Corporate Overview November 2018

Transcription

1 Corporate Overview November Alnylam Pharmaceuticals, Inc.

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 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 (patisiran) 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. 2

3 RNAi Therapeutics: New Class of Innovative Medicines Clinically Proven Approach with Transformational Potential Nobel Prize-winning science Silence any gene in genome Potent and durable mechanism of action Product engine for sustainable pipeline Now commercial 3

4 Alnylam Clinical Development Pipeline Focused in 4 Strategic Therapeutic Areas (STArs): Genetic Medicines Cardio-Metabolic Diseases Hepatic Infectious Diseases CNS Diseases HUMAN POC 1 BREAKTHROUGH DESIGNATION EARLY STAGE (IND or CTA Filed-Phase 2) LATE STAGE (Phase 2-Phase 4) REGISTRATION/ COMMERCIAL 3 COMMERCIAL RIGHTS hattr Amyloidosis 2 Global Givosiran Acute Hepatic Porphyria Global Fitusiran Hemophilia and Rare Bleeding Disorders 15-30% royalties Inclisiran Hypercholesterolemia Milestones & up to 20% royalties Lumasiran Primary Hyperoxaluria Type 1 Global ALN-TTRsc02 ATTR Amyloidosis Global 4 Cemdisiran Complement-Mediated Diseases Global ALN-AAT02 Alpha-1 Liver Disease ALN-HBV02 Hepatitis B Virus (VIR-2218) Infection 1 POC, proof of concept defined as having demonstrated target gene knockdown and/or additional evidence of activity in clinical studies 2 Approved in the U.S. for the polyneuropathy of hattr amyloidosis in adults, and in the EU for the treatment of hattr amyloidosis in adults with stage 1 or stage 2 polyneuropathy 3 Includes marketing application submissions As of November 2018 Subject to partner option rights option rights post-phase 2

5 Hereditary ATTR (hattr) Amyloidosis Description Mutations in TTR gene lead to deposition of misfolded protein as amyloid, causing polyneuropathy and other 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 5 Kipper Living with hattr Amyloidosis 1 Coelho T, et al. N Engl J Med. 2013;369(9): * Ando et al., Orphanet J Rare Dis, 2013; Ruberg et al., Circulation, 2012

6 Patisiran Clinical Development Background Patisiran 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 6

7 LS mean (SEM) mnis+7 from baseline LS mean (SEM) Norfolk-QOL from baseline Phase 3 Study Results Primary Endpoint Met Placebo Patisiran Worsening Improvement mnis p=9.26 x Worsening Baseline 9 Months 18 Months Improvement Norfolk-QOL p=1.10 x 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 7 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

8 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 8 * No deaths were considered related to study drug by the investigator Adams D, et al. N Engl J Med. 2018;379:11-21

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10 ONPATTRO (patisiran) Regulatory Status Approved U.S. Indication Data in Label For the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. Includes data from APOLLO primary and select secondary endpoints. This approval is part of a broader wave of advances that allow us to treat disease by actually targeting the root cause, enabling us to arrest or reverse a condition, rather than only being able to slow its progression or treat its symptoms New technologies like RNA inhibitors, that alter the genetic drivers of a disease, have the potential to transform medicine, so we can better confront and even cure debilitating illnesses. ~ Scott Gottlieb, MD, FDA Commissioner, Press Release, 8/10/2018 Approved EU Indication Data in SmPC* For the treatment of hereditary transthyretin-mediated amyloidosis (hattr amyloidosis) in adults with stage 1 or stage 2 polyneuropathy. Includes data from APOLLO primary and secondary endpoints, as well as exploratory cardiac endpoints. The safety and efficacy of Onpattro was evaluated in a pivotal trial involving 225 patients with hattr amyloidosis and symptomatic polyneuropathy. The study showed clinically-relevant improvements in the neurological manifestations of the disease and on patients quality of life, as well as a positive impact on cardiac parameters. ~ CHMP Opinion Press Release, 7/27/2018 JNDA Filing JNDA submitted September PMDA decision on application anticipated June * SmPC, Summary of Product Characteristics

11 ONPATTRO U.S. Launch Progress Encouraging Initial Demand Through First 7 Weeks 125 U.S. Patient Start Forms ~60% from patients previously participating in patisiran EAP NEUROLOGY CARDIOLOGY HEMATOLOGY Start Form submissions received from key physician specialties, reflecting both polyneuropathy & mixed patient phenotypes 11 Start Forms are requests submitted to Alnylam Assist patient hub to guide fulfillment of ONPATTRO prescriptions by physicians. Submitted Start Forms do not reflect all demand.

12 hattr Amyloidosis Market Opportunity Estimated Disease Prevalence* ~ 50,000 patients worldwide NEUROLOGIC PHENOTYPE > 50% have cardiomyopathy CARDIAC PHENOTYPE > 30% have neuropathy WITHIN ONPATTRO LABEL (based on approved U.S.P.I) 20K to 30K worldwide ~ 10K diagnosed 10K to 15K in U.S. < 3K diagnosed 5K to 10K in EU ~ 2K diagnosed 12 * Based on Alnylam estimates from interviews with key opinion leaders, THAOS registry, recent clinical trials and literature ONPATTRO is approved in the U.S. for the polyneuropathy of hattr amyloidosis in adults, and in the EU for the treatment of hattr amyloidosis in adults with stage 1 or stage 2 polyneuropathy Current diagnosis rates difficult to confirm and may be lower in initial launch years

13 U.S. Commercialization Underway Diagnosis Brand Choice Treatment Experience and Access TM TM Unified Commercial, Market Access, & Medical Affairs teams driving disease education, diagnosis & treatment, optimized patient experience, and access to care 13

14 Global Commercialization Efforts Underway EU and Asia in place EU launch underway (first market in Germany) Japan team on-board Preparing Canada and Switzerland Initiating Latin America, starting with Brazil UNITED STATES CEMEA* LATIN AMERICA ASIA Regional Support Market Access Supply Chain Country organizations built Country Manager Medical Affairs Sales and Marketing Local Market Access 14 * Canada, Europe, Middle East, North Africa

15 Mean [+/-SEM] TTR Knockdown Relative to Baseline (%) ALN-TTRsc02 Opportunity Advancing Continued Innovation for Patients with ATTR Amyloidosis Phase 1 Study Healthy Volunteers Placebo (N=20) 25mg (N=6) 100mg (N=6) 5mg (N=6) 50mg (N=6) 300mg (N=6) Mean max TTR KD of 97.1%; ~80% TTR KD at nearly 1 year after single 50 mg dose* Days Since First Dose Safety (N=80): No SAEs and no discontinuations due to AEs All AEs mild or moderate in severity 52 Inotersen DOSES PER YEAR 4 ALN-TTRsc02 DOSES PER YEAR ANTICIPATED Expect to initiate Phase 3 study in Late * As of data cutoff on 31May2017

16 ALN-TTRsc02 Market Opportunity* Potential for Significant Expansion in ATTR Amyloidosis hattr amyloidosis Pre-symptomatic hattr carriers Wild-type ATTR amyloidosis patients 16 * Intended to be illustrative and not intended to represent specific estimates of patient numbers

17 3:1 RANDOMIZATION Treatment Extension ALN-TTRsc02 Phase 3 Study Randomized, Open-Label Study in Hereditary ATTR Amyloidosis Patients Patient Population N ~ 160 hattr amyloidosis; any TTR mutation Neuropathy Impairment Score (NIS) of Prior tetramer stabilizer use permitted ALN-TTRsc02 25 mg SC q3 months or Reference Comparator (patisiran) 0.3 mg/kg IV q3w 9-Month Efficacy^ Assessment 18-Month Efficacy Assessment ALN-TTRsc02 25 mg SC q3 months Co-Primary Endpoints Change in mnis+7 from baseline Change in Norfolk QOL-DN from baseline Efficacy Assessments (vs APOLLO placebo) Secondary Endpoints 10-meter walk test (10-MWT) mbmi Activities of daily living (R-ODS) TTR reduction (within-study non-inferiority comparison) All-cause death and hospitalization (mitt)* All-cause death and hospitalization (patients w/ cardiac involvement)* Exploratory Endpoints Include NT-proBNP Echo parameters Technetium (select sites only, change from baseline) 17 ^ Primary endpoint for the study is at 9 months * All-cause death and hospitalization endpoints assessed at 18 months only

18 Acute Hepatic Porphyria Givosiran Description Family of ultra-rare orphan diseases causing incapacitating and potentially fatal attacks, leading to frequent hospitalizations and chronic pain Predominantly Severe, burning pain in abdomen, chest, back Weakness, numbness, respiratory failure female, commonly misdiagnosed Patient Population* 18 Rose Living with Porphyria ~5,000 Patients with sporadic attacks in U.S./EU ~1,000 Patients with recurrent attacks in U.S./EU * ORPHANET; The Porphyria Consortium Confusion, anxiety, seizures, hallucinations Lesions on sunexposed skin; chronic/blistering

19 Placebo (Phase 1) Givosiran Phase 1 and Interim OLE Study Results Mean Reductions in Annualized Attack Rate (AAR) of >90% Relative to Run-In* Phase 1 Run-in Period Treatment Period Open-Label Extension Run-in Period Givosiran 2.5 mg/kg Monthly Givosiran 2.5 mg/kg Quarterly Givosiran 5.0 mg/kg Monthly Givosiran 5.0 mg/kg Quarterly Placebo Attack Continued Dosing Phase 1 and OLE Safety: In OLE study (N=16): 4 patients with 5 SAEs, including one with anaphylactic reaction, assessed as definitely related to study drug. Patient had past history of asthma, oral allergy syndrome, and prior allergic reactions to acne cream and possibly latex gloves; patient discontinued from study Most common AEs: abdominal pain, fatigue, injection site erythema, nausea, myalgia, diarrhea, headache, and nasopharyngitis In Phase 1 (N=40): Six patients with SAEs, including one who developed acute pancreatitis complicated by pulmonary embolism resulting in death, considered unlikely related to study drug Majority of AEs mild-moderate in severity 19 Data as of 7Jun2018; * Aggregated across all dose groups; Note: Duration between Phase 1 and OLE studies is not shown; Attacks requiring hospitalization, urgent health care visit, or IV hemin at home; Mean time in Phase 1 Run-in and Treatment of 103 days and 165 days, respectively; mean time in OLE of 415 days.

20 1:1 RANDOMIZATION Phase 3 Study Design Randomized, Double-Blind, Placebo-Controlled Study in Acute Hepatic Porphyria Patients Enrollment completed well ahead of schedule 94 AHP patients, 36 sites, 18 countries N = 94 Patient Population Age 12 years Diagnosis of AHP 2 attacks within prior 6 months Willing to discontinue and/or not initiate hemin prophylaxis Givosiran SC qm 2.5 mg/kg or Placebo SC qm Interim Analysis (urinary ALA endpoint) Primary Endpoint Attacks requiring hospitalization, urgent care visit, home IV hemin at 6 months Key Secondary Endpoints ALA and PBG Hemin doses Symptoms QOL Open-Label Extension FDA Breakthrough and EMA PRIME Designations Statistical Considerations: N = 70 patients results in at least 90% power to detect 45% reduction in annualized attack rate at 2-sided alpha of 0.05 Unblinded interim analysis of urinary ALA levels in 30 patients at 3 months 20

21 Interim Results* Interim Efficacy Analysis & Safety Interim analysis cohort N = 43 AHP patients (41 AIP; 1 VP; 1 HCP) 23 randomized to givosiran; 20 randomized to placebo Treatment period: 3 months Interim efficacy analysis (ALA levels at 3 months in AIP patients) Statistically significant reduction in urinary ALA, relative to placebo (p < 0.001) Safety No deaths Serious Adverse Events (SAE) reported in: 5/23 (22%) of patients on givosiran 2/20 (10%) of patients on placebo One patient (4%) on givosiran discontinued treatment based on a protocol-defined stopping rule due to >8x ULN increase in liver transaminase, which resolved No treatment discontinuations in placebo group Expect to initiate rolling NDA submission by year-end 2018 Topline results on completed Phase 3 study expected in early * Data cut-off date of August 22, 2018

22 Givosiran Market Opportunity Givosiran has potential to address significant unmet needs Current treatment options inadequate 65% of patients have chronic symptoms during and between attacks Significant economic burden Average annual expenditure ranging from approximately $400,000 to $650,000, not reflecting indirect costs Disease significantly under-diagnosed Long diagnostic journey that can exceed 10 years Frequency of gene mutation (2-5:100,000) suggests much larger opportunity Education efforts underway to drive improved diagnosis and disease awareness Primary focus on neurologists, hematologists, gastroenterologists Partnerships with patient advocacy groups Initial opportunity in recurrent population Potential for further expansion Variegate porphyria Hereditary coproporphyria Sporadic attacks 173 tests submitted* 123 positive samples* 22 * As of September 25, 2018

23 Primary Hyperoxaluria Type 1 Lumasiran Description Rare autosomal recessive disorder of increased oxalate synthesis resulting in kidney stones and renal failure, with subsequent oxalate accumulation in extra-renal tissues Retinal Oxalosis Cardiomyopathy Onset generally pediatric, very limited treatment options Nephrocalcinosis Renal stones ESRD Patient Population ~3-5,000 U.S./EU Skeletal Involvement 23 Claire Living with PH1

24 Mean [+/- SEM] Urine Oxalate Content (mmol/24hr/1.73m 2 ) Lumasiran Phase 1/2 Study Updated Results* 75% Mean Reduction in Urinary Oxalate Mean maximal reduction in urinary oxalate of 75% relative to baseline after lumasiran dosing in all cohorts (N=20) Lumasiran 1.0 mg/kg monthly (N=8) Lumasiran 3.0 mg/kg monthly (N=8) Lumasiran 3.0 mg/kg quarterly (N=4) qmonth q3m Day on Study Part B Safety (N=20): No discontinuations from study treatment Majority of AEs mild or moderate, unrelated to study drug AEs reported in >3 lumasiran patients: vomiting, pyrexia, cough (N=6); abdominal pain, headache (N=5); rhinitis (N=4) No drug-related SAEs (most common: kidney stones (N=2 on lumasiran, 1 on placebo)) 24 * Part B data as of August 15, 2018; only data points with at least 3 contributing patients are represented; placebo data not shown due to limited valid collections Patients randomized (3:1 drug:placebo) to placebo received subsequent dosing of lumasiran and are included in the lumasiran dosing cohort in which they were randomized; Day 1 relative to first lumasiran dose; patient randomized to placebo 3 mg/kg quarterly received single dose of lumasiran on Day 1

25 2:1 Randomization ILLUMINATE-A: Lumasiran Phase 3 Study Randomized, Double-Blind Study in Primary Hyperoxaluria Type 1 Patients 6-Month Double Blind Treatment Period 54-Month Extension Period Patient Population N = 30 Adults & children 6 years Urinary oxalate excretion 0.7 mmol/24hr/1.73m 2 Confirmed alanine glyoxalate aminotransferase (AGXT) mutations egfr >45 ml/min/1.73m 2 Lumasiran Three monthly loading doses, then maintenance dose of 3.0 mg/kg or Placebo Equivalent volume for 3 monthly loading doses, then maintenance Lumasiran 3.0 mg/kg every 3 months (following loading doses for patients previously receiving placebo) Primary Endpoint Percent change in 24-hour urinary oxalate excretion Primary Analysis at 6 Months Secondary Endpoints Change in 24-hour urinary oxalate:creatinine ratio Proportion of patients with 24-hour urinary oxalate leve below ULN and 1.5x ULN Change in egfr Topline results expected in late 2019 NDA submission in early 2020 (assuming positive results) FDA Breakthrough and EMA PRIME Designations 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

26 26 Other Programs to Watch

27 2:1 2:1 Median ABR 27 Hemophilia and Rare Bleeding Disorders (RBD) Fitusiran Description Genetic deficiency results in inability to generate thrombin and stop bleeding, leading to recurrent bleeds into joints, muscles, and major internal organs PATIENT POPULATION 200,000 itusiran Phase 3 Program* Early 2017 Adults and adolescents with hemophilia A or B with inhibitors On-demand N~50 Adults and adolescents with hemophilia A or B without inhibitors On-demand N~100 worldwide 4,000 with inhibitors Fitusiran OR Endpoints: ABR Bypassing agent (BPA) consumption Quality of life OD BPA Safety Re-initiated Phase 2 OLE and ATLAS Phase 3 studies in December 2017; Endpoints: Expect topline Fitusiran ATLAS results ABR in 2019 Factor VIII or IX OR consumption 1 Clinical results as of Jun 15, 2017; Pasi Quality of et life al., ISTH, July 2017; updated to reflect cerebral OD Factor Safety venous sinus thrombosis case noted in safety box Sanofi Genzyme is leading and fully funding development (post-transition) of fitusiran DURABILITY Monthly SC fixed dose regimen Fitusiran Phase 2 OLE Study in Inhibitor Patients N=14 Pre-Study Median ABR=0 with 6 months [1-11] median duration of dosing in observation period* 0 N=14 Fitusiran Treatment Updated Safety in Phase 2 OLE (N=33): 3 SAEs considered possibly related to study drug Includes one fatal cerebral venous sinus thrombosis enhanced bleed management guidelines and risk mitigation measures added to study protocols following event Majority of AEs mild or moderate in severity, unrelated to study drug Reversible ALT increases >3x ULN in 11 (33%) patients, all with prior history of HCV infection

28 Hypercholesterolemia Inclisiran Description Highly prevalent disease caused by elevated levels of LDL-C that increase risk of atherosclerotic cardiovascular disease (ASCVD) Inclisiran ORION-1 Phase 2 Study DURABILITY Biannual SC dose regimen PATIENT POPULATION ~31 million in U.S. have LDL-C levels >240 mg/dl Completed enrollment in ORION 9, 10, 11 Phase 3 trials with ~3,500 patients; Expect topline results in 2019 >50% mean LDL-C lowering at Day 180 after two quarterly doses* Safety (N=501)*: No drug-related SAEs, no discontinuations due to AEs Two patient deaths due to MI and stroke, both unrelated to study drug No LFT elevations related to study drug Majority of AEs mild or moderate in severity 28 * ORION-1 Phase 2 Study; ESC, Aug 2017 The Medicines Company is leading and funding development of inclisiran from Phase 2 onward and will commercialize program, if successful

29 Other Clinical Programs Cemdisiran for complement-mediated diseases Numerous debilitating diseases caused by abnormal complement activity Clinical data from Phase 1/2 study in healthy volunteers 1 : Mean max C5 knockdown of 98%; durability supports qm to q3m SC dose regimen Safety (N=20): no SAEs; no discontinuations due to AEs; all reported AEs mild or moderate ALN-AAT02 for alpha-1 liver disease Orphan disease where mutant AAT misfolds and aggregates in hepatocytes, leading to liver cirrhosis Occurs in both children and adults; limited treatment options; substantial morbidity ALN-HBV02 (VIR-2218)* for hepatitis B virus infection Chronic viral infection leading to cirrhosis and hepatocellular cardinoma Current therapies not curative, have significant limitations ALN-HBV02 targets all four transcripts of viral genome for potential reduction of HBsAg levels and increase in seroconversion rates PATIENT POPULATION >100,000 total complementmediated diseases Expect Phase 2 IgA nephropathy study initiation in 2019 PATIENT POPULATION 2 ~12,000 worldwide Expect Phase 1/2 study initiation in late 2018 PATIENT POPULATION 3 ~400M (~25M) w/ chronic disease worldwide (U.S./EU) Phase 1/2 study ongoing ESC+ GalNAc Conjugate Technology 29 * In partnership with Vir Biotechnology 1 Data as of 03/02/ Stoller et al., GeneReviews,

30 Message Remaining RNAi Therapeutics in Development for CNS Diseases Limited Therapies to Prevent or Reverse Neurodegenerative Disease Sequence specific target knockdown across brain and spinal cord for two targets with single intrathecal dose* Target Gene Silencing in NHP CNS PBS P B S C o n tro l CTNNB C T N N B s ir N A Confirmed sirna uptake in several different cell types Widespread distribution and knockdown in all key anatomical regions of brain and spinal cord tissue Successful translation to NHP with robust silencing across CNS L u m b a r S p in e T h o r a c ic S p in e C e r v ic a l S p in e C e r e b e llu m P r e fr o n ta l C o r te x T e m p o r a l C o r te x H ip p o c a m p u s B r a in S te m L iv e r Examples of dominantly inherited genes within neurodegenerative diseases: Alzheimer s disease Parkinson s disease Frontotemporal dementia Huntington s disease Amyotrophic lateral sclerosis (ALS) Spinocerebellar ataxia Planned Next Steps 1 st DC in late st IND in late 2019/early INDs/year starting in * OTS 2018 Annual Meeting

31 31 Guidance and Goals

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33 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^ Partnered programs*: Givosiran Lumasiran TTRsc02 Fitusiran Inclisiran Acute hepatic porphyria Primary hyperoxaluria Type 1 ATTR amyloidosis Hemophilia Hypercholesterolemia * 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 approved in the EU for the treatment of hattr amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy Anticipated dates of launch based on current development timelines and assuming regulatory approval

34 34 Alnylam 2018 Goals 2018* *Early is Q1-Q2, Mid is Q2-Q3, and Late is Q3-Q4 PATISIRAN (hattr Amyloidosis) GIVOSIRAN (Acute Hepatic Porphyria) FITUSIRAN (Hemophilia and RBD) ALN-TTRsc02 (ATTR Amyloidosis) INCLISIRAN (Hypercholesterolemia) LUMASIRAN (Primary Hyperoxaluria Type 1) ADDITIONAL CLINICAL PROGRAMS Additional APOLLO Phase 3 data FDA approval U.S. launch J-NDA submission EMA approval EU launch Additional ROW submissions Additional Phase 1/Phase 2 OLE data ENVISION Phase 3 interim analysis topline NDA filing Complete ENVISION Phase 3 enrollment Continue ATLAS Phase 3 enrollment Start Phase 3 Complete ORION 9/10/11 (LDL-C) enrollment Start ORION 4 (CVOT) Phase 3 Start Phase 3 Continue to advance early/mid-stage pipeline; File new INDs; Present clinical data Early Mid Late

35 Financial Summary and Guidance 2018 Q3 Financial Results Cash $1.27B Includes $44.8M in restricted investments ONPATTRO Net Product Revenues $0.5M Total GAAP Operating Costs and Expenses $256.6M R&D Expenses $139.9M SG&A Expenses $116.6M Cost of Goods Sold $0.1M Non-GAAP Expenses Non-GAAP R&D Expenses* $94.2M Non-GAAP SG&A Expenses* $74.4M GAAP Net Loss $245.3M Non-GAAP Net Loss* $157.3M Shares Outstanding 101.0M Re-Affirmed 2018 Financial Guidance Cash, including restricted cash and restricted investments, of ~$1.0B Annual Non-GAAP Expenses Non-GAAP R&D Expenses* in the range of $420M to $460M Non-GAAP SG&A Expenses* in the range of $280M to $320M 35 * Non-GAAP measures and Non-GAAP Net Loss exclude stock-based compensation expenses.

36 To those who say impossible, impractical, unrealistic, we say: CHALLENGE ACCEPTED Alnylam Pharmaceuticals, Inc.