Fourth Quarter and Full Year 2016 Financial Results February 8, - PowerPoint PPT Presentation

Colin Living with Porphyria Fourth Quarter and Full Year 2016 Financial Results February 8, 2017 1

Agenda Welcome • Christine Regan Lindenboom Vice President, Investor Relations & Corporate Communications Q4 2016 Overview • John Maraganore, Ph.D. Chief Executive Officer Alnylam Clinical Pipeline • Akshay Vaishnaw, M.D., Ph.D. Executive Vice President of R&D Financial Results • Michael Mason Vice President, Finance and Treasurer 2017 Goals Update • Barry Greene President 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. 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; 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 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

John Maraganore, Ph.D. Chief Executive Officer Q4 2016 Overview 4

Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D Alnylam Clinical Pipeline 5

Alnylam ATTR Amyloidosis Portfolio Committed to Continued Innovation for Patients Patisiran ALN-TTRsc02 • IV administration • ESC “second generation” chemistry • Phase 2 completed • Anticipate quarterly SC dose • Phase 3 trial regimen ongoing; fully enrolled with top- • Phase 1 ongoing; initial positive line results expected in mid- 2017 data presented December 2016 • APOLLO-OLE study ongoing 6

ALN-TTRsc02 Phase 1 Preliminary Study Results* Single Ascending Dose Study in Healthy Volunteers 1.4 1.4 1.2 1.2 Mean [+/- SEM] TTR Relative to Baseline 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 Days since first dose Cohort Placebo (N=12) TTRSC02 (5mg) (N=6) TTRSC02 (25mg) (N=6) TTRSC02 (50mg) (N=6) TTRSC02 (100mg) (N=6) TTRSC02 (200mg) (N=6) TTRSC02 (300mg) (N=6) Max TTR knockdown of 98.4% with mean max of 97.1 ± 0.5% Most potent Alnylam investigational RNAi therapeutic to date *Data cut-off 26Oct2016; reported at Alnylam R&D Day in December 2016; no SAEs or discontinuations due to AEs; 7 all AEs mild or moderate

Fitusiran for Hemophilia Potential to Restore Hemostasis in Hemophilia Genetically validated, Biomarker for POC Definable path to approval liver-expressed target gene in Phase 1 and patient access Established Endpoint Plasma Biomarkers Hemophilia A FVIIa FVII Annualized Bleeding Rate (ABR) AT Lowering, FX FVIII FVIIIa Thrombin Generation 140 100 AT % Lowering Hemophilia B Peak Thrombin 120 FIX FIXa FIX 80 AT 100 Peak Thrombin (nM) AT FXa AT Activity (%) 60 80 FVa FV 60 40 Thrombin Prothrombin 40 20 20 Photo courtesy of Guy Young, M.D. Fibrinogen Fibrin Director, Hemostasis & Thrombosis Center at Children's Hospital Los Angeles and Professor of Pediatrics, USC 0 0 Keck School of Medicine -30 0 Days 60 120 Blood clot 8 Fitusiran Phase 1 results: Pasi et al. , WFH , July 2016

Fitusiran Interim Phase 1 Study Results* Ongoing Study in Hemophilia A & B Patients, Including Inhibitors Thrombin Generation by AT lowering Quartiles in Patients with Inhibitors Median ABRs in Patients with Inhibitors 35 250 31 Boxes denote median and interquartile range 30 Peak Thrombin Generation (nM) 200 25 150 20 Median ABR 15 100 10 6 50 5 0 0 0 AT Lowering AT Lowering AT Lowering AT Lowering N=4 Fitusiran < 25% 25-50% 50-75% >= 75% Pre-Study Onset qM SC (N=16) (N=10) (N=14) (N=16) Healthy Patients with Hemophilia with Inhibitors Volunteers DURABILITY Initial Evidence for Potential Restoration of Hemostasis Monthly SC fixed in Severe Hemophilia A and B dose regimen PLANNED NEXT STEPS Safety: Generally well tolerated with up to 14 months of dosing (N=32) • No drug-related SAEs; all AEs mild or moderate in severity Start ATLAS Phase 3 o Mild ISRs in 11 (34%) patients • No thromboembolic events; no lab evidence for pathologic clot formation studies • ALT increases >3x ULN observed in 6 (19%) patients o All asymptomatic, with no concurrent elevations of bilirubin >2x ULN in early 2017 o Reversible; all patients had medical history of HCV • No instances of anti-drug antibody formation Alnylam, Sanofi Genzyme 50-50 US/Can/Western Europe; Sanofi Genzyme ROW 9 *Clinical results as of Oct 6, 2016; Pasi et al. , Ragni et al., ASH , December 2016

Preliminary Fitusiran ATLAS Phase 3 Program* Plan to Initiate in Early 2017 Endpoints: • Adults and adolescents Fitusiran • ABR with hemophilia A or B • Bypassing agent 2:1 with inhibitors (BPA) consumption • On-demand OR • Quality of life • N~50 OD BPA • Safety Endpoints: • Adults and adolescents Fitusiran • ABR with hemophilia A or B • Factor VIII or IX 2:1 without inhibitors consumption OR • On-demand • Quality of life • N~100 OD Factor • Safety • Adults and adolescents Endpoints: with hemophilia A or B • ABR with or without PPX • Factor/BPA Fitusiran inhibitors Factor/BPA consumption • Prophylaxis • Quality of life • • N~100 Safety All completers will be eligible for fitusiran treatment in Phase 3 OLE study (ATLAS-OLE) 10 *Preliminary plans subject to further diligence and health authority feedback

Givosiran for Acute Hepatic Porphyrias Potential to Prevent Debilitating Attacks Genetically validated, Biomarker for POC Definable path to approval liver-expressed target gene in Phase 1 and patient access Potential Endpoints Serum and Urinary Biomarkers • Annualized attack rate ALA and PBG ALAS1 • ALA and PBG levels upstream of genetic defect -40 Placebo 0.35 mg/kg Mean (SEM) % ALA Knockdown 0.035 mg/kg 1.0 mg/kg -20 0.1 mg/kg 2.5 mg/kg 0 20 40 Up-regulation of ALAS1 60 80 100 0 1 2 3 4 5 6 7 8 9 10 Accumulation of toxic Time (Months) intermediates ALA and PBG 11 Givosiran Interim Phase 1 results: Sardh et al. , ASH , December 2016

Givosiran Interim Phase 1 Study Results* Ongoing Randomized, Double-Blind, Placebo-Controlled Study in Recurrent Attack Porphyria Patients Up to Maximum 86% 74% 75% Attack Free Interval lowering of ALA, Mean Decrease in Mean Decrease in 10.5x 95% Annualized Annualized lowering of PBG Attack Rate Hemin Use Relative to Run-In in ASHE subjects DURABILITY Initial Evidence for Clinical Activity in Recurrent Attack Monthly and possibly quarterly SC dose regimen Porphyria Patients PLANNED NEXT STEPS Safety: Generally well tolerated (N=8) • No discontinuations due to AEs Additional data from Phase 1 • Majority of AEs mild-moderate in severity • No clinically significant changes in vital signs, EKG, clinical laboratory in mid- 2017 parameters or physical examination Start Phase 3 • After data transfer date, one patient in blinded cohort experienced SAE of acute pancreatitis complicated by pulmonary embolism resulting in in late 2017 death, considered unlikely related to givosiran or placebo Alnylam retains global rights to the givosiran program 12 *Interim Phase 1 study results as of Nov 7, 2016; Sardh et al. , ASH , December 2016