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ThinkEquity Mid Year Check Up
Healthcare Conference
May 25, 2011
Alnylam Forward Looking Statements
This presentation contains forward-looking statements. There are a number of important factors that could cause actual results to differ materially from the results anticipated by these forward-looking statements. These important factors include those that we discuss in our most recent quarterly report on Form 10-Q under the caption “Risk Factors.” If one or more of these factors materialize, or if any underlying assumptions prove incorrect, our actual results, performance or achievements may vary materially from any future results, performance or achievements expressed or implied by these forward-looking statements.
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RNA Interference (RNAi) A New Class of Innovative Medicines
RNAi Therapeutics Harness natural pathway
» Catalytic mechanism » Mediated by small interfering RNAs or “siRNAs”
Treat disease with therapeutic gene silencing » Any gene in genome
Major breakthroughs in delivery achieved » Includes systemic RNAi with formulations and chemistries » Enable advancement of RNAi products to clinic and market
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Alnylam Strategy Build Top-Tier Biopharmaceutical Company Founded on RNAi
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RNAi Products
Alnylam Strategy Build Top-Tier Biopharmaceutical Company Founded on RNAi
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RNAi Products
RNAi Therapeutics The Time is Now: 3 Reasons
2. Growing human experience: safety and predictable PK >500 Subjects/patients enrolled overall
Systemic delivery in human trials » > 40 Patients dosed
» >160 Doses administered
» Over 6 months of dosing
RNAi therapeutics generally well tolerated
Pharmacologically relevant human tissue levels achieved
1. Delivery breakthroughs
enable clinical translation
3. Human RNAi proof of mechanism established
Patient A Pre-treatment
Patient B Post-treatment
Patient A Post-treatment
Untreated control colorectal cancer
Untreated control hepatocellular cancer
Untreated control normal liver
27.9%
29.2%
1.4%
0.6%
0.3%
0.1%
Rea
ds
/To
tal R
ea
ds
% Specific
cleavage
Evidence
of RNAi
NO
YES
YES
NO
NO
NO
5’ Location along mRNA 3’
6
0.0
0.2
0.4
0.6
0.8
1.0
1.2
TT
R m
RN
A L
eve
ls
(Re
lative
to
Con
trol)
0.03 0.1 0.3
siRNA
(MC3-LNP)
mg/kg
Control
Pre-Clinical Animal Studies
...ATAGGAGAGATGAGCTTCCTACACAGCACACAAACAAATG ...
AGATGAGCTTCCT... CAGCACACAAACA...
cleavage site
plot location vs. no of reeds
p<0.0001
Alnylam 5x15TM
Focused Product Development Pipeline for Innovative Medicines
RNAi for genetically defined disease as core strategy
5 Products by 2015 in advanced clinical
development
Product characteristics
» Major impact in high unmet need population
» Genetically defined target and disease
– Increased biological/clinical probability of success
» Leverage existing Alnylam delivery platform
– Validated in humans
» Early biomarker in Phase I for human POC
» Established clinically relevant endpoint for
NDA with focused patient database
» Potential for early commercialization paths
Rapid and clear path for new medicines that matter
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ALN-RSV
ALN-VSP
ALN-HTT
Core Programs
1. ALN-TTR
2. ALN-PCS
3. ALN-HPN
4. TBA
5. TBA
Partner
Programs
Transthyretin (TTR)-Mediated Amyloidosis (ATTR) Program Unmet Need and Product Opportunity
RNAi to treat genetic disease ATTR is significant orphan disease
» ~50,000 patients worldwide
Clinical pathology » Onset ~40 to >60 yr
» Two predominant forms – Familial amyloidotic polyneuropathy (FAP)
– Familial amyloidotic cardiomyopathy (FAC)
» Peripheral sensorimotor neuropathy, autonomic
neuropathy, and/or cardiomyopathy
» Fatal within 5-15 years
Liver transplant current standard of care » <3,000 Patients eligible
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TTR Target and ALN-TTR Program
Mutant TTR is genetic cause of ATTR >100 Defined mutations; Autosomal dominant
Misfolds and forms amyloid deposits in
nerves and heart
Wild-type TTR also accumulates in
amyloid plaques » Limits benefits of liver transplantation
Additional validation in mouse genetic models
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Gly6Ser
Leu12Pro
Val20Ile
Pro24Ser
Val28Met
Phe33Cys
Phe33Ile
Phe33Leu
Phe33Val
Lys35Asn
Asp38Ala
Glu42Asp
Glu42Gly
Ala45Asp
Ala45Ser
Ala45Thr
Thr49Ala
Thr49Pro
Glu51Gly
Gly53Glu
Leu55Arg
Leu55Pro
Leu55Gln
Thr59Lys
Glu61Lys
Ile68Leu
Lys70Asn
Ile73Val
Ser77Phe
Ser77Thy
Glu89Gln
Glu89Lys
Ala97Gly
Ala97Ser
Pro102Arg
Ile107Val
Leu111Met
Tyr114Cys
Tyr114His
Ala120Ser
Pro125Ser
Ala91Ser Thr118Met
Asp18Glu
Asp18Gly
Ala25Ser
Ala25Thr
Arg34Thr
Ala36Pro
Trp41Leu
Gly47Ala
Gly47Arg
Gly47Glu
Gly47Val
Ser50Arg
Glu54Gln
Glu54Gly
Leu58Arg
Leu58His
Thr60Ala
Phe64Leu
Phe64Ser
Tyr69His
Tyr69Ile
Val71Ala
Asp74His
Ile84Asn
Ile84Ser
His90Asn
Gln92Lys
Gly101Ser
Arg104Cys
Arg104His
Ala109Thr
Ala109Val
Ala109Ser
Ser112Ile
Tyr116Ser
Thr119Met
Val122Ala
Val122Ile Val122 (-) Cys10Arg
Ser23Asn Phe44Ser
Ser52Pro
Val30Ala
Val30Gly
Val30Leu
Val30 Met
5’ UTR
3’ UTR
ALN-TTR in clinical development Potent siRNA with pM IC50
Targets mutant and wild-type TTR
In vivo efficacy established in multiple
pre-clinical animal models
Phase I with ALN-TTR01
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ALN-TTR01 Phase I Study Extended Study Design
Randomized, placebo-controlled, single-dose escalation study
~36 Patients with ATTR
» Conducted in Portugal, Sweden, UK and France
Primary objective
» Safety and tolerability
Secondary objectives
» Characterize pharmacokinetics
» Assess preliminary pharmacodynamic activity
– Serum TTR levels
Treatment regimen
» Single ALN-TTR01 i.v. infusion
» Dose levels: 0.01-1.0 mg/kg
Status
» Initiated Q3 ’10; actively enrolling
» Expect to report human POC in Q3’11
» ALN-TTR02 program on track for IND in H2’11
– Employs 2nd generation LNPs
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Severe Hypercholesterolemia Program Unmet Need and Product Opportunity
RNAi to treat severe hypercholesterolemia
Elevated LDLc (“bad” cholesterol) is
validated risk factor for coronary artery
disease and MI
» Current target level <70 mg/dL
Significant unmet medical need
» >500,000 Patients with severe
hypercholesterolemia
– LDLc >200 mg/dL
– Inadequately managed by statins and other drugs
– Includes statin intolerant patients
– At risk for early MI, recurrent MI, death
» Multiple genetically defined patient subgroups
with increasing delineation
– Defines novel strategies for innovative medicines
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PCSK9 Target and ALN-PCS Program
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PCSK9 function well defined PCSK9 (proprotein convertase subtilisin/kexin type 9)
expressed predominantly in liver
Both intracellular and extracellular PCSK9 regulate LDL
receptor (LDLr) levels on hepatocytes » Increased PCSK9 decreases LDLr levels, elevating
plasma LDLc
Extracellular PCSK9 can be measured in plasma
PCSK9 genetically defined disease target
N. Engl. J. Med. (2006) 354:1264-1272; Am. J. Hum. Genet. (2006) 79: 514-523
Fre
qu
en
cy (
%)
Loss of Function
PSCK9 Mutation Plasma LDL Cholesterol
(mg/dL)
0
10
20
30
50 100 150 200 250 300
Loss of Function
PCSK9 Mutation
(N=85)
0
10
20
30
Wild-type PCSK9
(N=3278) 50th Percentile
0
4
8
12
No Yes
Co
ron
ary
Heart
Dis
ease (
%)
ALN-PCS in development Potent siRNA with pM IC50
In vivo efficacy established in multiple
pre-clinical animal models
IND Filing H1 ’11
Liver LDL
PCSK9
LDLr
LDL
Peripheral cells
VLDL Rem
VLDL Rem
PCSK9
PCSK9
LDLr
LDLr
LDLc
LDLc
ALN-PCS Pre-Clinical Efficacy Silencing PCSK9 Reduces LDLc
ALN-PCS demonstrates potent efficacy after single dose Rapid and dose-dependent reduction in PCSK9 protein
PCSK9 silencing results in >50% reduction in LDLc
Durable efficacy lasting >30 days
No decrease in HDL levels
PCSK9 Conference: From Gene to Therapeutic, Mar 2010
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siRNA
Dose
0
100
200
300
400
500
600
700
800
0 1 2 3 4 5
Weeks
LD
Lc
, m
g/d
L
0 1 2 3 4 5
0
10
20
30
40
50
60
70
80
90
100
PC
SK
9 p
rote
in, n
g/m
L
Weeks
control (1.00 mg/kg)
0.03 mg/kg
0.10 mg/kg
0.30 mg/kg
1.00 mg/kg
siRNA
Dose
Refractory Anemia Program Unmet Need and Product Opportunity
RNAi to treat refractory anemia
Anemia of chronic disease (ACD) across
multiple populations
» End-stage renal disease (ESRD)
» Cancer
» Chronic inflammatory disorders
Significant unmet need; e.g., ESRD
» ~500,000 patients in US with ESRD
» ~50,000 patients with refractory anemia
– Cannot attain target hemoglobin level >11g/dL
» Resistant to high doses of EPO and
i.v. iron and poor QOL
Significant unmet need; e.g., Cancer
» Anemia in multiple myeloma and MDS
Additional genetic causes
» E.g., Iron-refractory iron deficiency anemia
(IRIDA)
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Hepcidin Target and ALN-HPN Program
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Hepcidin is genetically defined target Hepcidin is central regulator of iron
homeostasis » Down-regulates ferroportin
─ Reduces iron uptake by enterocytes
─ Reduces mobilization by macrophages
Validated in human genetics » Mutations in hepcidin and hepcidin pathway
Expressed in liver, circulates in plasma
ALN-HPN in R2D siRNA optimization
In vivo efficacy in pre-clinical animal
model
IND Filing 2012
Genetic defects in hepcidin pathway lead to anemia
Gut
Liver
Hepcidin Elevated
hepcidin
levels
Inhibition of
dietary iron
uptake
Reduced iron delivery to
marrow results in ACD
Inhibition of
iron
release from
cellular
stores
IL6
Infection, LPS
High serum iron
Other (e.g., uremia)
Macrophage
Wild type
control
TMPRSS6 -/-
patient
Hb (g/dL) 14-18 7.9-9.4
Serum Fe (mg/dL) 92-184 12-18
Transferrin
saturation (%) 15-45 3.3-4.8
Altamura et al., Biochem J, 2010
Alnylam 5x15TM
Programs Definable Clinical Path
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Unmet
Need
Phase I Serum
Biomarkers
Early
Development
Advanced
Development
ALN-TTR Significant morbidity
and mortality 45-60
yrs of age with
neuropathy and
cardiomyopathy
• TTR
• Vitamin A
• Retinol binding
protein
Dose/regimen
for >50% TTR
reduction
FAP:
Improvement in
neuropathy
score (NIS-LL)
ALN-PCS Significant morbidity
and mortality
associated with
LDLc >200 mg/dL
• PCSK9
• LDLc
Dose/regimen
for >50% LDLc
reduction
LDLc reduction
in genetically
defined high risk
population
ALN-HPN Poor QOL and need
for blood
transfusions, very
high EPO and i.v.
iron doses
• Hepcidin
• Iron
• Hb
• Transferrin
saturation
Dose/regimen
for serum
hepcidin
reduction and
increase in Hb
>1 g/dL increase
in Hb in
refractory
anemia patients
Partner Programs
Respiratory Syncytial Virus
Significant unmet medical need
» >125,000 Pediatric hosp./yr in US
» >170,000 Adult hosp./yr in US
No effective therapies to treat RSV
Liver Cancer Prevalent solid tumor and common
site of metastatic disease » ~700,000/yr Incidence of HCC
worldwide
» ~500,000/yr Patients with liver mets
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Huntington’s Disease Significant inherited
neurodegenerative disease » Caused by mutations in huntingtin gene
» 30,000 US patients; 150,000 with 50% risk
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ALN-RSV01 Targets key viral gene blocking
replication
Phase IIb RSV-infected lung
transplant patient study ongoing » Received regulatory approval to
perform interim analysis ─ Increase enrollment up to 120
patients
» Data in 2012
50-50 US Partnership with Cubist
Partnered with Kyowa in Asia
ALN-VSP Targets two distinct genes involved in
cancer pathways » KSP for proliferation; VEGF for
angiogenesis
Phase I liver cancer study » Encouraging initial data and RNAi POM
» Enrollment completed
─ 41 Patients
─ Doses range: 0.1-1.5 mg/kg
─ Multiple patients continuing therapy
» Data to be presented at ASCO, June 3-7
Partner prior to Phase II
ALN-HTT Targets huntingtin gene
Pre-clinical development » IND candidate 2012
Drug-Device Collaboration with
CHDI and Medtronic » Alnylam/Medtronic 50/50 in U.S
» 50% funding from CHDI
Discovery Development Phase I Phase II Phase III
TTR-Mediated Amyloidosis
Severe Hypercholesterolemia
Refractory Anemia
Program 4 (TBA)
Program 5 (TBA)
Respiratory
Syncytial Virus
Liver Cancers
Huntington’s
Disease
Alnylam Development Pipeline
Partner Programs Alnylam 5x15 Programs
ALN-RSV01
ALN-TTR01
ALN-TTR02
ALN-VSP
ALN-PCS
ALN-HTT
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ALN-HPN
Alnylam Strategy Build Top-Tier Biopharmaceutical Company Founded on RNAi
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RNAi Products
Alnylam Strategy Build Top-Tier Biopharmaceutical Company Founded on RNAi
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RNAi Products
Alnylam Scientific Leadership Industry-Leading Science in World’s Top Journals
Nature, Nov ’04 PNAS, Aug ’08 Nature, Oct ’05
PNAS, Apr ’10
Nature, Mar ’06
Mol. Therapy, May ’10
Nat. Biotech, Sep ’07
Mol Therapy, Mar ’09 PNAS, Jan ’10
Nat. Biotech, Apr ’08
Nat. Biotech, Jan ’10
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Nature, Aug ’10
>100 Peer-reviewed papers in last 6 years
Dlin-MC3-DMA-b
Next Generation LNPs Remarkable Potency Improvements with Novel Lipids
FVII siRNA Dose (mg/kg)
Novel LNPs set new benchmark for systemic RNAi with ~100 fold improved potency Efficacy in pre-clinical models following single IV injection
Each LNP comprised of distinct cationic lipid component
Improvement in potency has resulted in ED50<0.01 mg/kg and broadened therapeutic index
Alnylam exclusive rights for RNAi therapeutics; Extended exclusive Alcana collaboration for 3rd year
ED50
0.1 1 10
0
20
40
60
80
100
120
% R
es
idu
al F
ac
tor
VII
DLinDMA
98N12-5(I)
DLinDAP
DLin-K-DMA
DLin-KC2-DMA-a
0.01
DLin-KC2-DMA-b
C12-200
0.001
Keystone: Advance in Biopharm., Jan 2010; Int’l Liposome Research Days, Aug 2010
22
Microfluidics is Emerging Approach for LNPs Precision NanoSystems Collaboration
Potential advantages/
applications Smaller LNPs (sLNPs) for
broader biodistribution
» i.e., Delivery beyond liver
More reproducible
Broader composition
parameter-space
Scalable
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79 µm high
siRNA Conjugates: Asialoglycoprotein Receptor (ASGPR)
ASGPR Highly expressed in
hepatocytes
» 0.5-1 million copies/cell
Clears serum
glycoproteins via clathrin-
mediated endocytosis
High rate of uptake
Recycling time ~15
minutes
Conserved across species
Ashwell and Morell, Adv Enzymol Relat Areas Mol Biol. 1974, 41, 99;
Lee, JBC, 1982, 257, 939; Cummings et al Essentials of Glycobiology 2008;
Park et al PNAS 2005
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RNAi Silencing with TTR-GalNAc Conjugates
Major advance in RNAi delivery: Potent in vivo efficacy with SC dosing Single SC dose; Transthyretin target
ED50 ~5 mg/kg
Durable; Effects lasting weeks after single dose
Re
lati
ve
TT
R m
RN
A (
%C
on
tro
l)
0
20
40
60
80
100
120
TTR-GalNAc (mg/kg)
Control 30 15 7.5 3.5 1.75 0.5
25
AAAS Meeting, Feb 2011
0
20
40
60
80
100
120
140
0 5 10 15 20 25 30 35 40 45
Re
lati
ve
TT
R m
RN
A
(% C
on
tro
l)
Days post treatment
30mg/kg TTR-GalNAc3 7.5 mg/kg TTR-GalNAc3
Delivery Summary
Alnylam leading advances on novel LNPs for RNAi therapeutics Collaboration with Alcana on novel lipids leading to highly
potent LNPs » Superior to 1st generation LNPs
» Collaboration extended for 3rd year in exclusive relationship
New collaboration with Precision NanoSystems on small LNPs (sLNPs) for delivery beyond liver
Additional LNP research at Alnylam and in exclusive collaboration with MIT
Major progress on conjugates opens even broader potential GalNAc-siRNA conjugates showing high in vivo potency,
excellent tolerability, and excellent SC availability
Continued progress defines a broad potential and disruptive opportunities
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Financials and Goals
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Financial Summary
2011 Q1 Financial Results Cash ~$343M
» ~$8 per share
GAAP Revenues ~$21M » Roche, Takeda, Cubist, InterfeRx, Reagent
and other licenses
GAAP Operating Expenses ~$37M » Includes non-cash stock-based compensation charges of ~$4M
Shares Outstanding ~42M
2011 Guidance Year-end Cash >$275M
» Excluding any new significant partnerships
28
Alnylam Goals Pipeline Goals 2011-2012
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Additional Corporate Goals 2011 Additional partnerships
Year-end cash >$275M
ALN-TTR01 2012
Q3 ’11
ALN-TTR02 H1 ’12 H2 ’11
ALN-PCS H2 ’11 H1 ’11
ALN-HPN 2012
Program 5 Q4 ’11
ALN-VSP Partner/2012 / Q2 ’11
Program 4 Q3 ’11
ALN-RSV01 2012
ALN-HTT 2012
R2D
Phase II
Start
Phase I
Human POC IND
Phase II
Data
Aln
yla
m 5
x1
5
Pro
gra
ms
P
art
ne
r P
rog
ram
s
Thank You
www.Alnylam.com
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