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CARDIO-METABOLIC
DISEASE
ALN-PCSsc, an Investigational
RNAi Therapeutic for the Treatment
of Hypercholesterolemia
September 16, 2015
1
© 2015 Alnylam Pharmaceuticals, Inc.
Agenda
Welcome
• Joshua Brodsky
Senior Manager, Investor Relations and Corporate Communications
Introduction
• Barry Greene
President and Chief Operating Officer
Overview of Hypercholesterolemia
• Marc S. Sabatine, M.D., M.P.H., Chairman, Thrombolysis in Myocardial Infarction (TIMI) Study Group at
Brigham and Women’s Hospital, Lewis Dexter, MD Distinguished Chair in Cardiovascular Medicine, and
Professor of Medicine, Harvard Medical School
Q&A Session
•
With Dr. Sabatine
ALN-PCSsc Program
• Kevin Fitzgerald, Ph.D.,
Vice President, Research
• David Kallend, MBBS,
Vice President and Global Medical Director, The Medicines Company
Q&A Session
2
Reminders
• Event will run for approximately 60 minutes
• Q&A Session at end of each presentation
◦ Submit questions at bottom of webcast screen
◦ Questions may be submitted at any time
• Replay, slides and audio available at www.alnylam.com
3
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.
4
Agenda
Welcome
• Joshua Brodsky
Introduction
• Barry Greene
Q&A Session
•
With Dr. Sabatine
ALN-PCSsc Program
Q&A Session
5
Alnylam RNAi Therapeutics Strategy
A Reproducible and Modular Path for Innovative Medicines
2. POC achieved in Phase 1
GCCCCUGGAGGG
 Blood-based biomarker with strong
disease correlation
◦ 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
6




Established endpoints
Focused trial size
Large treatment effect
Collaborative approach with
physicians, regulators,
patient groups, and payers
7
7
8
8
CARDIO-METABOLIC
DISEASE
A Vision for Innovation in ACVD
Anticipated Product Profile
Statins
PCSK9
MAb
ALN-PCSsc
Efficacy



Safety



Adherence



Dx – Rx cycle fit



Patient satisfaction






Value opportunity
Projected
9
9
Supported
A Vision for Innovation in ACVD
Potential to Revolutionize the Dx-Rx Cycle
• Quarterly or potentially biannual dosing of ALN-PCSsc
would uniquely align monitoring
and treatment cycle
• 3-6 monthly cholesterol check
• 3-6 monthly sc injection
• Oversight by physician with
treatment monitored, or given
by physician or retail pharmacy
24/7
• Adherence, patient satisfaction
and value improvement
potential
10
10
CARDIO-METABOLIC
DISEASE
Agenda
Welcome
• Joshua Brodsky
Introduction
• Barry Greene
Q&A Session
•
With Dr. Sabatine
ALN-PCSsc Program
Q&A Session
11
Effect of Absolute Reduction in LDL-C on
Relative Risk Reduction in CV Events
Reduction in Cardiovascular Events (%)
50
More LDL lowering and risk reduction
Ezetimibe
40
Fibrate
30
Bile acid resin
Niacin
20
Diet/unsat. Fatty acid
Ileal bypass
10
CTTC trials (statin)
IMPROVE-IT
0
10
20
30
40
50
60
70
80
Reduction in LDL-C (mg/dL)
-10
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
12
Lower Risk of Cardiovascular Events via
Multiple Genetic Variants Affecting LDL-C
9 polymorphisms from 6 different genes
affecting LDL-C levels in 312,321 subjects
Proportional Risk Reduction (SE)
30%
PCSK9
rs11591147
20%
APOE
CHD risk reduction per 1 mmol/L
(38.7 mg/dL) lower LDL-C:
rs4420638
SORT1
LDLR
rs646776
rs6511720
LDLR
10%
SORT1
rs2228671
HMGCR
rs12916
54.5% (95% CI: 48.8-59.5%)
rs599839
PCSK9
rs11206510
ABCG5/8
rs12916
0%
0
2
4
6
8
10
12
Lower LDL-C (mg/dL)
14
16
18
13
Ference BA et al. JACC 2012;60:2631–9
Impact of PCSK9 Loss of
Function Mutation on Risk of MI
Lifelong Impact of 16% Lower LDL translates into 60% Lower Risk
Site
Study
OR for MI
95% CI
p-value
Finland
FINRISK
0.30
(0.11, 0.84)
0.02
Sweden
Malmo Diet and Cancer Study
CV cohorts
0.32
(0.07, 1.61)
0.17
Spain
Registre Gironi del Cor
(REGICOR)
0.35
(0.15, 0.82)
0.02
Seattle
Heart Attack Risk in
Puget Sound
0.45
(0.21, 0.98)
0.049
Boston
MGH Premature CAD Study
0.59
(0.21, 1.69)
0.46
0.40
(0.26, 0.61)
0.0002
Combined analysis
0.01
0.1
1
Favors LOF
10
Favors Control
14
N Engl J Med. 2008;358:2299-2300
LDL Cholesterol & Coronary Events
CHD Events at 5 years (%)
30
4S
pbo
25
PROVE-IT TIMI 22
P40
PROVE-IT TIMI 22
A80
20
4S
S40
15
CARE
HPS P40
S40
10
TNT
A80
5
JUPITER
R20
TNT
A10
LIPID
P40
HPS
pbo
CARE LIPID
pbo
pbo
JUPITER
pbo
0
0
20
40
60
80
100
120
140
160
180
200
LDL Cholesterol (mg/dL)
15
Meta-analysis Supporting Benefit of
Lowering LDL-C, Even When Starting “Low”
>160,000 pts
Baseline LDL-C
CTT Cycle #2
Lancet 2010;
376:1670-81
Benefit similar
even if starting with
LDL-C <77 mg/dL
16
Risk Reduction in JUPITER by Baseline LDL-C
Baseline
HR (95% CI) for Primary Endpoint
Overall in trial, rosuvastatin
reduced LDL-C by 50%,
suggesting achieved LDL-C of
≤30 mg/dL in this subgroup
17
Hsia J et al. JACC 2011; 57:1666-75
Hazard Ratios for the Primary Endpoint
by Quartiles of LDL-C at Admission
Quartiles
(based on LDL-c
at admission)
Median LDL-c
at 4 mos (mg/dL)
Primary
Endpoint
EZ/S
(%)
Simvastatin
(%)
HR
EZ/S
Simvastatin
1
45
63
38.0
39.0
0.95
2
49
69
34.0
37.1
0.91
3
50
69
32.0
33.0
0.95
4
53
72
27.1
29.4
0.93
Overall
49
68
32.7
34.7
0.936
1.0
1.25
HR
Favors
Ezetimibe+Simvastatin
Favors
Simvastatin
0.8
Pint= 0.77
18
RP Giugliano et al. ACC 2015
Who Are The Patients Whose Needs are
Not Being Met by Current Therapies?
• Patients whose LDL-C cannot be controlled
with intensive statin ± other current therapies
– High-risk patients in whom we cannot get the LDL-C
low enough
– Most patients with heterozygous familial hyperchol.
(prevalence 1 in 200-500)
– Almost all patients with homozygous FH
• Patients who cannot take a statin, or an
effective dose
– Statin intolerance or statins are not clinically
appropriate (eg, drug-drug interactions)
19
LDL-C Control in
High-Risk Patients
• 18 million Americans are high-risk (NCEP) and
on lipid-modifying therapy
– ~½ have diabetes only
– ~½ have overt vascular disease
100%
80%
25%
Achieved LDL-C
60%
47%
40%
20%
0%
≥100
70-99
<70
28%
20
Jones PH et al. JAHA 2012;1:e001800
Even in Clinical Studies Using High Intensity
Therapy, Many Do Not Reach Goal
Percent of Subjects with LDL-C ≥70 mg/dL
Simvastatin + 10 mg Ezetimibe
100
Percentage of Patients
90
80
Atorvastatin + Placebo
94
83
80
70
77
64
61
60
50
43
36
40
30
20
10
0
n/N=
10 mg
20 mg
40 mg
80 mg
226/231
232/228
234/228
223/230
Statin Dose
21
Ballantyne CM, et al. Am Heart J 2005;149:464-73.
Long-term compliance with
medications, including statins, is poor
22
Am J Med. 2009;122(: 961.e7
Primary Endpoint:
AMG 145 Reduced LDL-C at 12 wks
LDL-C measured
using
ultracentrifugation
% Change LDL-C vs Placebo (SE) at Week 12
0
AMG 145 Q2W
70 mg
N = 79
105 mg
N = 79
AMG 145 Q4W
140 mg
N = 78
280 mg
N = 79
350 mg
N = 79
420 mg
N = 80
-10
-20
* p < 0.0001 for each dose vs placebo
-30
-40
-50
-41.8
-41.8
-50.0
-60
-70
-50.3
-60.2
-66.1
-80
LDL-C at 12 wks
Mean (mg/dL) 73
(SD)
(25)
53
44
69
60
58
(21)
(25)
(28)
(23)
(26)
23
Giugliano RP et al. and Sabatine MS. Lancet 2012:380 (online first).
AMG 145 Q2W Dose Response:
% Change in LDL-C Through 12 Wks
Mean % Change from Baseline in
Calculated LDL-C
10
0
–10
–20
p < 0.0001 for weeks 2-12 for each dose vs placebo
–30
–40
–50
–60
–70
number of
patients
78
79
79
78
74
78
76
77
77
77
76
76
78
75
77
77
Baseline
Week 2
Week 4
Week 6
–80
–90
–100
Study Drug
Administration
LDL-C calculated
using Friedewald
Placebo Q2W (n = 78)
AMG145 105 mg Q2W (n = 79)
76
76
73
75
Week 8
77
76
77
76
74
76
74
73
Week 10
Week 12
AMG145 70 mg Q2W (n = 79)
AMG145 140 mg Q2W (n = 78)
24
AMG 145 Q4W Dose Response:
% Change in LDL-C Through 12 Wks
Mean % Change from Baseline in
Calculated LDL-C
10
0
–10
–20
p < 0.0001 for weeks 2-12 for each dose vs placebo
–30
–40
–50
–60
–70
–80
–90
–100
Study Drug
Administration
number of
patients
77
79
79
80
71
75
70
69
77
77
78
78
76
74
72
76
Baseline
Week 2
Week 4
Week 6
Study Week
LDL-C calculated
using Friedewald
Placebo Q4W (n = 77)
AMG145 350 mg Q4W (n = 79)
75
77
76
74
Week 8
75
74
74
76
Week 10
76
78
77
77
Week 12
AMG145 280 mg Q4W (n = 79)
AMG145 420 mg Q4W (n = 80)
25
AMG 145 Dose Response:
% Change in LDL-C Wks 8-12 (placebo adjusted)
0
Percentage Change in Calculated
LDL-C vs. Placebo, Mean (SE)
–10
Week 9
Week 10
Week 11
Week 12
–20
–30
–40
–50
–60
–70
–80
Study Drug
Drug
Study
Administration
Administration
–90
–100
LDL-C calculated
using Friedewald
Week 8
70 mg
280
mg
105 mg
350
140 mg
420
22
n = 25
25
n = 27
29
n = 27
7
n=6
11
n = 10
16
n = 17
23
n = 25
28
n = 26
30
n = 26
n = 16
15
n = 18
20
n = 19
22
n = 26
28
n = 27
27
n = 28
26
OSLER Program
MONOTHERAPY
HYPERCHOL
ON A STATIN
STATININTOL
HETEROZYG
FAM HYPERCHOL
OTHER
Phase 2
trials
MENDEL-1
(n=406)
LAPLACE-TIMI 57
(n=629)
GAUSS-1
(n=157)
RUTHERFORD-1
(n=167)
YUKAWA-1
(n=307)
Phase 3
trials
MENDEL-2
(n=614)
LAPLACE-2
(n=1896)
GAUSS-2
(n=307)
RUTHERFORD-2
(n=329)
DESCARTES
(n=901)
4465 patients (74%) elected to enroll
into OSLER extension study program
THOMAS-1
(n=149)
THOMAS-2
(n=164)
Eligible if medically stable
and on study drug
1324 from Ph2 trials into OSLER-1
3141 from Ph3 trials into OSLER-2
Randomized
2:1
Evolocumab
plus standard of care
(n=2976)
Irrespective of treatment assignment
in parent study
Standard of care alone
(n=1489)
Median follow-up of 11.1 months (IQR 11.0-12.8)
7% discontinued evolocumab early
96% completed follow-up
27
Trial Sponsor: Amgen
LDL Cholesterol
140
Median LDL-C (mg/dL)
120
100
61% reduction (95%CI 59-63%), P<0.0001
80
Absolute reduction: 73 mg/dL (95%CI 71-76%)
60
40
Evolocumab plus standard of care
20
0
Baseline
4 weeks
12 weeks
24 weeks
36 weeks
48 weeks
N=4465
N=1258
N=4259
N=4204
N=1243
N=3727
(Parent study)
(OSLER)
28
Sabatine MS et al. NEJM 2015;372:1500-9
Cardiovascular Outcomes
Composite Endpoint: Death, MI, UA  hosp,
coronary revasc, stroke, TIA, or CHF  hosp
Cumulative Incidence (%)
3
2.18%
2
HR 0.47
95% CI 0.28-0.78
P=0.003
(N=1489)
1
0.95%
Evolocumab plus standard of care
(N=2976)
0
0
30
60
90
120
150
180
210
240
270
300
330
365
Days since Randomization
29
CV Events in Subgroups
Baseline Subgroup
Number
Evolocumab
Stnd of care alone
Overall
4465
0.95%
2.18%
Age
<65 yr
≥65 yr
3103
1362
0.73%
1.47%
1.29%
4.10%
Sex
Male
Female
2255
2210
1.28%
0.61%
2.37%
1.96%
LDL cholesterol
<120 mg/dL
≥120 mg/dL
2202
2263
0.55%
1.35%
1.53%
2.75%
Statin use
Yes
No
3128
1337
0.83%
1.24%
2.21%
2.11%
NCEP class
High or mod. high
Mod. or lower
2025
2440
1.51%
0.49%
3.51%
1.04%
Known vascular disease
Yes
1125
No
3340
2.31%
0.50%
5.01%
1.19%
NCEP = National Cholesterol
Education Program
% are KM event
rates at 1 year
Hazard Ratio (95% CI)
No significant
heterogeneity of
effect by any
subgroup
0.1
0.2
0.5
1
2.0
5.0
10.0
Evolocumab plus Standard of care alone
standard of care better
better
30
Safety
Evolocumab
+ stnd of care
(N=2976)
Standard of
care alone
(N=1489)
Any
69.2
64.8
Serious
7.5
7.5
Leading to discontinuation of evolocumab
2.4
n/a
Injection-site reactions
4.3
n/a
Muscle-related
6.4
6.0
Neurocognitive
0.9
0.3
ALT or AST >3×ULN
1.0
1.2
Creatine kinase >5×ULN
0.6
1.2
Adverse events (%)
Laboratory results (%)
31
Relationship between reduction in LDL-C and
Relative Risk Reduction in CV events
32
David D. Waters, and Priscilla Y. Hsue Circulation
Research. 2015;116:1643-1645
Agenda
Welcome
• Joshua Brodsky
Introduction
• Barry Greene
Q&A Session
•
With Dr. Sabatine
ALN-PCSsc Program
Q&A Session
33
Agenda
Welcome
• Joshua Brodsky
Introduction
• Barry Greene
Q&A Session
•
With Dr. Sabatine
ALN-PCSsc Program
Q&A Session
34
PCSK9 Therapeutic Hypothesis
LDL
LDLR
Anti-PCSK9
MAbs
Endosome
Lysosomal
degradation
Transiently block
PCSK9 binding
to LDL receptor
(LDLR)
LDLR
synthesis
PCSK9
Synthesis
Inhibitors
Durably block PCSK9
synthesis and all
intracellular and
extracellular PCSK9
functions
35 35
PCSK9
synthesis
ALN-PCS
PCSK9 mRNA
Nucleus
PCSK9
GalNAc-siRNA Conjugates
Subcutaneous RNAi Therapeutics
GalNAc3
GalNAc-siRNA
conjugate
ASGPR
(pH>5)
Asialoglycoprotein Receptor (ASGPR)
•
•
•
•
Highly expressed in hepatocytes
High rate of uptake
Recycling time ~15 minutes
Conserved across species
Clathrin-coated pit
protein
Recycling
ASGPR
Clathrin-coated
vesicle
ALN-PCSsc
• 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
36
RISC
Endosome
mRNA
Nucleus
CARDIO-METABOLIC
DISEASE
Potent PCSK9 Knockdown and LDL-C Lowering
Single Dose Data in NHP
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
0
20
40
60
80
6.0
10.0
0
20
40
60
80
100
100
0
20
ALN-PCSsc
(mg/kg)
37
3.0
-20
% LDL-C Lowering
(relative to pre-bleed)
% PCSK9 Knockdown
(relative to pre-bleed)
-20
Fitzgerald, AHA, Nov 2014
40
Days
60
80
100
0
ALN-PCSsc
(mg/kg)
20
40
60
Days
80
100
120
CARDIO-METABOLIC
DISEASE
ALN-PCSsc Phase 1 Study
Healthy Subjects with LDL-C >100mg/dl, On or Off Statins
Primary objectives
Secondary objectives
• Safety, tolerability
• PK, PCSK9 and LDL-C reduction
Part A: Single Dose (SAD) │Randomized 3:1, Single blind, Placebo controlled
25 mg x 1 SC
100 mg x 1 SC
300 mg x 1 SC
= dose
500 mg x 1 SC
800 mg x 1 SC
Part B: Multi-Dose (MD) │Randomized 6:2, Single blind, Placebo controlled, On or off statins
125mg qW x 4 SC
250mg q2W x 2 SC
300mg qM x 2 SC +/- Statin
500 mg qM x2 SC +/- Statin
38
Initial ALN-PCSsc Phase 1 Study Results
CARDIO-METABOLIC
DISEASE
Baseline Values for PCSK9 and LDL-C
SAD Phase
Treatment
(N)
Placebo
(6)
25mg
(3)
100 mg
(3)
300 mg
(3)
500 mg
(3)
800 mg
(6)
Overall
(24)
Mean (SEM) PCSK9 (ng/mL)
278.9
(40.6)
342.7
(39.2)
233.8
(22.6)
253.8
(12.9)
263.2
(14.4)
279.6
(27.3)
276.3
(13.9)
Mean (SEM) LDL-C (mg/dL)
142.2
(11.4)
184.0
(27.0)
161.7
(16.1)
173.2
(29.5)
135.0
(3.3)
161.3
(10.3)
157.6
(6.6)
500 mg
qM x2
(6)
500 mg
qM x2
S^
(5)
Overall
(45)
MD Phase
Placebo
(12)
125 mg
qWx4
(6)
250 mg
q2Wx2
(6)
300 mg
qM x2
(6)
300
mg
qM x2
S^
(4)
Mean (SEM) PCSK9
(ng/mL)
333.3
(29.0)
380.0
(20.7)
288.7
(21.9)
308.0
(25.6)
474.7
(86.7)
288.1
(28.2)
433.4
(48.0)
347.9
(16.0)
Mean (SEM) LDL-C
(mg/dL)
137.0
(11.1)
150.2
(7.6)
129.2
(10.2)
145.4
(12.9)
158.1
(15.6)
131.7
(20.2)
131.3
(11.2)
139.4
(4.9)
Treatment
(N)
39
S ^ = On a stable statin dose
Data in database as of 04 August 2015
CARDIO-METABOLIC
DISEASE
SAD Safety and Tolerability
ALN-PCSsc generally well tolerated
• No SAEs and no discontinuations due to AEs
• All AEs mild or moderate in severity
◦ At highest dose group (800 mg), one subject with mild localized injection site reaction
◦ No clinically significant changes in laboratory parameters
Common AEs (≥10% or more of ALN-PCSsc subjects)*
AE Preferred Term
Placebo
N=6
25 mg
N=3
100 mg
N=3
300 mg
N=3
500 mg
N=3
800 mg
N=6
Total
ALNPCSsc
N=18
Cough
0
0
1
0
1
0
2
Musculoskeletal pain
0
1
0
0
0
1
2
Nasopharyngitis
0
1
0
1
0
0
2
Rash
0
0
0
0
0
2**
2
40
*Subjects with one or more AEs 2/6 placebo; 9/18 ALN-PCSsc
**1 mild injection site reaction; 1 mild facial rash not associated with drug
CARDIO-METABOLIC
DISEASE
MD Safety and Tolerability
ALN-PCSsc generally well tolerated
• No SAEs and no discontinuations due to AEs
• All AEs mild or moderate in severity
◦ AE profile generally similar with or without statins
◦ At higher drug exposures 3 subjects with mild, localized injection site reaction
– One at 500 mg qM x2 with statin; two at 250 mg q2W x2
◦ One subject with clinically significant change in LFTs
– Subject receiving 500 mg ALN-PCSsc developed ALT ~4x ULN without rise in bilirubin; attributed to concomitant
statin therapy
Common AEs (≥10% or more of ALN-PCSsc subjects)*
AE
Preferred Term
Placebo
N=12
125 mg
qWx4
N=6
250 mg
q2Wx2
N=6
300 mg
qMx2
N=6
300 mg
qMx2
S^
N=4
500 mg
qMx2
N=6
500 mg
qMx2
S^
N=5
Total
ALNPCSsc
N=33
Headache
2
1
1
1
1
2
0
6
Back pain
2
1
0
0
0
2
1
4
Diarrhea
3
2
0
0
1
0
1
4
Nausea
0
2
0
0
0
2
0
4
41
*Subjects with one or more AEs 9/12 placebo; 22/33 ALN-PCSsc
S ^ =On stable dose of statin
CARDIO-METABOLIC
DISEASE
Single Dose Cohorts
Results support once-quarterly and possibly bi-annual, low volume, subcutaneous dose
regimen profile
• Up to 86% maximal and up to 82% mean maximum PCSK9 knockdown (p<0.001)
• Up to 78% maximal and up to 58% mean maximum LDL-C lowering (p<0.001)
◦ Comparable to reported results with anti-PCSK9 MAbs1
• Highly durable effects with LDL-C lowering lasting over 140 days after single injection
LDL-C Lowering
PCSK9 Knockdown
Treatment
-20
300 mg
25 mg
500 mg
100 mg
800 mg
0
Mean (SEM) % LDL-C Lowering
(Change from Baseline)
Mean (SEM) % PCSK9 Knockdown
-40
Treatment
Placebo
0
20
40
60
80
100
0
1
2
3
4
5
Day/Treatment combinations where N=1 not displayed
Data in database as of 04 August 2015;
24 subjects received ALN-PCSsc or placebo (3:1)
42
1
Zhang XL., et al., BMC Med., 2015
300 mg
25 mg
500 mg
100 mg
800 mg
20
40
60
80
0
1
2
3
Months
Months
Placebo
Days/Treatments where N=1 not displayed
LDL-C analyzed by Beta-Quantification
4
5
CARDIO-METABOLIC
DISEASE
Multiple Dose Cohorts
Robust and highly durable PCSK9 knockdown and LDL-C lowering
• Up to 94% maximal and up to 88% mean maximum PCSK9 knockdown (p<0.001)
• Up to 83% maximal and up to 64% mean maximum LDL-C lowering (p<0.001)
◦ Similar results in subjects with or without statin co-medication
◦ Comparable to reported results with anti-PCSK9 MAbs1
MD PCSK9 Knockdown
Mean (SEM) % PCSK9 Knockdown
-60
-40
MD LDL-C Lowering
300 mg qMX2
300 mg S^qMX2
500 mg qMX2
500 mg S^qMX2
20
-20
0
40
20
40
60
60
80
100
0
qW, q2W, or qM
1
2
3
4
5
Treatment
Placebo
125 mg qWX4
250 mg q2WX2
80
0
Months
qW, q2W, or qM
S^
Data in database as of 04 August 2015;
24 subjects received ALN-PCSsc or placebo
(3:1) 1 Zhang XL., et al., BMC Med., 2015
43
0
Mean (SEM) % LDL-C Lowering
Treatment
Placebo
125 mg qWX4
250 mg q2WX2
=On stable dose of statin
45 MD subjects dosed with ALN-PCSsc or placebo (3:1)
Two subjects excluded from all MD analyses:
One placebo subject elected to discontinue;
One subject in 300 mg statin group was incarcerated on Day 14
1
300 mg qMX2
300 mg S^qMX2
500 mg qMX2
2
3
Month
500 mg S^qMX2
4
5
CARDIO-METABOLIC
DISEASE
LDL-C reductions in PCSK9 Programs
Alirocumab
(REGN727)
Evolocumab
(AMG-145)
Bococizumab
ALN-PCSsc
Phase 1 SAD
100mg -39.9%
150mg -38.5%
250mg -45.7%
(Stein et al1)
70mg
210mg
420mg
(Dias et al2)*
-53%
-53%
-64%
SC data not available
25mg -26.0%
100mg -38.9%
300mg -50.1%
500mg -58.9%
800mg -52.8%
(Fitzgerald et al) **
Phase 1 MD
150mg -55.7%
150mg -57.0%
150mg -64.7%
(Stein et al1)
Q2W 140mg
Q4W 420mg
(Dias et al2)
-63 to 73%
-66%
SC data not available
QW 125mg
-45.3%
Q2W 250mg
-55.5%
Q4W 300mg
-59.4%
Q4W 300mg
-53.2%
Q4W 500mg
-53.6%
Q4W 500mg
-58.7%
(Fitzgerald et. al)***
Phase 2/3
lipid trials
Q2W 75/150mg -50.6%
(Cannon et al3)
Q2W 75/150mg -47.2%
(Roth et al4)#
Q2W 140mg
Q4W 420mg
(Koren et al5)
-47.2%
-52.5%
Q2W 50mg
-35%
Q2W 100mg -42.3%
Q2W 150mg -53.1%
Q4W 200mg -27%
Q4W 300mg -41.1%
(Ballantyne et al6)
To be performed
Phase 3
pooled data
Q2W 150mg
Q2W 75/150mg
(FDA Ad comm.)
Q2W 140mg
Q4W 420mg
(Stein et al7)
-65.7%
-65%
Trials ongoing
To be performed
FH
no statin
statin
-56.2%
-53%
no statin
no statin
no statin
statin
no statin
statin
*mean change from baseline to nadir
**LS mean change from baseline to group nadir after single dose
***LS mean change from baseline to group nadir after final dose
#no placebo control
1 Stein et al. NEJM, 366:1108-18. 2 Dias et al. JACC, 60(19):1888-98. 3 Cannon et al. EHJ 36, 1186-94. 4 Roth et al. IJC, 176, 55-61.5 Koren et al. Lancet 380: 19952006. 6 Ballantyne et al. AJC;115:1212-1221. 7 Stein et al. Abstract 1107-103 ACC San Diego 2015.
44
CARDIO-METABOLIC
DISEASE
Summary and Next Steps
ALN-PCSsc is promising first-in-class PCSK9 synthesis inhibitor
• Generally well tolerated
◦ No SAEs and no discontinuations due to AEs
◦ All AEs mild or moderate in severity
• Similar LDL-C reduction to published data reported for anti-PCSK9 MAbs* in subjects with and
without statin co-medication
◦ Single subcutaneous injection of ALN-PCSsc resulted in up to 86% maximal PCSK9 knockdown and
up to 78% maximal reduction LDL-C lowering, with up to mean maximal LDL-C reduction of 58%
◦ Two monthly doses of ALN-PCSsc resulted in up to 94% maximal knockdown of PCSK9 and up to
83% maximal reduction of LDL-C, with up to mean maximal LDL-C reduction of 64%
– Similar effects with or without concomitant statin
• Durability supports once-quarterly and possibly bi-annual, low volume SC dose regimen
◦ Knockdown of PCSK9 and lowering of LDL-C for over 4 months after single SC dose
– LDL-C significantly (P<0.001) reduced by mean 44% at day 140 after single dose
– Lowest maximal effect dose of 300 mg administered in 1.5 mL volume
• Results support continued development of ALN-PCSsc in ORION Development Program
◦ Phase 2 study expected to start by YE-2015
45
* Zhang XL., et al., BMC Med., 2015
CARDIO-METABOLIC
DISEASE
The Orion
Development Program
David Kallend
Vice President, Global Medical Director
Acute Cardiovascular Care
The Medicines Company
46
CARDIO-METABOLIC
DISEASE
The Orion Development Program
Goal to make ALN-PCSsc available quickly
with appropriate information for regulators and, upon approval, for
prescribers, patients & payers
Objectives:
• Keep chronic toxicology studies off the critical path
• Optimize dose, formulation, administration, and device – small volume,
infrequent, easy
• Execute efficient phase III program based on LDL-C efficacy endpoint
– Broad population of patients with ACVD
– Focused FH studies
– Compare head-to-head to monoclonal antibodies where appropriate
• Anticipate outcomes data and design phase IIIb/IV accordingly
47
47
CARDIO-METABOLIC
DISEASE
Benchmarking programs with approval on LDLc endpoints (US approval)
Parameter
Lipitor®
Crestor®
Praluent®
Repatha®
Initial US approval
(YR)
1996
2003
2015
2015
Comparator in
pivotal trials
Statins or Placebo
Statins or Placebo
Placebo or
Ezetemibe
Placebo or
Ezetimibe
Primary Endpoint
LDL-C
% change
LDL-C
% change
LDL-C
% change
LDL-C
% change
Efficacy database
(N)
2502 (active)
1020 (control)
2873
(active & control)
3182 (active)
1792 (control)
2928
(active & control)
Safety database
(N)
3092 (HV’s & Pts)
11,210 (due to additional
safety requirements)
3340 (active)
1894 (control)
4971
(active & control)
Long term
treatment ≥12 months
(N)
1749 (active)
2471 (active)
3627
(active & control)
1797
(active & control)
FH patients
(N)
491 He
59 Ho
776 He
44 Ho
735 He
329 He
99 Ho
48
48
Source: FDA Website
CARDIO-METABOLIC
DISEASE
Estimated sequence of events
Anticipated critical path
2015
2016
Anticipated non-critical path
2017
2018
2019
2020
Phase I completion
CMC Development (scale up, formulation, device, and supply)
Non-clinical long-term toxicology (including repro and carc)
Phase II including HoFH & MAbs
Phase III LDL lowering
NDA/MAA process
Potential outcomes study
Timelines are estimates based on current assumptions
49
CARDIO-METABOLIC
DISEASE
Summary
Clear path forward leading to applications for approval for LDL-C
lowering indication
Immediate next steps:
•
•
•
•
Complete Phase I observations
Start Phase II imminently
Scale up manufacturing and formulation development
Complete long term toxicology program
Ensure only the clinical program remains on the critical path
50
50
Agenda
Welcome
• Joshua Brodsky
Introduction
• Barry Greene
Q&A Session
•
With Dr. Sabatine
ALN-PCSsc Program
Q&A Session
51
Upcoming RNAi Roundtables
ALN-AS1 for the treatment of Acute Hepatic Porphyrias
Tuesday, September 24, 11:00 a.m. – 12:00 p.m. ET
• Bill Querbes, Ph.D., Associate Director, Research
• Moderator: John Maraganore, Ph.D., Chief Executive Officer
• Guest Speaker: Robert J. Desnick, M.D., Ph.D., Dean for Genetics and Genomic Medicine, Professor
and Chair Emeritus, Department of Genetics and Genomic Sciences, Icahn School of Medicine at
Mount Sinai Hospital
Replays, presentations, transcripts of all RNAi Roundtables available at www.alnylam.com/capella
52
Speaker Biographies
Barry Greene
President and Chief Operating Officer, Alnylam
Barry Greene joined Alnylam in 2003, and brings over 25 years of experience in healthcare, pharmaceutical, and biotechnology industries. Prior to Alnylam, he was
General Manager of Oncology at Millennium Pharmaceuticals, Inc., where he led the company’s global strategy and execution for its oncology business including
strategic business direction and execution, culminating in the successful approval and launch of VELCADE™(bortezomib) in mid 2003. Prior to joining Millennium in
February 2001, Barry served as Executive Vice President and Chief Business Officer for Mediconsult.com. Prior to Mediconsult.com, his past experiences include Vice
President of Marketing and Customer Services for AstraZeneca, formerly AstraMerck; Vice President Strategic Integration with responsibility for the AstraZeneca North
American post merger integration; and Partner, Andersen Consulting responsible for the pharmaceutical/biotechnology marketing and sales practice. Barry received his
B.S. in Industrial Engineering from University of Pittsburgh and served as Senior Scholar at Duke University, Fuqua School of Business. Barry also serves on the Boards
of Acorda Therapeutics and Karyopharm Therapeutics.
Marc S. Sabatine, M.D., M.P.H.,
Chairman, Thrombolysis in Myocardial Infarction (TIMI) Study Group at Brigham and Women’s Hospital, Lewis Dexter, MD Distinguished Chair in Cardiovascular
Medicine, and Professor of Medicine, Harvard Medical School
Dr. Marc S. Sabatine is chairman of the Thrombolysis in Myocardial Infarction (TIMI) Study Group at Brigham and Women’s Hospital (BWH) and holds the Lewis Dexter,
MD Distinguished Chair in Cardiovascular Medicine. A cardiovascular specialist, he is also a professor of medicine at Harvard Medical School (HMS). Dr. Sabatine
received his medical degree from HMS and completed a residency in internal medicine at Massachusetts General Hospital (MGH). He then completed a clinical
fellowship in cardiovascular disease at Massachusetts General Hospital and a fellowship in cardiovascular research at BWH. Dr. Sabatine is board certified in internal
medicine and cardiovascular disease and is a fellow of the American Heart Association, the American College of Cardiology and the European Society of Cardiology. As
the chairman of the TIMI Study Group—an academic research organization that has led major cardiovascular medicine clinical trials since its inception in 1984—Dr.
Sabatine leads large-scale international randomized controlled trials testing novel therapies for cardiovascular care that have shaped the practice of medicine.
Kevin Fitzgerald, Ph.D.,
Dr. Fitzgerald joined Alnylam in 2005 as Associate Director of Research and has served in roles of increasing responsibility and leadership since that time. His
achievements at Alnylam include leadership of the company’s RNAi delivery efforts, resulting in two clinically validated modes of siRNA delivery. He has led multiple
programs – including Alnylam’s PCSK9 program – from discovery through pre-clinical development, regulatory submissions, and early clinical development. Kevin was
lead author and coauthor on Alnylam’s seminal papers in The Lancet and the New England Journal of Medicine, which demonstrated the effects of RNAi therapeutics in
man. Prior to joining Alnylam, Kevin worked as a Senior Research Scientist and Group Leader at Bristol Myers Squibb, where he contributed to the development of
multiple pharmaceutical products, in addition to managing several technology and drug development alliances. Kevin received his B.S. in Genetics from Cornell
University and his Ph.D. in Molecular Biology from Princeton University. He completed his post-doctoral fellowship in oncology at Harvard Medical School.
David Kallend, MBBS,
Following graduation from Kings College Hospital School of Medicine in London, Dr. David Kallend worked in various hospital departments in the UK, predominantly at
the Royal Postgraduate Medical School Hammersmith Hospital, London, where his final post was Research Fellow in the Department of Surgery. In 1995 he joined the
pharmaceutical industry. He initially worked as an International Clinical Research Physician on imaging studies for Schering AG in Berlin, predominantly in the area of
magnetic resonance contrast media for clinical imaging. Following this he joined AstraZeneca in 1998, based in the UK, working mainly on the development of
rosuvastatin from Phase II to Phase IV and the post-approval phase. He was also involved as an advisor to other cardiovascular programs and collaborations. From
2005 to 2012 he was the Global Clinical Leader and a Group Medical Director for dalcetrapib at Roche in Switzerland. His current role is Vice President and Global
Medical Director for the early development lipid programs, Apo A-1 Milano and aPCSK9, at The Medicines Company.
53

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