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

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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

27

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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