Corporate Overview March 2018

Transcription

1 Corporate Overview March Alnylam Pharmaceuticals, Inc.

2 Recent News: Strategic Restructuring of Sanofi Alliance Alnylam and Sanofi have restructured alliance to streamline and optimize product development and commercialization Prior As Restructured U.S., Canada, W-EU ROW U.S., Canada, W-EU ROW Patisiran ALN-TTRsc02 Fitusiran Alnylam obtains global rights to ATTR amyloidosis products, Sanofi obtains global rights to fitusiran Opportunity to maximize value of all product opportunities on global basis Alnylam to receive 15-30% royalties on global fitusiran sales Sanofi Genzyme to receive up to 25% royalties on ROW patisiran sales and 15-30% royalties on global ALN-TTRsc02 sales Global ATTR amyloidosis product rights expected to unlock significant value creation opportunity Aligns patisiran and ALN-TTRsc02 development and commercialization efforts Enables comprehensive development of both products across full spectrum of ATTR amyloidosis disease Establishes global footprint for givosiran and future Alnylam products 2

3 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 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

4 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 4

5 Alnylam Clinical Development Pipeline Focused in 3 Strategic Therapeutic Areas (STArs): Genetic Medicines Cardio-Metabolic Diseases Hepatic Infectious 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 Fitusiran Hemophilia and Rare Bleeding Disorders Inclisiran Hypercholesterolemia 15-30% Royalties Milestones & up to 20% Royalties ALN- TTRsc02 ATTR Amyloidosis Global Cemdisiran Complement-Mediated Diseases Global Lumasiran Primary Hyperoxaluria Type 1 Subject to partner option rights 5 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

6 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 6 Leo 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

7 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 7 OLE, open-label extension; ClinicalTrials.gov Identifier: NCT Adams D, et al. BMC Neurology 2017

8 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 8 Adams et al., EU-ATTR Meeting, Nov 2017 *Improvement defined as patients with <0 point increase from baseline to 18 months

9 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 9 Adams et al., EU-ATTR Meeting, Nov 2017 *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) **p-values are nominal

10 Phase 3 Study Results Encouraging Safety & Tolerability Profile Overall, 13 deaths in APOLLO study; no deaths considered related to study drug Similar frequency of deaths in patisiran and placebo treatment groups Causes of death (e.g., cardiovascular, infection) consistent with NH Type of Adverse Event, Number of patients (%) Placebo (N=77) Adverse event (AE) 75 (97.4) Patisiran (N=148) 143 (96.6) 10 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 Additional notable safety findings Encouraging safety & tolerability in cardiac subpopulation Deaths in 5.6% of patisiran patients and 11.1% of placebo patients 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 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) 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 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

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 >350 physicians enrolled; >3000 tests, identified ~300 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 % Decrease in Annualized Attack Rate Givosiran Patient 3 (2.5 mg/kg q3m) Givosiran Interim Phase 1 Study Results* Randomized, Double-Blind, Placebo-Controlled Study in Recurrent Attack Porphyria Patients 0 73% Mean Decrease in Annualized Attack Rate Givosiran Compared to Placebo 2.5 mg/kg 2.5 mg/kg 5 mg/kg All q3m qm qm Cohorts Mean Cohort 1-3 (N=3) (N=3) (N=3) (N=9) Cohort 1 (N=3) Cohort 2 (N=3) Cohort 3 (N=3) (N=9) Run-in Run-in Period mmol/mol/cr Treatment Treatment Period PBG ALA Heme Porphyria Attack Study Day Safety: Generally well tolerated (N=9) No drug-related SAEs and no discontinuations due to AEs One patient 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 Alnylam has global rights to givosiran program *Interim Phase 1 study results as of Apr 21, 2017; Sardh et al., ICPP, June 2017; **Includes attacks treated in healthcare facility or with hemin

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* 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., ICPP, June 2017; Includes attacks treated in healthcare facility or with hemin

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 Expanding ALNYLAM ACT to porphyria patients

22 22 Other Programs to Watch

23 2:1 2:1 Median ABR 23 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 Quality of life Clinical results as OD of Factor Jun 15, 2017; Pasi Safety 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 1 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

24 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 Initiated Phase 3 study in November 2017; Expect topline results in 2019 >50% mean LDL-C lowering at Day 180 after two quarterly doses 1 Safety (N=501) 1 : 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 24 1 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

25 24h Urine Oxalate corrected for BSA (mmol/24hr/1.73m 2 ) Primary Hyperoxaluria 1 Lumasiran (ALN-GO1) Description Rare autosomal recessive disorder of increased oxalate synthesis resulting in kidney stone formation and renal failure PATIENT POPULATION ~2-5,000 worldwide Initial Phase 1/2 data in November 2017; Expect to report new results in late 2018 Lumasiran Phase 1/2 Study; Initial Low-Dose Cohort (1 mg/kg, q4w) Lumasiran Placebo ULN: 0.46 Delayed initial dosing of lumasiran in patient randomized to placebo Study Day >50% mean reduction in oxalate excretion 1 Part B Safety (N=8): No drug-related SAEs (most common: kidney stones (N=2)) No discontinuations Majority of AEs mild or moderate 25 1 Phase 1/2 Study; Frishberg et al., ASN, Nov 2017

26 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 PATIENT POPULATION ~5,000 ahus >100,000 total complementmediated diseases Cemdisiran Phase 1/2 Study in Healthy Volunteers 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 50 mg (N=3) 200 mg (N=3) 400 mg (N=3) Days since first visit 600 mg (N=3) 900 mg (N=3) Placebo (N=5) Expect to report Phase 2 ahus data in late Data as of 03/02/2016

27 Alpha-1 Antitrypsin (AAT) Deficiency Associated Liver Disease ALN-AAT02 Description Orphan disease where mutant AAT misfolds and aggregates in hepatocytes, leading to liver cirrhosis ALN-AAT Preclinical Study in Tg-PiZ mice 1 Nucleus PATIENT POPULATION* ~12,000 worldwide Placebo-Treated ALN-AAT-Treated IND/CTA filing expected in late 2018; 1 st program to employ ESC+ platform 27 *Stoller et al., GeneReviews, Seghal et al., DDW, May 2015

28 UK Biobank Consortium World-leading effort to connect genotype to full medical records for phenome-wide association studies Goal to generate 500K exome sequences linked to medical records by end K exomes sequenced to date Consortium members receive broad, ongoing access to UK Biobank data linked to exome sequences Exclusive for 1 year after generation Substantial value to Alnylam R&D efforts Modern drug discovery must incorporate human genetics Provides additional genetic validation for existing programs Identify/de-risk new programs In silico natural history data for new and existing programs Patient finding efforts 28

29 29 Guidance and Goals

30 30

31 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) 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 Continue to advance early/mid-stage pipeline; File new INDs; Present clinical data 2018* Early Mid Late 31

32 Financial Summary and Guidance 2017 Q4 Financial Results Cash $1.73B Includes $30.0M in restricted investments GAAP Revenues $37.9M Total GAAP Operating Expenses $185.2M R&D Expenses $117.8M G&A Expenses $67.4M Total Non-GAAP Operating Expenses* $158.1M Non-GAAP R&D Expenses* $102.9M Non-GAAP G&A Expenses* $55.2M GAAP Net Loss $142.2M Non-GAAP Net Loss* $115.1M Shares Outstanding 99.7M 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 $400 to $440M Non-GAAP SG&A Expenses in the range of $280 to $320M 32 * Non-GAAP measures exclude stock-based compensation expenses.

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