR, thrombin
generation, hemolytic activity,
LDL-C, HBsAg levels
3. Definable path to approval
and market
1. Liver-expressed target gene
 Involved in disease with high
unmet need
 Validated in human genetics
 GalNAc-siRNA enables SC dosing
with wide therapeutic index




Established endpoints
Focused trial size
Large treatment effect
Collaborative approach with
physicians, regulators,
patient groups, and payers
94
Emerging Profile for RNAi Therapeutics
Cardio-Metabolic Disease
Emerging profile for ESC-GalNAc-siRNA conjugates
 Attractive pharmacologic properties
»
»
»
»
Subcutaneous dose administration
High potency with microgram/kg (mcg/kg) doses
Low volume per injection, <1 mL
Durability for monthly (qM) and possibly quarterly (qQ) dose frequency
 Competitive profile with RNAi mechanism
» Block synthesis of disease-causing protein
» Efficacy independent of target protein blood levels
» Clamped knockdown with low inter-individual variability
 Well tolerated and wide therapeutic index
Unique opportunity for cardio-metabolic disease
 Growing human genetics data expands accessible target space
» Large populations continue to be genetically segmented
 Potential to address more common diseases impacting millions of people
 Improved compliance expected due to infrequent dosing
 Dual-targeting possible
95
Human Liver
Central Mediator of Multiple Inter-Related Cardio-Metabolic Diseases
Hypertension
AngiotensinRenin system
NAFLD/NASH
Cardiovascular
Disease
TGs
FFAs
Inflammation
Gluconeogenesis
Lipid
Storage
LDL/HDL
Fructose
LDL/HDL
Clearance
Type 2
Diabetes
Insulin
Resistance
Glucotoxicity
Glucose
Nutrients
Intra-abdominal
Obesity
Insulin
GI Tract
Retinopathy Nephropathy Neuropathy
Pancreas
96
Dyslipidemia
Key Risk Factor in Cardiovascular Disease
Dyslipidemia Pathophysiology and Disease Burden
 Key Contributors
» Genetic factors, obesity, poor nutrition, physical inactivity
 Cardiovascular disease leading cause of mortality in U.S.
 Dyslipidemia patient population growing rapidly, outpacing population growth
Altered Lipid Metabolism
Intestinal
Tract
Abnormal Lipid Profile
LDL
Triglycerides
HDL
Adipocytes
CDC, America’s Cholesterol Burden 2012; Heidenreich, 97
Circulation. 2011;123(8):933; KOL Interviews
ALN-PCSsc Program and PCSK9
Unmet need in hypercholesterolemia




Elevated LDL-C validated risk factor for CVD
34 million Americans have hypercholesterolemia (> 240 mg/dL)
Recent clinical studies
»
»
Many patients on statins do not meet LDL-C goal
Lower LDL-C is better
Multiple genetically defined patient subgroups
PCSK9 is a genetically validated target
GOF mutations associated with hypercholesterolemia and premature CHD
LOF mutations associated with hypocholesterolemia and decreased CHD risk
CHD Risk
WT PCSK9
12
30
Coronary Heart Disease (%)
20
10
Frequency (%)


0
30
LOF PCSK9
20
10
0
8
4
0
50
100
150
200
250
300
WT
LOF
Plasma LDL Cholesterol (mg/dl)
Pearson et al., L-TAP Study, Arch Intern Med; 160:459-67 (2005),
Blazing e al Am. Heart J; 168:205 (2014)
98
Cohen et al., N. Engl. J. Med.; 354:1264-1272 (2006)
PCSK9 Therapeutic Hypothesis
LDL
MAbs are
PCSK9 blockers
Endosome
RNAi
therapeutics
are PCSK9
synthesis
inhibitors
Catalytic degradation
of PCSK9 mRNA –
independent of
plasma levels
Bind 1:1 to PCSK9
protein – sensitive
to plasma levels
Lysosomal
degradation
LDLR
synthesis
PCSK9
synthesis
PCSK9
ALN-PCSsc
PCSK9 mRNA
Nucleus
99
ALN-PCS02 Phase 1 Study Results
Pharmacodynamics and Clinical Efficacy
PCSK9 knockdown and LDL-C reduction after single dose without statins

Randomized, placebo-controlled, single dose escalation study
»

Healthy volunteers with elevated LDL (n=32)
Rapid, dose-dependent, and durable knockdown of PCSK9 of up to 84% with mean lowering of 68% at
0.4 mg/kg group (p<0.0001)
Major reductions in LDL-C of up to 50% with mean lowering of 41% at 0.4 mg/kg group (p<0.01)
PCSK9
Mean Relative to Baseline and Placebo
% Knockdown PCSK9 Plasma Levels
-40
LDL-C
-20
0
20
40
60
ALN-PCS
dose group (mg/kg)
80
0.015
0.045
0.090
100
siRNA
Dose
0.150
0.250
0.400
% Reduction LDL-C
Mean Relative to Baseline and Placebo

-20
0
20
ALN-PCS
dose group (mg/kg)
40
0.015
0.045
0.090
0.150
0.250
0.400
60
5
10
15
Days
20
25
siRNA
Dose
5
10
15
Days
10
Fitzgerald et al., The Lancet (2013) 0
20
25
ALN-PCSsc Pre-Clinical Efficacy in NHP
Potent PCSK9 Knockdown and LDL-C Lowering: Single Dose Data
Highly durable PCSK9 knockdown and LDL-C reduction with single dose
 Single SC dose 1-10 mg/kg
 Up to 96% PCSK9 knockdown, up to 77% LDL-C lowering; absence of statins
 Highly durable effects, supports once-monthly or possibly once-quarterly dosing
»
>50% LDL-C lowering maintained for over 3 months in 10 mg/kg group
PCSK9
LDL-C
1.0
3.0
6.0
10.0
1.0
3.0
6.0
10.0
-20
% LDL-C Lowering
(relative to pre-bleed)
% PCSK9 Knockdown
(relative to pre-bleed)
-20
0
20
40
60
80
0
20
40
60
80
100
100
0
ALN-PCSsc
(mg/kg)
20
40
Days
60
80
100
0
ALN-PCSsc
(mg/kg)
20
40
60
Days
Fitzgerald, AHA, Nov 2014
10
1
80
100
120
ALN-PCSsc Pre-Clinical Efficacy in NHP
Potent PCSK9 Knockdown and LDL-C Lowering: Multi-Dose Data
Potent and stable PCSK9 knockdown and LDL-C lowering with monthly SC dosing
»
6 mg/kg 1st dose, 3 mg/kg monthly maintenance
Up to 92% PCSK9 knockdown, up to 77% LDL-C lowering; absence of statins
Clamped knockdown of PCSK9 and reduction in LDL-C levels with monthly maintenance
dosing for over 6 months
-40
LDL-C
PCSK9
-20
(Relative to pre-bleed)


Monthly SC dose regimen
% PCSK9 Knockdown and LDL-C Lowering

0
20
40
60
80
100
0
20
40
60
80 100 120 140 160 180 200
Days
Fitzgerald, AHA, Nov 2014
10
2
ALN-PCSsc Versus Anti-PCSK9 MAbs
Potential Differentiation
Differentiation for ALN-PCSsc
Rebound in LDL-C with qM dosing
for anti-PCSK9 MAb
 Clamps PCSK9 knockdown
and LDL-C lowering with
monthly or, possibly
quarterly SC dosing
» Independent of baseline or
fluctuating PCSK9 levels
 Potential for synergy with
statins
» Statins upregulate PCSK9 and
compromise MAb efficacy
McKenney et. al., JACC, 59, No.25, 2012
10
3
ALN-PCSsc Phase 1 Study
Study Design
 Randomized, single-blind, placebo-controlled, single ascending dose (SAD)
and multi-dose (MD), subcutaneous dose-escalation study
 Up to 76 volunteer subjects with elevated baseline LDL-C (≥100 mg/dL)
» MD phase to also include subjects both on and off statin co-medication
 3:1, ALN-PCSsc vs. placebo
Treatment Regimen
 SD or MD (qM x 2)
Study Objectives
 Primary: safety and tolerability of ALN-PCSsc
 Secondary: PK, clinical activity (% reduction of LDL-C and knockdown of
PCSK9 compared to baseline)
Status
 Phase 1 started
 Initial clinical data expected mid-2015
104
APOC3
Validated Liver Target for Reduction of TG Levels
Unmet need in hypertriglyceridemia
 >50M in U.S. have high triglycerides (>200 mg/dL)
» >3M have very high triglycerides (>500 mg/dL)
 Additional opportunity in ultra-rare orphan condition in
people lacking properly functioning lipoprotein lipase
(LPL)
» ~1,000 Patients with Familial Chylomicronemia Syndrome
VLDL
TG
hydrolysis
APOC3 inhibits lipoprotein lipase to prevent triglyceride
hydrolysis
 Loss-of-function individuals have lower triglyceride
levels, lower rates of coronary artery calcification, and
CVD risk
 Pro-inflammatory effects on vascular endothelium
 Primarily expressed in liver
Crosby NEJM 371:22 (2014)
Pollin, Science 322(5908):1702-5 (2008)
LPL
APOC3
IDL
TG
hydrolysis
LDL
105
HTGL
ALN-AC3 Targeting ApoC3
Potent ApoC3 Knockdown and TG Lowering
ALN-AC3 inhibits ApoC3 and reduces triglycerides
 94% reduction of human serum ApoC3 at 3 mg/kg
» Durable effect
Human ApoC3 Protein
-20
0
20
40
60
80
100
0
10
ALN-AC3
q2W x 5
20
30
40
Days
50
Triglyceride Lowering
1.0
% TG Lowering
(Relative to Pre-dose)
% ApoC3 Knockdown
(Relative to Pre-dose)
 Up to 50% lowering of triglycerides in db/db mouse model of
hyperlipidemia
60
70
0.8
0.6
0.4
1.25 mg/kg
2.5 mg/kg
5.0 mg/kg
0.2
0.0
0
5
10
ApoC3-GalNAc
qD x 5
Fitzgerald, ATVB, May 2014
15
Days
106
20
25
ANGPTL3
Validated Liver Target for Reduction of TG and LDL-C Levels
ANGPTL3 is genetically validated target
 Functions as lipase inhibitor
 Loss of function ANGPTL3 mutations associated with combined
hypolipidemia
» Increased LPL activity, increased insulin sensitivity
» Extremely low LDL-C, HDL-C, and triglycerides
» Decreased free fatty acids
LDL-C
Triglycerides
Musunuru et al., NEJM (2010)
Koishi, et al., Nat Gen (2002)
107
ALN-ANG Targeting ANGPTL3
Efficacy in Rodent Models
ALN-ANG inhibits ANGPTL3 and reduces circulating lipids
in ob/ob mice
 Up to 99% lowering of serum ANGPLT3
 Up to 80% reductions in triglycerides and LDL-C
-40
-20
-20
0
20
40
60
80
10
15
0
20
40
60
80
100
100
5
(Relative to PBS)
-40
% LDL Lowering
50
(Relative to PBS)
% TG Knockdown
0
100
0
LDL-C
Triglycerides
-50
(Relative to Pre-dose)
% ANGPTL3 Knockdown
ANGPTL3 Knockdown
0
5
10
15
0
5
Days
Days
PBS
ALN-ANG, 0.3mg/kg
10
Days
ALN-ANG, 1mg/kg
ALN-ANG, 3mg/kg
Fitzgerald, AHA, Nov 2014
108
15
Hypertension (HTN)
Significant Unmet Needs in Specific Populations
 Highly prevalent disease
Angiotensinogen
» Compliance is area of high unmet need
 High unmet need in preeclampsia for
safe and effective therapy
» >500,000 U.S./EU pregnancies complicated by
hypertension
» Preeclampsia in >200,000/year
–
–
10-20% of maternal or fetal perinatal deaths
Premature delivery associated with neonatal
intensive care, risk of morbidity and mortality
 Opportunity for RNAi therapeutic
targeting angiotensinogen in maternal
liver
» Pharmacologically validated pathway
» Control hypertension, preeclamptic symptoms
» Maintain pregnancy, extend gestation, and
avoid premature delivery
» RNAi therapeutic does not cross placenta,
avoiding fetal exposure
Renin
Inactive
Peptide
Inactive
Peptide
Angiotensin I
ACE, chymase,
carboxypeptidase,
tonin, cathepsin C
NEP
Natriuretic
peptides
Bradykinin
BKR
Angiotensin II
AT2R
NO
AT1R
Aldosterone
Vasodilation
Anti-fibrosis
Apoptosis
Natriuresis
Anti-inflammation
Modified from Paulis & Unger Nat. Rev. Cardiol. 7, 431–441 (2010)
Vasconstriction
Collagen synthesis
Anti-apoptosis
ROS generation
+
Na and water retention
109
(P)RR
ALN-AGT
Pre-clinical Efficacy in Model of Preeclampsia
ALN-AGT improves maternal preeclamptic symptoms without fetal exposure
 >90% Silencing maternal AGT
»
No fetal exposure of drug
»
»
>80% reduction in proteinuria
>75% reduction in maternal VEGF receptor-1 (FLT1)
 Improves hypertension with ~20 mmHg decrease in mean arterial pressure
 Improves preeclamptic symptoms
 Significant improvements in fetal outcomes
30
Albuminuria
4
Fetal Weight
100000
Tissue Exposure
20
10
0
ng siRNA/g tissue
Fetal Weight (g)
Albuminuria (mg/dL)
10000
3
2
1
PE RNAi
100
10
25,712
97
<LLOD
1
0.1
0
PE Control
1000
PE Control
PE RNAi
Maternal
Liver
110
Placenta
Fetal
Liver
NASH
Unmet Need and Program Opportunity
NASH is progressive fibrotic liver disease
 Leads to cirrhosis and liver failure
 ~1M diagnosed patients in U.S.
» NASH growth >> population growth
–
Fueled by expansion of metabolic co-morbidities
» Availability of therapy and novel diagnostics will
expand diagnosed patients in future
–
Estimated ~3M patients by 2030
 Third most common cause of liver
transplantation in U.S., and growing
Therapeutic options needed
 Currently no approved therapies
 Several agents in development but unmet
needs will remain
Number of liver targets for RNAi therapeutics
 Multiple Alnylam opportunities being pursued
Charlton. Gastroenterology. 141:1249 (2011;)
Bellentani. Ann Hepatol. 8(1):S4; (2009)
Younossi. Clin Gastroenterol Hepatol.;9(6):524 (2011)
111
Type 2 Diabetes
Unmet Need and Program Opportunity
Type 2 Diabetes one of fastest growing health
burdens in established markets
Insulin Resistance
 WW prevalence ~370M by 2030
» ~$245B costs in U.S. in 2012
Glucose Production by Liver
 Multiple disease complications
Glucose Uptake in Muscles
» Increased CV risk, renal disease,
retinopathies, neuropathies
 Growth due to aging population, lifestyle
choices, co-morbid conditions
Blood
Glucose
Opportunity clearly defined
 Novel therapeutics should deliver
demonstrable “dual benefit”
 Glucose control plus other benefit, such
as weight loss
Number of liver targets for RNAi therapeutics
 Multiple Alnylam opportunities being
pursued
» Includes dual-targeting
Beta-cell Dysfunction
Insulin Production
Genetic Factors, Obesity, Nutrition,
Physical Inactivity
Boyle. Popul Health Metr 8:29; (2010); American
Diabetes Association The Cost of Diabetes, (2012)
112
Cardio-Metabolic Disease STAr
Summary (1/2)
Significant opportunity for RNAi therapeutics as
transformative medicines in cardio-metabolic diseases
 High unmet medical need in multiple patient segments
» Dyslipidemia, hypertension, NASH, and type 2 diabetes
 Many important hepatocyte-expressed targets
 Increasing power of human genetics fueling more opportunities
 Emerging profile for ESC-GalNAc-siRNA highly attractive
» Potent and durable, with very wide therapeutic index
» Durability supports qM to qQ subcutaneous dose regimens
» Ability to achieve dual targeting
113
Cardio-Metabolic Disease STAr
Summary (2/2)
Alnylam Cardio-Metabolic Disease STAr advancing multiple programs
 Established human POC with RNAi therapeutics
» ALN-PCS02: robust knockdown of PCSK9 and reduction of LDL-C in Phase 1 study
 ALN-PCSsc in Phase 1 trial for hypercholesterolemia
» Initial data expected in mid ’15
» Partnered with The Medicines Company
 Additional programs in development for dyslipidemia and hypertensive
disorders of pregnancy
» Includes ALN-AC3, ALN-ANG, and ALN-AGT
 Multiple additional pipeline programs
» Expect ~1 IND/ year
Represents new opportunities for partnership
 Alnylam to retain meaningful product rights in core markets
 Leverage partner for expanded effort and geographic scope
114
Cardio-Metabolic Disease STAr
Q&A
115
BREAK
Welcome Back
Timothy Block, Ph.D.
President, Hepatitis B Foundation of
America and its Baruch S. Blumberg
Institute, and Professor, Drexel
University College of Medicine
118
Is a Cure for Hepatitis B Possible?
Necessary?
Tim Block, Ph.D.
Is a Cure for Hepatitis B Possible?
Necessary?
•
•
•
•
•
The problem of hepatitis B and liver cancer
Limits of current therapies for managing HBV
Rationale for new strategies
Summary of Experimental Strategies
Defining a cure
120
Shocking epidemiology: 350 million chronic carriers
350 million people with chronic HBV
HBsAg Prevalence
>=8% - High
2-7% - Intermediate
<2% - Low
Medical Management of
Chronic Hepatitis B (CHB)
122
Timeline of Approved Drugs for Chronic HBV
REVEAL Study: The Relationship Between Virus Number
and Hepatocirrhosis/Hepatocellular Carcinoma
4006 Study: antiviral therapy could slow
down the development of CHB
1992
Interferon approved
for CHB
1998
Lamivudine
2002
Adefovir
2004 2005 2006 2007 2008
Entecavir
PEG-IFN
Tenofovir
Telbivudine
Tenofovir approved in US for HBV, in 2008, but not yet approved in China for HBV
123
7 Medications for Chronic HBV Management
• The IFNs
• The polymerase inhibitors
Treatment Guidelines for the Management of CHB
HBeAg +
Recommendation
Group
HBeAg -
DNA
ALT
DNA
ALT
genomes/mL
x ULN
genomes/mL
x ULN
AASLD
105
>2
104
>2
Lok & McMahon 2007
US Panel
105
>1
104
>1
Keefe 2006
EASL
105
>2
105
>2
deFranchis 2002
Asia-Pacific
105
>2
104
>2
Liver Int 26:47-58
Reference
So, what’s the problem?
124
China
120 Million
Chronic HBV
Carriers
~50 Million
within
Treatment
Guidelines
~8M Treated
125
USA
1.2-2 Million
Chronic HBV
Carriers
~500-800,000
within
Treatment
Guidelines
~75,000
Treated
126
10 Year Liver Mortality (%)
HBsAg+, Negative Family History, No Alcohol
100
90
80
Treatable
70
(HBeAg+, abn ALT)
60
50
40
30
“Untreatable”
20
(HBeAg-, nl ALT)
10
0
30
40
50
60
Age in years
A. Evans, 2012 127
Antiviral Therapy for Chronic HBV Infection and
Development of Hepatocellular Carcinoma in USA
• Analyzed electronic health records of 2671 adult participants in the
Chronic Hepatitis Cohort Study (CHeCS) diagnosed with chronic HBV
infection from 1992 through 2011
– Crude HCC incidence rate was 4.2 cases/1000 person years
• 67/2671 patients developed HCC over follow-up period (3%)
• 20/820 cases in the group receiving treatment (2.4%)
• 47/1851 cases occurred in the untreated group (2.5%) aHR 0.50; 95% CI 0.350.72; p < 0.001
– After adjustments for matched pairs/subgroups analysis:
• treatment vs. no treatment: aHR 0.39; 95% CI 0.27-0.56; p <0.001
• treatment vs. no treatment matched by serum markers for cirrhosis: aHR 0.24;
95% CI 0.15-0.39; p <0.001 (no interaction noted between treatment and
fibrosis markers)
• treatment vs. no treatment matched by HBV-DNA/ALT when viral load >20,000
IU/ml: aHR 0.17; 95% CI 0.06-0.52; p=0.002
– 10 year Rx reduces cancer deaths by 50% (Lok, 2013)
Gordon SC et al Clin Gastro & Hep 2014 http://dx.doi.org/10.1016/j.cgh.2013.09.062
128
Why?
129
Even After Years of Rx
Chevaliez et al 2012 J Hepatology
Zoulim et al, Gastro.2004; 48 wk ADF
130
Nests of infected cells
(cccDNA containing)
remain
131
Defining a Cure: Goals
• Clinically: returning a chronic hepatitis B
carrier to the level of risk of death due to liver
disease of someone with a resolved infection
• Functionally: enduring suppression of all
measurable viral markers (antigenemia and
viremia) and restoration of humoral sAb
132
Need
• Something new that complements current
compounds
• An immuno-enhancer
133
Landscape of New Rx
• What is in human trials, now?
• What is at the pre-human trial stage?
134
Experimental HBV Therapeutics in Clinical Trials
In vitro
AGX1009 prodrug-ten
optimized
Animal efficacy
Gilead
Yeast Immune Compl
Cap Med U, Beijing, insufficient efficacy
Elvucitabine pol inhib
Achillion
CYT107 IL-7
Phase 3
Arrowhead
Cytheris SA, discontinued, results unknown
MIV 210 pro-drug
Medivir, Discontinued
Besifovir pol inhibi
Idong, Discontinued
Isis HBV-Rx antisense
Isis
MycB entry inhibitor
Gmb
NVR1221 capsid inhibitor
Novira
GS-4774; vaccine
Gilead
GS9620 Toll7
Gilead
DV601 Vac+nuc acid adj
Dynavax
RepA9 sAg inhibitor
Replicor
BAY41-109 capsid
Phase 2
Agenix/SHRG/YSY
GS-7340 prodrug-ten
ARC 520 (RNAi)
Phase I
AiCuris
DAA:
Indirect:
135
Experimental HBV Therapeutics in Preclinical Development
In vitro
OCB-030/NVP019
CMX157 prodrug ten
TKM HBV
Tekmira
ddRNAi-
Benitec
Briniprint/SMAC
Tetralogic
GLS-4 capsid
Sunshine
Innovio
Altravax HBV
Altravax
Capsid Inhibitor (2 Programs)
OnCore
S Antigen Secretion Inhibitor
OnCore
Phase 3
Blumberg/Drexel
Editope
Blumberg
Capsid Inhibitor
Assembly
STING Agonist
OnCore*
OnCore
HDAC
OnCore*
Chimegene Therapeutic Vaccine
Akshaya
H- Tropolones RNaseH
Phase 2
Agenix
Inv-HBV
cccDNA Formation Inhibitors
Phase I
Chimerix
Alnylam
DVR-pregrna
Animal efficacy
Oncore/Neurovive
ALN HBV
AGX 1009 prodrug ten
Optimized
St. Louis U
* In collaboration with the Blumberg Institute
136
Categories of Anti-HBV Strategies
Direct Acting Antivirals
• In Use
– Polymerase
• Potential
–
–
–
–
–
–
–
RNaseH
RNAi
Capsid inhibitors
sAg
eAg
Virus attachment
CRISPR/CAS
In-Direct Acting Antivirals
Immuno-modulatory
• In Use
–
•
–
Interferons
Potential
–
–
–
–
Essential host functions
• In Use
•
Therapeutic vaccines
Toll R agonists
STING, other innate defense
Interleukins, other cytokines
None for HBV
Potential
–
–
–
–
–
Epigentic modifiers
Entry
Morphogenesis
Exit
Glycan processing
137
The HBV Therapeutic Development Landscape as of October, 2014
Pre-clinical
DAA
TTP sAg
DVR
capsid
cccDNA
forma
Indirect
Host modifier
Human Phase Trials
AGX1009
prodrug
GLS-4
capsid
CMX157
prodrug
Benza
capsid
TKM-HBV
CpAMS
capsid
ALN- HBV
Isis HBV
antisense
ARC520
RNAi
NVR122
1 capsid
Bay4110
9 capsid
GS7340
Pro-ten
MycB
entry
RepA9
sAg
ddRNAi
HBV
NV100
Editope
Briniprin
t SMAC
HDAC
Indirect
Immunomodulator
Chimgene
HBV
STING
Altravax
HBV
Inovio
HBV
GS4774
vac
DV501
Vac
GS9620
Toll
138
Conclusions
• Goal of therapy: return those with chronic B to the
level of risk of people with resolved infections
• New medications will be needed to do this
• At least 12 steps in the virus life cycle can be targeted
• cccDNA is regulated differently than integrated HBV,
and can be repressed and degraded
• Pharmacological activation of neighboring non
hepatocyte cells could be a means of inducing
sterilization of hepatocytes of HBV
139
A cure is possible
A cure is necessary
140
Acknowledgments
• Drexel University
– Jinhong Chang, Ju-Tao Guo, Fang Guo, Xuessen Zhao,
Fei Liu, Pinghu Zhang, HaiTao Guo, David Cai
• The Baruch S. Blumberg Institute, Hepatitis B Foundation
– Andy Cuconati, Yanming Du, Michael Xu, Michael Goetz,
Matt Campang, Bill Kinney
• Support from: The US NIH, NIAID, NCI and The Hepatitis B
Foundation and Commonwealth of Pennsylvania
141
Laura Sepp-Lorenzino, Ph.D.
VP, Entrepreneur-in-Residence and Program Leader
Hepatic Infectious Disease Pipeline
142
143
Alnylam Development Pipeline
Discovery
Development
Phase 1
Phase 2
Phase 3
GENETIC MEDICINES
Patisiran (ALN-TTR02)
TTR-Mediated Amyloidosis
Revusiran (ALN-TTRsc)
ALN-AT3
Hemophilia and Rare Bleeding Disorders
ALN-CC5
Complement-Mediated Diseases
ALN-AS1
Hepatic Porphyrias
Alpha-1 Antitrypsin Deficiency
ALN-AAT
Beta-Thalassemia/Iron-Overload Disorders
ALN-TMP
Primary Hyperoxaluria Type 1
ALN-GO1
Additional Genetic Medicine Programs
CARDIO-METABOLIC DISEASES
ALN-PCSsc
Hypercholesterolemia
Mixed Hyperlipidemia/Hypertriglyceridemia
ALN-ANG
Hypertriglyceridemia
ALN-AC3
Hypertension/Preeclampsia
ALN-AGT
Additional Cardio-Metabolic Programs
HEPATIC INFECTIOUS DISEASES
Hepatitis B Virus Infection
ALN-HBV
Hepatitis D Virus Infection
ALN-HDV
Chronic Liver Infection
ALN-PDL
Additional Hepatic Infectious Disease Programs
Alnylam Development Pipeline
Discovery
Development
Phase 1
Phase 2
Phase 3
Patisiran (ALN-TTR02)
Revusiran (ALN-TTRsc)
ALN-AT3
ALN-CC5
ALN-AS1
ALN-AAT
ALN-TMP
ALN-GO1
ALN-PCSsc
ALN-ANG
ALN-AC3
ALN-AGT
HEPATIC INFECTIOUS DISEASES
Hepatitis B Virus Infection
ALN-HBV
Hepatitis D Virus Infection
ALN-HDV
Chronic Liver Infection
ALN-PDL
Additional Hepatic Infectious Disease Programs
Alnylam RNAi Therapeutics Strategy
A Reproducible and Modular Path for Innovative Medicines
2. POC achieved in Phase 1
 Blood-based biomarker with
strong disease correlation
GCCCCUGGAGGG
» e.g., Serum TTR, thrombin
generation, hemolytic activity,
LDL-C, HBsAg levels
3. Definable path to approval
and market
1. Liver-expressed target gene
 Involved in disease with high
unmet need
 Validated in human genetics
 GalNAc-siRNA enables SC dosing
with wide therapeutic index




Established endpoints
Focused trial size
Large treatment effect
Collaborative approach with
physicians, regulators,
patient groups, and payers
146
Emerging Profile for RNAi Therapeutics
Hepatic Infectious Disease
Emerging profile for ESC-GalNAc-siRNA conjugates
 Attractive pharmacologic properties
»
»
»
»
Subcutaneous dose administration
High potency with microgram/kg (mcg/kg) doses
Low volume per injection, <1 mL
Durability for monthly (qM) and possibly quarterly (qQ) dose frequency
 Competitive profile with RNAi mechanism
» Block synthesis of disease-causing protein
» Efficacy independent of target protein blood levels
» Clamped knockdown with low inter-individual variability
 Well tolerated and wide therapeutic index
Unique opportunity for hepatic infectious disease
 Pathogen genomics informs selection of highly conserved, pan-genotypic RNAi
therapeutics
 Combination approach feasible
 Infrequent dosing expected to yield improved compliance
 Room temperature stability enables global deployment
 Short R&D timelines enable rapid identification of RNAi therapeutics for emerging
global infectious diseases
147
Hepatic Infectious Diseases
Strategic Considerations
Hepatic
Infectious
Diseases
Primarily involve liver
•
Hepatitis viruses: A, B, C, D, E
Have obligate liver stage
•
Malaria
Major liver involvement in disease
•
Filoviruses (Ebola, Marburg) and other
hemorrhagic viruses
Infection occasionally causes severe
liver disease
•
Herpesviruses: HSV, EBV, CMV
•
Adenoviruses
148
Hepatic Infectious Diseases
Programs and Target Opportunities
Pathogen Targets
RNA viral genomes,
replication intermediates,
viral transcripts
Host Factors
Subverted to support
pathogen lifecycle;
Non essential to
host
Immune
Modulators
Immune evasion
149
Hepatic Infectious Diseases
Programs and Target Opportunities
HBV
HDV
HEV
Others
Pathogen Targets
RNA viral genomes,
replication intermediates,
viral transcripts
Host Factors
Subverted to support
pathogen lifecycle;
Non essential to
host
Immune
Modulators
Immune evasion
150
Hepatitis B Virus (HBV) Infection
Chronic HBV (CHB) infection is significant WW problem
 One third of world population infected
 400M people with chronic disease
» 25M in U.S./EU
 Most unaware of infection
 High prevalence expected for next 3 decades
» Despite availability of HBV vaccine
Clinical manifestations severe
 Chronic inflammation leading to cirrhosis and HCC
Current therapies not curative and have significant limitations
 Reduce viral load, resulting in improved liver histology,
decrease in cirrhosis and HCC but do not eliminate virus
Future therapies aim to enable “functional cure”
 Regain sustained immune control over infection, with
eventual elimination of virus’ cccDNA
http://www.hepb.org/hepb/statistics.htm
151
Novel CHB Therapies Aim to Cure
Goal: Enable Functional Cure
 Achieve state of immunological control of infection
»
HBsAg sero-clearance and sero-conversion
 Prevent progression of disease to cirrhosis, liver failure or HCC
 Clearance of circulating viral DNA, normalization of ALT and histology
Inhibit Viral Lifecycle
Therapeutic Strategies



Reduce circulating virus and inhibit new/re-infection
Entry, nucleocapsid assembly, cccDNA maintenance inhibitors
complement novel reverse transcriptase inhibitors (NUCs)
Silencing of viral transcripts
Reduce Tolerogenic Proteins


HBsAg secretion inhibitors
Knockdown of HBsAg and HBeAg
Break Immune Tolerance



Boost immune response to aid in clearing virus
TLR7 agonist, therapeutic vaccines, immune checkpoint inhibitors
Knockdown of PD-L1
152
HBV Targeting with RNAi Therapeutics
Compact Genome Provides Multiple Opportunities
Genome structure
2
 3.2 kb partially double stranded DNA
genome
 Replication occurs through RNA
intermediate
 4 overlapping viral transcripts encoding
7 viral proteins translated across 3
reading frames
3
1
siRNA targeting
 0.7 kb region which overlaps across 4
transcripts
 1.4 kb region which overlaps across 3
transcripts
4
Depending on location, single siRNA
could silence 1 to 4 transcripts
Kidd-Ljunggren K, J Gen Virol 83:1267–1280 (2002)
153
RNAi Therapeutics for HBV
HBV-Infected Chimpanzees (1/3)
Sequence-specific antiviral response following single dose
Viral titers up to 1010 copies /mL
>2 log10 reduction in circulating viral DNA in highest titer animal
Mean 1.9 log10 decrease in viral DNA day 2- 6 post dose
Control siRNA-LNP confirms specificity
Absolute Titer
Normalized Titer
Control
siRNA-LNP
0.25 mg/kg IV
Δ Viral Load (log10 copies/ml)
(copies/mL plasma)
10 10
10 9
10 8
10 7
HBV
siRNA-LNP
0.25 mg/kg IV
1
Control
siRNA-LNP
0.25 mg/kg IV
0
(relative to day 0)
HBV
siRNA-LNP
0.25 mg/kg IV
10 11
Plasma viral DNA




-1
-2
10 4
10 3
-3
0
20
40
60
Days
80
100
0
20
40
60
80
Days
BLOQ = determinations were below the lower level of quantitation
Meyers, TIDES, May 2014
154
A
C
B
D
100
RNAi Therapeutics for HBV
HBV-Infected Chimpanzees (2/3)
Dose-dependent antiviral response with intra-subject ascending doses
 Mean 2.9 log10 decrease in viral DNA day 2- 6 post 0.5 mg/kg dose
» >4 log10 reduction in circulating viral DNA achieved in highest titer animal
 Mean 2.0 log10 reduction in HBsAg at 0.5 mg/kg dose
» Up to 2.3 log10 reduction achieved
Plasma HBsAg (Surface Antigen)
Plasma Viral Load (bDNA)
siRNA (mg/kg)
siRNA (mg/kg)
0
log10 Δ HBsAg
-1
-2
-3
-4
A
C*
B
D
-5
-20
0
20
40
60
80
100 120 140 160
Days
(relative to average of pre-dose values)
Log10 Δ Viral Load
(relative to average pre-dose)
0.125 0.25 0.50
0.125 0.25 0.50
1
0
-1
-2
-3
-20
0
20
40
60
80
Days
*low titer animal dropped below LLOQ from day 23-day 98
Meyers, TIDES, May 2014
155
A
C
B
D
100 120 140 160
RNAi Therapeutics for HBV
HBV-Infected Chimpanzees (3/3)
Potential evidence for therapeutic flare
 ALT normalized in highest titer chimp
 Possible therapeutic immune flare in 2/4 chimps
» Correlated with small increases in IL6 and IFNg
siRNA (mg/kg)
0.125
600
0.25
0.50
A
C
B
D
High baseline ALT reversed
with siRNA treatment
ALT(U/L)
400
2x ALT increase consistent w/
therapeutic immune flare
200
0
-20
0
20
40
60
80
100
Days
Meyers, TIDES, May 2014
156
ALN-HBV Target Product Profile
Functional Cure of CHB
ALN-HBV
Target Product Profile
Indication
• Chronic hepatitis B (CHB) treatment – enable functional cures
Dose and
Regimen
• <150 mg fixed dose, monthly for 12-24 months alone or in combination
with standard of care
Route of
Administration
• Subcutaneous injection, < 1 mL injection volume, self-administration with
auto-injector device, room temperature stability
Efficacy
• Achieve functional cure as defined by HBsAg sero-clearance and HBsAb
sero-conversion
Safety
• <1% incidence of drug discontinuation
• No black box warning
• Well tolerated, including in combination with immune-modulator therapy
157
GalNAc-Conjugates as Anti-Viral Approach
Clinical Validation
 Regulus RG-101
» GalNAc-anti miR122 in
development for HCV
 Clinical activity
» Single 2 mg/kg SC
dose demonstrated
potent and sustained
viral load reduction
 RG-101 well tolerated
158
ALN-HBV Lead Optimization
Iterative Approach to Fine-Tune siRNA Chemistry
Multiple siRNAs selected targeting 3 and 4 viral transcripts
with high degree of conservation across genotypes (A-H) (>94%)
Enhanced Stabilization Chemistry (ESC)
Superior activity
Template Design
Design of
SAR set
In vitro
metabolic stability
Inferior activity
(GalNAc)3
5′-sense
5′-antisense
siRNA
synthesis
Chemistry
optimization at
each position
AD-65381 IC50 0.0193
In vitro
Potency
Liver/plasma PK
RISC loading
HBV efficacy models
(GalNAc)3
5′-sense
5′-antisense
Exploratory
Rat toxicology
Lead Candidate
Target remaining (% of F7)
120
105
90
75
60
45
30
15
0
-7
1x10
Sepp-Lorenzino, AASLD, Nov. 2014
0.0001
0.1
Concentration(nM)
159
100
ALN-HBV Development Candidate (DC) Selected
Potent ESC-GalNAc-Conjugate for IND in Late ’15
Potent, multi-log HBsAg knockdown of ALN-HBV DC in murine model
»
Up to 3.9 log10 reduction; mean 1.8 log10 reduction 5-10 days after single dose
Specificity confirmed with control siRNA
DC selection achieves 2014 goal; IND filing expected in late ’15
ALN-HBV
1000
Control siRNA
1000
100
100
HBsAg (ng/mL)


Mouse model with AAV-HBV vector
Single SC dose of siRNA at 3 mg/kg
ALN-HBV DC achieves potent knockdown of HBsAg
HBsAg (ng/mL)



10
1
0.1
10
1
0.1
Each line represents individual animal
0.01
0.01
0
Days
5
10
Each line represents individual animal
0
Days
5
10
160
Hepatitis D Virus (HDV) Infection
HDV is highly pathogenic, resulting in
aggressive hepatitis
 RNA subvirus, which can only propagate in
presence of HBV
 15-20M patients infected WW
»
80K patients in U.S.
 Acquired at same time or subsequent to
HBV infection
» >90% of latter patients develop chronic
disease (CHD)
 Chronic HBV/HDV infection more
aggressive than CHB
» 3x greater rates of cirrhosis occurring earlier
(70-80% of cases within 5-10 yr)
» 10x higher mortality rates
No Data
Very Low
High
15-20M patients infected WW
Gish, et al J Gastroenterol Hepatol. (2013); Farci & Niro, Semin
Liver Dis., (2012); Ciancio & Rizzetto, Nature Reviews
Gastroenterology & Hepatology (2014); http://hepatitis-delta.org/
161
RNAi Therapeutics for HDV Treatment
RNAi therapeutics for HDV represent
compelling market opportunity
L-sAg
M-sAg
HBsAg
HBV Gene
Products
HDV RNA
 No curative therapies available
HDV Ag p24 & p27
» PEG-IFN is only available treatment for CHD,
but very low rates of cures
 Novel therapies in development include
Export
NTCP
» Entry inhibitors to prevent re-infection
» Farnesyltransferase inhibitors to inhibit posttranslational modification of HDV viral antigens
 Opportunity for direct antiviral effect with
dual RNAi therapeutic approach
HBsAg
Assembly
L-HDAg
Entry
S-HDAg
RNA Pol I
» ALN-HBV
–
Knockdown of S Ag will inhibit HDV life cycle
» ALN-HDV
–
ADAR
1
Nuclear
Import
gRNA
agRNA
Silencing RNA genome, replication anti-genome
and viral transcripts
162
RNA
Pol II
Hepatitis E Virus (HEV) Infection
Hepatitis E is WW problem

20M infections/yr
»
»

3M acute cases, a subset develop into fulminant hepatitis
57K deaths (~2%); disproportionately high lethality in pregnant
women (~20%)
Oro-fecal transmission makes it prevalent in regions with
poor sanitation
»
Sporadic outbreaks in developed countries increasing
Clinical manifestations can be severe


Acute infection with high risk of chronicity in
immunocompromised patients
66% of HEV-infected organ transplant patients develop
chronic HEV infection (CHE); 10% develop cirrhosis
http://upload.wikimedia.org/wikipedia/commons/thumb/3/33/Hep
atitis_E_virus.jpg/230px-Hepatitis_E_virus.jpg
No treatment options exist beyond supportive care


Vaccine recently approved in China
Ribavirin in clinical testing in organ transplant population
HEV is RNA virus, ideally susceptible to RNAi

HEV genome is polyadenylated single-strand RNA
translated into 6 proteins
Kamar et al Emerging Infect. Dis. (2011)
163
Hepatic Infectious Diseases
Programs and Target Opportunities
HBV
HDV
HEV
Others
Pathogen Targets
Host Factors
RNA viral genomes,
replication intermediates,
viral transcripts
Subverted to support
pathogen lifecycle;
Non essential to
host
Immune
Modulators
Immune evasion
PD-L1
164
Liver-Restricted Immune Reactivation
ALN-PDL
 Obligate liver pathogens exploit tolerant
liver environment
» Enhance immune suppression via multiple
mechanisms
 Activation of PD1/PD-L1 immune
checkpoint associated with establishment
and maintenance of chronic infections,
including HBV
 RNAi knockdown of liver PD-L1 would
enhance NK and T-cell activity against
infected hepatocytes
» Without risk of broad systemic tolerance
suppression
 Alnylam POC studies conducted in
mouse model of adenoviral infection
» Demonstrated that PD-L1 knockdown
associated with increased viral clearance
165
Hepatic Infectious Disease STAr
Summary (1/2)
Significant opportunity for RNAi therapeutics as
transformative medicines in hepatic infectious diseases
 Major global health problems with significant disease burden
 Many hepatocyte-specific pathogens and/or pathogens with major liver
disease pathology
 Reproducible and modular RNAi therapeutic platform as approach for
emerging pathogens
» Potential for expedited timelines
 Emerging profile for ESC-GalNAc-siRNA highly attractive
»
»
»
»
Potent and durable, with very wide therapeutic index
Durability supports qM to qQ subcutaneous dose regimens
Room temperature stability for global needs
Potential to achieve multi-targeting for broad coverage and resistance
166
Hepatic Infectious Disease STAr
Summary (2/2)
Alnylam Hepatic Infectious Disease STAr advancing key programs
 Established human POC with RNA therapeutics
» Regulus RG-101 in HCV employing Alnylam GalNAc-conjugate platform
 ALN-HBV DC selected and on track for IND in late ’15
» Best-in-class potential with subcutaneous, qM profile and wide therapeutic index
 Additional programs in development for HDV infection and chronic liver infections
via liver-specific PD-L1 blockade
» Multi-pronged strategy for HBV and other hepatic infectious diseases
 Many additional pipeline programs
» Expect 3-4 INDs over next 5-6 years
Represents new opportunities for partnership
 Alnylam to retain meaningful product rights in core markets
 Leverage partner for expanded effort and geographic scope
167
Barry Greene
President and Chief Operating Officer
Looking Ahead
168
Alnylam RNAi Therapeutics Strategy
A Reproducible and Modular Path for Innovative Medicines
2. POC achieved in Phase 1
 Blood-based biomarker with
strong disease correlation
GCCCCUGGAGGG
» e.g., Serum TTR, thrombin
generation, hemolytic activity,
LDL-C, HBsAg levels
3. Definable path to approval
and market
1. Liver-expressed target gene
 Involved in disease with high
unmet need
 Validated in human genetics
 GalNAc-siRNA enables SC dosing
with wide therapeutic index




Established endpoints
Focused trial size
Large treatment effect
Collaborative approach with
physicians, regulators,
patient groups, and payers
169
Alnylam Strategic Therapeutic Areas (STAr)
Genetic Medicines
 Genetically validated
liver targets for rare
orphan diseases
 High unmet needs in
focused markets
 SC dosing
 Alnylam direct commercial
in NA and EU
 Genzyme alliance for
ROW commercial
»
Through end-2019
Cardio-Metabolic Disease
 Genetically validated liver
targets for dyslipidemia,
NASH, type 2 diabetes,
and hypertension
 Development path in
morbid subpopulations
 Access to larger
populations thereafter
 Emerging genetics
 qM or qQ SC dosing
 Partnership opportunities
Hepatic Infectious Disease
 Liver pathogen and/or
host targets
 Sub-acute duration of
treatment (~12 mo)
 Multiple siRNAs possible,
if needed
 Defined opportunities with
very large markets
 qM or qQ SC dosing
 Partnership opportunities
17
0
Alnylam Development Pipeline
Discovery
Development
Phase 1
Phase 2
Phase 3
GENETIC MEDICINES
Patisiran (ALN-TTR02)
TTR-Mediated Amyloidosis
Revusiran (ALN-TTRsc)
ALN-AT3
Hemophilia and Rare Bleeding Disorders
ALN-CC5
Complement-Mediated Diseases
ALN-AS1
Hepatic Porphyrias
Alpha-1 Antitrypsin Deficiency
ALN-AAT
Beta-Thalassemia/Iron-Overload Disorders
ALN-TMP
Primary Hyperoxaluria Type 1
ALN-GO1
Additional Genetic Medicine Programs
CARDIO-METABOLIC DISEASES
ALN-PCSsc
Hypercholesterolemia
Mixed Hyperlipidemia/Hypertriglyceridemia
ALN-ANG
Hypertriglyceridemia
ALN-AC3
Hypertension/Preeclampsia
ALN-AGT
Additional Cardio-Metabolic Programs
HEPATIC INFECTIOUS DISEASES
Hepatitis B Virus Infection
ALN-HBV
Hepatitis D Virus Infection
ALN-HDV
Chronic Liver Infection
ALN-PDL
Additional Hepatic Infectious Disease Programs
Multi-Year Pipeline Progression
D
Clinical Data Expected
PATISIRAN
Phase 2 OLE
(ALN-TTR02) TTR-FAP
APOLLO Phase 3
REVUSIRAN
Phase 2 OLE
(ALN-TTRsc) TTR-FAC
ENDEAVOUR Phase 3
Phase 1
ALN-AT3
(Hemophilia and RBDs)
2015
2016
D
D
Subsequent 1-2 Years
D
D
D
D
D
D
D
D
Phase 2
D
Phase 3
Phase 1/2
ALN-CC5
(Complement Disease)
D
D
D
Phase 2
D
Phase 3
ALN-AS1
Phase 1
(Hepatic Porphyrias)
Phase 2/3
D
D
D
Phase 1
ALN-AAT
(Alpha-1 Antitrypsin Deficiency)
D
Phase 2
Phase 3
ALN-GO1
Phase 1
(Primary Hyperoxaluria)
Phase 2/3
Phase 1
ALN-PCSsc
(Hypercholesterolemia)
Phase 2
D
D
D
D
Phase 3
ALN-HBV
Phase 1
(Hepatitis B Virus Infection)
Phase 2
Additional Programs
Research
Additional Phase 1 and 2 Studies
D
Alnylam 2014-2015 Pipeline Goals
2015
Late ‘14
PATISIRAN
APOLLO Phase 3 Accrual
(ALN-TTR02) TTR-FAP
Phase 2 OLE data
ENDEAVOUR Phase 3 Start
REVUSIRAN
(ALN-TTRsc) TTR-FAC
ENDEAVOUR Phase 3 Accrual
Phase 2 OLE Data
ALN-AT3
Phase 1 Data
(Hemophilia and RBDs)
Start Phase 2
CTA Filing
ALN-CC5
(Complement Disease)
Start Phase 1/2
Initial Phase 1/2 Data
ALN-AS1
CTA Filing
(Hepatic Porphyrias)
Start Phase 1
ALN-AAT
(Alpha-1 Antitrypsin Deficiency)
ALN-GO1
(Primary Hyperoxaluria)
IND Filing
Development Candidate
ALN-PCSsc
Start Phase 1
(Hypercholesterolemia)
Initial Phase 1 Data
ALN-HBV
(Hepatitis B Virus Infection)
IND Filing
* Early is Q1-Q2, Mid is Q2-Q3, and Late is Q3-Q4; **IND or IND equivalent
Early
Mid
Late
Ongoing
Hepatic Infectious Disease STAr
Q&A
174
Thank You
www.alnylam.com