illuminate-a phase 3 study of lumasiran

1© 2019 Alnylam Pharmaceuticals, Inc.

December 17, 2019

ILLUMINATE-A Phase 3 Study of LumasiranTopline Results

BensonLiving with Primary

Hyperoxaluria Type 1

2

Agenda

Welcome

• Christine Lindenboom

Vice President, Investor Relations & Corporate Communications

Introduction

• John Maraganore, Ph.D.

Chief Executive Officer

Disease Overview & ILLUMINATE-A Topline Results

• Akshay Vaishnaw, M.D., Ph.D.

President of R&D

Commercial Preparedness & Next Steps

• Barry Greene

President

Q&A Session

3

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 and successfully demonstrate the efficacy and safety of our product candidates, including lumasiran;

pre-clinical and clinical results for our product candidates, including lumasiran; actions or advice of regulatory agencies, including with

respect to lumasiran; delays, interruptions or failures in the manufacture and supply of our product candidates, including lumasiran;

intellectual property matters including potential patent litigation relating to our platform, products or product candidates, including lumasiran;

the timing of regulatory submissions for our product candidates, including lumasiran, and our ability to obtain and maintain regulatory

approval, pricing and reimbursement for such products, including lumasiran; our progress in continuing to establish a commercial and ex-

United States infrastructure; our ability to successfully launch, market and sell our approved products globally, including lumasiran, if

approved by regulatory agencies; competition from others using similar technology and developing products for similar uses, including for

the treatment of PH1; 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 or risks 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. The safety and efficacy of lumasiran are being evaluated in the ILLUMINATE Phase 3 program and have not yet been reviewed

by the FDA, EMA or any other regulatory agency. 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.

4

John Maraganore, Ph.D.

Chief Executive Officer

Introduction

5

Lumasiran Registrational ProgramRobust Registrational Program to Evaluate Lumasiran Across all Ages and Full PH1 Disease Spectrum

EAP - NCT04125472

Expanded Access Protocol (EAP) for PH1 patients at least 6 years old

with preserved renal function recently initiated in U.S.

Double-blind,

placebo-controlled

trial in PH1

patients at least 6

years old with

preserved renal

function

Single arm, open-

label study in PH1

patients less than

6 years old with

preserved renal

function

Single arm, open-

label study in PH1

patients with

impaired renal

function, including

advanced disease

Eloise Viola, living with PH1

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POS for Alnylam RNAi Therapeutic PlatformComparison of Historical Industry Trial Metrics to Alnylam Portfolio***

* Wong et al., Biostatistics (2019) 20, 2, pp. 273–286

** Alnylam programs biomarker-driven at all stages of development (100%) *** Past rates of Alnylam and industry respectively may not be predictive of the future

Probability of Success (POS) by Phase Transition

Factors likely contributing to higher rates of Alnylam success

• All programs start against genetically validated target (vs. historical industry rate of 2%)*

• Biomarkers integral to all programs (vs. historical industry rate of 7%)*

• Phase 1 data on target engagement and appropriate dose/regimen for further development

35.227.4

59.0

5.5

44.538.6

60.2

10.0

83.387.5

80.0

58.4

0

10

20

30

40

50

60

70

80

90

100

% POS, Phase 1 to 2 % POS, Phase 2 to 3 % POS, Phase 3 % POS, Cumulative

Industry (overall)* Industry (biomarker-driven programs)* Alnylam**

Pe

rce

nt P

OS

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Multiple Launches Planned in Next 12-24 Months

* Sanofi Genzyme is leading and funding development of fitusiran and will commercialize fitusiran, if successful;

The Medicines Company is leading and funding development of inclisiran and will commercialize Inclisiran, assuming regulatory approvals

ONPATTRO is approved in Canada for the polyneuropathy of hATTR amyloidosis in adults, the EU for the treatment of hATTR amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy, and Japan for the treatment of transthyretin (TTR) type familial

amyloidosis with polyneuropathy; For additional information on ONPATTRO, see Full Prescribing Information † Alnylam has filed for marketing authorization for givosiran in Europe and Brazil and plans to file in Japan and other countries in 2020; For additional information on GIVLAARI, see Full Prescribing Information

Anticipated dates of launch based on current development timelines for investigational therapeutics and assuming positive pivotal study data and regulatory approval.

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

Inclisiran Fitusiran

Hypercholesterolemia Hemophilia

NDA/MAA planned Phase 3 enrolling

2020 2021

Lumasiran Vutrisiran

Primary hyperoxaluria type 1 ATTR amyloidosis

NDA/MAA planned Phase 3 enrolling

2019

GIVLAARI is indicated in the

U.S. for the treatment of adults

with acute hepatic porphyria† Ph3 Ph3

Robust pipeline fuels sustainable product launches beyond 2021,

leveraging global commercial infrastructure

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4

144

6

9

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

President of R&D

Disease Overview &

ILLUMINATE-A Topline Results

ClaireDiagnosed with Primary

Hyperoxaluria Type 110

Primary Hyperoxaluria Type 1

Description

Rare autosomal recessive disorder

of increased oxalate synthesis

resulting in kidney stones and renal

failure, with subsequent oxalate

accumulation in extra-renal tissues

Onset generally

pediatricvery limited treatment options

Patient Population

~3,000 – 5,000U.S./EU

Retinal Oxalosis

Cardiomyopathy

Skeletal

Involvement

Nephrocalcinosis

Renal stones

ESRD

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Primary Hyperoxaluria Type 1 and Lumasiran Therapeutic Hypothesis

HAO1, hydroxyacid oxidase 1

Liebow A, et al. J Am Soc Nephrol. 2017.

The safety and efficacy of lumasiran have not been evaluated by the U.S. Food and Drug Administration (FDA) or any other health agencies.

Lumasiran Therapeutic Hypothesis:

PH1 enzymatic defect

Lumasiran

Pathophysiology:

• Due to defect in liver peroxisomal enzyme

alanine:glyoxylate aminotransferase (AGT)

Lumasiran (ALN-GO1):

• Investigational SC-administered small

interfering RNA (siRNA)

‒ Harnesses natural RNA interference (RNAi)

mechanism

Therapeutic Hypothesis:

• Lumasiran targets the mRNA for HAO1

which encodes glycolate oxidase (GO) in

the liver; the decreased production of GO

reduces hepatic oxalate production

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

Lumasiran Phase 3 Study

† 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

ILLUMINATE-B: global Phase 3 pediatric study in patients under six years of age; ILLUMINATE-C: single-arm, open-label study in patients with impaired renal function

Lumasiran

3xqM loading dose,

then q3M

3.0 mg/kg SC†

Placebo

3xqM loading dose,

then q3M SC

or

2:1

RA

ND

OM

IZA

TIO

N

Open-Label

Extension

Patient Population

• Adults & children ≥6 years

• Urinary oxalate excretion ≥0.7

mmol/24hr/1.73m2

• Confirmed alanine glyoxylate

aminotransferase (AGXT) mutations

• eGFR >30 mL/min/1.73m2

Primary Endpoint

• Percent change from

baseline in 24-hour

urinary oxalate excretion

averaged from months 3

to 6

FDA Breakthrough and

EMA PRIME Designations

NDA and MAA filings

expected in early 2020

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Topline Efficacy Results


Primary Endpoint p-value

Percent change from baseline in 24-hour urinary oxalate excretion averaged across months 3 to 6

relative to placebo1.69 x 10 -14

Tested Secondary Endpoints p-value

Absolute change from baseline in 24-hour urinary oxalate corrected for body surface area (BSA),

averaged across months 3 to 61.23 x 10 -11

Percent change from baseline in 24-hour urinary oxalate:creatinine ratio, averaged across months 3 to 6 5.03 x 10 -10

Percent change from baseline in plasma oxalate averaged across months 3 to 6 2.86 x 10 -8

Proportion of patients with 24-hour urinary oxalate level ≤ 1.5x ULN at month 6 8.34 x 10 -7

Proportion of patients with 24-hour urinary oxalate level ≤ ULN at month 6 0.001

Absolute change from baseline in plasma oxalate averaged across months 3 to 6 3.89 x 10 -7

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Topline Safety Results


• No serious or severe adverse events

• Lumasiran generally well tolerated

• Most common adverse events were injection site reactions

– All mild and transient

• Overall profile generally consistent with previously reported results from

lumasiran Phase 1/2 and OLE studies

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Barry Greene

President

Commercial Preparedness &

Next Steps

16

Planned Next Steps for Lumasiran

2020 20212019

Topline ILLUMINATE-B

Results Expected Mid-2020

ILLUMINATE-A Enrollment

Completed Jun. 2019

NDA/MAA Filings

Early 2020

Potential Approval: U.S. & EU

Late 2020

Positive Topline ILLUMINATE-A

Results Dec. 2019

Topline ILLUMINATE-C

Results Expected 2021

Detailed ILLUMINATE-A Results

Mar. 2020 (OxalEurope)

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Ultra-Rare Orphan Disease with Potential First-in-Class/Best-in-Class Medicine

Lumasiran Market Opportunity

1 Cochat P, et al. N Engl J Med. 2013;369:649-6582 Hopp R, et al. J Am Soc Nephrol. 2015;26:2559-25703 Harambat J, et al. Kidney Int. 2010;77(5):443-449

>$500M potential market opportunity

LUMASIRAN | PRIMARY HYPEROXALURIA TYPE 1

COST BURDEN

$1M+

average cost (transplant &

lifelong immunosuppression)

DISEASE BURDEN

30–65%

reach end-stage renal

disease before diagnosis3

PREVALENCE

~3–5K

patients in U.S./EU1

DIAGNOSIS

~50%

currently diagnosed2; mean time

to diagnosis ~6 years3

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Increasing PH1 Awareness Education Initiatives Developed for Physicians

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Launch of Children’s Animation Video Series for PH1

• First-of-its-kind animated video series for kids about kids living with

PH1; fills a significant gap in educational content for young patients

• 4-part video series; extensions in development

• Enthusiastic reception from PH1 community

• Developed in partnership with the Oxalosis & Hyperoxaluria

Foundation (OHF)

Learn more at ph1ofakind.com

Kim Hollander – Executive Director, OHF

The emotions children experience when diagnosed with PH1 can be overwhelming. Many parents are left searching for ways to explain what’s going on to not only their small children, but also the people who make up their support system. I’m so excited to see PH1 of a Kind come to life – it will be an incredibly valuable resource that this community so very much needs and deserves.

“

“

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ILLUMINATE-A Topline Results

Q&A Session

illuminate-a phase 3 study of lumasiran

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