Alnylam Pharmaceuticals : HELIOS-B Topline Results

Positive Topline Results from HELIOS-B Phase 3 Study of Vutrisiran

June 24, 2024

© 2024 Alnylam Pharmaceuticals, Inc.

Agenda

Welcome

• Christine Lindenboom
  Senior Vice President, Investor Relations & Corporate Communications

Introduction

• Yvonne Greenstreet, MBChB, MBA Chief Executive Officer

HELIOS-B Topline Results

• Pushkal Garg, M.D. Chief Medical Officer

Commercialization Strategy

• Tolga Tanguler
  Chief Commercial Officer

Q&A Session

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. All statements other than historical statements of fact regarding Alnylam's expectations, beliefs, goals, plans or prospects including, without limitation, Alnylam's estimations regarding the size of the potential patient population and the number of patients who are dissatisfied with their current treatment regimens; Alnylam's expectations regarding the safety and efficacy of vutrisiran for the treatment of ATTR amyloidosis with cardiomyopathy, including its potential to be standard of care in ATTR-CM; the potential for vutrisiran to halt disease progression that patients experience with ATTR-CM, including across key measures of disease burden; the potential for vutrisiran to obtain regulatory approval for the treatment of ATTR amyloidosis with cardiomyopathy; Alnylam's belief that vutrisiran is well positioned to address unmet medical need as the first and only RNAi therapeutic for both polyneuropathy and cardiomyopathy manifestations of ATTR amyloidosis; the expected timing of the presentation of full data from the HELIOS-B clinical trial and the filing of a U.S. Supplemental New Drug Application for vutrisiran; Alnylam's plans to use a Priority Review Voucher in connection with the Supplemental New Drug Application for vutrisiran; the potential for vutrisiran's clinical profile to support first-line positioning in newly diagnosed patients and in those patients who continue to experience disease progression with stabilizers; the potential for vutrisiran to have a market-leading profile in ATTR-CM; and the potential for vutrisiran to unlock future growth and value creation should be considered forward-looking statements.

Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation, risks and uncertainties relating to: Alnylam's ability to successfully execute on its "Alnylam P5x25 " strategy; Alnylam's ability to successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for Alnylam's product candidates, including vutrisiran; actions or advice of regulatory agencies and Alnylam's ability to obtain regulatory approval for its product candidates, including vutrisiran, as well as favorable pricing and reimbursement; successfully launching, marketing and selling Alnylam's approved products globally; and any delays, interruptions or failures in the manufacture and supply of Alnylam's product candidates or its marketed products; as well as those risks more fully discussed in the "Risk Factors" filed with Alnylam's 2023 Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC), as may be updated from time to time by Alnylam's subsequent Quarterly Reports on Form 10-Q and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

3

Yvonne Greenstreet, MBChB, MBA Chief Executive Officer

Introduction

4

POSITIVE TOPLINE RESULTS

5

6

Pushkal Garg, M.D.

Chief Medical Officer

HELIOS-B Topline Results

7

ATTR Amyloidosis

Rare, Progressively Debilitating, and Fatal Disease

Description

Caused by a misfolded transthyretin (TTR) protein that accumulates as amyloid deposits in multiple tissues including heart, nerves, and GI tract1

Hereditary ATTR (hATTR) Amyloidosis

~50,000

patients worldwide2

Wild-Type ATTR (wtATTR) Amyloidosis

~200,000-300,000

patients worldwide3

1. Coelho T, et al. N Engl J Med. 2013;369(9):819-829

Protein synthesis

RNAi therapeutics target

disease upstream via

rapid knockdown

of TTR

Proteolysis

• dissociation
  Misfolding

Aggregation & deposition

2. Ando, et al. Orphanet J Rare Dis, 2013; Ruberg, et al. Circulation, 2012 (includes hATTR amyloidosis patients with polyneuropathy and cardiomyopathy); Gertz, et al. Am J Manag Care. 2017;23:S107-S112

8 3. Information based on Alnylam modeling data

Vutrisiran Phase 3 Study

Randomized, Double-Blind Outcomes Study in ATTR Amyloidosis Patients with Cardiomyopathy

N = 655

Patient Population

• ATTR amyloidosis; wild- type or any TTR mutation
• Confirmed cardiomyopathy and medical history of symptomatic heart failure
• NYHA ≤ III; minimum walk and NT-proBNP limits at baseline
• 40% of patients on tafamidis at baseline

1:1 RANDOMIZATION*

Vutrisiran

SC q3M

25 mg

or

Placebo

SC q3M

Primary Endpoint

• Composite outcome of all-cause mortality and recurrent CV events up to 36 months, in:
• • Overall population
  • Monotherapy population

Secondary Endpoints

• 6-MWTdistance (change from baseline at month 30)
• KCCQ score (change from baseline at month 30)
• All-causemortality (up to month 42)
• NYHA Class (percent stable or improved at month 30)

Positive topline results reported June 2024

sNDA submission using Priority Review Voucher

expected late 2024

ClinicalTrials.gov Identifier: NCT04153149

9 * Randomization stratified by: 1) baseline tafamidis use (yes versus no); 2) ATTR disease type (hATTR versus wtATTR amyloidosis with cardiomyopathy); and 3) NYHA Class I or II and age <75 years versus all other.

Prespecified Primary and Secondary Endpoint Structure

Overall population	Monotherapy population
(N=654)	(N=395)
PRIMARY ENDPOINT
Composite outcome of all-cause mortality
and recurrent CV events up to 36 months
SECONDARY ENDPOINT
6-minute walk test (6-MWT)
(change from baseline at 30 months)
Kansas City Cardiomyopathy Questionnaire (KCCQ)
(change from baseline at 30 months)
All-cause mortality
(up to 42 months)
New York Heart Association (NYHA) Class
(% stable or improved at 30 months)

10 Note: The safety and efficacy of AMVUTTRA (vutrisiran) for the treatment of ATTR amyloidosis with cardiomyopathy have not been established or evaluated by the FDA, EMA or any other health authority.