Corporate Overview

September 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

– Creates unique opportunities for innovative medicines

3

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 » > 60 Patients dosed

» >200 Doses administered

» >12 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’

4

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

Genetically defined target/disease

Existing Alnylam delivery platform

Early biomarkers in Phase I

Clear and rapid development and

commercial paths

5

ALN-RSV

ALN-VSP

ALN-HTT

Core Programs

1. ALN-TTR

2. ALN-PCS

3. ALN-HPN

4. ALN-APC

5. TBA

Partner

Programs

Discovery Development Phase I Phase II Phase III

TTR-Mediated Amyloidosis

Severe Hypercholesterolemia

Hemophilia

Refractory Anemia

Program 5 (TBA)

Respiratory

Syncytial Virus

Liver Cancers

Huntington’s

Disease

Alnylam Development Pipeline

6

Partner Programs Alnylam 5x15 Programs

ALN-RSV01

ALN-TTR01

ALN-TTR02

ALN-VSP

ALN-PCS

ALN-HTT

ALN-APC

ALN-HPN

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

7

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 Targets mutant and wild-type TTR

In vivo efficacy established in multiple

pre-clinical animal models

Phase I with ALN-TTR01

IND for ALN-TTR02 in H2 ’11

ALN-TTR Therapeutic Efficacy V30M TTR Transgenic Model

ALN-TTR01 treatment results in TTR amyloid regression Treatment paradigm in animals with existing amyloid plaques

>90% Regression of existing V30M hTTR deposits in peripheral tissues

Similar animal model data in prevention paradigm

9

ALN-TTR01

Control siRNA

0

10

20

30

40

50

60

70

Sciatic

nerve

Dorsal root

ganglion

Esophagus Colon Stomach

Re

lati

ve

TT

R T

iss

ue

Le

ve

ls

Control siRNA ALN-TTR01

Dorsal Root Ganglion

100%

98.8%

98.5%

97%

98.8%

Int’l Amyloidosis Symp., April 2010

ALN-TTR01 Phase I Study 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 data in Q4’11

– International Symposium on FAP, November 20-22, 2011

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2nd Generation ALN-TTR Program ALN-TTR02

ALN-TTR02 shows >10-fold

improved in vivo efficacy in animal

models ALN-TTR02 uses 2nd generation

MC3 LNP formulation

Single i.v. infusion; Serum TTR

levels post-dosing

Potent, dose-dependent, and

durable TTR silencing

On track to file IND in H2 ’11

11

Se

rum

TT

R C

on

ce

ntr

ati

on

(%

Co

ntr

ol P

re-d

os

e)

Time (days)

0

20

40

60

80

100

120

0 5 10 15 20 25 30

ALN-TTR01

(1.0 mg/kg)

ALN-TTR02

(0.1 mg/kg)

Control

siRNA

Dose

Oligo Ther Soc., Sep 2011

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

12

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 clinical development Targets both intracellular and

extracellular PCSK9

In vivo efficacy established in multiple

pre-clinical animal models

CTA filed July 2011

Liver LDL

PCSK9

LDLr

LDL

Peripheral cells

VLDL Rem

VLDL Rem

PCSK9

PCSK9

LDLr

LDLr

LDLc

LDLc

ALN-PCS Pre-Clinical Efficacy Phenocopies Human Genetics

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

14

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

ALN-PCS Phase I Study

Study Design

Randomized, placebo-controlled, single-dose escalation study

~32 healthy volunteer subjects with elevated baseline LDLc (>116mg/dL)

» Conducted in UK

Primary objective

» Safety and tolerability

Secondary objectives

» Characterization of pharmacokinetics

» Assess preliminary pharmacodynamic activity

– Plasma PCSK9 protein and LDLc levels

Treatment regimen

» Dose levels: 0.015 to 0.25 mg/kg

Status

» Filed CTA, July 2011

– Phase I trial to be initiated upon clearance

» Expect to report human POC data in Q4’11

15

Hemophilia Program Unmet Need and Product Opportunity

RNAi to treat hemophilia

Hemophilias are recessive X-linked monogenic

bleeding disorders

» Hemophilia A defined by loss of function mutations

in Factor VIII

– >40,000 Patients in EU/US

» Hemophilia B defined by loss of function mutations

in Factor IX

– ~9,500 Patients in EU/US

Hemophilia A “inhibitor” patients define segment

of highest unmet need and cost*

» ~1/3 Patients with severe hemophilia A

» >6 Bleeds/patient/year

» >5 in-hospital days/patient/year

» >$300,000/patient/year

» Very poor quality of life

Only available therapies: rFVIIa (NovoSevenTM)

and FEIBA

» Short half-life, requiring frequent dosing

» Not optimally effective

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*Gringeri et al., Blood 2003

Protein C Target and ALN-APC Program

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Protein C (PC) is genetically defined target Activated Protein C (APC) defines key

natural anticoagulant pathway » Inactivates factors Va and VIIIa

» Attenuates thrombin generation

Heterozygous PC deficiency associated

with increased thrombin generation

Expressed in liver; circulates in plasma

ALN-APC in R2D siRNA optimization

In vivo efficacy in pre-clinical animal

models

IND Filing 2013

APC Resistance (i.e., Factor VLeiden)

Co-inheritance associated with milder

bleeding in hemophilia patients

Kurnik et al., Hematologica, 2007

No

Co-Inheritance

With

Co-Inheritance

First bleed age

(range)

0.9

(0.1– 4.0)

1.5

(0.5 – 7.1)

Annual bleeding

frequency (range)

6.0

(0 – 30)

1.8

(0 – 7)

Intrinsic system

FIXa

FVIIa FVII

FVIIIa

Extrinsic system

FVa FV

FX

FXa

Fibrinogen Fibrin

Thrombin

Hemophilia B

Hemophilia A

Prothrombin

APC PC

FIX

FVIII

Blood

clot

ALN-APC Pre-clinical Efficacy Robust and Durable Silencing After Single Dose

ALN-APC demonstrates potent efficacy after single dose Dose-dependent silencing with ED50 ~0.02 mg/kg

Rapid and durable efficacy after single injection

Significant reduction in Protein C plasma levels

Duration of effect on

Protein C mRNA

Time (days)

Pro

tein

C m

RN

A (

% C

on

tro

l P

re-d

ose

)

0

20

40

60

80

100

120

140

0 4 8 12 16

ALN-APC

(0.3mg/kg)

Control siRNA

(0.3mg/kg)

18

Reduction in

Protein C protein levels

Purified human

protein C (ng)

ALN-APC Control

siRNA

150

100

75

50

35

25

20

PC (41 KD) aPC (35 KD)

light

chain (21 KD)

100

200

500

0

20

40

60

80

100

1.0 1.0 0.3 0.1 0.03 0.01 0.003

Control

siRNA

(mg/kg)

ALN-APC (mg/kg)

Pro

tein

C m

RN

A (

% C

on

tro

l)

Dose-Dependent Silencing

of Protein C mRNA

ED50 ~ 0.02 mg/kg

siRNA

Dose Oligo Ther Soc., Sep 2011

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

» 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)

19

Hepcidin Pathway and ALN-HPN Program

20

Hepcidin pathway is genetically defined 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 for multiple

hepcidin pathway targets

In vivo efficacy in pre-clinical animal

models

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 Paths with Phase I POC

21

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

ALN-APC Significant bleeding,

hospitalizations, and

costs associated with

severe hemophilias,

including “Inhibitor” pts

• Protein C

• Thrombin

generation

• Thrombo-

elastography

Dose/regimen to

normalize thrombin

generation

Reduced #bleeds

over 6-12 mo

period

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

22

Huntington’s Disease Significant inherited

neurodegenerative disease » Caused by mutations in huntingtin gene

» 30,000 US patients; 150,000 with 50% risk

22

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 completed » Results reported at ASCO 2011

─ ALN-VSP generally well-tolerated

─ 41 Patients; ranging from 0.1 - 1.5mg/kg

─ Recommended Phase II dose is 1.0

mg/kg q2w

─ 5 Patients on extension study

» Demonstrated both clinical activity and RNAi

POM

─ 64% Disease control at Phase II dose

─ 1 PR in endometrial cancer patient

─ RNAi demonstrated in biopsy samples

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

RNAi Technologies and New Ventures

RNAi pathway

cartoon

RNAi

Bioprocessing/

Biologics

Other Non-Coding RNAs (e.g., RNAa) Vaccines

Genomics

microRNA Therapeutics

23

Stem Cells

Regulus Therapeutics Leading microRNA Therapeutics Company

Co-Founded by Alnylam and Isis

Focused on microRNA therapeutics

Key IP for microRNA therapeutics field

Lead programs Anti-miR122 for HCV infection

Anti-miR21 for heart failure/fibrosis/cancer

Anti-miR33 for hypercholesterolemia

Two partnerships with GSK Immuno-inflammatory collaboration

HCV collaboration

Partnership with sanofi-aventis 4 microRNA targets, including lead

fibrosis program targeting microRNA-21

24

>700 microRNAs in human genome Regulate expression of

> 1/3 of all human genes

Regulate entire gene networks and

biological pathways

Defines whole new frontier for

pharmaceutical research

Alnylam Biotherapeutics Enabling Innovations in the Manufacture of Biologics

Transformative for biologics manufacturing

RNAi enables production of proteins and Mabs

» Powerful and established cell biology tool applied at

scale

– Transient genetic manipulation

– Target multiple pathways specifically and rapidly

Leverage Alnylam position in RNAi

» IP estate and expertise

» Delivery technology and collaborations

Demand for improved production technology

» Integrate from early to late stage production

Formed 2 collaborations with biotech/pharma

» ~$2M of revenue in 2010

Additional collaborations expected in 2011

25

Need for Innovations

in Manufacturing Growing pipeline of biologics

» Opportunity to increase

yield and quality

New technologies needed

Financials and Goals

26

Financial Summary

2011 Q2 Financial Results Cash ~$316M

» ~$7.50 per share

GAAP Revenues ~$21M » Roche, Takeda, Cubist, and other licenses

GAAP Operating Expenses ~$34M » Includes non-cash stock-based compensation charges of ~$4M

Shares Outstanding ~43M

2011 Guidance Year-end Cash >$250M

27

Alnylam Goals Pipeline Goals 2011-2012

28

Additional Corporate Goals 2011 Additional partnerships

Year-end cash >$250M

ALN-TTR01 2012

Q4 ’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

ALN-APC 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

2013

Thank You

www.Alnylam.com

29