54
December 12, 2014 Alnylam Pharmaceuticals R&D Day
December 12, 2014
Alnylam Pharmaceuticals
R&D Day
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 forward-
looking 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
David Meeker, M.D. President and Chief Executive Officer
Genzyme, a Sanofi Company
3
| www.genzyme.com
Dione (with her mother) Pompe disease Brazil
1980 1990 2000 2010
Milestones in Genzyme History
1981 Genzyme founded
1983 Henri Termeer joins Genzyme
1986 Genzyme IPO
1991 Genzyme’s first product
approved for type 1 Gaucher
disease
1994 Second-generation enzyme
replacement therapy approved
for type 1 Gaucher disease
1996 Manufacturing plant opens in
Allston, MA
1998 Therapy approved to facilitate
thyroid cancer treatment and
testing
2003 Therapies approved for Fabry
disease and MPS-I disease
2004 New global headquarters opens
in Cambridge, MA
2006 Therapy approved for Pompe
disease
2008 Science Center opens in
Framingham, MA
2011 Genzyme becomes
a Sanofi company
2011 David Meeker appointed CEO
2012 Manufacturing plant opens in
Framingham, MA
2012 Oral therapy approved for MS
2013 Therapy approved for HoFH
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
Genetic Disease
Gaucher disease type 1 (2 treatments),
Fabry disease, Pompe disease,
MPS I disease
Endocrinology
Facilitating thyroid cancer treatment
and testing
Cardiovascular
Homozygous Familial
Hypercholesterolemia (HoFH)
Mikhail
Gaucher
disease
Joan
Thyroid
Cancer
LATE STAGE PIPELINE Patisiran (with Alnylam) familial amyloid polyneuropathy Phase 3 Revusiran (with Alnylam) familial amyloidotic cardiomyopathy Phase 3
Shani
MS
Tiger
MS
Once-daily oral therapy for relapsing
remitting MS
Infusion therapy for relapsing
remitting MS – 2 annual treatment
courses
Acid sphingomyelinase Niemann Pick disease type B Phase 2
About Sanofi
• Global healthcare leader
• Diversified offering of medicines, consumer healthcare products, vaccines,
generics, and animal health
• Major biopharmacy player: 45% of revenues generated by biologics, 80%
of projects in development are biologics
• 112 industrial sites in 41 countries
• More than 110,000 employees in 100 countries
• 2013 sales: ~ €33 billion
“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 1991 2001 2011
A Lifetime Commitment
Brian Gaucher disease type 1
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
Sol
Pompe
disease
Ayama
(with his mother)
Pompe disease
Critical Elements
VALUE
PARTNERSHIP
COMMITMENT
• 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
Myths
Transformational expanded collaboration
on Rare Genetic Diseases
Genetic Medicine Pipeline Highlights
Akshay Vaishnaw, M.D., Ph.D.
Executive Vice President and Chief Medical Officer
15
16
Discovery Development Phase 1 Phase 2 Phase 3
GENETIC MEDICINES
TTR-Mediated Amyloidosis
Hemophilia and Rare Bleeding Disorders
Complement-Mediated Diseases
Hepatic Porphyrias
Alpha-1 Antitrypsin Deficiency
Beta-Thalassemia/Iron-Overload Disorders
Primary Hyperoxaluria Type 1
Additional Genetic Medicine Programs
CARDIO-METABOLIC DISEASES
Hypercholesterolemia
Mixed Hyperlipidemia/Hypertriglyceridemia
Hypertriglyceridemia
Hypertension/Preeclampsia
Additional Cardio-Metabolic Programs
HEPATIC INFECTIOUS DISEASES
Hepatitis B Virus Infection
Hepatitis D Virus Infection
Chronic Liver Infection
Additional Hepatic Infectious Disease Programs
Alnylam Development Pipeline
ALN-AT3
ALN-CC5
ALN-AS1
ALN-AAT
ALN-HBV
ALN-TMP
ALN-AGT
ALN-GO1
ALN-PCSsc
ALN-HDV
ALN-PDL
Patisiran (ALN-TTR02)
Revusiran (ALN-TTRsc)
ALN-ANG
ALN-AC3
Discovery Development Phase 1 Phase 2 Phase 3
GENETIC MEDICINES
TTR-Mediated Amyloidosis
Hemophilia and Rare Bleeding Disorders
Complement-Mediated Diseases
Hepatic Porphyrias
Alpha-1 Antitrypsin Deficiency
Beta-Thalassemia/Iron-Overload Disorders
Primary Hyperoxaluria Type 1
Additional Genetic Medicine Programs
Alnylam Development Pipeline
ALN-AT3
ALN-CC5
ALN-AS1
ALN-AAT
ALN-HBV
ALN-TMP
ALN-AGT
ALN-GO1
ALN-PCSsc
ALN-HDV
ALN-PDL
Patisiran (ALN-TTR02)
Revusiran (ALN-TTRsc)
ALN-ANG
ALN-AC3
19
Transthyretin-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; 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
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
20
Patisiran Open-Label Extension (OLE) Study
21
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
22
Patisiran Phase 2 OLE Preliminary Study Results Change in mNIS+7 at 6 Months (N=19)
Change from Baseline to Month 6
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
mN
IS+
7 (
po
ints
)
0
25
50
75
100
125
Months on treatment
0 6 1 2 3 4 5
Each line represents individual patient
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%)
Natural History Tafamidis Fx1A-201 Diflunisal Phase 3
Mean (SEM)
D mNIS+7 at 6 mos.
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
Historical Data Sets
Adams, ANA Oct. 2014
Phase 3 Trial of Patisiran in FAP Study Ongoing
23
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)
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
Revusiran (ALN-TTRsc) Familial Amyloidotic Cardiomyopathy (FAC)
24
GalNAc-siRNA Conjugates Subcutaneous RNAi Therapeutics
ASGPR
(pH>5)
GalNAc-siRNA
conjugate
Clathrin-coated pit
Clathrin-coated
vesicle
Endosome
Recycling
ASGPR
mRNA
Nucleus
protein
RISC
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
GalNAc3
25
GalNAc-siRNA Conjugates Wide Therapeutic Index from Non-Clinical GLP Studies
26
NOAEL1 4 or 7
weeks (mg/kg)
NOAEL 13 weeks
(mg/kg)
NOAEL 6 mos
Rat (mg/kg)
NOAEL 9 mos
NHP (mg/kg)
Expected Human
Therapeutic
Index (TI)2
Rat NHP Rat NHP
Revusiran3 30 ≥300 N/A N/A 30 ≥200 >80
ALN-AT33,4 1 0.3 N/A N/A Ongoing Ongoing >10
ALN-PCSsc ≥250 ≥250 Ongoing Ongoing Planned Planned >500
ALN-CC5 ≥50 ≥100 Ongoing Ongoing Planned Planned >200
ALN-AS1 N/A N/A ≥30 ≥150 Planned Planned >500
1No Adverse Event Level (NOAEL) 2TI calculated as NOAEL in NHP/Expected dose in man 37 week studies 4NOAEL in hemophilia mice >100 mg/kg, qW x 7
Revusiran Phase 1 Study Results
27
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
Zimmermann, HFSA, Sep. 2013; Manoharan, TIDES, May 2014
100
80
60
40
20
0
-20
Days Revusiran (mg/kg), qd x5; qw x5
% M
ean
TT
R K
no
ckd
ow
n
Rela
tive t
o B
aselin
e (
± S
EM
)
2.5 (n=3) 5.0 (n=3)
10.0 (n=3)
Placebo (n=3)
Revusiran
dose groups
Days %
Me
an
TT
R K
no
ckd
ow
n
Rela
tive t
o B
aselin
e
100
80
60
40
20
0
0 10 20 30 40 50 60
Human
NHP
Revusiran Single 10.0 mg/kg
Injection
Preliminary Revusiran Phase 2 Study Results*
28
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
* Results as of October 3, 2014; Maurer, AHA, November 2014
Me
an
(S
EM
) %
Se
rum
TT
R K
no
ckd
ow
n
( R
el.
to
Ba
se
lin
e)
Days since first visit
100
80
60
40
20
0
0.0
0.1
0.2
0.3
0.4
0.6
0.7
0.8
0.9
1.0
Revusiran Dose Group
0 10 20 30 40 50 60 70 80 90 100
5.0 mg/kg 7.5 mg/kg
Revusiran (mg/kg), qd x5; qw x5
N=22
N=19
N=18
N=15
N=3
Treatment 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
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
29
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
Revusiran Open-Label Extension (OLE) Study
30
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
Phase 3 Trial of Revusiran in FAC Study Initiated
31
Randomized, double-blind, placebo-controlled, global study 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
Secondary Endpoints Composite CV mortality and CV hospitalization, change NYHA class, change in Kansas City
Cardiomyopathy Questionnaire (KCCQ)
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
Hemophilia and Rare Bleeding Disorders Program Unmet Need and Product Opportunity
32
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)
AT
FIX
FVIII
Antithrombin and ALN-AT3 Program
33
Antithrombin (AT) is genetically defined
target AT is key natural anticoagulant
» Inactivates factors Xa and thrombin
» Attenuates thrombin generation
Human AT deficiency associated
with increased thrombin generation
Expressed in liver; circulates in plasma
Co-inheritance of thrombophilic traits in hemophilia Associated with milder bleeding, reduced factor
requirements, fewer complications
Includes heterozygous
» Antithrombin deficiency
» Factor VLeiden
» Protein C deficiency
» Protein S deficiency
Kurnik et al., Haematologica; 92:982-5 (2007); Ettingshausen et al., Thromb Haemost; 85:218-20
(2001); Negrier et al., Blood; 81:690-5 (1993); Shetty et al., Br J Haematol; 138:541-4 (2007)
FIXa
FVIIa FVII
FVIIIa
FVa FV
FX
FXa
Fibrinogen Fibrin
Thrombin Prothrombin
Blood clot
Intrinsic system Extrinsic system
Hemophilia B
Hemophilia A
FVIII
FIX
AT
ALN-AT3 in clinical development ESC-GalNAc-siRNA for SC dosing
Positive initial Phase 1 results
Orphan drug status in U.S./EU (HA/HB)
Phase 1 MAD study in patients ongoing
Genetic Validation for ALN-AT3 Co-Inheritance of Type 3 VWD and AT Deficiency
34
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
Fischer, WFH, May 2014
Severe
Bleeding
Type 3 VWD
AT Levels at
57% Normal
Mild
Bleeding
Sib
1
Sib
2
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
Akinc, ISTH, July 2013
Recovery
Recovery 0.25 mg/kg qw x 12
Recovery 1.5 mg/kg qw x 5
100
80
60
40
20
0
-20 0 20 40 60 80 100 120 140 160
% M
ea
n A
T K
no
ck
do
wn
(P
re-d
ose
= 1
)
Day
1 mg/kg q2w x 4
0.125 mg/kg qw x 12 0.5 mg/kg qw x 8
Normal Hemophilia A (Induced)
Pre-dose
ALN-AT3 (mg/kg) qw
Rela
tive
Th
rom
bin
Ge
nera
tio
n†
(Pe
ak T
hro
mb
in)
0.0
0.2
0.4
0.6
0.8
1.0
1.2
Saline
1.6
0.25
~60%
AT
KD
0.5
p<0.01
~80%
AT
KD
†similar results obtained by ETP (p<0.01 at 0.50 mg/kg)
35
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
Akinc, ISTH, July 2013
Recovery
Recovery 0.25 mg/kg qw x 12
Recovery 1.5 mg/kg qw x 5
100
80
60
40
20
0
-20 0 20 40 60 80 100 120 140 160
% M
ea
n A
T K
no
ck
do
wn
(P
re-d
ose
= 1
)
Day
1 mg/kg q2w x 4
0.125 mg/kg qw x 12 0.5 mg/kg qw x 8
Normal Hemophilia A (Induced)
Pre-dose
ALN-AT3 (mg/kg) qw
Rela
tive
Th
rom
bin
Ge
nera
tio
n†
(Pe
ak T
hro
mb
in)
0.0
0.2
0.4
0.6
0.8
1.0
1.2
Saline
1.6
0.25
~60%
AT
KD
0.5
p<0.01
~80%
AT
KD
†similar results obtained by ETP (p<0.01 at 0.50 mg/kg)
36
ALN-AT3 Survival Benefit in Hemophilia A Mice Results from GLP Chronic Toxicology Study
37
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
Interim results through week 25 » 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)
Survival of HA Mice
Days
0 50 100 150 200
0
50
100
% S
urv
iva
l
Saline
10 mg/kg ALN-AT3
30 mg/kg ALN-AT3
Treatment Groups
Akinc ASH, Dec. 2014
ALN-AT3 Phase 1 Study Dose-Escalation Study in Two Parts
38
Primary objectives Safety, tolerability
Secondary objectives AT knockdown, thrombin generation
30 mcg/kg x 1 SC
45 mcg/kg qW x 3 SC
15 mcg/kg qW x 3 SC G
Part A
Single-
Ascending
Dose (SAD)
Part B
Multiple-
Ascending
Dose (MAD)
TBD mcg/kg qW x 3 SC
Randomized 3:1, N=4
Single-blind
Placebo-controlled
Healthy volunteers
Open-label
Hemophilia A or B
N=3/cohort
Ongoing
Up to 4 additional
cohorts
f
ALN-AT3 Phase 1 Study Part A (SAD)* Pharmacodynamics and Clinical Activity
39
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
Days
40
30
20
10
0
-10
-20
ALN-AT3
30 mcg/kg
Placebo
0 10 20 30 40 50 60 70 80
Me
an
% A
T K
no
ck
do
wn
Treatment Group
*Cohort 1 data as of Nov. 24, 2014; cohort 2 data as of Dec. 5, 2014
Sorensen ASH, Dec. 2014
ALN-AT3 Phase 1 Study Part A (SAD)* Pharmacodynamics and Clinical Activity
40
-100
0
100
200
%In
cre
as
e P
ea
k T
hro
mb
in G
en
era
tio
n
% AT Knockdown
-20 -10 0 10 20 30 40
150
50
-50
(r= 0.44, p=0.004)
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) » Consistent with increased sensitivity for thrombin generation increase with AT knockdown
in background of normal levels of Factor VIII or IX
*Cohort 1 data as of Nov. 24, 2014; cohort 2 data as of Dec. 5, 2014
Sorensen ASH, Dec. 2014
ALN-AT3 Phase 1 Study Part B (MAD)* Cohort 1 and 2 Interim Pharmacodynamics and Clinical Activity
41
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
Cohort 2 (n=1) results » AT knockdown in first subject up to 57%; data from local lab reporting
» Thrombin generation results pending cohort completion
*Cohort 1 data as of Nov. 24, 2014; cohort 2 data as of Dec. 5, 2014
Sorensen ASH, Dec. 2014
Days 0 5 10 15 20 25 30
60
40
20
0
-20
80
% A
T M
ea
n K
no
ck
do
wn
ALN-AT3 Treatment Group
15mcg/kg 45mcg/kg
ALN-AT3 Phase 1 Study* Safety/Tolerability; All TEAEs
42
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)
Adverse event
Cohort 1
N=4 Relationship to Study Drug
Atypical chest pain 1 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
Cohort 1
N=3
Cohort 2
N=1
Relationship to
Study Drug
Muscle Bleed 2 0 Not related
Venipuncture bleed 2 0 Not related
Idiopathic abdominal pain 1 0 Not related
Joint Bleed 1 0 Not related
Myalgia 1 0 Possibly related
Nose Bleed 1 0 Not related
Oral mucosal bleed 0 1 Not related
Part A (SAD), Healthy Adult Volunteers
Part B (MAD), Hemophilia Subjects
*Cohort 1 data as of Nov. 24, 2014; cohort 2 data as of Dec. 5, 2014
Sorensen ASH, Dec. 2014
Phase 1 Phase 2 Phase 3
Clinical Development Plan ALN-AT3 for the Treatment of Hemophilia and RBD
43
On-demand
(Non-Inhibitor)
Pediatric (< 12 y.o.)
± Inhibitor
Inhibitor
Prophylaxis
(Non-Inhibitor)
RBDs
Hemophilia A/B
± Inhibitor
Adult Healthy Volunteers
and Hemophilia A/B
Broad-based development plan to maximize product opportunity
Key Objectives
• Safety, PK, clinical activity (AT
knockdown, thrombin generation)
• Initial dose finding
Key Objectives
• Safety, PK, clinical activity (AT
knockdown, thrombin generation,
bleeding frequency)
• Extended dosing (3-6 mo)
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
44
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 » Susceptibility to increased Neisserial
infections
» Many C5 deficient mouse strains
Majority expressed in liver; circulates in
plasma
Complement C5 is clinically validated target Eculizumab is anti-C5 Mab
Approved in PNH and aHUS » In PNH, >80% inhibition of hemolytic activity
associated with clinical benefit1
Potential advantages of synthesis inhibition
vs. protein binding approach
45
Initiation
C3 Convertase
C5 Convertase
Terminal Pathway
Factor B
Alternative Pathway Classical Pathway Lectin Pathway
C3 C1
C3 C4 and C2
C3b
C3bBb C4bC2a
C3a Opsonization
Inflammation C3bBbC3b C4bC2aC3b
C5 C5a
C5b
Membrane attack complex (MAC)
C5b-C9
ALN-CC5
1Hillmen et al., NEJM; 350:552-9 (2004)
Hemolysis Inhibition and Clinical Efficacy
46
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
Hill et al., Blood;106:2559-2565 (2005) Cugno et al., J Thromb Haemost; 10.1111/jth.12615 (2014)
Se
rum
C5 a
ctivity (
%,
sR
BC
he
mo
lysis
assa
y)
Weeks following last eculizumab infusion
Se
rum
C5 a
ctivity (
%,
cR
BC
he
mo
lysis
assa
y)
Dosing: 900 mg every 14 days
(subjects 1 & 2 required shorter interval of 12 days) Dosing: 800 - 2000 mg
PNH aHUS
Incomplete effects
of eculizumab
Loss of activity between
eculizumab doses
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%
47 Borodovsky, ASH, Dec. 2014
Serum C5
q2W and qM Regimens
2xW Regimen Days
0 20 40 60 80 100 120 140 160 180 200 220
-20
0
20
40
60
80
100
2xw q2w qm
%C
5 K
no
ckd
ow
n
(No
rmalized
to
Pre
-ble
ed
)
Days
Complement Activity (q2W)
%A
cti
vit
y o
r h
em
oly
sis
red
ucti
on
0 20 40 60 80 100 120 140 160 180 200 220
0
20
40
60
80
100
CAP
Hemolysis
q2W Regimen
ALN-CC5 Phase 1/2 Study Dose-Escalation Study Including Patients with PNH
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
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
48
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
Status ESC-GalNAc-siRNA for SC dosing
CTA filed; initiate Phase 1 early ’15
Initial data expected mid ’15
Part
A Part
B Part
C
Phase 1/2 Phase 2 Phase 3
Clinical Development Plan ALN-CC5 for the Treatment of Complement-Mediated Diseases
49
aHUS
Pediatric (< 12 y.o.)
PNH
MG
NMO
OLE PNH
Patients
Adult Healthy Volunteers
and PNH patients
Broad-based development plan to maximize product opportunity
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
MN
Other Complement Mediated
Diseases
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
50
ALN-AS1 in R2D ESC-GalNAc-siRNA for SC dosing
Proof of concept and efficacy in animal models
DC selected
CTA filing late ’14
Additional Genetic Medicine Programs
51
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
Large number of opportunities based on scientific, clinical, and market insights
Genetic Medicine STAr Next Wave Target Assessment
52
Target ID - Liver-expressed protein
“Next Wave” Triage
100’s Targets
Discarded Targets
Target Validation • In vitro and in vivo data generation
• Animal model / collaboration
• KOL panel
• Additional commercial assessment
10’s Targets
External Validation
• Scientific, clinical,
and regulatory review
• KOL Interactions
Primary prescriber unmet
need assessment
(if necessary)
Scientific Review
Commercial Review
Internal Validation
• Literature review
• Genetic medicine criteria
• Preliminary prioritization Deprioritized Targets
Genetic Medicine STAr Summary (1/2)
53
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
Genetic Medicine STAr Summary (2/2)
54
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
