Conference Call to Discuss FDA Approval of ONPATTRO (patisiran) August 10, 2018 1
Agenda Welcome Christine Lindenboom Vice President, Investor Relations & Corporate Communications Introduction John Maraganore, Ph.D. Chief Executive Officer ONPATTRO (patisiran) Label & Data Pushkal Garg, M.D. Senior Vice President, Chief Medical Officer Commercialization Efforts Barry Greene President Summary & Next Steps Yvonne Greenstreet, MBChB Executive Vice President, Chief Operating 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. 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; our ability to successfully launch, market and sell our approved products globally; our 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. 3
John Maraganore, Ph.D. Chief Executive Officer Introduction 4
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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^ 6 2019 2020 2021 Givosiran Lumasiran TTRsc02 Fitusiran Inclisiran Acute hepatic porphyrias Primary hyperoxaluria ATTR amyloidosis Hemophilia Hypercholesterolemia Partnered programs*: 2020-2021 * 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 not yet approved in the EU; On July 27, 2018, CHMP recommended for approval to treat hattr amyloidosis in adults with stage 1 or stage 2 polyneuropathy Anticipated dates of launch based on current development timelines and assuming regulatory approval
Pushkal Garg, M.D. Senior Vice President, Chief Medical Officer ONPATTRO (patisiran) Label & Data 7
Hereditary ATTR (hattr) Amyloidosis Description Mutations in TTR gene lead to deposition of misfolded protein as amyloid, causing multisystem disease manifestations 1 GI: Diarrhea Nausea Vomiting Median survival 4.7 years from diagnosis CARDIAC: Heart failure Arrhythmia GU: Proteinuria Kidney failure UTI Incontinence Impotence Patient Population* ~50,000 worldwide AUTONOMIC: Falls Lightheadedness Weight loss PERIPHERAL: Numbness/tingling Pain Weakness Impaired walking 8 Kipper Living with hattr Amyloidosis 1 Coelho T, et al. N Engl J Med. 2013;369(9):819-829 * Ando et al., Orphanet J Rare Dis, 2013; Ruberg et al., Circulation, 2012
ONPATTRO Clinical Development Background ONPATTRO Therapeutic Hypothesis Production of mutant and wild type TTR Unstable circulating TTR tetramers reduced Randomized, double-blind, placebo-controlled study of patisiran in 225 hattr amyloidosis patients with polyneuropathy Organ deposition of monomers, amyloid (β-pleated) fibril prevented, clearance promoted Results published July 2018 Neuropathy stabilization or improvement 9
LS mean (SEM) mnis+7 from baseline LS mean (SEM) Norfolk-QOL from baseline Primary Endpoint Met Phase 3 Study Results Placebo Patisiran Worsening Improvement mnis+7 35 30 25 20 15 10 5 p=9.26 x 10-24 0-5 -10 Worsening Baseline 9 Months 18 Months Improvement 20 15 10 5 0-5 -10 Norfolk-QOL p=1.10 x 10-10 Baseline 9 Months 18 Months At 18 months -6.0 point change relative to baseline 34.0 point difference relative to placebo 56.1% of patients improved* At 18 months -6.7 point change relative to baseline 21.1 point difference relative to placebo 51.4% of patients improved* All secondary endpoints encompassing QOL, walk speed, activities of daily living, mbmi and autonomic dysfunction met 10 Adams D, et al. N Engl J Med. 2018;379:11-21 * Improvement defined as patients with <0 point increase from baseline to 18 months
Phase 3 Study Results Safety & Tolerability Profile Event Placebo Patisiran (N=77) (N=148) no. of patients (%) Any adverse event (AE) 75 (97) 143 (97) Any severe AE 28 (36) 42 (28) Any serious adverse event (SAE) 31 (40) 54 (36) AE leading to discontinuation of the trial regimen 11 (14) 7 (5) AE leading to withdrawal from the trial 9 (12) 7 (5) Death* 6 (8) 7 (5) Majority of AEs mild or moderate in severity No safety signals related to steroid pre-medication regimen or TTR reduction No hepatic, renal or hematologic (including platelet) safety signals 11 * No deaths were considered related to study drug by the investigator Adams D, et al. N Engl J Med. 2018;379:11-21
ONPATTRO Label Indication Statement Dosing & Administration ONPATTRO is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. Dosing: 0.3 mg/kg (patients <100 kg) 30 mg (patients 100 kg) Premedication (day of infusion): IV dexamethasone, 10 mg IV H1 and H2 blockers Oral acetaminophen Administration: Should be performed by healthcare professional. Safety No contraindications Warnings and Precautions Infusion-related reactions: Monitor for signs and symptoms during infusion. Slow or interrupt the infusion if clinically indicated. Discontinue the infusion if a serious or life-threatening infusion-related reaction occurs. Reduced serum vitamin A levels and recommended supplementation: Supplement with the recommended daily allowance of vitamin A. Refer to an ophthalmologist if ocular symptoms suggestive of vitamin A deficiency occur. Common adverse reactions are upper respiratory tract infections and infusion-related reactions No required laboratory monitoring 12
Barry Greene President Commercialization Efforts 13
Pricing & Considerations OUTCOMES & SAFETY Shown to improve polyneuropathy and reverse neuropathy impairment in majority of patients UNMET NEED First and only FDA-approved treatment available in U.S. for the polyneuropathy of hattr amyloidosis in adults RARE DISEASE < 3,000 patients currently diagnosed in U.S. NEW CLASS OF MEDICINES First RNAi therapeutic after 16 years of R&D based on Nobel Prize-winning science Average Annual List Price $450,000 $9,500 per vial Average Effective Net Price $345,000 Based on average of 2.7 vials administered an average of 17.5 times per year Initial launch period, anticipate mandatory rebates to government institutions Price may vary per individual insurance coverage and dosing 14
Making ONPATTRO Available Diagnosis, Education, Patient Support, and Access are Key Priorities COMMERCIAL FIELD TEAM Account Management Marketing Patient Services Reimbursement Market Access MEDICAL AFFAIRS 6,700+ samples submitted* 460+ pathogenic TTR mutations* DISEASE EDUCATION SUPPORT SERVICES Wide range of personalized services, including access to inhouse Case Managers and fieldbased Patient Education Liaisons. Includes financial support for eligible patients. 15 * As of 7/30/2018
ONPATTRO Value-Based Agreements (VBA) Demonstrating Commitment to Patient Access Proactively Engage & Educate Payers Disease awareness and understanding Clinical trial data Enable Patient Access to ONPATTRO Proactively discuss options for VBA design with payers to support access Highly relevant to specifics of disease state and ONPATTRO label Feasible to implement within payer and physician data systems Clear and flexible to align needs of patients, payers, and Alnylam Ensure Value Delivered As part of VBA, Alnylam contractually commits to: Real-world benefit aligning with pre-determined criteria Rebate paid to payer when criteria are not met* No arbitrary price increases Payers commit to working with Alnylam to optimize patient access based on ONPATTRO label 16 * Subject to best price protection
Yvonne Greenstreet, MBChB Executive Vice President, Chief Operating Officer Summary & Next Steps 17
Upcoming Goals and Milestones EUROPE EMA approval expected in September 2018 Expected first launch country: Germany (launch ready) Provide patisiran to eligible adults in UK with hattr amyloidosis through MHRA Early Access to Medicines Scheme ASIA & ROW Increasing presence in Japan Head of Asia recently hired JNDA filing with Japanese Pharmaceuticals and Medical Devices Agency in mid-2018 Additional regulatory submissions by year end Continued infrastructure build out for global commercialization Continue Global OLE study Full 12-month safety and efficacy data to be presented at AANEM in October 2018 18
ONPATTRO FDA Approval Q&A Session 19
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