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Hepatocyte-Targeted RNAi Therapeutics: A Reproducible and Modular Platform for Innovative Medicines Laura Sepp-Lorenzino January 28, 2016
© 2016 Alnylam Pharmaceuticals, Inc.
2
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.
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Harness natural pathway
Catalytic mechanism
Silence any gene in genome
Upstream of today’s medicines
RNAi Therapeutics New Class of Innovative Medicines
Clinically proven approach
4
Overcoming the Delivery Challenge PK/Tissue
Distribution Cellular Uptake and Trafficking
RISC Loading
0
20
40
60
80
100
0 1 2 3 4
% In
ject
ed d
ose
Time (h)
Plasma Liver Spleen RT-qPCR
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Addressing the Challenges Alnylam Platforms for Functional Delivery to Target Tissue (Liver)
HN
O
O
O
O
O
O
HN
HN
HN
HN
NH
NH
O
OHOH
HOAcNH
O
O
O
OHOH
HOAcNH
O
O
O
OHOH
HOAcNH
O
O
N
OH
OO
O
P
O
OO
Conjugates • Single component system with defined
siRNA conjugate • Administered subcutaneously • Unassisted endosomal escape
Lipid Nanoparticles (LNPs) • Multi-component lipid formulation with
encapsulated siRNA • Administered intravenously • Assisted endosomal escape
siRNA • Chemically-modified siRNA • Potent and durable activity • Metabolically stable • No innate immune activation
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RNAi Delivery to Liver Solved IV and SC Platforms (NHP) Enables advancement of innovative medicines to patients • Liver target gene silencing with lipid nanoparticle (LNP) technology and IV dosing • Advancement of proprietary conjugate platform for clinical translation and SC dosing ◦ Initial conjugates with Standard Template Chemistry (STC) achieve target knockdown with qW SC dosing ◦ Improvements with conjugates employing Enhanced Stabilization Chemistry (ESC) platform with qM/qQ SC dosing
100
80
60
40
20
0
-20
% T
TR m
RN
A Si
lenc
ing
(Rel
ativ
e to
Con
trol)
0.03 0.1 0.3 Patisiran
(MC3-LNP) mg/kg
Control 100
80
60
40
20
0
-20
% T
TR m
RN
A Si
lenc
ing
(R
elat
ive
to C
ontro
l)
Revusiran (STC-GalNAc-conjugate)
mg/kg
5.0 1.0 0.2 Control ALN-AT3
(ESC-GalNAc-conjugate) mg/kg
100
80
60
40
20
0
-20
% A
T m
RN
A Si
lenc
ing
(Rel
ativ
e to
Pre
-dos
e)
0.5 0.25 0.125 Control
LNP STC-Conjugate ESC-Conjugate
Sah, Keystone: Adv in Biopharm., Jan. 2010; Maier et al., Oligo Ther Soc., Sep. 2011; Akinc, ISTH, July 2013
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GalNAc-siRNA Conjugates Subcutaneous Investigational 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
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First Ever Demonstration of Robust RNAi Activity with Conjugates in Humans by STC GalNAc-siRNA Revusiran Phase 1: Randomized, double-blind, placebo-controlled SAD and MAD study in healthy volunteers • Rapid, dose-dependent, consistent, and durable knockdown of serum TTR
» Significant knockdown of serum TTR (p<0.01) up to 94% TTR knockdown; mean knockdown up to 92.4%
Zimmermann, Heart Failure Society of America, Sept. 2013
100
80
60
40
20
0
-20
Days Revusiran (mg/kg), qd x5; qw x5
% M
ean
TTR
Kno
ckdo
wn
R
elat
ive
to B
asel
ine
(± S
EM)
2.5 (n=3) 5.0 (n=3) 10.0 (n=3)
Placebo (n=3)
Revusiran dose groups
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siRNA Conjugates Encounter Various Metabolic Enzymes En Route to Site of Action
SC Injection site Capillary Uptake
Lymphatics
Central Compartment
(systemic circulation)
D/M
Kidney
D/M
Liver Effect Site
Biliary excretion
Endosome
RISC
Lysosome1
Hepatocyte
Nucleases (5′ exo, 3′ exo, endo) Peptidases
Excretion
Phosphatases Nucleases Peptidases N-acetylgalactosidase many others
P-bodies and associated exonucleases Kinases - Clp1 Phosphatases
Cytosol
GalNAc-siRNA conjugate
Schröder et. al., The Proteome of the Lysosome, Proteomics.10:4053-4076 (2010) (adapted from Mark Cancilla, Merck)
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ESC Leads to Higher Liver Exposure
Manoharan, TIDES, May 2014
Liver Exposure and Metabolic Stability, Single SC Dose, 25 mg/kg in Mice
Metabolic profiling in liver 8h post dose
= 2′-F = 2′-O-methyl
(GalNAc)3
S 5′
= Enzymatic cleavage site (thickness reflects frequency of corresponding cleavage products observed)
Standard Template Chemistry (STC)
AS 5′
5′ AS
S 5′
Enhanced Stabilization Chemistry (ESC)
Liver Exposure
Target Compound Tmax (h)
Cmax (µg/g)
AUC0-t (h·µg/g)
AUC0-48 (h·µg/g)
AT3 STC 2 59.5 735 735
AT3 ESC 8 285 21,546 9,697
10
100
1000
10000
100000
1000000
0 50 100 150 200
Live
r Con
cent
ratio
n (n
g/g)
Time (h)
SC
ESC
Liver Exposure
STC
11
ESC Significantly Enhances Efficacy and Duration Reduction of AT Protein After Single SC Dose in NHP
Potent and durable silencing achieved after single SC dose • >10-fold improvement in efficacy over standard template chemistry • Substantially extended duration of effect
% K
nock
dow
n se
rum
AT
(R
elat
ive
to p
re-d
ose)
Day
100
80
60
40
20
0
-10 0 10 20 30 40
STC-AT3 (10 mg/kg)
ESC-AT3 (10 mg/kg)
ESC-AT3 (1 mg/kg)
Single SC dose
Manoharan, TIDES, May 2014
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Superior TTR Knockdown with ALN-TTRsc02 SD 1 mg/kg ALN-TTRsc02 Compared to MD 5 mg/kg Revusiran
Cumulative Dose
(mg/kg)
eAUC (ug/mL*day)
Revusiran 45 19405 ± 1559
ALN-TTRsc02 1 8626 ± 1774
Meyers, OTS, October 2015
13
0.01
0.1
1
10
100
2005 2007 2009 2011 2013 2015 2017
ED50
(mg/
kg)
Year
Continuous Improvements in Potency Through Optimization of Conjugate Design
Partial modification
STC
ESC
Advanced ESC
Conjugate potency in mouse (ED50, single s.c. dose )
projected
14
GalNAc-siRNA Conjugates
In Vivo • No evidence for cytokine induction, complement
activation, changes in clotting parameters • Single target organ in rat; liver (typically vacuolar
changes at top dose) by light microscopy ◦ No EM changes of note (revusiran chronic toxicology
studies), including mitochondrial ultrastructure
In vitro assays ◦ PBMC stimulation screen ◦ Off target screen ◦ Safety evaluation of novel chemistries (e.g., 2’ F)
Wide Therapeutic Index from Non-Clinical GLP Studies
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 15 0.35 N/A N/A 0.55
0.55 >105
ALN-PCSsc ≥250 ≥250 ≥250 ≥250 Planned Planned >500
ALN-CC5 ≥50 ≥100 50 100 Ongoing Ongoing >200
ALN-AS1 N/A N/A ≥30 ≥150 Planned Planned >500
ALN-AAT N/A N/A ≥50 ≥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 5 Secondary to exaggerated pharmacology
15
Alnylam Reproducible and Modular Platform Strategic Framework for Innovative Medicines
1
Genetically validated, liver-expressed target gene
• High unmet need disease • Opportunity for highly
competitive profile • Delivery with GalNAc conjugate
platform
2 Biomarker for POC in Phase 1
• Blood or urine based • Informative disease correlation • Establish dose/regimen for
late-stage development
3 Definable path to approval and market
• Clinical development plans with established endpoints
• Demonstrable value for payers
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Reproducible and Modular Platform Rapid Path from Idea to Human POC with 100% Success to Date
IDEA DEVELOPMENT CANDIDATE
CTA/IND HUMAN POC
6 months 12-18 months 6-9 months
Success Rate at each stage to date: 100% 100% 100%
17
Reproducible and Modular Platform Fundamentally New Approach to Drug Development
0
100
100 % Mean KD in NHP
% M
en K
D in
hum
an
Excellent Translation
Select Dose/Regimen
Increased POS due to Genetically Validated Targets Phase 3
Data
100
80
60
40
20
0
0 1 2 3 4 Months
% M
ean
KD
Start of Phase 3
Human POC
Pre-clinical
POC
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Genetic Medicines
Cardio-Metabolic Diseases
Hepatic Infectious Diseases
RNAi therapeutics for rare diseases
RNAi therapeutics for dyslipidemia, NASH, type 2 diabetes, hypertension, and other major diseases
RNAi therapeutics for major liver infections beginning with hepatitis B & D
Alnylam Strategic Therapeutic Areas (STArs)
Investigational pipeline focused in 3 STArs
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Alnylam Development Pipeline
20
Mea
n (S
em) %
AT
Kno
ckdo
wn
40 100
80
60
40
20
0
-20
Time (Days) 0 10 20 30 50 60 70
15 mcg/kg (N=3) 45 mcg/kg (N=6) 75 mcg/kg (N=3)
Mea
n (S
EM) %
C5
Kno
ckdo
wn
100
80
60
40
20
0
-20
0 10 20 30 40 50 60 70
50 mg 200 mg 400 mg
Placebo
Time (Days)
Mea
n (S
EM) P
CSK
9 K
nock
dow
n
100
80
60
40
20
0
-20
-40
-60
Time (Months) 0 1 2 3 4 5 6
Placebo
25 mg
100 mg
300 mg
500 mg
800 mg
Potent and Durable Target Silencing in Humans by ESC-GalNAc-siRNA Drug Candidates
ALN-AT3
ALN-CC5
ALN-PCSsc
Mea
n (S
EM) %
ALA
Cha
nge
-100
-75
-50
-25
0
25
50
0 5 10 15 20 25 30 35 40 45 Time (Days)
Placebo 0.035 mg/kg 0.1 mg/kg
0.35 mg/kg 1.0 mg/kg
ALN-AS1
21
Competitive and Differentiated Profiles Robust Human Experience to Date*
Number of Programs 7
Number of Clinical Studies 16
Total Patients or Volunteers Dosed >300
Longest Duration of Exposure >24 months
Total siRNA Doses Administered >4,500
*Numbers are approximate as many studies are ongoing 16-January-2016
22
Key Features of Alnylam Investigational RNAi Therapeutics Potential Attributes for Differentiation and Value
UNDRUGGABLE TARGETS
CLAMPED PHARMACODYNAMICS (PD)
NOT
MAXIMUM KNOCKDOWN (KD) EFFICACY
Up to
99%
DURABILITY
As few as 2 doses per year
VS. 26
or more doses per year SUBCUTANEOUS
(SC) ROUTE
ROOM TEMP
23 23
24
>10 Clinical
readouts in 2016
Potential Multi-Year Pipeline Progression
25
>5 Programs in Phase 3 in
2017
Potential Multi-Year Pipeline Progression
26
1st Phase 3 data readout
and, if positive,
NDA in 2017
Potential Multi-Year Pipeline Progression
27
RNAi Therapeutics Pave the Way for New Oligo Platforms
Lessons Learned • Exciting new biology ≠ therapeutic platform
• Significant multi-functional, R+D effort required ◦ Specificity, robustness, reproducibility, species translation ◦ Therapeutic window after single and chronic exposure ◦ Manufacturing, controls, quality, cost of goods
• Delivery ◦ Liver delivery presents many, many opportunities ◦ Tremendous progress on < drug exposure for > effects ◦ Other tissues/organs present additional upside
• Product clinical development and commercialization strategy ◦ Early focus on clinical and commercial differentiation ◦ Transformational medicines ◦ Successful, high impact products on market define ultimate validation
29
Competitive and Differentiated Profiles RNAi vs. Monoclonal Antibody (MAb)
mRNA
Protein Synthesis
Nucleus RNAi siRNA durably blocks protein synthesis in catalytic process Clamped effect
26 doses/year
2 doses/year
MAbs Transiently block protein in stoichiometric process, consumed by ongoing protein synthesis
Potential resurgence of disease symptoms
Sustained suppression of disease symptoms
GalNAc
Saw-tooth effect
Clamped effect