Corporate Overview November 2017 1 Alnylam Forward Looking - PowerPoint PPT Presentation

Colin Living with Porphyria Corporate Overview November 2017 1

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. 2

RNAi Therapeutics New Class of Innovative Medicines Harness natural pathway Catalytic mechanism Silence any gene in genome Upstream of today’s medicines Clinically proven approach 3

Alnylam Platform and R&D Safety Building a Pipeline of Potentially Transformative Medicines Genetically validated, Biomarker for Definable path liver-expressed POC in to approval and target gene Phase 1 patient access 4

Alnylam Clinical Development Pipeline Focused in 3 Strategic Therapeutic Areas (STArs): Genetic Medicines Cardio-Metabolic Diseases HUMAN POC* REGISTRATION/ COMMERCIAL Hepatic Infectious Diseases EARLY STAGE LATE STAGE COMMERCIAL RIGHTS (IND or CTA Filed-Phase 2) (Phase 2-Phase 3) ● US, Canada, Hereditary ATTR Patisiran Amyloidosis Western Europe ● 50% Hemophilia and Rare Fitusiran** US, Canada, Bleeding Disorders Western Europe ● Milestones & Inclisiran Hypercholesterolemia Royalties ● Acute Hepatic Givosiran Global Porphyrias ● Complement- Cemdisiran Global Mediated Diseases ● Subject to Primary ALN-GO1 partner option Hyperoxaluria Type 1 rights ● Subject to Hereditary ATTR ALN-TTRsc02 partner option Amyloidosis rights *POC, Proof of concept - defined as having demonstrated target gene knockdown and/or additional evidence of activity in clinical studies 5 **Fitusiran currently on hold with intent to resume dosing as soon as possible upon agreement with regulatory authorities on risk mitigation/safety monitoring

Leo Living with hATTR Amyloidosis Hereditary ATTR Amyloidosis Patisiran 6

Hereditary ATTR (hATTR) Amyloidosis PATIENT POPULATION* DESCRIPTION ~50,000 Orphan multi-system disease caused by mutant transthyretin (TTR) amyloid deposits in worldwide CNS nerves, heart, GI tract, Ocular and other tissues Nephropathy Cardiovascular GI Significant morbidity and fatal within 2-15 A utonomic neuropathy Peripheral sensory-motor neuropathy years from symptom onset Image based on Conceicao et al ., J Peripher Nerv Syst, 2016;21:5 – 9 7 *Ando et al., Orphanet J Rare Dis, 2013; Ruberg et al., Circulation, 2012

Patisiran for hATTR Amyloidosis Potential for Disease Modification by Reducing Pathogenic Protein Genetically validated, Biomarker for POC Definable path to approval liver-expressed target gene in Phase 1 and patient access Established Endpoint Neurological Impairment Score Serum Biomarker TTR mNIS+7 Postural BP -40 % Mean Serum TTR KD Relative to BL 304 or HRdb (2) -20 Reflexes (20) Nerve Conduction 0 Studies (10) Quantitative Sensory Testing (80) 20 40 Mutant Transthyretin (TTR) is 60 Placebo 0.15 mg/kg disease-causing protein 0.01 mg/kg 0.30 mg/kg 80 0.05 mg/kg 0.50 mg/kg Motor Control siRNA 0.4 mg/kg strength/weakness 100 0 5 10 15 20 25 30 35 40 45 50 55 60 (192) Study Day 8 0 Patisiran Phase 1 results: Coelho et al., N Engl J Med ;369:819-29 (2013)

APOLLO Phase 3 Study Design Primary Endpoint • Change in mNIS+7 from baseline at 18 months Patisiran 0.3 mg/kg IV Secondary Endpoints • Norfolk QOL-DN q3w* Patient Population 2:1 RANDOMIZATION † • NIS-weakness • hATTR amyloidosis: any • R-ODS TTR mutation, FAP • 10-meter walk Stage 1 or 2 • mBMI or • Neurological impairment • COMPASS-31 score (NIS) of 5-130 Select Exploratory Endpoints • Prior tetramer stabilizer • EQ-5D QOL use permitted • NIS+7 Placebo • Serum TTR levels IV q3W* • Cardiac assessments • Grip strength • Skin biopsies for nerve fiber density and amyloid ClinicalTrials.gov Identifier: NCT01960348 † Stratification factors for randomization include: neuropathy impairment score (NIS: < 50 vs. ≥ 50), early onset V30M (< 50 ye ars of age at onset) vs. all other mutations (including late onset V30M), and previous tetramer stabilizer use (tafamidis or diflunisal) vs. no previous tetramer stabilizer use *To reduce likelihood of infusion-related reactions, patients receive following premedication or equivalent at least 60 min before each study drug infusion: dexamethasone; oral acetaminophen/paracetamol; H2 blocker (e.g., ranitidine or famotidine); and H1 blocker (e.g., diphenhydramine). 99% of patients who completed APOLLO study enrolled in Global OLE Study OLE, open-label extension; ClinicalTrials.gov Identifier: NCT02510261 9 Adams D, et al. BMC Neurology 2017

APOLLO Phase 3 Study Results Patisiran Meets Primary and all Secondary Endpoints mNIS+7 at 18 mos Norfolk-QOL at 18 mos • -6.0 point change relative to baseline • -6.7 point change relative to baseline • 34.0 point difference relative to placebo • 21.1 point difference relative to placebo 35 20 • 56.1% of patients improved • 51.4% of patients improved LS mean (SEM ) ∆Norfolk -QOL from baseline 30 LS mean (SEM ) ∆mNIS +7 from baseline 15 25 20 10 15 5 10 Worse p=1.10 x 10 -10 5 0 Better Worse p=9.26 x 10 -24 0 Better -5 -5 -10 -10 Baseline 9 Months 18 Months Baseline 9 Months 18 Months Placebo Patisiran mNIS+7 reference range: 0-304 points Norfolk-QOL reference range: -4 to 136 10 *Improvement defined as patients with <0 point increase from baseline to 18 months

APOLLO Phase 3 Study Results Patisiran Meets Key Exploratory Endpoints in Cardiac Subpopulation* Biomarker Echocardiographic Functional LV Wall Longitudinal NT-proBNP 10MWT Thickness Strain Worse Worse Worse Better 350 0.12 1.5 0.4 300 0.1 1.25 Mean ∆ LV wall thickness from baseline at 18 mos (cm) Mean ∆l ongitudinal strain from baseline at 18 mos (%) Mean ∆ 10-MWT gait speed from baseline at 18 mos Median ∆ NT-proBNP from baseline at 18 mos (ng/L) 0.3 250 0.08 1 200 0.06 0.75 0.2 150 0.04 0.5 100 0.1 0.02 0.25 50 (m/sec) 0 0 0 0 p=0.0154** -50 -0.02 -0.25 p=7.74 x 10 -8 ** -0.1 -100 -0.04 -0.5 -150 -0.06 -0.75 -0.2 -200 -0.08 -1 -250 -0.3 -0.1 -1.25 -300 p=0.0173** p=7.42 x 10 -9 ** -350 -0.12 -1.5 -0.4 Better Better Better Worse Placebo Patisiran *Cardiac subpopulation: patients with pre-existing cardiac amyloid involvement without confounding medical conditions (i.e., patients with baseline LV wall thickness ≥1.3 cm and no aortic valve disease or hypertension in medical history) 11 **p-values are nominal