Alnylam Pharmaceuticals, Inc. · NASDAQ:ALNY
Alnylam Pharmaceuticals — Investor Day (December 2014)
175 slides from Alnylam Pharmaceuticals's investor day presentation, Dec 12, 2014
Slide 1: Alnylam Pharmaceuticals R&D Day
Alnylam Pharmaceuticals R&D Day December 12, 2014
Slide 2: Alnylam Forward Looking Statements
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 1934. There are a number of important factors that could cause actual results to differ material
Slide 3: Agenda
Agenda 8:00 – 9:30 a.m. Welcome Cynthia Clayton Vice President, Investor Relations and Corporate Communications Alnylam Pipeline Growth Strategy John Maraganore, Ph.D. Chief Executive Officer Collaborating to Develop Genetic Medicines David Meeker, M.D. President and CEO, Genzyme, a Sanofi com
Slide 4: Agenda
Agenda 9:30 – 10:50 a.m. Cardio-Metabolic Disease Daniel Rader, M.D. Chair, Department of Genetics, Perelman School of Medicine, University of Pennsylvania Cardio-Metabolic Pipeline Rachel Meyers, Ph.D. Vice President, Research and RNAi Lead Development Q&A Session Moderated by Barry Greene Br
Slide 5: Agenda
Agenda 10:50 a.m. – 12:00 p.m. Hepatic Infectious Disease Timothy Block, M.D. President, Hepatitis B Foundation of America and its Baruch S. Blumberg Institute, and Professor, Drexel University College of Medicine Hepatic Infectious Disease Pipeline Laura Sepp-Lorenzino, Ph.D. Vice President, En
Slide 6: Alnylam Pipeline Growth Strategy
John Maraganore, Ph.D. Chief Executive Officer Alnylam Pipeline Growth Strategy 6
Slide 7: RNA Interference (RNAi)
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 » Distinct mechanism of action vs. other drug classes » Unique opportunities
Slide 8: RNAi Clinically Validated
RNAi Clinically Validated Multiple Alnylam Programs; IV and SC Delivery Human Safety and PK Human Clinical Activity: >3500 Doses Patisiran and Revusiran administered >90% Knockdown of serum » Includes >2 years TTR, disease causing protein duration Initial evidence for disease Generally well
Slide 9: Alnylam RNAi Therapeutics Strategy
Alnylam RNAi Therapeutics Strategy A Reproducible and Modular Path for Innovative Medicines 2. POC achieved in Phase 1 Blood-based biomarker with strong disease correlation » e.g., Serum TTR, thrombin GCCCCUGGAGGG generation, hemolytic activity, LDL-C, HBsAg levels 3. Definable path to approval an
Slide 10: Alnylam 5x15
Alnylam 5x15 TM Focused Product Development 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 discl
Slide 11: GalNAc-siRNA Conjugates
GalNAc-siRNA Conjugates Subcutaneous RNAi Therapeutics GalNAc3 GalNAc-siRNA Asialoglycoprotein Receptor (ASGPR) conjugate Highly expressed in hepatocytes ASGPR High rate of uptake (pH>5) Recycling time ~15 minutes Clathrin-coated pit Conserved across species Revusiran, ALN-AT3, ALN-PCSsc, AL
Slide 12: RNAi Therapeutics Profile
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 » Durability for monthly (qM) and possibly quarterly (qQ) dose frequen
Slide 13: Strategic Therapeutic Areas
STAr STRATEGIC THERAPEUTIC @ AREAS ey YAlnylam
Slide 14: Genetic Medicines
STAr GENETIC MEDICINES ay D2 Alnylam
Slide 15: Cardio-Metabolic Disease
STAr CARDIO- METABOLIC DISEASE 6y YAlnylam
Slide 16: Hepatic Infectious Disease
STAr HEPATIC INFECTIOUS @ DISEASE ®y 2 Alnylam
Slide 17: Alnylam Strategic Therapeutic Areas (STAr)
Alnylam Strategic Therapeutic Areas (STAr) Genetic Medicines Cardio-Metabolic Disease Hepatic Infectious Disease Genetically validated Genetically validated liver Liver pathogen and/or liver targets for rare targets for dyslipidemia, host targets orphan diseases NASH, type 2 diabetes, Sub-ac
Slide 18: Alnylam Strategic Therapeutic Areas (STAr)
Alnylam Strategic Therapeutic Areas (STAr) GCCCCUGGAGGG 18
Slide 19: Alnylam Development Pipeline
Alnylam Development Pipeline Discovery Development Phase 1 Phase 2 Phase 3 GENETIC MEDICINES Patisiran (ALN-TTR02) TTR-Mediated Amyloidosis Revusiran (ALN-TTRsc) Hemophilia and Rare Bleeding Disorders ALN-AT3 Complement-Mediated Diseases ALN-CC5 Hepatic Porphyrias ALN-AS1 Alpha-1 Antitrypsin Deficie
Slide 20: David Meeker, M.D.
David Meeker, M.D. President and Chief Executive Officer Genzyme, a Sanofi Company 20
Slide 21: www.genzyme.com
Dione (with her mother) Pompe disease Brazil www.genzyme.com |
Slide 22: Milestones in Genzyme History
Milestones in Genzyme History 2003 Therapies approved for Fabry disease and MPS-I disease 2004 New global headquarters opens in Cambridge, MA 2006 Therapy approved for Pompe 1981 Genzyme founded disease 1983 Henri Termeer joins Genzyme 2008 Science Center opens in 1986 Genzyme IPO Framingham, MA 198
Slide 23: Our Global Commitment
Our Global Commitment Headquartered Expanding Collaborating with patient Serving in the U.S. manufacturing communities, physicians, patients in with global locations capabilities in the universities, hospitals, more than 100 charitable organizations, in more than 40 U.S. and E.U. countries companies
Slide 24: Rare Diseases & Multiple Sclerosis
Rare Diseases & Multiple Sclerosis Mikhail Gaucher Shani disease MS Joan Tiger Thyroid MS Cancer Genetic Disease Gaucher disease type 1 (2 treatments), Once-daily oral therapy for relapsing Fabry disease, Pompe disease, remitting MS MPS I disease Infusion therapy for relapsing Endocrinology remittin
Slide 25: About Sanofi
About Sanofi • Global healthcare leader • Diversified offering of medicines, consumer healthcare products, vaccines, generics, and animal health • Major biopharmacy player: 45% of revenues generated by biologics, 80% of projects in development are biologics • 112 industrial sites in 41 countries • M
Slide 26: A Lifetime Commitment
A Lifetime Commitment “My mom was just tremendous and an amazing role model for me. I know the doctors told her that I was going to die but her perseverance, dedication and ability to work closely with Genzyme and search around the world to develop a treatment was amazing.” – Brian Berman, Type 1 Ga
Slide 27: Understanding of unmet needs of patients
Understanding of unmet needs of patients 61% of Gaucher patients would like their treatment to be an oral formulation(1) (1) PeopleMetrics survey in Gaucher patients (n= 238) What improvements would you like to see in treatments for Gaucher Disease?
Slide 28: Taking Care of People
Taking Care of People Ayama (with his mother) Pompe disease Sol Pompe disease
Slide 29: Critical Elements
Critical Elements VALUE PARTNERSHIP COMMITMENT
Slide 30: Myths
Myths • Developing drugs for Rare Diseases is easy (easier?) • Orphan Designation allows you to price higher • Orphan disease pricing is not sustainable • Commercializing an orphan disease product is easy
Slide 31: Transformational expanded collaboration on Rare Genetic Diseases
Transformational expanded collaboration on Rare Genetic Diseases
Slide 32: Genetic Medicine Pipeline Highlights
Akshay Vaishnaw, M.D., Ph.D. Executive Vice President and Chief Medical Officer Genetic Medicine Pipeline Highlights 32
Slide 33: Genetic Medicines
STAr GENETIC MEDICINES ay LAlnylam.
Slide 34: Alnylam Development Pipeline
Alnylam Development Pipeline Discovery Development Phase 1 Phase 2 Phase 3 GENETIC MEDICINES Patisiran (ALN-TTR02) TTR-Mediated Amyloidosis Revusiran (ALN-TTRsc) Hemophilia and Rare Bleeding Disorders ALN-AT3 Complement-Mediated Diseases ALN-CC5 Hepatic Porphyrias ALN-AS1 Alpha-1 Antitrypsin Deficie
Slide 35: Alnylam Development Pipeline
Alnylam Development Pipeline Discovery Development Phase 1 Phase 2 Phase 3 GENETIC MEDICINES Patisiran (ALN-TTR02) TTR-Mediated Amyloidosis Revusiran (ALN-TTRsc) Hemophilia and Rare Bleeding Disorders ALN-AT3 Complement-Mediated Diseases ALN-CC5 Hepatic Porphyrias ALN-AS1 Alpha-1 Antitrypsin Deficie
Slide 36: Transthyretin-Mediated Amyloidosis (ATTR) Program
Transthyretin-Mediated Amyloidosis (ATTR) Program Unmet Need and Product Opportunity RNAi to treat genetic disease ATTR is significant orphan disease » ~50,000 Patients worldwide Clinical pathology » Onset ~40 to >60 yr; fatal within 5-15 years » Two predominant forms – Familial amyloidotic poly
Slide 37: Patisiran (ALN-TTR02)
Patisiran (ALN-TTR02) Familial Amyloidotic Polyneuropathy (FAP) Patisiran in clinical development International Nonproprietary Name designation for ALN-TTR02 = Patisiran (pa-TEE-sa-ran) Orphan drug status in US/EU Fast track designation by FDA Administered by IV infusion Positive Phase 1 r
Slide 38: Patisiran Open-Label Extension (OLE) Study
Patisiran Open-Label Extension (OLE) Study FAP patients dosed in Phase 2 trial eligible for Phase 2 OLE study Clinical endpoints evaluated every 6 months for up to 2 years » Clinical endpoints same as APOLLO Phase 3 study » Dosing at 0.30 mg/kg IV every 3 weeks Study objectives » Primary: Safety
Slide 39: Patisiran Phase 2 OLE Preliminary Study Results
Patisiran Phase 2 OLE Preliminary Study Results Change in mNIS+7 at 6 Months (N=19) Neuropathy Impairment Score (mNIS+7) stable after 6 months treatment with patisiran Mean decrease of 0.95 points observed Compares favorably with an up to 10 point increase estimated from historical data sets S
Slide 40: Phase 3 Trial of Patisiran in FAP
Phase 3 Trial of Patisiran in FAP Study Ongoing Randomized, double-blind, placebo-controlled, global study Sample size and randomization » N=200 » 2:1, Patisiran vs. placebo Key eligibility criteria » V30M and non-V30M FAP » Baseline FAP stages 1 and 2 Treatment regimen » Patisiran 0.30 mg/kg
Slide 41: Revusiran (ALN-TTRsc)
Revusiran (ALN-TTRsc) Familial Amyloidotic Cardiomyopathy (FAC) Revusiran in clinical development International Nonproprietary Name designation for ALN-TTRsc = Revusiran (re-VOO-si-ran) Subcutaneous delivery Completed GLP tox studies confirming wide therapeutic index Positive Phase 1 study r
Slide 42: GalNAc-siRNA Conjugates
GalNAc-siRNA Conjugates Subcutaneous RNAi Therapeutics GalNAc3 GalNAc-siRNA Asialoglycoprotein Receptor (ASGPR) conjugate Highly expressed in hepatocytes ASGPR High rate of uptake (pH>5) Recycling time ~15 minutes Clathrin-coated pit Conserved across species Revusiran, ALN-AT3, ALN-PCSsc, AL
Slide 43: GalNAc-siRNA Conjugates: Wide Therapeutic Index
GalNAc-siRNA Conjugates Wide Therapeutic Index from Non-Clinical GLP Studies NOAEL1 4 or 7 NOAEL 13 weeks NOAEL 6 mos NOAEL 9 mos Expected Human weeks (mg/kg) (mg/kg) Rat (mg/kg) NHP (mg/kg) Therapeutic Index (TI)2 Rat NHP Rat NHP Revusiran3 30 ≥300 N/A N/A 30 ≥200 >80 ALN-AT33,4 1 0.3 N/A N/A Ongoi
Slide 44: Revusiran Phase 1 Study Results
Revusiran Phase 1 Study Results Randomized, double-blind, placebo-controlled SAD and MAD study in healthy volunteers Rapid, dose-dependent, consistent, and durable knockdown of serum TTR with SC dosing » Significant knockdown of serum TTR (p<0.01) up to 94% TTR knockdown; Mean knockdown up to 92.4
Slide 45: Preliminary Revusiran Phase 2 Study Results
Preliminary Revusiran Phase 2 Study Results* Open label, multi-dose study in patients with TTR cardiac amyloidosis, FAC and SSA N=26; 14 FAC/12 SSA Up to 98.2% TTR knockdown with similar effects toward WT and mutant protein Treatment N Individual Max Mean ± SD KD (%) Max KD (%) All 22 98.2 87.2
Slide 46: Revusiran Phase 1 and 2 Studies Clinical Safety Summary
Revusiran Phase 1 and 2 Studies Clinical Safety Summary Total of 92 dosed with ALN-TTRsc Phase 1 = 66 healthy adult volunteers Phase 2 = 26 patients with TTR cardiac amyloidosis Generally well tolerated Phase 1: 4 non drug-related discontinuations Phase 2: no discontinuations Across both s
Slide 47: Revusiran Open-Label Extension (OLE) Study
Revusiran Open-Label Extension (OLE) Study Patients dosed in Phase 2 trial eligible for Phase 2 OLE study Dosing for up to 2 years » Fixed subcutaneous dose of 500 mg; QDx5 followed by QW Study objectives » Primary: Safety and tolerability of long-term dosing with revusiran » Secondary: Effects
Slide 48: Phase 3 Trial of Revusiran in FAC
Phase 3 Trial of Revusiran in FAC Randomized, double-blind, placebo-controlled, global study Study Initiated Sample size and randomization » N=200 » 2:1, revusiran vs. placebo Key eligibility criteria » Documented TTR mutation, including V122I or other » Amyloid deposits on biopsy (cardiac or no
Slide 49: Hemophilia and Rare Bleeding Disorders Program
Hemophilia and Rare Bleeding Disorders Program Unmet Need and Product Opportunity RNAi to treat hemophilia and rare bleeding disorders (RBD) Hemophilias are recessive X-linked monogenic bleeding disorders » Hemophilia A: loss of function in Factor VIII – >40,000 Patients in EU/US » Hemophilia B: l
Slide 50: Antithrombin and ALN-AT3 Program
Antithrombin and ALN-AT3 Program Intrinsic system Extrinsic system Antithrombin (AT) is genetically defined Hemophilia B FVIIa FVII FX target FIX FIXa AT is key natural anticoagulant Hemophilia A » Inactivates factors Xa and thrombin FVIII FVIIIa » Attenuates thrombin generation FXa AT AT Human
Slide 51: Genetic Validation for ALN-AT3
Genetic Validation for ALN-AT3 Co-Inheritance of Type 3 VWD and AT Deficiency Human genetic data support targeting AT for treatment of hemophilia and rare bleeding disorders Sib Sib Type 3 von Willebrand disease (VWD) 1 2 is severe genetic bleeding disorder Recently reported study of two Type 3
Slide 52: ALN-AT3 Pre-Clinical Efficacy
ALN-AT3 Pre-Clinical Efficacy Potent AT Knockdown and Normalization of Thrombin Generation Potent AT knockdown and normalized thrombin generation in non-human primates (NHP) Weekly SC doses for >5 months result in potent, dose-dependent, and durable AT knockdown In NHP hemophilia “inhibitor” mod
Slide 53: ALN-AT3 Pre-Clinical Efficacy
ALN-AT3 Pre-Clinical Efficacy Potent AT Knockdown and Normalization of Thrombin Generation Potent AT knockdown and normalized thrombin generation in non-human primates (NHP) Weekly SC doses for >5 months result in potent, dose-dependent, and durable AT knockdown In NHP hemophilia “inhibitor” mod
Slide 54: ALN-AT3 Survival Benefit in Hemophilia A Mice
ALN-AT3 Survival Benefit in Hemophilia A Mice Results from GLP Chronic Toxicology Study ALN-AT3 shows disease modifying effects in hemophilia A (HA) mice Ongoing 26 week GLP toxicology study » 3 Study groups (N=70/group): saline, 10 mg/kg ALN-AT3, and 30 mg/kg ALN-AT3; SC, qW x 26 Interim result
Slide 55: ALN-AT3 Phase 1 Study
ALN-AT3 Phase 1 Study Dose-Escalation Study in Two Parts Primary objectives Safety, tolerability Secondary objectives AT knockdown, thrombin generation Part A Randomized 3:1, N=4 Single- Single-blind Ascending 30 mcg/kg x 1 SC f Placebo-controlled Dose (SAD) Healthy volunteers Open-label 15
Slide 56: ALN-AT3 Phase 1 Study Part A (SAD)
ALN-AT3 Phase 1 Study Part A (SAD)* Pharmacodynamics and Clinical Activity AT knockdown after single dose in human volunteers Maximum AT knockdown relative to baseline up to 28% Mean maximum AT knockdown of 19% ± 4.4% (mean ± SEM) » Placebo vs. treated, ANOVA p < 0.01 AT knockdown durable for
Slide 57: ALN-AT3 Phase 1 Study Part A (SAD)
ALN-AT3 Phase 1 Study Part A (SAD)* Pharmacodynamics and Clinical Activity Increase in thrombin generation with AT knockdown Significant association between AT knockdown and peak thrombin generation Up to 152% increase in peak thrombin generation Mean maximum increase of peak thrombin 138% ± 8
Slide 58: ALN-AT3 Phase 1 Study Part B (MAD)
ALN-AT3 Phase 1 Study Part B (MAD)* Cohort 1 and 2 Interim Pharmacodynamics and Clinical Activity Initial data on AT knockdown after multi-dose in hemophilia subjects Cohort 1 (n=3) results » Mean maximum AT knockdown of 27% ± 13% (mean ± SEM) » Maximum AT knockdown up to 52% in most advanced subj
Slide 59: ALN-AT3 Phase 1 Study Safety/Tolerability
ALN-AT3 Phase 1 Study* Safety/Tolerability; All TEAEs Part A (SAD), Healthy Adult Volunteers Cohort 1 Adverse event N=4 Relationship to Study Drug Atypical chest pain 1 Unlikely related Coryza 1 Not related Headache 1 Possibly related Panic like symptoms 1 Unlikely related Upper Respiratory Tract In
Slide 60: Clinical Development Plan
Clinical Development Plan ALN-AT3 for the Treatment of Hemophilia and RBD Broad-based development plan to maximize product opportunity Phase 1 Phase 2 Phase 3 Adult Healthy Volunteers Hemophilia A/B Inhibitor and Hemophilia A/B ± Inhibitor Key Objectives Key Objectives On-demand • Safety, PK, clinic
Slide 61: Complement Disease Program
Complement Disease Program Unmet Need and Program Opportunity Complement-Mediated Diseases Excessive complement activity drives disease pathophysiology in many indications » Paroxysmal nocturnal hemoglobinuria (PNH) » Atypical hemolytic uremic syndrome (aHUS) » Neuromyelitis optica (NMO) » Myasthe
Slide 62: Complement C5 and ALN-CC5 Program
Complement C5 and ALN-CC5 Program Complement C5 is genetically validated target Key component of terminal pathway Alternative Pathway Classical Pathway Lectin Pathway » C5 cleavage releases C5a; initiates Initiation C3 C1 membrane attack complex (MAC) formation C3 C5 deficiency associated with m
Slide 63: Hemolysis Inhibition and Clinical Efficacy
Hemolysis Inhibition and Clinical Efficacy Hemolysis inhibition to ~≤20% normal associated with clinical efficacy in PNH and aHUS No evidence that “>99.99%” hemolytic activity inhibition required Evidence of incomplete effects of eculizumab and loss of activity between IV doses PNH aHUS Hill et
Slide 64: ALN-CC5 Pre-Clinical Efficacy
ALN-CC5 Pre-Clinical Efficacy Potent C5 Knockdown and Complement Activity Inhibition SC Administration of ALN-CC5 in non-human primates for over 7 months Potent dose-dependent C5 knockdown up to 99.2% » Mean maximum knockdown of 98.4% ±0.7% » Expect qM dosing regimen in humans based on translation
Slide 65: ALN-CC5 Phase 1/2 Study
ALN-CC5 Phase 1/2 Study Dose-Escalation Study Including Patients with PNH Part A Part Part B Study Design C Randomized, double-blind, Study Design placebo-controlled SAD Randomized, double-blind, Study Design study in healthy volunteers placebo-controlled MAD Open-label MAD study in (up to N=4
Slide 66: Clinical Development Plan
Clinical Development Plan ALN-CC5 for the Treatment of Complement-Mediated Diseases Broad-based development plan to maximize product opportunity Phase 1/2 Phase 2 Phase 3 Adult Healthy Volunteers OLE PNH PNH and PNH patients Patients Key Objectives Other Complement Mediated • Safety, PK, and Clinica
Slide 67: Acute Intermittent Porphyria (AIP) Program
Acute Intermittent Porphyria (AIP) Program Unmet Need, Product Opportunity, and Program Status AIP is autosomal dominant disorder Ultra-rare orphan disease » ~5,000 Patients with annual attacks U.S./EU » ~500 Patients with recurrent attacks U.S./EU High unmet need and cost Patients present with
Slide 68: Additional Genetic Medicine Programs
Additional Genetic Medicine Programs AAT Deficiency Associated Liver Disease Commonest mutant allele (PiZZ) homozygosity results in liver cirrhosis » Cell injury, ER stress, and autophagy resulting in fibrosis » WW prevalence ~20,000 ALN-AAT targets alpha-1antitrypsin PiZZ allele Efficacy in p
Slide 69: Genetic Medicine STAr Next Wave Target Assessment
Genetic Medicine STAr Next Wave Target Assessment Large number of opportunities based on scientific, clinical, and market insights Target ID - Liver-expressed protein 100’s Targets “Next Wave” Triage Internal Validation External Validation • Literature review • Scientific, clinical, • Genetic medici
Slide 70: Genetic Medicine STAr Summary (1/2)
Genetic Medicine STAr Summary (1/2) Significant opportunity for RNAi therapeutics as transformative medicines in rare diseases Potential to make meaningful impact on patient’s lives » Close connection to patients, caregivers, and providers Large number of genetically validated disease targets ex
Slide 71: Genetic Medicine STAr Summary (2/2)
Genetic Medicine STAr Summary (2/2) Alnylam Genetic Medicine STAr advancing large number of programs Established human POC in 4 RNAi therapeutic programs » Includes active programs (patisiran, revusiran, and ALN-AT3) Patisiran and revusiran in Phase 3 trials for TTR amyloidosis » Both FAP and FA
Slide 72: Pipeline Growth Strategy and Genetic Medicine STAr Q&A
Pipeline Growth Strategy and Genetic Medicine STAr Q&A 72
Slide 73: Daniel Rader, M.D.
Daniel Rader, M.D. Chair, Department of Genetics, Perelman School of Medicine, University of Pennsylvania 73
Slide 74: Cardiometabolic Disease: an Epidemic
Cardiometabolic Disease: an Epidemic Insulin resistance Type 2 diabetes Inflammation Hypertension Dyslipidemia Fatty liver Cardiovascular disease
Slide 75: Prevalence of obesity
Prevalence of obesity (% adults with BMI > 30)
Slide 76: Body fat distribution
Body fat distribution Visceral fat Subcutaneous fat Obese Lean National Geographic; Aug 2004
Slide 77: Diseases associated with obesity
Diseases associated with obesity Diabetes Thrombophlebitis Type 2 diabetes Dyslipidemia Lymphedema Hypertension Psoriasis Heart disease Depression Stroke Pseudotumor cerebri Sleep apnea Dementia Hypoventilation Cancer (breast, Asthma endometrium, ovary, Chan J et al. Diabetes Care 1994;17:961; Coldi
Slide 78: Hospitalization Costs for Chronic Complications of Diabetes in the US
Hospitalization Costs for Chronic Complications of Diabetes in the US Ophthalmic Others disease Neurologic CVD accounts disease for 64% of Renal total costs Peripheral disease vascular disease Total costs 12 billion US $ Cardiovascular disease American Diabetes Association. Economic Consequences
Slide 79: Slide 79
Slide 80: Dyslipidemia and coronary disease
Dyslipidemia and coronary disease A-I TG, CE B CE LDL HDL TG-rich lipoproteins Lp(a)
Slide 81: The Liver LDL Receptor regulates plasma LDL levels
The Liver LDL Receptor regulates plasma LDL levels For illustration purposes only 81 81
Slide 82: PCSK9 regulates LDL uptake and is a major target
PCSK9 is a liver-derived protein that regulates LDL uptake and is a major target for therapeutic inhibition For illustration purposes only 82 82
Slide 83: Triglyceride-rich lipoproteins are an important cause of cardiovascular disease
Triglyceride-rich lipoproteins are an important cause of cardiovascular disease B TG CE LPL CE B
Slide 84: Multiple liver-derived proteins influence triglyceride metabolism
Multiple liver-derived proteins influence triglyceride metabolism B TG CE A-V LPL C-III CE ANGPTL3 B ANGPTL4
Slide 85: Non-alcoholic fatty liver disease (NAFLD)
Non-alcoholic fatty liver disease (NAFLD) Adipose Liver Normal Steatosis Steatohepatitis Fibrosis (inflammation and (collagen deposition) (fatty liver) stellate cell activation) NASH Cirrhosis
Slide 86: The Burden of NAFLD in the US
The Burden of NAFLD in the US Obese 90 million NAFLD 75 million NASH 12.5 million 0% 10% 20% 30% 40% AASLD guidelines 2012. US Census Bureau.
Slide 87: Mortality in NAFLD
Mortality in NAFLD 20% 18-year Mortality 15% 17.5% Causes 1. CV 10% 2. Cancer 3. Liver 5% 2.7% 0% NAFL NASH Rafiq, et al. CJH 2009; Ong, et al. J Hepatol 2008.
Slide 88: Pathophysiology of NAFLD and Cardiometabolic disease
Pathophysiology of NAFLD and Cardiometabolic disease Anstee, Nature Reviews Gastro and Hepatol 2013
Slide 89: The Liver is a Central Mediator of Cardiometabolic Diseases
The Liver is a Central Mediator of and Therapeutic Target for Cardiometabolic Diseases Angiotensin- Hypertension Renin system NAFLD/NASH Cardiovascular Disease Lipid FFAs TGs Storage LDL/HDL Inflammation Gluconeogenesis Fructose LDL/HDL Clearance Glucose Insulin Type 2 Resistance Intra-abdominal Dia
Slide 90: Cardio-Metabolic Pipeline
Rachel Meyers, Ph.D. Vice President, Research and RNAi Lead Development Cardio-Metabolic Pipeline 90
Slide 91: Cardio-Metabolic Disease
ST-Ar CARDIO- METABOLIC DISEASE ay LAlnylam.
Slide 92: Alnylam Development Pipeline
Alnylam Development Pipeline Discovery Development Phase 1 Phase 2 Phase 3 GENETIC MEDICINES Patisiran (ALN-TTR02) TTR-Mediated Amyloidosis Revusiran (ALN-TTRsc) Hemophilia and Rare Bleeding Disorders ALN-AT3 Complement-Mediated Diseases ALN-CC5 Hepatic Porphyrias ALN-AS1 Alpha-1 Antitrypsin Deficie
Slide 93: Alnylam Development Pipeline
Alnylam Development Pipeline Discovery Development Phase 1 Phase 2 Phase 3 Patisiran (ALN-TTR02) Revusiran (ALN-TTRsc) ALN-AT3 ALN-CC5 ALN-AS1 ALN-AAT ALN-TMP ALN-GO1 CARDIO-METABOLIC DISEASES Hypercholesterolemia ALN-PCSsc Mixed Hyperlipidemia/Hypertriglyceridemia ALN-ANG Hypertriglyceridemia ALN-A
Slide 94: Alnylam RNAi Therapeutics Strategy
Alnylam RNAi Therapeutics Strategy A Reproducible and Modular Path for Innovative Medicines 2. POC achieved in Phase 1 Blood-based biomarker with strong disease correlation » e.g., Serum TTR, thrombin GCCCCUGGAGGG generation, hemolytic activity, LDL-C, HBsAg levels 3. Definable path to approval an
Slide 95: Emerging Profile for RNAi Therapeutics
Emerging Profile for RNAi Therapeutics Cardio-Metabolic Disease 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 » Durability for monthly (qM) an
Slide 96: Human Liver
Human Liver Central Mediator of Multiple Inter-Related Cardio-Metabolic Diseases Angiotensin- Hypertension Renin system NAFLD/NASH Cardiovascular Disease Lipid FFAs TGs Storage LDL/HDL Inflammation Gluconeogenesis Fructose LDL/HDL Clearance Glucose Insulin Type 2 Resistance Intra-abdominal Diabetes
Slide 97: Dyslipidemia
Dyslipidemia Key Risk Factor in Cardiovascular Disease Dyslipidemia Pathophysiology and Disease Burden Key Contributors » Genetic factors, obesity, poor nutrition, physical inactivity Cardiovascular disease leading cause of mortality in U.S. Dyslipidemia patient population growing rapidly, out
Slide 98: ALN-PCSsc Program and PCSK9
ALN-PCSsc Program and PCSK9 Unmet need in hypercholesterolemia Elevated LDL-C validated risk factor for CVD 34 million Americans have hypercholesterolemia (> 240 mg/dL) Recent clinical studies » Many patients on statins do not meet LDL-C goal » Lower LDL-C is better Multiple genetically defi
Slide 99: PCSK9 Therapeutic Hypothesis
PCSK9 Therapeutic Hypothesis LDL MAbs are PCSK9 blockers Endosome Bind 1:1 to PCSK9 protein – sensitive to plasma levels Lysosomal degradation RNAi therapeutics LDLR are PCSK9 synthesis synthesis PCSK9 PCSK9 inhibitors synthesis Catalytic degradation of PCSK9 mRNA – ALN-PCSsc independent of plasma l
Slide 100: ALN-PCS02 Phase 1 Study Results
ALN-PCS02 Phase 1 Study Results Pharmacodynamics and Clinical Efficacy PCSK9 knockdown and LDL-C reduction after single dose without statins Randomized, placebo-controlled, single dose escalation study » Healthy volunteers with elevated LDL (n=32) Rapid, dose-dependent, and durable knockdown of
Slide 101: ALN-PCSsc Pre-Clinical Efficacy in NHP: Single Dose
ALN-PCSsc Pre-Clinical Efficacy in NHP Potent PCSK9 Knockdown and LDL-C Lowering: Single Dose Data Highly durable PCSK9 knockdown and LDL-C reduction with single dose Single SC dose 1-10 mg/kg Up to 96% PCSK9 knockdown, up to 77% LDL-C lowering; absence of statins Highly durable effects, suppo
Slide 102: ALN-PCSsc Pre-Clinical Efficacy in NHP: Multi-Dose
ALN-PCSsc Pre-Clinical Efficacy in NHP Potent PCSK9 Knockdown and LDL-C Lowering: Multi-Dose Data Potent and stable PCSK9 knockdown and LDL-C lowering with monthly SC dosing Monthly SC dose regimen » 6 mg/kg 1st dose, 3 mg/kg monthly maintenance Up to 92% PCSK9 knockdown, up to 77% LDL-C lowerin
Slide 103: ALN-PCSsc Versus Anti-PCSK9 MAbs
ALN-PCSsc Versus Anti-PCSK9 MAbs Potential Differentiation Rebound in LDL-C with qM dosing for anti-PCSK9 MAb Differentiation for ALN-PCSsc Clamps PCSK9 knockdown and LDL-C lowering with monthly or, possibly quarterly SC dosing » Independent of baseline or fluctuating PCSK9 levels Potential for
Slide 104: ALN-PCSsc Phase 1 Study
ALN-PCSsc Phase 1 Study Study Design Randomized, single-blind, placebo-controlled, single ascending dose (SAD) and multi-dose (MD), subcutaneous dose-escalation study Up to 76 volunteer subjects with elevated baseline LDL-C (≥100 mg/dL) » MD phase to also include subjects both on and off statin
Slide 105: APOC3
APOC3 Validated Liver Target for Reduction of TG Levels Unmet need in hypertriglyceridemia >50M in U.S. have high triglycerides (>200 mg/dL) » >3M have very high triglycerides (>500 mg/dL) Additional opportunity in ultra-rare orphan condition in VLDL people lacking properly functioning lipoprote
Slide 106: ALN-AC3 Targeting ApoC3
ALN-AC3 Targeting ApoC3 Potent ApoC3 Knockdown and TG Lowering ALN-AC3 inhibits ApoC3 and reduces triglycerides 94% reduction of human serum ApoC3 at 3 mg/kg » Durable effect Up to 50% lowering of triglycerides in db/db mouse model of hyperlipidemia Human ApoC3 Protein Triglyceride Lowering -20
Slide 107: ANGPTL3
ANGPTL3 Validated Liver Target for Reduction of TG and LDL-C Levels ANGPTL3 is genetically validated target Functions as lipase inhibitor Loss of function ANGPTL3 mutations associated with combined hypolipidemia » Increased LPL activity, increased insulin sensitivity » Extremely low LDL-C, HDL-C
Slide 108: ALN-ANG Targeting ANGPTL3
ALN-ANG Targeting ANGPTL3 Efficacy in Rodent Models ALN-ANG inhibits ANGPTL3 and reduces circulating lipids in ob/ob mice Up to 99% lowering of serum ANGPLT3 Up to 80% reductions in triglycerides and LDL-C ANGPTL3 Knockdown Triglycerides LDL-C % ANGPTL3 Knockdown -40 -50 -40 (Relative to Pre-dos
Slide 109: Hypertension (HTN)
Hypertension (HTN) Significant Unmet Needs in Specific Populations Highly prevalent disease Angiotensinogen » Compliance is area of high unmet need High unmet need in preeclampsia for Renin safe and effective therapy Inactive Inactive Angiotensin I Peptide Peptide » >500,000 U.S./EU pregnancies
Slide 110: ALN-AGT Pre-clinical Efficacy in Model of Preeclampsia
ALN-AGT Pre-clinical Efficacy in Model of Preeclampsia ALN-AGT improves maternal preeclamptic symptoms without fetal exposure >90% Silencing maternal AGT » No fetal exposure of drug Improves hypertension with ~20 mmHg decrease in mean arterial pressure Improves preeclamptic symptoms » >80% red
Slide 111: NASH
NASH Unmet Need and Program Opportunity NASH is progressive fibrotic liver disease Leads to cirrhosis and liver failure ~1M diagnosed patients in U.S. » NASH growth >> population growth – Fueled by expansion of metabolic co-morbidities » Availability of therapy and novel diagnostics will expand
Slide 112: Type 2 Diabetes
Type 2 Diabetes Unmet Need and Program Opportunity Type 2 Diabetes one of fastest growing health burdens in established markets Insulin Resistance WW prevalence ~370M by 2030 » ~$245B costs in U.S. in 2012 Glucose Production by Liver Multiple disease complications Glucose Uptake in Muscles » Inc
Slide 113: Cardio-Metabolic Disease STAr Summary (1/2)
Cardio-Metabolic Disease STAr Summary (1/2) Significant opportunity for RNAi therapeutics as transformative medicines in cardio-metabolic diseases High unmet medical need in multiple patient segments » Dyslipidemia, hypertension, NASH, and type 2 diabetes Many important hepatocyte-expressed targ
Slide 114: Cardio-Metabolic Disease STAr Summary (2/2)
Cardio-Metabolic Disease STAr Summary (2/2) Alnylam Cardio-Metabolic Disease STAr advancing multiple programs Established human POC with RNAi therapeutics » ALN-PCS02: robust knockdown of PCSK9 and reduction of LDL-C in Phase 1 study ALN-PCSsc in Phase 1 trial for hypercholesterolemia » Initial
Slide 115: Cardio-Metabolic Disease STAr Q&A
Cardio-Metabolic Disease STAr Q&A 115
Slide 116: BREAK
BREAK
Slide 117: Welcome Back
Welcome Back
Slide 118: Timothy Block, Ph.D.
Timothy Block, Ph.D. President, Hepatitis B Foundation of America and its Baruch S. Blumberg Institute, and Professor, Drexel University College of Medicine 118
Slide 119: Is a Cure for Hepatitis B Possible? Necessary?
Is a Cure for Hepatitis B Possible? Necessary? Tim Block, Ph.D.
Slide 120: Is a Cure for Hepatitis B Possible?
Is a Cure for Hepatitis B Possible? Necessary? • The problem of hepatitis B and liver cancer • Limits of current therapies for managing HBV • Rationale for new strategies • Summary of Experimental Strategies • Defining a cure 120
Slide 121: Shocking epidemiology: 350 million chronic carriers
Shocking epidemiology: 350 million chronic carriers 350 million people with chronic HBV HBsAg Prevalence >=8% - High 2-7% - Intermediate <2% - Low
Slide 122: Medical Management of Chronic Hepatitis B (CHB)
Medical Management of Chronic Hepatitis B (CHB) 122
Slide 123: Timeline of Approved Drugs for Chronic HBV
Timeline of Approved Drugs for Chronic HBV REVEAL Study: The Relationship Between Virus Number and Hepatocirrhosis/Hepatocellular Carcinoma 4006 Study: antiviral therapy could slow down the development of CHB 1992 1998 2002 2004 2005 2006 2007 2008 Interferon approved Lamivudine Adefovir Entecavir T
Slide 124: Medications for Chronic HBV Management
7 Medications for Chronic HBV Management • The IFNs • The polymerase inhibitors Treatment Guidelines for the Management of CHB HBeAg + HBeAg - Recommendation DNA ALT DNA ALT genomes/mL x ULN genomes/mL x ULN Reference Group AASLD 105 >2 104 >2 Lok & McMahon 2007 US Panel 105 >1 104 >1 Keefe 2006 EAS
Slide 125: China
China 120 Million Chronic HBV Carriers ~50 Million within Treatment Guidelines ~8M Treated 125
Slide 126: USA
USA 1.2-2 Million Chronic HBV Carriers ~500-800,000 within Treatment Guidelines ~75,000 Treated 126
Slide 127: 10 Year Liver Mortality
10 Year Liver Mortality (%) HBsAg+, Negative Family History, No Alcohol 100 90 80 Treatable 70 (HBeAg+, abn ALT) 60 50 40 30 “Untreatable” 20 (HBeAg-, nl ALT) 10 0 30 40 50 60 Age in years A. Evans, 2012 127
Slide 128: Antiviral Therapy for Chronic HBV Infection and Hepatocellular Carcinoma in USA
Antiviral Therapy for Chronic HBV Infection and Development of Hepatocellular Carcinoma in USA • Analyzed electronic health records of 2671 adult participants in the Chronic Hepatitis Cohort Study (CHeCS) diagnosed with chronic HBV infection from 1992 through 2011 – Crude HCC incidence rate was 4.2
Slide 129: Why?
Why? 129
Slide 130: Even After Years of Rx
Even After Years of Rx Chevaliez et al 2012 J Hepatology Zoulim et al, Gastro.2004; 48 wk ADF 130
Slide 131: Nests of infected cells (cccDNA containing) remain
Nests of infected cells (cccDNA containing) remain 131
Slide 132: Defining a Cure: Goals
Defining a Cure: Goals • Clinically: returning a chronic hepatitis B carrier to the level of risk of death due to liver disease of someone with a resolved infection • Functionally: enduring suppression of all measurable viral markers (antigenemia and viremia) and restoration of humoral sAb 132
Slide 133: Need
Need • Something new that complements current compounds • An immuno-enhancer 133
Slide 134: Landscape of New Rx
Landscape of New Rx • What is in human trials, now? • What is at the pre-human trial stage? 134
Slide 135: Experimental HBV Therapeutics in Clinical Trials
Experimental HBV Therapeutics in Clinical Trials In vitro optimized Animal efficacy Phase I Phase 2 Phase 3 AGX1009 prodrug-ten Agenix/SHRG/YSY GS-7340 prodrug-ten Gilead Yeast Immune Compl Cap Med U, Beijing, insufficient efficacy Elvucitabine pol inhib Achillion ARC 520 (RNAi) Arrowhead CYT107 IL-
Slide 136: Experimental HBV Therapeutics in Preclinical Development
Experimental HBV Therapeutics in Preclinical Development In vitro Optimized Animal efficacy Phase I Phase 2 Phase 3 OCB-030/NVP019 Oncore/Neurovive CMX157 prodrug ten Chimerix ALN HBV Alnylam TKM HBV Tekmira ddRNAi- Benitec Briniprint/SMAC Tetralogic GLS-4 capsid Sunshine AGX 1009 prodrug ten Agenix
Slide 137: Categories of Anti-HBV Strategies
Categories of Anti-HBV Strategies Direct Acting Antivirals In-Direct Acting Antivirals • In Use Immuno-modulatory Essential host functions – Polymerase • In Use • In Use • Potential – Interferons – None for HBV – RNaseH • Potential • Potential – RNAi – Therapeutic vaccines – Epigentic modifiers – To
Slide 138: The HBV Therapeutic Development Landscape as of October, 2014
The HBV Therapeutic Development Landscape as of October, 2014 Pre-clinical Human Phase Trials GS7340 Isis HBV ARC520 Pro-ten AGX1009 antisense RNAi GLS-4 prodrug TTP sAg MycB DAA capsid CMX157 NVR122 entry prodrug Benza 1 capsid DVR capsid TKM-HBV capsid Bay4110 RepA9 CpAMS ALN- HBV 9 capsid sAg cap
Slide 139: Conclusions
Conclusions • Goal of therapy: return those with chronic B to the level of risk of people with resolved infections • New medications will be needed to do this • At least 12 steps in the virus life cycle can be targeted • cccDNA is regulated differently than integrated HBV, and can be repressed and d
Slide 140: A cure is possible; a cure is necessary
A cure is possible A cure is necessary 140
Slide 141: Acknowledgments
Acknowledgments • Drexel University – Jinhong Chang, Ju-Tao Guo, Fang Guo, Xuessen Zhao, Fei Liu, Pinghu Zhang, HaiTao Guo, David Cai • The Baruch S. Blumberg Institute, Hepatitis B Foundation – Andy Cuconati, Yanming Du, Michael Xu, Michael Goetz, Matt Campang, Bill Kinney • Support from: The US NI
Slide 142: Hepatic Infectious Disease Pipeline
Laura Sepp-Lorenzino, Ph.D. VP, Entrepreneur-in-Residence and Program Leader Hepatic Infectious Disease Pipeline 142
Slide 143: Hepatic Infectious Disease
STAr HEPATIC INFECTIOUS @ DISEASE ay SL Alnylam.
Slide 144: Alnylam Development Pipeline
Alnylam Development Pipeline Discovery Development Phase 1 Phase 2 Phase 3 GENETIC MEDICINES Patisiran (ALN-TTR02) TTR-Mediated Amyloidosis Revusiran (ALN-TTRsc) Hemophilia and Rare Bleeding Disorders ALN-AT3 Complement-Mediated Diseases ALN-CC5 Hepatic Porphyrias ALN-AS1 Alpha-1 Antitrypsin Deficie
Slide 145: Alnylam Development Pipeline
Alnylam Development Pipeline Discovery Development Phase 1 Phase 2 Phase 3 Patisiran (ALN-TTR02) Revusiran (ALN-TTRsc) ALN-AT3 ALN-CC5 ALN-AS1 ALN-AAT ALN-TMP ALN-GO1 ALN-PCSsc ALN-ANG ALN-AC3 ALN-AGT HEPATIC INFECTIOUS DISEASES Hepatitis B Virus Infection ALN-HBV Hepatitis D Virus Infection ALN-HDV
Slide 146: Alnylam RNAi Therapeutics Strategy
Alnylam RNAi Therapeutics Strategy A Reproducible and Modular Path for Innovative Medicines 2. POC achieved in Phase 1 Blood-based biomarker with strong disease correlation » e.g., Serum TTR, thrombin GCCCCUGGAGGG generation, hemolytic activity, LDL-C, HBsAg levels 3. Definable path to approval an
Slide 147: Emerging Profile for RNAi Therapeutics
Emerging Profile for RNAi Therapeutics Hepatic Infectious Disease 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 » Durability for monthly (qM)
Slide 148: Hepatic Infectious Diseases Strategic Considerations
Hepatic Infectious Diseases Strategic Considerations Primarily involve liver Hepatic • Hepatitis viruses: A, B, C, D, E Infectious Have obligate liver stage Diseases • Malaria Major liver involvement in disease • Filoviruses (Ebola, Marburg) and other hemorrhagic viruses Infection occasionally cause
Slide 149: Hepatic Infectious Diseases Programs and Target Opportunities
Hepatic Infectious Diseases Programs and Target Opportunities Pathogen Targets Host Factors RNA viral genomes, Subverted to support replication intermediates, pathogen lifecycle; viral transcripts Non essential to host Immune Modulators Immune evasion 149
Slide 150: Hepatic Infectious Diseases Programs and Target Opportunities
Hepatic Infectious Diseases Programs and Target Opportunities HBV HDV HEV Others Pathogen Targets Host Factors RNA viral genomes, Subverted to support replication intermediates, pathogen lifecycle; viral transcripts Non essential to host Immune Modulators Immune evasion 150
Slide 151: Hepatitis B Virus (HBV) Infection
Hepatitis B Virus (HBV) Infection Chronic HBV (CHB) infection is significant WW problem One third of world population infected 400M people with chronic disease » 25M in U.S./EU Most unaware of infection High prevalence expected for next 3 decades » Despite availability of HBV vaccine Clinica
Slide 152: Novel CHB Therapies Aim to Cure
Novel CHB Therapies Aim to Cure Goal: Enable Functional Cure Achieve state of immunological control of infection » HBsAg sero-clearance and sero-conversion Prevent progression of disease to cirrhosis, liver failure or HCC Clearance of circulating viral DNA, normalization of ALT and histology I
Slide 153: HBV Targeting with RNAi Therapeutics
HBV Targeting with RNAi Therapeutics Compact Genome Provides Multiple Opportunities Genome structure 2 3 3.2 kb partially double stranded DNA genome Replication occurs through RNA intermediate 4 overlapping viral transcripts encoding 1 7 viral proteins translated across 3 reading frames siRNA
Slide 154: RNAi Therapeutics for HBV: HBV-Infected Chimpanzees (1/3)
RNAi Therapeutics for HBV HBV-Infected Chimpanzees (1/3) Sequence-specific antiviral response following single dose Viral titers up to 1010 copies /mL >2 log10 reduction in circulating viral DNA in highest titer animal Mean 1.9 log10 decrease in viral DNA day 2- 6 post dose Control siRNA-LNP
Slide 155: RNAi Therapeutics for HBV: HBV-Infected Chimpanzees (2/3)
RNAi Therapeutics for HBV HBV-Infected Chimpanzees (2/3) Dose-dependent antiviral response with intra-subject ascending doses Mean 2.9 log10 decrease in viral DNA day 2- 6 post 0.5 mg/kg dose » >4 log10 reduction in circulating viral DNA achieved in highest titer animal Mean 2.0 log10 reduction
Slide 156: RNAi Therapeutics for HBV: HBV-Infected Chimpanzees (3/3)
RNAi Therapeutics for HBV HBV-Infected Chimpanzees (3/3) Potential evidence for therapeutic flare ALT normalized in highest titer chimp Possible therapeutic immune flare in 2/4 chimps » Correlated with small increases in IL6 and IFNg siRNA (mg/kg) 0.125 0.25 0.50 600 A C B D High baseline ALT re
Slide 157: ALN-HBV Target Product Profile
ALN-HBV Target Product Profile Functional Cure of CHB ALN-HBV Target Product Profile Indication • Chronic hepatitis B (CHB) treatment – enable functional cures Dose and • <150 mg fixed dose, monthly for 12-24 months alone or in combination Regimen with standard of care Route of • Subcutaneous inject
Slide 158: GalNAc-Conjugates as Anti-Viral Approach
GalNAc-Conjugates as Anti-Viral Approach Clinical Validation Regulus RG-101 » GalNAc-anti miR122 in development for HCV Clinical activity » Single 2 mg/kg SC dose demonstrated potent and sustained viral load reduction RG-101 well tolerated 158
Slide 159: ALN-HBV Lead Optimization
ALN-HBV Lead Optimization Iterative Approach to Fine-Tune siRNA Chemistry Multiple siRNAs selected targeting 3 and 4 viral transcripts with high degree of conservation across genotypes (A-H) (>94%) Enhanced Stabilization Chemistry (ESC) Superior activity Template Design 5′-sense (GalNAc)3 Inferior a
Slide 160: ALN-HBV Development Candidate Selected
ALN-HBV Development Candidate (DC) Selected Potent ESC-GalNAc-Conjugate for IND in Late ’15 Potent, multi-log HBsAg knockdown of ALN-HBV DC in murine model Mouse model with AAV-HBV vector Single SC dose of siRNA at 3 mg/kg ALN-HBV DC achieves potent knockdown of HBsAg » Up to 3.9 log10 reducti
Slide 161: Hepatitis D Virus (HDV) Infection
Hepatitis D Virus (HDV) Infection HDV is highly pathogenic, resulting in aggressive hepatitis RNA subvirus, which can only propagate in presence of HBV 15-20M patients infected WW » 80K patients in U.S. Acquired at same time or subsequent to HBV infection » >90% of latter patients develop chro
Slide 162: RNAi Therapeutics for HDV Treatment
RNAi Therapeutics for HDV Treatment L-sAg RNAi therapeutics for HDV represent HBV Gene Products M-sAg HBsAg compelling market opportunity HDV RNA No curative therapies available HDV Ag p24 & p27 » PEG-IFN is only available treatment for CHD, but very low rates of cures Novel therapies in develop
Slide 163: Hepatitis E Virus (HEV) Infection
Hepatitis E Virus (HEV) Infection Hepatitis E is WW problem 20M infections/yr » 3M acute cases, a subset develop into fulminant hepatitis » 57K deaths (~2%); disproportionately high lethality in pregnant women (~20%) Oro-fecal transmission makes it prevalent in regions with poor sanitation » Spo
Slide 164: Hepatic Infectious Diseases Programs and Target Opportunities
Hepatic Infectious Diseases Programs and Target Opportunities HBV HDV HEV Others Pathogen Targets Host Factors RNA viral genomes, Subverted to support replication intermediates, pathogen lifecycle; viral transcripts Non essential to host Immune Modulators Immune evasion PD-L1 164
Slide 165: Liver-Restricted Immune Reactivation
Liver-Restricted Immune Reactivation ALN-PDL Obligate liver pathogens exploit tolerant liver environment » Enhance immune suppression via multiple mechanisms Activation of PD1/PD-L1 immune checkpoint associated with establishment and maintenance of chronic infections, including HBV RNAi knockd
Slide 166: Hepatic Infectious Disease STAr Summary (1/2)
Hepatic Infectious Disease STAr Summary (1/2) Significant opportunity for RNAi therapeutics as transformative medicines in hepatic infectious diseases Major global health problems with significant disease burden Many hepatocyte-specific pathogens and/or pathogens with major liver disease patholo
Slide 167: Hepatic Infectious Disease STAr Summary (2/2)
Hepatic Infectious Disease STAr Summary (2/2) Alnylam Hepatic Infectious Disease STAr advancing key programs Established human POC with RNA therapeutics » Regulus RG-101 in HCV employing Alnylam GalNAc-conjugate platform ALN-HBV DC selected and on track for IND in late ’15 » Best-in-class potent
Slide 168: Looking Ahead
Barry Greene President and Chief Operating Officer Looking Ahead 168
Slide 169: Alnylam RNAi Therapeutics Strategy
Alnylam RNAi Therapeutics Strategy A Reproducible and Modular Path for Innovative Medicines 2. POC achieved in Phase 1 Blood-based biomarker with strong disease correlation » e.g., Serum TTR, thrombin GCCCCUGGAGGG generation, hemolytic activity, LDL-C, HBsAg levels 3. Definable path to approval an
Slide 170: Alnylam Strategic Therapeutic Areas (STAr)
Alnylam Strategic Therapeutic Areas (STAr) Genetic Medicines Cardio-Metabolic Disease Hepatic Infectious Disease Genetically validated Genetically validated liver Liver pathogen and/or liver targets for rare targets for dyslipidemia, host targets orphan diseases NASH, type 2 diabetes, Sub-ac
Slide 171: Alnylam Development Pipeline
Alnylam Development Pipeline Discovery Development Phase 1 Phase 2 Phase 3 GENETIC MEDICINES Patisiran (ALN-TTR02) TTR-Mediated Amyloidosis Revusiran (ALN-TTRsc) Hemophilia and Rare Bleeding Disorders ALN-AT3 Complement-Mediated Diseases ALN-CC5 Hepatic Porphyrias ALN-AS1 Alpha-1 Antitrypsin Deficie
Slide 172: Multi-Year Pipeline Progression
Multi-Year Pipeline Progression D Clinical Data Expected 2015 2016 Subsequent 1-2 Years PATISIRAN Phase 2 OLE D D D (ALN-TTR02) TTR-FAP APOLLO Phase 3 D REVUSIRAN Phase 2 OLE D D D (ALN-TTRsc) TTR-FAC ENDEAVOUR Phase 3 D Phase 1 D ALN-AT3 Phase 2 D (Hemophilia and RBDs) Phase 3 D Phase 1/2 D D ALN-C
Slide 173: Alnylam 2014-2015 Pipeline Goals
Alnylam 2014-2015 Pipeline Goals 2015 Late ‘14 Early Mid Late Ongoing PATISIRAN APOLLO Phase 3 Accrual (ALN-TTR02) TTR-FAP Phase 2 OLE data ENDEAVOUR Phase 3 Start REVUSIRAN ENDEAVOUR Phase 3 Accrual (ALN-TTRsc) TTR-FAC Phase 2 OLE Data ALN-AT3 Phase 1 Data (Hemophilia and RBDs) Start Phase 2 CTA Fi
Slide 174: Hepatic Infectious Disease STAr Q&A
Hepatic Infectious Disease STAr Q&A 174
Slide 175: Thank You
Thank You www.alnylam.com
Alnylam Pharmaceuticals — Investor Day (December 2014) on 6ix