Corporate Overview May 2018

Transcription

1 Corporate Overview May 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; 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 entering commercial stages 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 3) REGISTRATION/ COMMERCIAL 2 COMMERCIAL RIGHTS Patisiran Hereditary ATTR Amyloidosis Global Givosiran Acute Hepatic Porphyrias Global Hemophilia and Rare Fitusiran Bleeding Disorders Inclisiran Hypercholesterolemia 15-30% Royalties Milestones & up to 20% Royalties ALN- TTRsc02 ATTR Amyloidosis Global Lumasiran Primary Hyperoxaluria Type 1 Global Cemdisiran Complement-Mediated Diseases Global 4 1 POC, proof of concept defined as having demonstrated target gene knockdown and/or additional evidence of activity in clinical studies 2 Includes marketing application submissions

5 Hereditary ATTR (hattr) Amyloidosis Patisiran Description Mutations in TTR gene lead to deposition of misfolded protein as amyloid, causing multi-system disease manifestations 1 GI: Diarrhea Nausea Vomiting Significant morbidity and fatal within 2-15 years from symptom onset Patient Population* ~50,000 worldwide CARDIAC: Heart failure Arrhythmia AUTONOMIC: Falls Lightheadedness Weight loss GU: Proteinuria Kidney failure UTI Incontinence Impotence 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 2:1 RANDOMIZATION Phase 3 Study Design Randomized, Double-Blind, Placebo-Controlled Study in hattr Amyloidosis Patients with Polyneuropathy Patient Population hattr amyloidosis: any TTR mutation, FAP Stage 1 or 2 Neurological impairment score (NIS) of Includes patients with NYHA Class 1 or 2 cardiac disease Patisiran 0.3 mg/kg IV q3w* or Placebo IV q3w* Primary Endpoint Change in mnis+7 from baseline at 18 months Secondary Endpoints Norfolk QOL-DN NIS-weakness Activities of daily living (R-ODS) 10-meter walk mbmi Autonomic function (COMPASS-31) Select Exploratory Endpoints EQ-5D QOL NIS+7 Serum TTR levels Cardiac assessments Grip strength Skin biopsies for nerve fiber density and amyloid ClinicalTrials.gov Identifier: NCT *To reduce likelihood of infusion-related reactions, patients received following premedication or equivalent at least 60 min before each study drug infusion: 10 mg (low dose) dexamethasone; oral acetaminophen; H1 and H2 blockers. 99% of patients who completed APOLLO study enrolled in Global OLE study 6 OLE, open-label extension; ClinicalTrials.gov Identifier: NCT Adams D, et al. BMC Neurology 2017

7 LS mean (SEM) mnis+7 from baseline LS mean (SEM) Norfolk-QOL from baseline Phase 3 Study Results Patisiran Met Primary and all Secondary Endpoints Placebo Patisiran Worsening Improvement mnis p=9.26 x Baseline 9 Months 18 Months Worsening 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 and autonomic dysfunction met 7 Adams et al., EU-ATTR Meeting, Nov 2017 *Improvement defined as patients with <0 point increase from baseline to 18 months

8 Median NT-proBNP from baseline at 18 mos (ng/l) Mean LV wall thickness from baseline at 18 mos (cm) Mean longitudinal strain from baseline at 18 mos (%) Mean 10-MWT gait speed from baseline at 18 mos (m/sec) Phase 3 Study Results Patisiran Met Key Exploratory Endpoints in Cardiac Subpopulation* Placebo Patisiran Biomarker Echocardiographic Functional NT-proBNP LV Wall Thickness Longitudinal Strain 10MWT 350 Worsening 0.12 Worsening 1.5 Worsening 0.4 Improvement p=7.74 x 10-8 ** p=0.0173** p=0.0154** p=7.42 x 10-9 ** Improvement Improvement -1.5 Improvement -0.4 Worsening 8 Adams et al., EU-ATTR Meeting, Nov 2017 *Cardiac subpopulation (N=126): 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) **p-values are nominal

9 Phase 3 Study Results Recurrent Hospitalization and Death Events by Treatment Arm (Post-Hoc Analysis)* Mean Cumulative Function: average number of events per patient by a certain time Composite Rate of All-Cause Hospitalization and Mortality Composite Rate of Cardiac Hospitalization and All-Cause Mortality Approximately 50% reduction in event rate ** Approximately 45% reduction in event rate Placebo Patisiran Placebo Patisiran Analysis of hospitalization/death data was conducted post-hoc based on data collected from AE CRFs; hospitalization/death events caused by SAEs within 28 days of last dose of study drug were included; hospitalization events caused by SAEs within SOC of cardiac disorder were classified as cardiac hospitalization 9 Adams et al., AAN Meeting, Apr 2018 *mitt population **For any hospitalization/death analysis: negative binomial regression rate ratio (RR) 0.49 [0.30, 0.79]; Anderson-Gill hazard ratio (HR) 0.48 [0.34, 0.69] For cardiac hospitalization/death analysis: negative binomial regression rate ratio (RR) 0.54 [0.25, 1.16]; Anderson-Gill hazard ratio HR) 0.54 [0.28, 1.01] AE, adverse event; CRF, case report forms; SAEs, serious adverse events; SOC, system organ class

10 Phase 3 Study Results Encouraging Safety & Tolerability Profile Overall, 13 deaths in APOLLO study; no deaths considered related to study drug Lower percent deaths in patisiran vs. placebo treatment groups Causes (e.g., cardiovascular, infection) consistent with NH Majority of AEs mild or moderate in severity Most common AEs more frequently observed in patisiran arm vs. placebo included peripheral edema (29.7% vs. 22.1%) and infusion-related reactions (18.9% vs. 9.1%) Both AEs decreased over time; IRRs led to discontinuation in only 1 patient (0.7%); peripheral edema led to no discontinuations Type of Adverse Event, Number of patients (%) Placebo (N=77) Adverse event (AE) 75 (97.4) Patisiran (N=148) 143 (96.6) Severe AE 28 (36.4) 42 (28.4) Serious AE (SAE) 31 (40.3) 54 (36.5) AE w/ discontinuation 11 (14.3) 7 (4.7) 10 Additional notable safety findings Encouraging safety & tolerability in cardiac subpopulation Lower percent deaths in patisiran (5.6%) vs. placebo (11.1%) treatment groups No safety signals related to steroid pre-medication regimen or TTR KD No safety signals regarding liver function tests, hematology including thrombocytopenia, or renal dysfunction related to patisiran AE w/ withdrawal 9 (11.7) 7 (4.7) Death 6 (7.8) 7 (4.7) Adams et al., EU-ATTR Meeting, Nov 2017

11 hattr Amyloidosis and APOLLO Assessments Mutant & wild-type TTR in liver Patisiran Misfolded mutant & wild-type TTR amyloid fibrils in circulation deposit in nerves and tissues of many organs Sensorimotor Nerves Autonomic Nerves Heart Clinical Manifestations Loss of sensation Muscle weakness Impaired ambulation Orthostatic hypotension Syncope/falls Constipation/diarrhea Urinary retention/utis Heart failure Arrythmias/syncope Impaired exercise tolerance APOLLO Assessments mnis+7 NIS-W subdomain QST subdomain Reflexes subdomain Norfolk-QOL R-ODS disability 10-MWT Grip strength AE profile mnis+7 Postural BP subdomain Norfolk-QOL Autonomic subdomain mbmi COMPASS-31 Orthostatic hypotension GI & bladder subdomains AE profile NT-proBNP Echo longitudinal strain Echo LV thickness 10-MWT AE profile 11

12 hattr Amyloidosis Market Opportunity Estimated Disease Prevalence ~50,000 hattr amyloidosis patients worldwide with some endemic hot-spots Estimated Global Breakdown* Continuum of peripheral/autonomic neuropathy and cardiac symptoms >50% of patients with neurologic phenotype have cardiomyopathy ( mixed phenotype ) >30% of patients with cardiac phenotype have neuropathy ( mixed phenotype ) PN ~3K U.S. EUCAN ROW** Prevalence Mixed CM PN Mixed CM PN Mixed 8-12K 15-22K ~7K 1-3K 2-4K ~2K ~4K Current Diagnosis Rate ~10-30% ~20-50% ~10-30% CM ~8K 12 *Based on Alnylam estimates from interviews with key opinion leaders, THAOS registry, recent clinical trials and literature **ROW prevalence includes only select countries (e.g., Japan, Brazil, Turkey); Prevalence likely higher (e.g., 36% of APOLLO enrollment was from ROW countries) Current diagnosis rates difficult to confirm and may be lower in initial launch years

13 Patisiran Pathway to Patients and Market Building a Customer-Centric Organization Only product in hattr amyloidosis, investigational or approved, to demonstrate disease reversal* Fast Track Orphan Drug Designation Breakthrough Status NDA submitted FDA approval U.S. launch Accelerated Assessment MAA submitted EMA approval Reimbursement EU launch J-NDA submission ROW submissions Japan launch ROW launches Staged build of >250 employees in customerfacing activities WW Ongoing patient ID efforts in U.S./EUCAN, expanding WW Manufacturing and supply chain for U.S./EUCAN, expanding WW 13 *Negative mean change from baseline for mnis+7 and Norfolk QOL-DN scores in the APOLLO Phase 3 study; patisiran has not yet been reviewed or approved for marketing by FDA or any other regulatory authority

14 Raising hattr Awareness and Improving Care Diagnosis, Education, Patient Support, and Access are Key Priorities Diagnosis Education Support Access HCP Website Care Days Expanded Access Program Started 2014, expanded in 2016 Free genetic screening Now includes panels for neuropathy, cardio >400 physicians enrolled; ~4,600 tests, identified ~350 patients with hattr mutations hattramyloidosis.com Patient Website Local support program in partnership with local KOLs Agenda includes disease overview, tips for living with hattr, and support and resources 4 programs hosted in 2017; total attendance over 100 people Providing expanded access to patisiran to patients who meet program criteria Now open at >15 sites in U.S.; compassionate use ongoing in EU Alnylam Patient Access Principles Screened heart failure patients for prevalence of TTR mutations >1000 enrolled, identified 77 patients with hattr mutations hattrbridge.com Advocacy Working collaboratively to improve care for hattr Data Big Data Projects Integrating data sources to inform MD targeting for field engagement 14

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 Asymptomatic hattr carriers Wild-type ATTR amyloidosis patients 16 *Intended to be illustrative and not intended to represent specific estimates of patient numbers

17 Acute Hepatic Porphyrias 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* 17 Rose Living with Porphyria ~5,000 Patients with sporadic attacks in U.S./EU *ORPHANET; The Porphyria Consortium ~1,000 Patients with recurrent attacks in U.S./EU Confusion, anxiety, seizures, hallucinations Lesions on sunexposed skin; chronic/blistering

18 Mean (SEM) AAR Mean (SEM) AAR Givosiran Interim Phase 1 and OLE Study Results Decreased Annualized Attack Rates (AAR)* Observed with up to 22 Months of Total Treatment in Phase 1 and OLE 25 83% Mean Decrease in AAR Givosiran Compared to Placebo 25 93% Decrease in AAR Givosiran Compared to Phase 1 Run-In % -75% 10-93% Placebo (N=4) 2.5 mg/kg (N=3) 5.0 mg/kg (N=4) mg/kg (N=3) mg/kg (N=3) 0 Run-in Treatment (givosiran**) 1.2 Quarterly Monthly Phase 1 (N=12) OLE (N=12) Phase 1 and OLE Safety: In OLE study (N=16): Two patients with 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, nausea, injection site erythema, headache, injection site pruritis, fatigue, 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 DURABILITY Monthly SC dose regimen 18 Phase 1 and interim OLE study results as of Feb 26, 2018; Sardh et al., EASL, April 2018 *Includes attacks treated in healthcare facility or with hemin **Aggregated across all dose groups Mean time in Phase 1 run-in and treatment of 103 days and 165 days, respectively; mean time in OLE of 322 days

19 1:1 RANDOMIZATION Phase 3 Study Design Randomized, Double-Blind, Placebo-Controlled Study in Acute Hepatic Porphyria Patients N ~ 75 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 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 Interim analysis planned in mid-2018 FDA Breakthrough and EMA PRIME Designations Statistical Considerations: 70 patients will have 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 Includes blinded assessment to adjust sample size for primary endpoint 19

20 Annualized Attack Rate Urinary ALA (mmol/mol creatinine) Phase 3 Study Interim Analysis for Potential Accelerated Approval Alignment with FDA that reduction of urinary ALA is reasonably likely to predict clinical benefit Interim analysis with ~30 patients after 3 mo dosing; expect topline data in mid-2018 Expect NDA submission in late 2018 and potential FDA approval in mid Relationship of ALA Lowering with Annualized Attack Rate in Recurrent Attack Patients* 60 ALA Lowering in Recurrent Attack Patients at 2.5 mg/kg qm** Run-In Period Treatment Period 2.5 mg/kg/mo (N=3) placebo (N=4) % >0-25% >25-50% >50-75% >75% ULN ALA increased from baseline More ALA lowering from patient s baseline Time, Days 20 *Sardh et al., EASL, April 2018; Includes attacks treated in healthcare facility or with hemin **Sardh et al., ICPP, June 2017

21 Givosiran Market Opportunity 21 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 Expanded Alnylam Act to porphyria patients

22 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 Onset generally pediatric, very limited treatment options Retinal Oxalosis Cardiomyopathy Nephrocalcinosis Renal stones ESRD Skeletal Involvement Patient Population ~3-5,000 U.S./EU 22

23 24h Urine Oxalate corrected for BSA (mmol/24hr/1.73m 2 ) Lumasiran Phase 1/2 Study Initial Results* >50% Mean Reduction in Oxalate Excretion Phase 1/2 Study; Initial Low-Dose Cohort (1 mg/kg, q4w) Lumasiran Placebo Delayed initial dosing of lumasiran in patient randomized to placebo ULN: Study Day Part B Safety (N=8): No drug-related SAEs (most common: kidney stones (N=2)) No discontinuations Majority of AEs mild or moderate One treatment-related AE (mild and transient injection site reaction) 23 *Phase 1/2 Study; Frishberg et al., ASN, Nov 2017

24 Lumasiran Phase 3 Study Significant Acceleration in Advancement to Patients Alignment reached on pivotal trial design Primary Endpoint reduction in urinary oxalate at 6 months Sample Size ~25 patients 2020 Initiate Phase 3 study (mid) Report topline results Submit NDA* (early) FDA Breakthrough and EMA PRIME Designations 24 *Assuming positive results

25 25 Other Programs to Watch

26 2:1 2:1 Median ABR 26 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 OR Factor VIII or IX consumption Quality of life Safety OD Factor 1 Clinical results as of Jun 15, 2017; Pasi et al., ISTH, July 2017; updated to reflect cerebral 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

27 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 27 *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

28 Mean (+/- SEM) C5 knockdown relative to baseline (%) Complement-Mediated Diseases Cemdisiran (ALN-CC5) Description Numerous debilitating diseases caused by abnormal complement activity Paroxysmal nocturnal hemoglobinura (PNH), atypical hemolytic-uremic syndrome (ahus), myasthenia gravis, neuromyelitis optica, membranous nephropathy Cemdisiran Phase 1/2 Study in Healthy Volunteers mg (N=3) 600 mg (N=3) 200 mg (N=3) 900 mg (N=3) mg (N=3) Placebo (N=5) Days since first visit PATIENT POPULATION ~5,000 ahus >100,000 total complementmediated diseases Mean max C5 knockdown of 98%; Durability supports qm to q3m SC dose regimen 1 Part A Safety (N=20): No SAEs No discontinuations due to AEs All reported AEs mild or moderate Expect Phase 2 ahus initial data in late Data as of 03/02/2016

29 RNAi Therapeutics for CNS Diseases No Current Therapies to Prevent or Reverse Neurodegenerative Disease Sequence specific target knockdown across brain and spinal cord for two targets with single intrathecal dose* Confirmed sirna uptake in several different cell types Widespread distribution and knockdown in all key anatomical regions of brain and spinal cord tissue 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 st IND in late 2019/early INDs/year starting in *TIDES 2018 Annual Meeting

30 30 Guidance and Goals

31 31

32 32 Alnylam 2018 Goals *Early is Q1-Q2, Mid is Q2-Q3, and Late is Q3-Q4 PATISIRAN (hattr Amyloidosis) GIVOSIRAN (Acute Hepatic Porphyrias) 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 2018* Early Mid Late

33 Financial Summary and Guidance 2018 Q1 Financial Results Cash $1.60B Includes $30.0M in restricted investments GAAP Revenues $21.9M Total GAAP Operating Expenses $169.3M R&D Expenses $96.9M G&A Expenses $72.4M Total Non-GAAP Operating Expenses* $149.7M Non-GAAP R&D Expenses* $86.7M Non-GAAP G&A Expenses* $63.0M GAAP Net Loss $141.2M Non-GAAP Net Loss* $121.6M Shares Outstanding 100.5M Updated 2018 Financial Guidance Cash, including restricted cash and restricted investments, of ~$1.0B Annual Non-GAAP Operating 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 33 *Non-GAAP measures exclude stock-based compensation expenses.

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