First Quarter 2018 Financial Results

Transcription

1 First Quarter 2018 Financial Results May 3,

2 Agenda Welcome Christine Lindenboom Vice President, Investor Relations & Corporate Communications Q Overview John Maraganore, Ph.D. Chief Executive Officer Alnylam Clinical Pipeline Akshay Vaishnaw, M.D., Ph.D. President of R&D Financial Summary and Guidance Manmeet Soni Chief Financial Officer Commercial Readiness Barry Greene President 2018 Goals Update Yvonne Greenstreet, MBChB Executive Vice President, Chief Operating Officer Q&A Session 2

3 Alnylam Forward Looking Statements & Non-GAAP Financial Measures 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-K 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. This presentation contains non-gaap financial measures, including net loss adjusted to exclude certain non-cash expenses. These measures are not in accordance with, or an alternative to, accounting principles generally accepted in the U.S. (GAAP), and may be difference from non-gaap financial measures used by other companies. The item included in GAAP presentations but excluded for purposes of determining non-gaap financial measures for the periods presented in this presentation is stock-based compensation expense. The company believes the presentation of non-gaap financial measures provides useful information to management and investors regarding the company s financial conditions and results of operations. When GAAP financial measures are viewed in conjunction with non-gaap financial measures, investors are provided with a more meaningful understanding of the company s ongoing operating performance. In addition, these non-gaap financial measures are among those indicators the company uses as a basis for evaluating performance, allocating resources and planning and forecasting future periods. Non-GAAP financial measures are not intended to be considered in isolation or as a substitute for GAAP financial measures. A reconciliation between GAAP and non- GAAP measures is provided later in this presentation. 3

4 John Maraganore, Ph.D. Chief Executive Officer Q Overview 4

5 Bring Innovation to Patients and Markets Around World Patisiran Givosiran Lumasiran TTRsc02 hattr amyloidosis Acute hepatic porphyrias Primary hyperoxaluria ATTR amyloidosis Partnered programs*: Fitusiran Inclisiran Hemophilia Hypercholesterolemia 5 *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 Anticipated dates of launch based on current development timelines and assuming regulatory approval

6 Akshay Vaishnaw, M.D., Ph.D. President of R&D Alnylam Clinical Pipeline 6

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 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 8 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

9 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) 9 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

10 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 10 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

11 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

12 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 12 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

13 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 13

14 24h Urine Oxalate corrected for BSA (mmol/24hr/1.73m 2 ) Primary Hyperoxaluria Type 1 Lumasiran Description Rare autosomal recessive disorder of increased oxalate synthesis resulting in kidney stone formation and renal failure PATIENT POPULATION ~3-5,000 in U.S./EU Expect to initiate Phase 3 study in mid-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 FDA Breakthrough and EMA PRIME Designations 14 1 Phase 1/2 Study; Frishberg et al., ASN, Nov 2017

15 Lumasiran Phase 3 Study Alignment with FDA on Design of Pivotal Trial Primary endpoint of reduction in urinary oxalate at 6 months Sample size of approximately 25 patients Expect to: Start Phase 3 study in mid-2018 Report topline results in 2019 Submit NDA in early 2020 (assuming positive Phase 3 results) Represents significant acceleration in advancement of lumasiran to patients 15

16 2:1 2:1 Median ABR 16 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 *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

17 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 17 *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

18 Manmeet Soni Chief Financial Officer Financial Summary and Guidance 18

19 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 19 *Non-GAAP measures exclude stock-based compensation expenses. See Appendix for a reconciliation between GAAP and non-gaap measures.

20 Barry Greene President Commercial Readiness 20

21 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 21 *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

22 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 22

23 Yvonne Greenstreet, MBChB Executive Vice President, Chief Operating Officer 2018 Goals Update 23

24 24 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

25 Q Financial Results Q&A Session 25

26 26 THANK YOU

27 Q Financial Results Appendix 27

28 Alnylam Pharmaceuticals, Inc. Reconciliation of Selected GAAP Measures to Non-GAAP Measures (In thousands, except per share amounts) 28