1

Corporate Overview

October 2015

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.

3

RNAi Therapeutics

A New Class of Innovative Medicines

• Harness natural pathway

◦ Catalytic mechanism

◦ Mediated by small interfering RNA

or “siRNA”

• Therapeutic gene silencing

◦ Any gene in genome

◦ Distinct mechanism of action vs. other drug

classes

◦ Unique opportunities for innovative

medicines

• Clinically validated platform

◦ Human POC in multiple programs

– Papers in NEJM and Lancet

4

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

mR

NA

Sil

en

cin

g

(Rela

tive t

o C

ontr

ol)

0.03 0.1 0.3

Patisiran

(MC3-LNP)

mg/kg

Control 100

80

60

40

20

0

-20

% T

TR

mR

NA

Sil

en

cin

g

(Rela

tive t

o C

ontr

ol)

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 S

ile

nc

ing

(R

ela

tive t

o P

re-d

ose)

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

5

Alnylam RNAi Therapeutics Strategy A Reproducible and Modular Path for Innovative Medicines

GCCCCUGGAGGG

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

3. Definable path to

approval and market Established endpoints

Focused trial size

Large treatment effect

Collaborative approach with

physicians, regulators,

patient groups, and payers

2. POC achieved in Phase 1 Blood-based biomarker with strong

disease correlation ◦ e.g., Serum TTR, thrombin

generation, hemolytic activity,

LDL-C, HBsAg levels

6

Alnylam Strategic Therapeutic Areas (STAr)

Genetic Medicines

• Genetically validated

liver targets for rare

orphan diseases

• High unmet needs in

focused markets

• SC dosing

• Alnylam direct

commercial in NA and

EU

• Genzyme alliance for

ROW commercial

◦ Through end-2019

Cardio-Metabolic Disease

Genetically validated liver

targets for dyslipidemia,

NASH, type 2 diabetes,

and hypertension

Development path in

genetically defined,

high unmet need

subpopulations

o Access to larger

populations thereafter

Emerging genetics

qM, qQ, or potentially

bi-annual SC dosing

Partnership opportunities

Hepatic Infectious Disease

Liver pathogen and/or

host targets

Sub-acute duration of

treatment (~12 mo)

Multiple siRNAs possible,

if needed

Defined opportunities with

very large markets

qM or qQ SC dosing

Partnership opportunities

7

8

GENETIC MEDICINES

9

Transthyretin-Mediated Amyloidosis (ATTR) Program

Progressive, debilitating monogenic disease • ATTR is significant orphan disease

◦ ~50,000 Patients worldwide

• Clinical pathology ◦ Onset ~40 to >60 yr; fatal within 2-15 years

◦ Two predominant forms – Familial amyloidotic polyneuropathy (FAP)

– Familial amyloidotic cardiomyopathy (FAC)

• Halting disease progression remains unmet need ◦ Liver transplantation required early

◦ TTR stabilizers provide modest benefit

Mutant transthyretin (TTR) is genetic cause • Autosomal dominant with >100 defined mutations

• Misfolds and forms amyloid deposits in nerves, heart, other tissues

RNAi opportunity as potentially transformative therapy • Knockdown disease-causing protein

• Aim to halt progression, possibly achieve regression

• Value proposition supported by pharmacoeconomics and cost of

disease burden

• Concentrated provider base and active patient community

Unmet Need and Product Opportunity

GENETIC MEDICINES

10

RNAi Therapeutics for ATTR Amyloidosis

Patisiran for Familial Amyloidotic

Polyneuropathy (FAP)

• Intravenous administration

• Positive Phase 2 results in FAP

patients

• Phase 2 Open-Label Extension

(OLE) study ongoing

◦ Clinical endpoints every 6 months

◦ Positive 12-month data reported at

AAN, April 2015

◦ 18-month data expected in late 2015

• Phase 3 trial ongoing

◦ Over 40 sites in over 15 countries

◦ Expect APOLLO to enable NDA

submission ~2017

◦ APOLLO-OLE ongoing

Patisiran and Revusiran

Revusiran for Familial Amyloidotic Cardiomyopathy (FAC)

• Subcutaneous administration

◦ STC “first generation” chemistry

• Positive Phase 2 study results

◦ TTR cardiac amyloidosis patients

• Phase 2 Open-Label Extension (OLE) study ongoing

◦ Clinical endpoints every 6 months

◦ Report data at least once annually

• study ongoing

◦ Prevalence of TTR mutations in suspected cardiac amyloidosis

◦ Multi-center study; up to 1,000 patients

• Phase 3 trial ongoing

• Also advancing ALN-TTRsc02

◦ ESC “second generation” chemistry

◦ Data and guidance expected at OTS, October 2015

GENETIC MEDICINES

11

*Phase 2 OLE results based on data in database as of July 15, 2015

^Collaboration with Kelly Lab at Scripps and Misfolding Diagnostics, Inc.

Adams, AAN Apr. 2015

Suhr, ANA, Sept. 2015

Months

Non-native TTR Native (tetrameric) TTR

Up to

96% TTR KD

Patisiran Phase 2 OLE Preliminary Study Results* Change in mNIS+7 at 12 Months Evidence that neuropathy progression potentially halted at 12 months • Mean decrease of 3.1 points observed

◦ Similar result in patients with/without concurrent TTR stabilizer therapy

• Compares favorably with 13 to 18 point increase estimated from historical data sets

• Sustained TTR knockdown through 18 months (mean max KD of 91%; max KD up to 96.2%)

• Generally well tolerated out to 21 months ◦ No drug-related SAEs

◦ Mild flushing (22.2%) and infusion-related reactions (18.5%) most common adverse events

◦ No significant lab findings, no drug-related discontinuations

Potent knockdown of disease-causing non-native TTR (NNTTR) species of approximately 90%^

~90% NNTTR KD

Change in mNIS+7 at 6 and 12 months

Individual Patient Data

0

50

100

150

0 6 12

mN

IS+

7

Individual Patient Data

GENETIC MEDICINES

12

APOLLO Phase 3 Study Design

OR

Patient Population

• FAP: any

TTR mutation,

Stages 1 and 2

• Neurological

impairment score

(NIS) of 5-130

• Prior tetramer

stabilizer use

permitted

Patisiran IV infusion

q3W, 0.3 mg/kg

Placebo IV infusion

q3W

Primary Endpoint

• mNIS+7 at 18 months

Secondary Endpoints

• Norfolk QOL-DN

• NIS-weakness

• mBMI

• 10-meter walk test

• COMPASS-31

Exploratory Endpoints

• EQ-5D QOL

• NIS+7

• Serum TTR levels

• Cardiac assessments

• Grip strength

• Rausch-built Overall

Disability Scale

2:1

RA

ND

OM

IZA

TIO

N

All completers eligible for patisiran treatment on Phase 3 OLE study (APOLLO-OLE)

Statistical Considerations • Placebo-estimated mNIS+7 progression rate of 17.8 points/yr

derived from natural history study of 283 FAP patients

• Study with 90% power to detect as little as 37.5% difference in ΔmNIS+7 between treatment groups with 2-sided alpha=0.05

• Blinded interim analysis (IA) of variance for sample size adjustment

• Potential IA for efficacy under consideration; regulatory discussions pending

Clinicaltrials.gov # NCT01960348

GENETIC MEDICINES

13

Revusiran Phase 2 Study Results Open label, multi-dose study in TTR cardiac amyloidosis patients

• Includes patients with FAC and senile systemic amyloidosis (SSA)

• Up to 98.2% TTR knockdown with similar effects toward WT and mutant protein

• Generally well tolerated

◦ Transient mild ISRs in 15% patients; 1 SAE (LFT increase to ~4x ULN in 1 patient, resolved with continued dosing)

◦ No study discontinuations and no changes in renal function, other lab chemistries, or hematologic parameters

◦ In Phase 2 OLE, reported 3 discontinuations due to ISRs, including some with associated diffuse rash; otherwise generally well

tolerated in broader study population

Results as of March 15, 2015; Gilmore, ACC, March 2015

Re

lati

ve

to

Ba

se

lin

e

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Days since first visit

5.0 mg/kg (n=23)

7.5 mg/kg (n=3)

Revusiran (mg/kg), qd x5; qw x5

0 10 20 30 40 50 60 70 80 90 100

Treatment N Individual

Max KD

(%)

Mean ± SD

Max KD

(%)

All 26 98.2 85.9 ± 9.2

5.0 mg/kg 23 97.7 85.1 ± 9.3

7.5 mg/kg 3 98.2 92.1 ± 5.4

GENETIC MEDICINES

14

APOLLO Phase 3 Study Design

OR

Patient Population

• Documented TTR

mutation, including

V122I or other

• Amyloid deposits

on biopsy (cardiac

or non-cardiac)

• History of heart

failure

• Evidence of

cardiac amyloid

involvement by

echocardiogram

Revusiran 500mg SC

qD x 5, then qW

for 18 mos

Placebo SC qD x 5,

then qW for 18 mos

Co-Primary Endpoints

• Change in 6-MWD at

18 months compared

to baseline

• Percent reduction in

serum TTR over 18

months

Secondary Endpoints

• Composite CV mortality

and CV hospitalization

• Change in NYHA class

• Change in Kansas City

Cardiomyopathy

Questionnaire (KCCQ)

2:1

RA

ND

OM

IZA

TIO

N

All completers eligible for revusiran treatment on Phase 3 OLE study

Statistical Considerations • Placebo-estimated decline in 6-MWD of ~140 meters over 18 months in natural history study

of 137 FAC patients (N=39 for 6-MWD data)

• 90% Power to detect as little as 39% difference in 18 mo change from baseline 6-MWD between treatment groups with significance level of p <0.05

• Un-blinded interim analysis for futility when ~50% of patients reach 18 mos

Clinicaltrials.gov # NCT02319005

GENETIC MEDICINES

15

Hemophilia and Rare Bleeding Disorders Program

High unmet needs in hemophilia and rare bleeding

disorders (RBD)

• Hemophilias are recessive X-linked

monogenic bleeding disorders

◦ Hemophilia A: loss of function in Factor VIII

– >40,000 Patients in EU/U.S.

◦ Hemophilia B: loss of function in Factor IX

– ~9,500 Patients in EU/U.S.

• Segments of high unmet need remain

◦ E.g., “Inhibitor” patients1,2

– 2,000 Patients in major markets; up to 6,000 WW

– >15-25 Bleeds/year; >5 in-hospital days/year

– ~$300,000/year avg. cost; up to $1M/year

• Hemophilia A and B represent >$9B market

◦ Premium pricing established

◦ Value supported by pharmacoeconomics

◦ Well organized patient advocacy

◦ Significant opportunity for global expansion

1 WFH 2012 Global Survey; 2 Antunes et al., Haemophilia. 20:65-72 (2014)

Unmet Need and Product Opportunity

GENETIC MEDICINES

16

Antithrombin and ALN-AT3 Program

Antithrombin (AT) is genetically defined target

• AT is key natural anticoagulant

◦ Inactivates Factor Xa and thrombin

◦ Attenuates thrombin generation

• Human AT deficiency associated with increased thrombin generation

• Expressed in liver; circulates in plasma

Co-inheritance of thrombophilic traits in hemophilia1

• Associated with milder bleeding, reduced factor requirements, fewer complications

• Includes heterozygous

• Antithrombin deficiency

• Factor VLeiden

• Protein C deficiency

• Protein S deficiency

1Kurnik et al., Haematologica; 92:982-5 (2007); Ettingshausen et al., Thromb Haemost; 85:218-20 (2001);

Negrier et al., Blood; 81:690-5 (1993); Shetty et al., Br J Haematol; 138:541-4 (2007) 2Seghal et al., Nat Med, doi:10.1038/nm.3847

AT

FIX

FVIII

FIXa

FVIIa FVII

FVIIIa

FVa FV

FX

FXa

Fibrinogen Fibrin

Thrombin Prothrombin

Blood clot

Intrinsic system Extrinsic system

Hemophilia B

Hemophilia A

FVIII

FIX

AT

ALN-AT3 in clinical development Extensive pre-clinical efficacy and safety data in

hemophilia models2

Orphan drug status in U.S./EU (HA/HB) Positive initial Phase 1 results; new Phase 1 data

at ISTH, June 20-25, 2015 Additional data expected late ’15

GENETIC MEDICINES

17

ALN-AT3 Interim Phase 1 Study Results

% A

T K

no

ck

do

wn

100

80

60

40

20

0

-20

Time (Days)

0 10 20 30 40 50 60 70

15 mcg/kg (N=3)

45 mcg/kg (N=6)

75 mcg/kg (N=3) Pe

ak

Th

rom

bin

Ge

nera

tio

n (

nM

)

Healthy Volunteers

AT KD < 33%

N=12

AT KD 33-66%

N=9

AT KD > 66%

N=2

0

50

100

150

200

250

300

350

Severe Hemophilia

N=4

Potent, dose-dependent, and durable AT knockdown at low microgram/kilogram (mcg/kg) SC doses

• Up to 86% AT knockdown and mean maximum AT knockdown of 59 ± 7% (p<0.05); durable, lasting ~60 days

Evidence for potential re-balancing of hemostasis in severe hemophilia with normalized thrombin generation and

marked improvements in whole blood clotting

• Mean thrombin generation increase of 350 ± 239% at AT knockdown >66% (p<0.05)

• Over 3-fold shortening of Clot Formation Time (CFT) in whole blood by ROTEMTM assay (p<0.05)

ALN-AT3 generally well tolerated in both healthy volunteers and hemophilia patients

• No SAEs; all AEs mild or moderate, and transient; no discontinuations

Study ongoing; additional results expected in late 2015

• New guidance to proceed directly to Phase 3 in mid-2016

Sorensen, ISTH, June 2015; Data as of June 2, 2015

AT Knockdown Thrombin Generation

GENETIC MEDICINES

18

ALN-AT3 Interim Phase 1 Study Results Exploratory Post Hoc Analysis of Bleeding

Reduced ABR associated with increased AT knockdown and thrombin generation

• In small number of patients, ABR=0 at AT knockdown >66% (p <0.001)

Maximum bleed-free interval of 114 days in severe hemophilia patient

• Patient has self-reported ABR of 22 bleeds/yr

• Timing of bleeding events correspond with level of AT knockdown and thrombin generation

• No increases in D-dimer levels throughout period

AT KD <33% AT KD 33-66% AT KD >66%

Patients 12 9 2

Cumulative

Days

509 414 106

Cumulative

Bleeds

33 18 0

ABR, Mean

(SEM)

22 ± 5 14 ± 5 0

0

4

8

12

16

20

24

28

Es

tim

ate

d A

BR

Time (Days)

100

80

60

40

20

0

-20

% A

T K

no

ck

do

wn

0 14 28 42 56 70 84 98 126 154 182

AT % Knockdown

Peak Thrombin

Bleed Event

Factor Administration

0

50

100

150

200

250

300

350

Pe

ak

Th

rom

bin

(nM

)

0

0.2

0.4

0 14 28 42 56 70 84 98 112 126 140 154 168 182

D-d

imer

(m

cg

/mL

)

Time (Days)

Sorensen, ISTH, June 2015; Data as of June 2, 2015

GENETIC MEDICINES

19

Wide range of complement-mediated diseases

• Excessive complement activity drives disease pathophysiology

in many indications

◦ Paroxysmal nocturnal hemoglobinuria (PNH)

◦ Atypical hemolytic uremic syndrome (aHUS)

◦ Neuromyelitis optica (NMO)

◦ Myasthenia gravis (MG)

◦ Many others

• SolirisTM (eculizumab) is blockbuster drug

◦ >$1.5B in reported 2013 sales

◦ >$2.1B in reported 2014 sales

New therapeutic options needed

• Consistent level of efficacy

◦ Inadequate complement inhibition demonstrated in 49% of

eculizumab-treated patients; correlated with poorer clinical outcomes1

• SC delivery for more tolerable treatment regimen

• Reduce access barriers

Complement Disease Program Unmet Need and Program Opportunity

1de Latour, Blood. 2015 Jan 29;125(5):775-83. dot: 10.1182/blood-2014-03-560540.

GENETIC MEDICINES

20

Complement C5 and ALN-CC5 Program

Complement C5 is genetically

validated target

• Key component of terminal pathway

◦ C5 cleavage releases C5a; initiates

membrane attack complex (MAC) formation

• Human C5 deficiency associated with

minimal complications

◦ Increased susceptibility to Neisserial infections

◦ Also, many C5-deficient mouse strains

• Majority expressed in liver; circulates

in plasma

Complement C5 is clinically

validated target

• Eculizumab is anti-C5 Mab

• Approved in PNH and aHUS

◦ In PNH, >80% inhibition of hemolytic activity

associated with clinical benefit1

• Potential advantages of synthesis inhibition

vs. protein binding approach

1Hillmen et al., NEJM; 350:552-9 (2004)

ALN-CC5 in clinical development

Pre-clinical efficacy in animal models

Positive initial SAD Phase 1/2 data at

EHA, June 2015

Additional data expected late ’15

Initiation

C3 Convertase

C5 Convertase

Terminal Pathway

Factor B

Alternative Pathway Classical Pathway Lectin Pathway

C3 C1

C3 C4 and C2

C3b

C3bBb C4bC2a

C3a Opsonization

Inflammation C3bBbC3b C4bC2aC3b

C5a

C5b

Membrane attack complex (MAC)

C5b-C9

ALN-CC5 C5

GENETIC MEDICINES

21

ALN-CC5 Phase 1/2 Study Dose-Escalation Study Including Patients with PNH

PART

A PART

B PART

C Study Design • Randomized, double-

blind, placebo-controlled

MAD study in healthy

volunteers (up to N=28)

Primary Objective • Safety and tolerability of

multi-dose in healthy

volunteers

Secondary Objectives • PK/PD and clinical activity

◦ C5 levels, hemolysis

suppression

Study Design • Randomized, double-

blind, placebo-controlled

SAD study in healthy

volunteers (up to N=32)

Primary Objective • Safety and tolerability of

single dose in healthy

volunteers

Secondary Objectives • PK/PD and clinical activity

◦ C5 levels, hemolysis

suppression

Study Design

• Open-label MAD study in

PNH patients (N=8)

Primary Objective

• Safety and tolerability of

multi-dose in PNH

patients

Secondary Objectives • PK/PD and clinical

activity ◦ C5 levels, hemolysis

suppression

• LDH reduction

GENETIC MEDICINES

22

ALN-CC5 Initial SAD Phase 1/2 Results

Sorensen, EHA, June 2015; data as of May 26, 2015

Potent C5 Knockdown and Inhibition of Complement Activity

Serum C5 Knockdown

C5 knockdown and complement inhibition with single dose ALN-CC5 • Potent, dose-dependent, and durable C5 knockdown up to 96%

◦ Mean maximum knockdown of 94 ± 2.0% (p <0.003 vs. placebo); n=4 for each cohort

◦ Durable effects lasting months, supportive of qM subcutaneous dose regimen

• Initial evidence for potentially clinically meaningful reduction in complement activity with single doses ◦ Complement activity (CAP and CCP) reduced up to 92%

◦ Single dose ALN-CC5 reduced serum hemolytic activity up to 61%

• ALN-CC5 generally well tolerated - all TEAEs mild in severity; no SAEs, ISRs or discontinuations as of data cutoff

% H

em

oly

sis

re

du

cti

on

Mean

(+

/- S

EM

)

Days since first visit

100

80

60

40

20

0

-20

0 10 20 30 40 50 60 70

Inhibition of Serum Hemolytic Activity

50 mg ALN-CC5 200 mg ALN-CC5 400 mg ALN-CC5 Placebo

Me

an

(+

/- S

EM

) C

5 K

no

ck

do

wn

Re

lati

ve

to

Ba

se

lin

e

100

80

60

40

20

0

-20

0 10 20 30 40 50 60 70

Days since first visit

GENETIC MEDICINES

23

Acute Intermittent Porphyria (AIP) Program

AIP is autosomal dominant disorder

• Ultra-rare orphan disease

◦ ~5,000 Patients with annual attacks U.S./EU

◦ ~500 Patients with recurrent attacks U.S./EU

High unmet need and cost

• Patients present with acute or recurrent attacks

• Limited treatment options

◦ Blood-derived hemin given IV via central line

◦ No prophylactic treatment to prevent attacks

Opportunity to treat and prevent porphyria attacks

• Orphan disease with substantial morbidity

• Value supported by significant burden of disease

• study ongoing in patients

◦ Prospective observational study to monitor attacks

RNAi therapeutics to halt disease symptoms

• Targets ALAS1, upstream of genetic defect

• Blocks toxic intermediates (ALA/PBG)

• ALN-AS1 to treat and/or prevent attacks

Unmet Need, Product Opportunity, and Program Status

GENETIC MEDICINES

24

Aminolevulinate Synthase-1 and ALN-AS1 Program

Aminolevulinate synthase-1

(ALAS1) is key regulator of pathway

• ALAS1 rate-limiting enzyme in heme

synthesis

• PBGD deficiency results in upregulation of

ALAS1 and accumulation of toxic

intermediates ALA and PBG

◦ ALA and PBG cause porphyria attacks

symptoms

• Liver ALAS1 drives disease

ALA Synthase

ALA Dehydratase

PBG Deaminase

Glycine

d-Aminolevulinic acid (ALA)

Porphobilinogen (PBG)

Succinyl CoA

+Fe2+

ALN-AS1

Acute intermittent

porphyria

Heme

ALN-AS1 in clinical development

Positive initial Phase 1 results

Phase 1 study ongoing with multi-dose cohorts

Expect transition to recurrent attack patients in

early 2016

GENETIC MEDICINES

25

Potent, dose-dependent, and durable ALAS1 mRNA silencing after single dose • ALAS1 mRNA elevated ~3-fold in asymptomatic “high excreter” (ASHE) patients with AIP

• Up to 59% silencing and up to 44 ± 8% mean (SEM) maximal silencing; p<0.01 vs. Placebo

Lowering of ALA and PBG, toxic heme synthesis intermediates that mediate attacks • Potent, dose-dependent, and durable effects

• Up to 82% and 93% lowering of ALA and PBG, respectively; Up to mean maximal reduction of 77 ± 7% for

ALA (p=0.03) and 73 ± 6% for PBG (p=0.06)

Day

Mean

(S

EM

) %

AL

AS

1 m

RN

A C

han

ge f

rom

Baselin

e

Data in database as of 02 September 2015

ALN-AS1 Initial SAD Phase 1/2 Results ALAS1 mRNA Silencing and Lowering of ALA and PBG

-100

-75

-50

-25

0

25

50

0 5 10 15 20 25 30 35 40 45

Day

Mean

(S

EM

) %

AL

A C

han

ge f

rom

Baselin

e

-100

-75

-50

-25

0

25

50

0 5 10 15 20 25 30 35 40 45

Day

Mean

(S

EM

) %

PB

G C

han

ge f

rom

Baselin

e

Treatment

Placebo

0.035 mg/kg

0.1 mg/kg

0.35 mg/kg

1.0 mg/kg

ALA PBG ALAS1 mRNA

-100

-75

-50

-25

0

25

50

0 5 10 15 20 25 30 35 40 45

GENETIC MEDICINES

26

Additional Genetic Medicine Programs

Alpha-1 Antitrypsin (AAT) Deficiency Associated Liver Disease • Commonest mutant allele (PiZZ) homozygosity results in liver cirrhosis

◦ Z-AAT protein misfolds and aggregates in hepatocytes, leading to liver injury, fibrosis, cirrhosis, hepatocellular carcinoma (HCC)

◦ WW prevalence ~12,000

• High unmet need and cost ◦ Occurs in both children and adults; limited treatment options

◦ Orphan disease with substantial morbidity; value supported by significant burden of disease

• ALN-AAT targets alpha-1antitrypsin gene in PiZZ patients

• Efficacy in pre-clinical animal models ◦ >90% AAT knockdown; Reduction in fibrosis; reduced incidence of liver tumors

• Phase 1 ongoing; initial data expected in early ’16

Primary Hyperoxaluria Type 1 (PH1) • Loss of function mutations in liver peroxisomal alanine-glyoxylate

aminotransferase (AGT) ◦ Renal damage from increased oxalate, nephrocalcinosis, and renal obstruction

• ALN-GO1 targets glycolate oxidase (GO), enzyme upstream of AGT

• Efficacy in pre-clinical animal models ◦ Up to 99% KD of liver GO mRNA; up to 98% mean reduction in urinary oxalate

◦ Pre-clinical durability supports monthly and potentially quarterlyl dosing

• DC selected; CTA filing planned late ’15; Phase 1 start expected early ’16

GENETIC MEDICINES

27

CARDIO-METABOLIC

DISEASE

28

PCSK9 and ALN-PCSsc Program

Unmet need in hypercholesterolemia

• Elevated LDL-C validated risk factor for

coronary heart disease (CHD)

• 34 million Americans have

hypercholesterolemia (> 240 mg/dL)

• Recent clinical studies

◦ Many patients on statins do not meet

LDL-C goal

◦ Lower LDL-C is better (IMPROVE-IT)

• Multiple genetically defined patient subgroups

PCSK9 is genetically validated target

• GOF mutations associated with

hypercholesterolemia and premature CHD

• LOF mutations associated

with hypocholesterolemia and decreased

CHD risk

Pearson et al., L-TAP Study, Arch Intern Med; 160:459-67 (2005),

Blazing e al Am. Heart J; 168:205 (2014)

Cohen et al., N. Engl. J. Med.; 354:1264-1272 (2006)

Plasma LDL Cholesterol (mg/dl)

0

10

20

30

WT PCSK9

0

10

20

30

50 100 150 200 250 300

LOF PCSK9

Fre

qu

en

cy (

%)

0

4

8

12

WT LOF

Co

ron

ary

Heart

Dis

ease (

%)

CHD Risk

CARDIO-METABOLIC

DISEASE

29

Initial ALN-PCSsc Phase 1 Study Results Support once-quarterly and possibly bi-annual, low volume, subcutaneous dose regimen profile

• 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)

◦ Comparable to reported results with anti-PCSK9 MAbs1

• Highly durable effects with LDL-C lowering lasting over 140 days after single injection

• Generally well tolerated with no clinically significant adverse events to date

◦ No SAEs, no drug-related discontinuations; all AEs mild or moderate

◦ At higher drug exposures, 4 mild injection site reactions (ISRs); one in SAD cohort and 3 in MD cohorts

◦ One subject with ALT ~4x ULN, attributed to concomitant statins

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

Fitzgerald, ESC, August 2015

Days/Treatments where N=1 not displayed

LDL-C analyzed by Beta-Quantification

80

60

40

20

0

Me

an

(S

EM

) %

LD

L-C

Lo

we

rin

g

(Ch

an

ge

fro

m B

ase

lin

e)

0 1 2 3 4 5 Months

Single Dose LDL-C Lowering

100

80

60

40

20

0

-20

-40

0 1 2 3 4 5

Months

Me

an

(S

EM

) %

PC

SK

9 K

no

ck

do

wn

(Ch

an

ge

fro

m B

as

eli

ne)

Placebo

25 mg

100 mg

300 mg

500 mg

800 mg

Treatment

Single Dose PCSK9 Knockdown

Day/Treatment combinations where N=1 not displayed

Placebo

25 mg

100 mg

300 mg

500 mg

800 mg

Treatment

CARDIO-METABOLIC

DISEASE

30

HEPATIC INFECTIOUS

DISEASE

31

Hepatitis B Virus (HBV) Infection

Chronic HBV (CHB) infection is significant WW problem • One third of world population infected

• 400M people with chronic disease ◦ 25M in U.S./EU

• Most unaware of infection

• High prevalence expected for next 3 decades ◦ Despite availability of HBV vaccine

Clinical manifestations severe • Chronic inflammation leading to cirrhosis and hepatocellular

carcinoma (HCC)

Current therapies not curative and have significant limitations • Reduce viral load, resulting in improved liver histology,

decrease in cirrhosis and HCC but do not eliminate virus

Future therapies aim to enable “functional cure” • Regain sustained immune control over infection, with eventual

elimination of viral cccDNA

http://www.hepb.org/hepb/statistics.htm

HEPATIC INFECTIOUS

DISEASE

32

RNAi Therapeutics for HBV

Dose-dependent antiviral response with intra-subject ascending doses • Mean 2.9 log10 decrease in viral DNA day 2-6 post 0.5 mg/kg dose ◦ >4 log10 reduction in circulating viral DNA achieved in highest titer animal

• Mean 2.0 log10 reduction in HBsAg at 0.5 mg/kg dose ◦ Up to 2.3 log10 reduction achieved

Meyers, TIDES, May 2014

Efficacy in HBV-Infected Chimpanzees

*low titer animal dropped below LLOQ from day 23-day 98

log

10 Δ

HB

sA

g

(rela

tive t

o a

vera

ge o

f pre

-dose v

alu

es)

-20 0 20 40 60 80 100 120 140 160 -3

-2

-1

0

Days

0.125 0.25 0.50

siRNA (mg/kg)

0.125 0.25 0.50

siRNA (mg/kg)

log

10 Δ

Vir

al L

oa

d

(rela

tive t

o a

vera

ge p

re-d

ose)

-20 0 20 40 60 80 100 120 140 160 -5

-4

-3

-2

0

Days

-1

A

B

C

D

Plasma Viral Load (bDNA) Plasma HBsAg (Surface Antigen)

A

B

C*

D

HEPATIC INFECTIOUS

DISEASE

33

ALN-HBV Development Candidate (DC) Potent ESC-GalNAc-Conjugate for SC Administration

HB

sA

g (

ng

/mL

)

0 10 5 0.01

0.1

1

10

100

1000

Control siRNA

0 5 10 0.01

0.1

1

10

100

1000

HB

sA

g (

ng

/mL

)

Days

Each line represents individual animal

LLOQ

ALN-HBV

Days

Each line represents individual animal

Potent, multi-log HBsAg knockdown in murine model • Mouse model with AAV-HBV vector

• ALN-HBV DC achieves potent knockdown of HBsAg ◦ Single SC dose of siRNA at 3 mg/kg; specificity confirmed with control siRNA

◦ Up to 3.9 log10 reduction; mean 1.8 log10 reduction 5-10 days after single dose

• IND filing expected in late ’15

34

Guidance and Goals

35 35

36

2015

Early Mid Late Ongoing

PATISIRAN (TTR-FAP)

APOLLO Phase 3 Accrual

Phase 2 OLE data

Start Phase 3 OLE

REVUSIRAN (TTR-FAC)

ENDEAVOUR Phase 3 Accrual

Phase 2 OLE Data

Natural History Results

ALN-AT3 (Hemophilia and RBDs)

Phase 1 Data

Start Phase 1 OLE

ALN-CC5 (Complement-Mediated Disease)

Start Phase 1/2

Initial Phase 1/2 Data

Enroll PNH Patients in Phase 1/2 Study

ALN-AS1 (Hepatic Porphyrias)

Start Phase 1

Initial Phase 1 Data

ALN-AAT (Alpha-1 Antitrypsin Deficiency)

IND Filing

Start Phase 1

ALN-GO1 (Primary Hyperoxaluria)

Development Candidate

IND Filing

ALN-PCSsc (Hypercholesterolemia)

Initial Phase 1 Data

Start Phase 2

ALN-HBV (Hepatitis B Virus Infection)

IND Filing

* Early is Q1-Q2, Mid is Q2-Q3, and Late is Q3-Q4; **IND or IND equivalent

Alnylam 2015 Pipeline Goals

36

37

Select Scientific and Clinical Meetings

ALN-PCSsc European Society of Cardiology (ESC) August 29-September 2 (London)

ALN-GO1 European Society for Paediatric Nephrology (ESPN) September 3-5 (Brussels)

ALN-AS1 International Congress of Porphyrins and Porphyrias

(ICPP) September 12-16 (Dusseldorf)

Patisiran American Neurological Association (ANA) September 27-29 (Chicago)

ALN-TTRsc02 Oligonucleotide Therapeutics Society (OTS)* October 11-14 (Leiden, The Netherlands)

Patisiran

Revusiran European Congress of ATTR Amyloidosis* November 2-3 (Paris)

ALN-PCSsc American Heart Association (AHA)* November 7-11 (Orlando)

ALN-HBV American Association for the Study of Liver Diseases

(AASLD, “The Liver Meeting”®) November 13-17 (San Francisco)

ALN-AT3

ALN-CC5 American Society of Hematology (ASH)* December 5-8 (Orlando)

Mid-to-Late ’15

* Pending abstract acceptance

38

Financial Summary and Guidance

2015 Q2 Financial Results

• Cash ~$1.40B

• GAAP Revenues $8.7M

• Total GAAP Operating Expenses $81.6M

◦ Research and Development Expense $67.0M

◦ General and Administrative Expense $14.6M

• GAAP Net Loss of $71.8M

• Shares Outstanding ~84.5M

2015 Guidance

• Year-end cash >$1.2B

39

Thank You

www.alnylam.com