Alnylam Pharmaceuticals R&D Day

Transcription

1 Alnylam Pharmaceuticals R& ay ecember 12, 2014

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, successfully demonstrate the efficacy and safety of our drug candidates, obtain, maintain and protect intellectual property, enforce our patents and defend our patent portfolio, obtain regulatory approval for products, establish and maintain business alliances; our dependence on third parties for access to intellectual property; and the outcome of litigation, 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 forwardlooking 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 John Maraganore, Ph.. Chief Executive Officer Alnylam Pipeline Growth Strategy 3

4 RNA Interference (RNAi) A New Class of Innovative Medicines RNAi Therapeutics Harness natural pathway» Catalytic mechanism» Mediated by small interfering RNA or sirna Therapeutic gene silencing» Any gene in genome» istinct mechanism of action vs. other drug classes» Unique opportunities for innovative medicines Clinically validated platform 4

5 RNAi Clinically Validated Multiple Alnylam Programs; IV and SC elivery Human Safety and PK >3500 oses administered» Includes >2 years duration Generally well tolerated Both IV and SC Human Clinical Activity: Patisiran and Revusiran >90% Knockdown of serum TTR, disease causing protein Initial evidence for disease stabilization» Patisiran Phase 2 OLE Both IV and SC Human Clinical Efficacy: ALN-PCS02 Up to 57% reduction of LL-C w/out statins Up to 84% knockdown of PCSK9 ALN-PCSsc Phase 1 started Human Clinical Activity: ALN-AT3 Positive results in ongoing Phase 1 in hemophilia» Up to 57% knockdown of antithrombin Highly potent and durable effects with mcg/kg SC dose Coelho et al., N Eng J Med;369: (2013); Adams, ANA, Oct. 2014; Mauer, AHA, Nov Fitzgerald, et al., The Lancet, EOP (2013); Sorenson, ASH ec

6 Alnylam RNAi Therapeutics Strategy A Reproducible and Modular Path for Innovative Medicines GCCCCUGGAGGG 2. POC achieved in Phase 1 Blood-based biomarker with strong disease correlation» e.g., Serum TTR, thrombin generation, hemolytic activity, LL-C, HBsAg levels 1. Liver-expressed target gene Involved in disease with high unmet need Validated in human genetics GalNAc-siRNA enables SC dosing with wide therapeutic index 3. efinable path to approval and market Established endpoints Focused trial size Large treatment effect Collaborative approach with physicians, regulators, patient groups, and payers 6

7 Alnylam 5x15 TM Focused Product evelopment Pipeline for Genetic Medicines RNAi therapeutics as genetic medicines In 2011: 5 Key products in clinical development through 2015 Expect to exceed 2011 guidance» 6-7 Clinical-stage products» At least 2 in Phase 3» 5-6 Human POCs 15 Programs disclosed to date» >10 Additional programs yet to be disclosed Product characteristics Genetically defined target/disease Existing Alnylam delivery platform Phase 1 proof of concept Clear and rapid development Significant commercial opportunity 7

8 GalNAc-siRNA Conjugates Subcutaneous RNAi Therapeutics GalNAc 3 Asialoglycoprotein Receptor (ASGPR) Highly expressed in hepatocytes High rate of uptake Recycling time ~15 minutes Conserved across species GalNAc-siRNA conjugate ASGPR (ph>5) Clathrin-coated pit Revusiran, ALN-AT3, ALN-PCSsc, ALN-CC5 sirna conjugated to N-acetylgalactosamine (GalNAc) ligand Efficient delivery to hepatocytes following subcutaneous administration Wide therapeutic index Enhanced stabilization chemistry (ESC) used with all programs after revusiran» Significantly improved potency and durability protein RISC Recycling ASGPR mrna Nucleus Clathrin-coated vesicle Endosome 8

9 RNAi Therapeutics Profile Emerging profile for ESC-GalNAc-siRNA conjugates Attractive pharmacologic properties» Subcutaneous dose administration» High potency with microgram/kg (mcg/kg) doses» Low volume per injection, <1 ml» urability for monthly (qm) and possibly quarterly (qq) dose frequency Competitive profile with RNAi mechanism» Block synthesis of disease-causing protein» Efficacy independent of target protein blood levels» Clamped knockdown with low inter-individual variability Well tolerated and wide therapeutic index Supports pipeline growth beyond rare disease opportunities 9

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14 Alnylam Strategic Therapeutic Areas (STAr) Genetic Medicines Genetically validated liver targets for rare orphan diseases High unmet needs in focused markets SC dosing Alnylam direct commercial in NA and EU Genzyme alliance for ROW commercial» Through end-2019 Cardio-Metabolic isease Genetically validated liver targets for dyslipidemia, NASH, type 2 diabetes, and hypertension evelopment path in morbid subpopulations Access to larger populations thereafter Emerging genetics qm or qq SC dosing Partnership opportunities Hepatic Infectious isease Liver pathogen and/or host targets Sub-acute duration of treatment (~12 mo) Multiple sirnas possible, if needed efined opportunities with very large markets qm or qq SC dosing Partnership opportunities 14

15 Alnylam Strategic Therapeutic Areas (STAr) GCCCCUGGAGGG 15

16 GENETIC MEICINES TTR-Mediated Amyloidosis Hemophilia and Rare Bleeding isorders Complement-Mediated iseases Hepatic Porphyrias Alpha-1 Antitrypsin eficiency Beta-Thalassemia/Iron-Overload isorders Primary Hyperoxaluria Type 1 Alnylam evelopment Pipeline iscovery evelopment Phase 1 Phase 2 Phase 3 Patisiran (ALN-TTR02) Revusiran (ALN-TTRsc) ALN-AT3 ALN-CC5 ALN-AS1 ALN-AAT ALN-TMP ALN-GO1 Additional Genetic Medicine Programs CARIO-METABOLIC ISEASES Hypercholesterolemia ALN-PCSsc Mixed Hyperlipidemia/Hypertriglyceridemia Hypertriglyceridemia Hypertension/Preeclampsia ALN-ANG ALN-AC3 ALN-AGT Additional Cardio-Metabolic Programs HEPATIC INFECTIOUS ISEASES Hepatitis B Virus Infection Hepatitis Virus Infection Chronic Liver Infection ALN-HBV ALN-HV ALN-PL Additional Hepatic Infectious isease Programs

17 Clinical ata Expected PATISIRAN (ALN-TTR02) TTR-FAP REVUSIRAN (ALN-TTRsc) TTR-FAC ALN-AT3 (Hemophilia and RBs) ALN-CC5 (Complement isease) ALN-AS1 (Hepatic Porphyrias) ALN-AAT (Alpha-1 Antitrypsin eficiency) ALN-GO1 (Primary Hyperoxaluria) ALN-PCSsc (Hypercholesterolemia) ALN-HBV (Hepatitis B Virus Infection) Phase 2 OLE APOLLO Phase 3 Phase 2 OLE ENEAVOUR Phase 3 Phase 1 Phase 2 Phase 3 Phase 1/2 Phase 2 Phase 3 Phase 1 Phase 2/3 Phase 1 Phase 2 Phase 3 Phase 1 Phase 2/3 Phase 1 Phase 2 Phase 3 Phase 1 Phase 2 Multi-Year Pipeline Progression Subsequent 1-2 Years Additional Programs Research Additional Phase 1 and 2 Studies

18 Alnylam Pipeline Goals 2015 Late 14 Early Mid Late Ongoing PATISIRAN (ALN-TTR02) TTR-FAP REVUSIRAN (ALN-TTRsc) TTR-FAC ALN-AT3 (Hemophilia and RBs) ALN-CC5 (Complement isease) ALN-AS1 (Hepatic Porphyrias) ALN-AAT (Alpha-1 Antitrypsin eficiency) ALN-GO1 (Primary Hyperoxaluria) APOLLO Phase 3 Accrual Phase 2 OLE data ENEAVOUR Phase 3 Start ENEAVOUR Phase 3 Accrual Phase 2 OLE ata Phase 1 ata Start Phase 2 CTA Filing Start Phase 1/2 Initial Phase 1/2 ata CTA Filing Start Phase 1 IN Filing evelopment Candidate ALN-PCSsc (Hypercholesterolemia) ALN-HBV (Hepatitis B Virus Infection) * Early is Q1-Q2, Mid is Q2-Q3, and Late is Q3-Q4; **IN or IN equivalent Start Phase 1 Initial Phase 1 ata IN Filing

19 Thank You