Second Quarter 2017 Financial Results

Transcription

1 Colin Living with Porphyria Second Quarter 2017 Financial Results August 9,

2 Agenda Welcome Christine Regan 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. Executive Vice President of R&D Financial Results Manmeet Soni Chief Financial Officer 2017 Goals Update Barry Greene President 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 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. 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 different 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 net loss provides useful information to management and investors regarding the company s financial condition 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, non-gaap net loss is 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 net loss is provided later in this presentation. 3

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

5 Strategic Context for Q Earnings Call APOLLO Phase 3 topline results expected in mid-2017 If positive, plan to file NDA by year-end; MAA shortly thereafter Building world-class team and capabilities in preparation for potential transition to commercial stage Includes Quality, Compliance, Medical Affairs, Manufacturing, and Commercial teams Buildup in U.S., Canada and Western Europe, and then Global Initiated ATLAS Phase 3 for fitusiran in hemophilia and expect to initiate two additional Phase 3 studies by YE ATLAS Phase 3 program for fitusiran, an investigational RNAi therapeutic for the treatment of hemophilia, initiated in July Givosiran, an investigational RNAi therapeutic for the treatment of acute hepatic porphyrias, in late 2017 In collaboration with The Medicines Company, inclisiran, an investigational RNAi therapeutic for the treatment of hypercholesterolemia, in late

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

7 Alnylam ATTR Amyloidosis Portfolio Committed to Continued Innovation for Patients Patisiran IV administration Phase 2 completed Phase 3 trial ongoing; fully enrolled with topline results expected in mid APOLLO-OLE study ongoing ALN-TTRsc02 ESC second generation chemistry Anticipate quarterly SC dose regimen Phase 1 ongoing; initial positive data presented December

8 ΔmNIS+7 from baseline to Month 24 Mean (SEM) ΔmNIS+7 from baseline at 24 mos~ Natural History Placebo (N=66) Diflunisal (N=64) Patisiran Phase 2 OLE Final Study Results Change in mnis+7 at 24 Months out of 27* patients (74%) with no change or an improvement in mnis+7 at month 24 compared to baseline (9.4) 29.6 (3.1) (2.7) (nonlinear; N=283) 1# // Diflunisal Ph 3 Study 2+ // Patisiran Ph 2 OLE^ (N=26) -7.0 (2.0) Individual ΔmNIS+7 at Month 24 (n=26) Adams et al., AAN, April 2017; SEM: Standard Error of the Mean; *One patient discontinued prior to the Month 24 assessment and is included in the denominator ~Assessments drawn from studies in patients with similar baseline neurologic impairment and not based on head-to-head studies #Predicted progression of median NIS value from Gompertz curve fit 1 +Linear interpolation from 2-year NIS progression measurement in longitudinal analysis set ^Patisiran results similar in patients with/without concurrent TTR stabilizer therapy; mnis+7 using full mnis+7 set; partial imputation was used to recover mnis+7 data points where components were missing at one or more replicate measurements (per patient/visit) 1. Adams D et al. Neurology. 2015;85; Berk JL et al. JAMA. 2013;310: Mean ΔmNIS+7 Across hattr Amyloidosis Studies at 24 mos ~

9 Mean Absolute Change from Baseline in Dermal Amyloid Content, % Patisiran Phase 2 OLE Final Study Results TTR Amyloid Content in Skin: Lower Limb Blinded analysis of tandem skin punch biopsies performed at central lab; statistical significance testing performed post-hoc Dermal amyloid content in both distal thigh and distal leg decreased over time relative to baseline Statistically significant decrease in absolute change for distal thigh at 6, 18 and 24 months and at all time points for distal leg 0 Mean Absolute Change from Baseline in Dermal Amyloid Content 6 months 12 months 18 months 24 months Median Relative Change from Baseline in Dermal Amyloid Content Distal Thigh N Median Relative Percent Change (IQR) Distal thigh dermal amyloid content in Patient months (-75.7, 0) * N= * N=22 N= * N= * N=20 Distal Thigh (Baseline Amyloid content (n=24): 10.9%) Distal Leg (Baseline Amyloid content (N=24): 15.8%) * N= * N= * N=19 12 months (-87.5, 0) 18 months (-89.7, -8.3) 24 months (-78.3, 0) Distal Leg N Median Relative Percent Change (IQR) 6 months (-74.3, 0) 12 months (-85.8, 0) 18 months (-91.3, -10) 24 months (-78.3, -21.6) Baseline * P<0.05 IQR, Interquartile Range; 1 patient excluded due to baseline value of 0 and a non-zero post-baseline value 24months Red: Amyloid by Congo red staining 9 Adams et al., AAN, April 2017

10 Patisiran Phase 2 OLE Final Study Results Summary of Safety and Tolerability 10 Adverse Events (AE) reported in 10% of patients AE by Preferred Term Patisiran (N=27) Flushing 7 (25.9%) Diarrhea 6 (22.2%) Infusion related reaction 6 (22.2%) Nasopharyngitis 6 (22.2%) Urinary tract infection 6 (22.2%) Vomiting 6 (22.2%) Wound 6 (22.2%) Nausea 5 (18.5%) Insomnia 4 (14.8%) Neuralgia 4 (14.8%) Pyrexia 4 (14.8%) Anemia 3 (11.1%) Bronchitis 3 (11.1%) Cataract 3 (11.1%) Infusion site extravasation 3 (11.1%) Edema peripheral 3 (11.1%) Macular degeneration 3 (11.1%) Musculoskeletal pain 3 (11.1%) Osteoporosis 3 (11.1%) Adams et al., AAN, April patients (25.9%) with 10 reports of serious adverse events (SAE); not related to study drug One discontinuation for gastroesophageal cancer at ~20 months; patient subsequently died One death due to myocardial infarction after patient completed 24 months of treatment One patient with 3 reports (distal femur fracture/proximal tibia fracture/osteonecrosis/ligament rupture, dehydration/acute prerenal failure/urinary tract infection and thermal burn) One patient with 2 reports (ankle fracture/foot fracture/ osteonecrosis and ankle arthrodesis) One patient with venous thrombosis of the lower limb One patient with foot abscess and osteomyelitis One patient with pacemaker implantation due to amyloid cardiomyopathy Majority of AEs were mild or moderate 5 patients (18.5%) had severe AEs not related to study drug Related AEs reported in 4 patients were infusion related reaction (22.2%) and flushing (22.2%), all of which were mild No clinically significant changes in liver function tests, renal function, or hematologic parameters, including platelets

11 ALN-TTRsc02 Opportunity Potential for Best-in-Class Profile Revusiran*/Inotersen ALN-TTRsc02 52 DOSES PER YEAR 4 DOSES PER YEAR ANTICIPATED Ongoing Study in Normal Healthy Volunteers Mean max TTR KD of 97.1 ± 0.5%; >80% TTR KD at Day 90 after single 50 mg dose** Safety: Generally well tolerated in healthy volunteers (N=48) No SAEs or discontinuations due to AEs; all AEs mild or moderate 9 AEs in 5 subjects considered possibly related to treatment; all mild ISRs reported in 2 subjects symptoms mild and transient No clinically significant changes in physical exams or lab parameters (e.g., LFTs) Most potent Alnylam RNAi therapeutic to date 11 *Alnylam discontinued development of revusiran in October 2016 **Data cut-off 26Oct2016; reported at Alnylam R&D Day in December 2016

12 Mean [+/- SEM] TTR Relative to Baseline ALN-TTRsc02 Phase 1 Preliminary Study Results Single Ascending Dose Study in Healthy Volunteers Days since first dose Cohort Placebo (N=20) TTRSC02 (5mg) (N=6) TTRSC02 (25mg) (N=6) TTRSC02 (Optional; 25mg) (N=6) TTRSC02 (Subjects of Japanese descent; 25mg) (N=6) TTRSC02 (50mg) (N=6) TTRSC02 (Optional; 50mg) (N=6) TTRSC02 (Subjects of Japanese descent; 50mg) (N=6) TTRSC02 (100mg) (N=6) TTRSC02 (200mg) (N=6) TTRSC02 (300mg) (N=6) No SAEs and no discontinuations due to AEs All AEs mild or moderate in severity 14 AEs in 8 subjects considered possibly related to treatment; majority mild Events included injection site erythema, injection site pain, injection site bruising, rhinorrhea, pruritus, cough, nausea, fatigue, genital rash and abdominal pain No clinically significant changes in lab parameters, EKG or physical exam 12 As of data cutoff on 31May2017

13 AT Activity (%) Fitusiran for Hemophilia Potential to Restore Hemostasis in Hemophilia Genetically validated, liver-expressed target gene Biomarker for POC in Phase 1 Definable path to approval and patient access Hemophilia A FVIII Hemophilia B FIX FVIIIa FIXa FXa Prothrombin FVIIa FVII FX AT AT FVa FV Thrombin Fibrinogen Fibrin Blood clot Plasma Biomarkers AT Lowering, Thrombin Generation AT % Lowering Peak Thrombin Days Fitusiran Phase 1 results: Pasi et al., WFH, July Peak Thrombin (nm) Established Endpoint Annualized Bleeding Rate (ABR) Photo courtesy of Guy Young, M.D. Director, Hemostasis & Thrombosis Center at Children's Hospital Los Angeles and Professor of Pediatrics, USC Keck School of Medicine

14 Fitusiran Phase 2 OLE Study Results* Ongoing Study in Hemophilia A & B Patients, Including Inhibitors Approximately 80% AT lowering Significant increase in thrombin generation to lower end of normal range Median estimated ABR of 1 in all patients with up to 20 months treatment Median estimated ABR of 0 in inhibitor patients DURABILITY Monthly SC fixed dose regimen Safety in Phase 2 OLE: Generally well tolerated, median 11 months of dosing (N=33) 2 SAEs considered possibly related to study drug o Asymptomatic ALT and AST elevation in patient with chronic HCV infection o Seizure with confusion in patient with history of seizure disorder Majority of AEs mild or moderate in severity, unrelated to study drug o Mild ISRs in 6 (18%) patients No thromboembolic events; no lab evidence for pathologic clot formation ALT increases >3x ULN observed in 11 (33%) patients o All asymptomatic, with no concurrent elevations of bilirubin >2x ULN o Reversible; all patients had medical history of HCV No instances of anti-drug antibody formation Initial Evidence for Potential Restoration of Hemostasis in Severe Hemophilia A and B PLANNED NEXT STEPS ATLAS Phase 3 results in mid- to late Alnylam, Sanofi Genzyme US/Can/Western Europe; Sanofi Genzyme ROW *Clinical results as of Jun 15, 2017; Pasi et al., ISTH, July 2017

15 2:1 2:1 Fitusiran ATLAS Phase 3 Program Initiated in July 2017 Adults and adolescents with hemophilia A or B with inhibitors Currently manage bleeds with on-demand bypassing agent therapy N~50 9 months fitusiran OR 9 months on-demand BPA Primary Endpoints: ABR Secondary Endpoints: Spontaneous ABR Joint ABR QOL (Haem-A-QOL) Adults and adolescents with hemophilia A or B without inhibitors Currently manage bleeds with on-demand (OD) factor replacement therapy N~100 9 months fitusiran OR 9 months on-demand factor Primary Endpoints: ABR Secondary Endpoints: Spontaneous ABR Joint ABR QOL (Haem-A-QOL) Adults and adolescents with hemophilia A or B with or without inhibitors Currently manage bleeds prophylactically N~100 6 months PPX factor/bpa 7 months fitusiran Primary Endpoints: ABR in factor/bpa and fitusiran period Secondary Endpoints: Spontaneous ABR Joint ABR QOL (Haem-A-QOL) Patients who complete the study may be eligible for fitusiran treatment in ATLAS-OLE study 15 ATLAS-INH powered to detect as little as a 60% reduction from control to fitusiran ATLAS-A/B powered to detect as little as a 50% reduction from control to fitusiran

16 Acute Hepatic Porphyrias Disease Overview Acute Hepatic Porphyrias (AHP) 1,2 Inborn errors of heme synthesis from liver enzyme defects AIP (Acute Intermittent Porphyria) most common, with a mutation in hydroxymethylbilane synthase (HMBS) Disease Pathophysiology Induction of ALAS1 leads to accumulation of toxic heme intermediates ALA/PBG that cause disease manifestations Acute Attacks and Chronic Manifestations Autonomic Nervous System Severe abdominal pain, hypertension Central Nervous System Mental status changes, seizures Peripheral Nervous System Muscle weakness, paralysis Treatment and Unmet Need Glucose and hemin used to treat acute attacks and by some specialists to prevent attacks Unmet need for more efficacious, long acting, and safer therapies to prevent attacks and improve chronic disease manifestations Disease triggers ALA Synthase 1 (ALAS1) Glycine δ- Aminolevulinic acid (ALA) ALAD Porphobilinogen (PBG) HMBS (PBGD) Hydroxymethylbilane Uroporphyrinogen Coproporphyrinogen CPOX Protoporphyrinogen PPOX Feedback inhibition Protoporphyrin FECH Heme Succinyl CoA ALAD Porphyria Acute Intermittent Porphyria (AIP) Hereditary Coproporphyria (HCP) Variegate Porphyria (VP) Fe Bonkovsky, et al. Am J Med. 2014;127(12): ; 2.Elder, et al. JIMD. 2013;36(5):

17 Givosiran: Investigational RNAi Therapeutic Therapeutic Hypothesis Reduction of Liver ALAS1 Protein to Lower ALA/PBG ALA/PBG induce porphyria symptoms ALAS1 protein Givosiran (ALN-AS1) results in knockdown of ALAS1 and lowers ALA/PBG production to prevent attacks and disease symptoms Givosiran 17

18 Givosiran Interim Phase 1 Study Results* Ongoing Randomized, Double-Blind, Placebo-Controlled Study in Recurrent Attack Porphyria Patients Up to 79% lowering of ALA, 77% lowering of PBG 73% Mean Decrease in Annualized Attack Rate** compared with placebo 73% Mean Decrease in Annualized Hemin Use Initial evidence for further reductions in annualized attack rate with extended dosing in OLE DURABILITY 18 Monthly and possibly quarterly SC dose regimen Safety: Generally well tolerated (N=9) No drug-related SAEs and no discontinuations due to AEs As reported previously, 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 AEs possibly related include ISRs, hypersensitivity, myalgia, headache, moderate renal impairment (in patient with history of same), and erythema No clinically significant changes in vital signs, EKG, or clin labs Alnylam retains global rights to the givosiran program Initial Evidence for Clinical Activity in Recurrent Attack Porphyria Patients PLANNED NEXT STEPS Start Phase 3 in late 2017 *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 FDA Breakthrough and EMA PRIME Designations

19 Annualized Attack Rate Annualized Hemin Doses Interim Givosiran Phase 1 (Part C, Cohorts 1-2 OLE) Study Results Clinical Activity Givosiran activity maintained, potential for further reductions in attack rate with extended dosing Mean Annualized Attack Rate Cohorts 1 and Run-In Treatment OLE N=6 N=6 N=6 N=6 N=6 N=6 Run-In Treatment OLE Mean Annualized Hemin Doses Cohorts 1 and Data cut date of 21 Apr Run-In Treatment OLE Mean Days on Study

20 Annualized Attack Rate Interim Givosiran Phase 1 (Part C, Cohorts 1-2 OLE) Study Results Clinical Activity, Placebo Mean Annualized Attack Rate Placebo Run-In Placebo Treatment OLE N=2 N=2 N=2 Mean Days on Study Run-In Treatment OLE Data cut date of 21 Apr 2017

21 Interim Givosiran Phase 1 (Part C and OLE) Study Results Safety and Tolerability Part C (Cohorts 1-3) 3 patients had 4 SAEs (excluding porphyria attacks), none assessed as related to study drug 1 patient in Cohort 3 had fatal SAE of hemorrhagic pancreatitis, complicated by pulmonary embolism, as previously reported. Assessed unlikely related due to presence of gallbladder sludge All randomized patients reported AEs Majority of AEs were mild to moderate; 25% patients had severe AEs, assessed as unrelated to study drug AEs in 3 patients: Abdominal pain, headache, nasopharyngitis, nausea, vomiting 4 patients had related AEs: Injection site reactions (mild and self-limiting), hypersensitivity, myalgia, headache, moderate renal impairment (in patient with history of moderate renal impairment) and erythema No other discontinuations due to AEs or other clinically significant changes in EKG, clinical laboratory or physical examination OLE (Cohorts 1-2) Overall safety experience in OLE is consistent with Phase 1 Study No SAEs (excluding porphyria attacks) or discontinuations due to AEs 4 patients reported AEs; Most assessed as mild or moderate in severity 2 patients experienced mild or moderate AEs that were considered related or possibly related to study drug (epistaxis, hypertension and renal impairment, in same patient with history of moderate renal impairment as noted above) No clinically significant changes in EKG, clinical laboratory or physical examination reported All Safety Data in database as of 5 May

22 Other Programs to Watch Inclisiran for Hypercholesterolemia* ALN-CC5 for Complement-Mediated Diseases 53% mean LDL-C lowering at Day 180 after two quarterly doses 1 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 PLANNED NEXT STEPS FOR INCLISIRAN: Start Phase 3 study in late 2017 Sustained control of disease hemolysis with up to 67% reduction in eculizumab dose in PNH patients 2 Safety (N=6): No SAEs, no discontinuations due to AEs 1 AE of hemolysis in setting of URI; moderate in severity and considered unrelated to study drug 1 AE of asymptomatic, transient grade 3 elevation of LFTs; considered possibly related *The Medicines Company is leading and funding development of inclisiran from Phase 2 onward and will commercialize the program, if successful ALN-GO1 for Primary Hyperoxaluria 1 (PH1) ALN-HBV for Hepatitis B Virus (HBV) Infection Safety (N=32): No SAEs, no discontinuations due to AEs All AEs mild or moderate, with exception of one subject with transient, asymptomatic CPK elevation considered unrelated to study drug RECENT ACTIVITY FOR ALN-GO1: First PH1 Patient Dosed in March 2017 Up to 8-fold increase in plasma glycolate in healthy volunteers 3 Pre-clinical results: 4 up to 3.6 log 10 HBsAg reduction 22 1 ORION-1 Phase 2 Study; Ray et al., ACC, Mar Phase 1/2 Study; Hill et al., ASH, Dec Phase 1/2 Study; Milliner et al., IPNA, Sep Mouse model; Sepp-Lorenzino et al., Liver Meeting, Nov 2015

23 Manmeet Soni Chief Financial Officer Q Financial Results 23

24 Financial Summary and Guidance 2017 Q2 Financial Results Cash $1.25B Includes $355.2M of net proceeds from the May 2017 public offering Includes $21.4M of proceeds from Sanofi Genzyme s purchase of common stock Includes $150.0M in restricted investments GAAP Revenues $15.9M Total GAAP Operating Expenses $136.4M Research and Development Expenses $90.6M General and Administrative Expenses $45.8M GAAP Net Loss $118.4M Non-GAAP Net Loss* $94.4M Shares Outstanding 91.7M 2017 Guidance Year-end cash >$1.0B Includes $150.0M in restricted investments * Non-GAAP net loss excludes stock-based compensation expenses. See Appendix for a reconciliation between GAAP and non-gaap net loss. 24

25 Barry Greene President 2017 Goals Update 25

26 Transition to Potential Commercialization Planned Rapid Launch Succession Givosiran ~2020 Fitusiran ~2019 Patisiran ~2018 Manufacturing build-out to ensure consistent drug supply underway Alewife facility fully operational and ready for patisiran launch Norton drug substance facility expected to be commercially operational in 2020 Building commercial capabilities to prepare for upcoming product launches Patisiran in US, Canada, and Western Europe Fitusiran co-develop/co-commercialize in US, Canada, and Western Europe Givosiran globally 26

27 Alnylam 2017 Pipeline Goals *Early is Q1-Q2, Mid is Q2-Q3, and Late is Q3-Q4 PATISIRAN (hattr Amyloidosis) Phase 2 OLE data APOLLO Phase 3 top-line APOLLO Phase 3 results NDA/MAA filing 2017* Early Mid Late FITUSIRAN (Hemophilia and RBD) GIVOSIRAN (Acute Hepatic Porphyrias) Phase 2 OLE data ATLAS Phase 3 program start Phase 1, Part C data Phase 3 study start ORION-1 Phase 2 data INCLISIRAN** (Hypercholesterolemia) ADDITIONAL CLINICAL PROGRAMS ORION-2 HoFH study start ORION-3 Phase 2 OLE study start ASCVD Phase 3 study start Continue to advance early/mid-stage pipeline; Present clinical data **Based on The Medicines Company guidance as of January

28 Q Financial Results Q&A Session 28

29 29 Thank You

30 30 Appendix

31 Alnylam Pharmaceuticals, Inc. Reconciliation of GAAP Net Loss to Non-GAAP Net Loss (In thousands, except per share amounts) Three Months Ended June 30, Six Months Ended June 30, GAAP net loss $ (118,420) $ (90,129) $ (225,710) $ (193,103) Adjustment: Stock-based compensation expenses 24,030 15,816 39,747 39,296 Non-GAAP net loss $ (94,390) $ (74,313) $ (185,963) $ (153,807) GAAP net loss per common share-basic and diluted $ (1.34) $ (1.05) $ (2.59) $ (2.26) Adjustment (as detailed above) Non-GAAP net loss per common share-basic and diluted $ (1.07) $ (0.87) $ (2.14) $ (1.80) 31