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November 7, 2018

Third Quarter 2018 Financial Results

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Welcome• Christine Lindenboom

Vice President, Investor Relations & Corporate Communications

Q3 2018 Overview• John Maraganore, Ph.D.

Chief Executive Officer

Alnylam Clinical Pipeline• Akshay Vaishnaw, M.D., Ph.D.

President of R&D

Commercial Highlights• Barry Greene

President

Financial Summary and Guidance• Manmeet Soni

Chief Financial Officer

2018 Goals Update• Yvonne Greenstreet, MBChB

Executive Vice President, Chief Operating Officer

Q&A Session

Agenda

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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 and successfully demonstrate the efficacy and safety of our product

candidates; pre-clinical and clinical results for our product candidates; actions or advice of regulatory agencies; delays, interruptions

or failures in the manufacture and supply of our product candidates; our ability to obtain, maintain and protect intellectual property,

enforce our intellectual property rights and defend our patent portfolio; our ability to obtain and maintain regulatory approval, pricing

and reimbursement for products; our progress in establishing a commercial and ex-United States infrastructure; successfully

launching, marketing and selling its approved products globally, its ability to successfully expand the indication for ONPATTRO in the

future; competition from others using similar technology and developing products for similar uses; our ability to manage our growth

and operating expenses, obtain additional funding to support our business activities and establish and maintain business alliances;

the outcome of litigation; and the risk of government investigations; as well as those risks more fully discussed in our most recent

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.

This presentation contains non-GAAP financial measures, including expenses adjusted to exclude certain non-cash expenses and

non-recurring gains outside the ordinary course of the Company’s business. These measures are not in accordance with, or an

alternative to, GAAP, and may be different from non-GAAP financial measures used by other companies. The items included in GAAP

presentations but excluded for purposes of determining non-GAAP financial measures for the periods presented herein are stock-

based compensation expense and the gain on litigation settlement. The Company has excluded the impact of stock-based

compensation expense, which may fluctuate from period to period based on factors including the variability associated with

performance-based grants for stock options and restricted stock units and changes in the Company’s stock price, which impacts the

fair value of these awards. The Company has excluded the impact of the gain on litigation settlement because the Company believes

this item is a one-time event occurring outside the ordinary course of the Company’s business.

Alnylam Forward Looking Statements

& Non-GAAP Financial Measures

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Q3 2018 Overview

John Maraganore, Ph.D.

Chief Executive Officer

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Goal to Bring Innovation to Patients and Markets Around World

2018

ONPATTRO is indicated in the

U.S. for the treatment of the

polyneuropathy of hereditary

transthyretin-mediated

amyloidosis in adults^

Partnered programs*: 2020-2021

Fitusiran Inclisiran

Hemophilia Hypercholesterolemia

2019 2020 2021

Givosiran Lumasiran TTRsc02

Acute hepatic

porphyrias

Primary

hyperoxaluria

Type 1

ATTR

amyloidosis

* Sanofi Genzyme is leading and funding development (post-transition) of fitusiran and will commercialize program, if successful;

The Medicines Company is leading and funding development of inclisiran and will commercialize program, if successful

^ ONPATTRO is approved in the EU for the treatment of hATTR amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy

Anticipated dates of launch based on current development timelines and assuming regulatory approval

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Alnylam Clinical Pipeline

Akshay Vaishnaw, M.D., Ph.D.

President of R&D

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Effects of Patisiran, an RNA Interference Therapeutic,

on Cardiac Parameters in Patients with Hereditary

Transthyretin-Mediated Amyloidosis:

An Analysis of the APOLLO Study

APOLLO Results Published in Leading Medical Journals

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Randomized, Open-Label Study in Hereditary ATTR Amyloidosis Patients

ALN-TTRsc02 Phase 3 Study

^ Primary endpoint for the study is at 9 months

* All-cause death and hospitalization endpoints assessed at 18 months only

Secondary Endpoints• 10-meter walk test (10-MWT)

• mBMI

• Activities of daily living (R-ODS)

• TTR reduction (within-study non-inferiority comparison)

• All-cause death and hospitalization (mITT)*

• All-cause death and hospitalization (patients w/ cardiac

involvement)*

Efficacy Assessments (vs APOLLO placebo)

Co-Primary Endpoints• Change in mNIS+7 from baseline

• Change in Norfolk QOL-DN from

baseline

Exploratory Endpoints Include

• NT-proBNP

• Echo parameters

• Technetium (select sites only,

change from baseline)

Patient Population

N ~ 160

• hATTR amyloidosis;

any TTR mutation

• Neuropathy

Impairment Score

(NIS) of 5-130

• Prior tetramer

stabilizer use

permitted

ALN-TTRsc02 25 mg SC

q3 months

Reference

Comparator

(patisiran)0.3 mg/kg

IV q3W

or

3:1

R

AN

DO

MIZ

AT

ION

ALN-TTRsc02

25 mg SC

q3 months

9-Month

Efficacy^Assessment

18-Month

EfficacyAssessment

Tre

atm

en

t E

xte

nsio

n

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Interim Results*Interim Efficacy Analysis & Safety

Interim analysis cohort• N = 43 AHP patients (41 AIP; 1 VP; 1 HCP)

• 23 randomized to givosiran; 20 randomized to placebo

• Treatment period: ≥3 months

Interim efficacy analysis (ALA levels at 3 months in AIP patients)• Statistically significant reduction in urinary ALA, relative to placebo (p < 0.001)

Safety• No deaths

• Serious Adverse Events (SAE) reported in:

• 5/23 (22%) of patients on givosiran

• 2/20 (10%) of patients on placebo

• One patient (4%) on givosiran discontinued treatment based on a protocol-defined stopping rule due to >8x ULN increase in liver transaminase, which resolved

• No treatment discontinuations in placebo group

Expect to initiate rolling NDA submission by year-end 2018

Topline results on completed Phase 3 study expected in early 2019

* Data cut-off date of August 22, 2018

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75% Mean Reduction in Urinary Oxalate

Lumasiran Phase 1/2 Study Updated Results*

* Part B data as of August 15, 2018; only data points with at least 3 contributing patients are represented; placebo data not shown due to limited valid collections† Patients randomized (3:1 drug:placebo) to placebo received subsequent dosing of lumasiran and are included in the lumasiran dosing cohort in which they were

randomized; Day 1 relative to first lumasiran dose; patient randomized to placebo 3 mg/kg quarterly received single dose of lumasiran on Day 1

Mean maximal reduction in urinary oxalate of 75% relative to baseline after lumasiran dosing in all cohorts (N=20)

Part B Safety (N=20):

• No discontinuations from study treatment

• Majority of AEs mild or moderate, unrelated to study drug

• AEs reported in >3 lumasiran patients: vomiting, pyrexia, cough (N=6); abdominal pain,

headache (N=5); rhinitis (N=4)

• No drug-related SAEs (most common: kidney stones (N=2 on lumasiran, 1 on placebo))

qMonth

†q3M

Mean [+

/-S

EM

] U

rine O

xala

te C

onte

nt

(mm

ol/24hr/

1.7

3m

2)

Lumasiran 1.0 mg/kg monthly (N=8)

Lumasiran 3.0 mg/kg monthly (N=8)

Lumasiran 3.0 mg/kg quarterly (N=4)

Day on Study

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Randomized, Double-Blind Study in Primary Hyperoxaluria Type 1 Patients

ILLUMINATE-A: Lumasiran Phase 3 Study

Patient Population

N = 30

• Adults & children ≥6 years

• Urinary oxalate excretion

≥0.7 mmol/24hr/1.73m2

• Confirmed alanine glyoxalate

aminotransferase (AGXT)

mutations

• eGFR >45 mL/min/1.73m2

2:1

Ra

nd

om

iza

tio

nLumasiran

3.0 mg/kg every 3 months

(following loading doses for patients

previously receiving placebo)

or

Lumasiran

Three monthly loading doses, then

maintenance dose of 3.0 mg/kg†

Placebo

Equivalent volume for 3 monthly

loading doses, then maintenance

6-Month Double Blind

Treatment Period 54-Month Extension Period

Secondary Endpoints• Change in 24-hour urinary

oxalate:creatinine ratio

• Proportion of patients with 24-hour urinary

oxalate leve below ULN and 1.5x ULN

• Change in eGFR

Primary Analysis at 6 Months

Primary Endpoint• Percent change in 24-hour urinary

oxalate excretion

Topline results expected in late 2019

NDA submission in early 2020

(assuming positive results)

FDA Breakthrough and EMA PRIME

Designations

† 3.0 mg/kg once monthly for 3 consecutive months (loading dose phase) followed by 3.0 mg/kg once every 3 months

(maintenance phase) starting 1 month after last loading dose

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Inclisiran & Fitusiran

Partnered Late Stage Programs

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Preliminary Fitusiran Phase 3 Program*Plan to Initiate in Early 2017

*Preliminary plans subject to further diligence and health authority feedback;

Patients in ATLAS studies will be allowed to roll over into open-label extension

• Adults and adolescents

with hemophilia A or B

with inhibitors

• On-demand

• N~50

2:1

Fitusiran

OD BPA

Endpoints:

• ABR

• Bypassing agent

(BPA) consumption

• Quality of life

• Safety

OR

• Adults and adolescents

with hemophilia A or B

with or without

inhibitors

• Prophylaxis

• N~100

FitusiranPPX

Factor/BPA

Endpoints:

• ABR

• Factor/BPA

consumption

• Quality of life

• Safety

• Adults and adolescents

with hemophilia A or B

without inhibitors

• On-demand

• N~100

2:1

Fitusiran

OD Factor

Endpoints:

• ABR

• Factor VIII or IX

consumption

• Quality of life

• Safety

OR

INCLISIRANhypercholesterolemia

FITUSIRANhemophilia and

rare bleeding disorders

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Alnylam Clinical Development PipelineFocused in 4 Strategic Therapeutic Areas (STArs):

Genetic Medicines

Cardio-Metabolic Diseases

Hepatic Infectious Diseases

CNS Diseases

1 POC, proof of concept – defined as having demonstrated target gene knockdown and/or additional evidence of activity in clinical studies2 Approved in the U.S. for the polyneuropathy of hATTR amyloidosis in adults, and in the EU for the treatment of hATTR amyloidosis in adult patients with

stage 1 or stage 2 polyneuropathy3 Includes marketing application submissions

As of September 2018

HUMAN

POC1

BREAKTHROUGH

DESIGNATIONEARLY STAGE

(IND or CTA Filed-Phase 2)

LATE STAGE (Phase 2-Phase 4)

REGISTRATION/

COMMERCIAL3

COMMERCIAL

RIGHTS

hATTR Amyloidosis2 ● Global

GivosiranAcute Hepatic

Porphyrias ● Global

FitusiranHemophilia and Rare

Bleeding Disorders ● 15-30% royalties

Inclisiran Hypercholesterolemia ● Milestones & up to

20% royalties

LumasiranPrimary Hyperoxaluria

Type 1 ● Global

ALN-TTRsc02 ATTR Amyloidosis ● Global

CemdisiranComplement-Mediated

Diseases ● Global

ALN-AAT02 Alpha-1 Liver Disease ● Subject to partner

option rights

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Limited Therapies to Prevent or Reverse Neurodegenerative Disease

RNAi Therapeutics in Development for CNS Diseases

Sequence specific target knockdown across brain and spinal cord in NHPs for two targets with single intrathecal dose*

• Confirmed siRNA uptake in several

different cell types

• Widespread distribution and

knockdown in all key anatomical

regions of brain and spinal cord tissue

• Successful translation to NHP with

robust silencing across CNS

* OTS 2018 Annual Meeting

Examples of dominantly inherited genes within

neurodegenerative diseases:

• Alzheimer’s disease

• Parkinson’s disease

• Frontotemporal dementia

• Huntington’s disease

• Amyotrophic lateral sclerosis (ALS)

• Spinocerebellar ataxia

Planned Next Steps

1st DC in late 2018

1st IND in late 2019/early 2020

1-2 INDs/year starting in 2020

Messag

e R

em

ain

ing

Lu

mb

ar

Sp

ine

Th

ora

cic

Sp

ine

Cerv

ical S

pin

e

Cere

bellu

m

Pre

fro

nta

l C

or t

ex

Tem

po

ral C

or t

ex

Hip

po

cam

pu

s

Bra

in S

tem

Liv

er

0 .0 0

0 .2 5

0 .5 0

0 .7 5

1 .0 0

1 .2 5

1 .5 0

P B S C o n tro l

C T N N B s iR N A

PBS

CTNNBTarget Gene Silencing in NHP CNS

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Commercial Highlights

Barry Greene

President

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Encouraging Initial Demand Through First 7 Weeks

ONPATTRO U.S. Launch Progress

125U.S. Patient

Start Forms

~60% from patients previously participating in patisiran EAP

NEUROLOGY CARDIOLOGY HEMATOLOGY

Start Form submissions received from key physician specialties, reflecting both

polyneuropathy & mixed patient phenotypes

Start Forms are requests submitted to Alnylam Assist patient hub to guide fulfillment of ONPATTRO prescriptions by physicians.

Submitted Start Forms do not reflect all demand.

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Global Commercialization Efforts Underway

EU and Asia in place

• EU launch underway (first

market in Germany)

• Japan team on-board

• Preparing Canada and

Switzerland

• Initiating Latin America,

starting with Brazil

Regional Support

• Market Access

• Supply Chain

Country organizations built

• Country Manager

• Medical Affairs

• Sales and Marketing

• Local Market Access

UNITED STATES CEMEA* LATIN AMERICA ASIA

* Canada, Europe, Middle East, North Africa

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U.S. Commercialization Underway

1 2 3

Diagnosis Brand Choice Treatment Experience

and Access

Unified Commercial, Market Access, & Medical Affairs teams driving disease education,

diagnosis & treatment, optimized patient experience, and access to care

TM

TM

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Financial Summary

and Guidance

Manmeet Soni

Chief Financial Officer

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Financial Summary and Guidance

2018 Q3 Financial Results

• Cash $1.27B

– Includes $44.8M in restricted investments

• ONPATTRO Net Product Revenues $0.5M

• Total GAAP Operating Costs and

Expenses $256.6M

– R&D Expenses $139.9M

– SG&A Expenses $116.6M

– Cost of Goods Sold $0.1M

• Non-GAAP Expenses

– Non-GAAP R&D Expenses* $94.2M

– Non-GAAP SG&A Expenses* $74.4M

• GAAP Net Loss $245.3M

• Non-GAAP Net Loss* $157.3M

• Shares Outstanding 101.0M

Re-Affirmed 2018 Financial Guidance

• Cash, including restricted cash and restricted

investments, of ~$1.0B

• Annual Non-GAAP Expenses

– Non-GAAP R&D Expenses* in the range of $420M to

$460M

– Non-GAAP SG&A Expenses* in the range of $280M to

$320M

* Non-GAAP measures and Non-GAAP Net Loss exclude stock-based compensation expenses

See Appendix for a reconciliation between GAAP and non-GAAP measures.

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2018 Goals Update

Yvonne Greenstreet, MBChB

Executive Vice President, Chief Operating Officer

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Alnylam 2018 Goals 2018*Early Mid Late

PATISIRAN(hATTR Amyloidosis)

Additional APOLLO Phase 3 data

FDA approval

U.S. launch

J-NDA filing

EMA approval

EU launch

Additional ROW submissions

GIVOSIRAN(Acute Hepatic Porphyrias)

Additional Phase 1/Phase 2 OLE data

ENVISION Phase 3 interim analysis topline

NDA filing

Complete ENVISION Phase 3 enrollment

FITUSIRAN(Hemophilia and RBD)

Continue ATLAS Phase 3 enrollment

ALN-TTRsc02(ATTR Amyloidosis)

Start Phase 3

INCLISIRAN(Hypercholesterolemia)

Complete ORION 9/10/11 (LDL-C) enrollment

Start ORION 4 (CVOT) Phase 3

LUMASIRAN(Primary Hyperoxaluria Type 1)

Start Phase 3

ADDITIONAL CLINICAL

PROGRAMS

Continue to advance early/mid-stage pipeline;

File new INDs; Present clinical data

*Early is Q1-Q2, Mid is Q2-Q3, and Late is Q3-Q4

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Q&A Session

Q3 2018 Financial Results

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THANK YOU

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Appendix

Q3 2018 Financial Results

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Alnylam Pharmaceuticals, Inc.Reconciliation of Selected GAAP Measures to Non-GAAP Measures

(In thousands, except per share amounts)