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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.

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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

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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

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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

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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

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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

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Alnylam Reproducible and Modular Platform Strategic Framework for Innovative Medicines

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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%

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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

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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

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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

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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

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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

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>10 Clinical

readouts in 2016

Potential Multi-Year Pipeline Progression

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>5 Programs in Phase 3 in

2017

Potential Multi-Year Pipeline Progression

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1st Phase 3 data readout

and, if positive,

NDA in 2017

Potential Multi-Year Pipeline Progression

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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

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Thank you! http://www.alnylam.com/capella/

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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