Alnylam Pharmaceuticals, Inc. · NASDAQ:ALNY
Alnylam Pharmaceuticals — TIDES 2018
41 slides from Alnylam Pharmaceuticals's conference presentation, May 8, 2018
Slide 1: Delivering on RNAi Therapeutics: Patisiran and Beyond
Delivering on RNAi Therapeutics: Patisiran and Beyond TIDES, May 8, 2018 © 2018 Alnylam Pharmaceuticals, Inc. 1
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: RNAi Therapeutics: New Class of Innovative Medicines
RNAi Therapeutics: New Class of Innovative Medicines Clinically Proven Approach with Transformational Potential Nobel Prize-winning science Silence any gene in genome Potent and durable mechanism of action Product engine for sustainable pipeline Now entering commercial stages 3
Slide 4: Addressing Delivery Challenge
Addressing Delivery Challenge Alnylam Platforms for Functional siRNA Delivery to Target Tissue Sense strand Antisense strand Lipid Nanoparticles (LNPs) • Multi-component lipid = formulation (~100 nm in GalNAc size) GalNAc-siRNA Conjugates • Encapsulated siRNA • Single chemical entity • Highly effici
Slide 5: Alnylam R&D Strategy
Alnylam R&D Strategy Building a Pipeline of Potentially Transformative Medicines Genetically validated, Biomarker for Definable path liver-expressed POC in to approval and target gene Phase 1 patient access 5
Slide 6: Alnylam Clinical Development Pipeline
Alnylam Clinical Development Pipeline Focused in 3 Strategic Therapeutic Areas (STArs): Genetic Medicines Cardio-Metabolic Diseases HUMAN BREAKTHROUGH EARLY STAGE LATE STAGE REGISTRATION/ COMMERCIAL Hepatic Infectious Diseases POC1 DESIGNATION (IND or CTA Filed-Phase 2) (Phase 2-Phase 3) COMMERCIAL2
Slide 7: Extensive Human Safety Experience
Extensive Human Safety Experience Encouraging Results to Date Number of Number of Clinical Total Patients or Greatest Duration Programs Studies Volunteers Dosed of Exposure >10 >25 >1200 >48 months Minimal platform related findings* • Low incidence (2.9%) of generally mild, asymptomatic, reversible
Slide 8: Agenda
Agenda • RNAi Therapeutics for hATTR Amyloidosis • RNAi Therapeutics for Other Rare and Common Diseases • New Frontiers for RNAi Therapeutics 8
Slide 9: Hereditary ATTR (hATTR) Amyloidosis
Hereditary ATTR (hATTR) Amyloidosis Patisiran and ALN-TTRsc02 Description Mutations in TTR gene lead to deposition of misfolded protein GI: as amyloid, causing multi-system Diarrhea Nausea disease manifestations1 Vomiting CARDIAC: GU: Heart failure Proteinuria Significant morbidity Arrhythmia Kidney
Slide 10: TTR Knockdown for hATTR Amyloidosis
TTR Knockdown for hATTR Amyloidosis 10
Slide 11: Phase 3 Study Design
Phase 3 Study Design Randomized, Double-Blind, Placebo-Controlled Study in hATTR Amyloidosis Patients with Polyneuropathy Patient Population Patisiran Primary Endpoint 2:1 RANDOMIZATION 0.3 mg/kg • Change in mNIS+7 from baseline at 18 months • hATTR amyloidosis: IV q3W* any TTR mutation, Secondary S
Slide 12: Phase 3 Study Results: Serum TTR Knockdown
Phase 3 Study Results Serum TTR Knockdown 87.8% mean max serum TTR knockdown from baseline for patisiran over 18 months -10 10 Mean [± SEM] Serum TTR Knockdown, % 0 0 10 -10 20 -20 30 -30 Placebo (N=77) 40 Patisiran (N=148) -40 50 -50 60 -60 70 -70 80 -80 90 -90 100 -100 0 3 6 9 12 15 18 21 24 27 30
Slide 13: Patisiran Met Primary and all Secondary Endpoints
Phase 3 Study Results Patisiran Met Primary and all Secondary Endpoints Placebo Patisiran mNIS+7 Worsening Norfolk-QOL Worsening 35 20 LS mean (SEM) ∆Norfolk-QOL from baseline LS mean (SEM) ∆mNIS+7 from baseline 30 15 25 20 10 15 5 10 p=1.10 x 10-10 5 0 p=9.26 x 10-24 0 -5 -5 -10 -10 Improvement Bas
Slide 14: Patisiran Met Key Exploratory Endpoints in Cardiac Subpopulation
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 Worsening Worsening Worsening Improvement 350 0.12 1.5 0.4 250 0.3 Mean ∆10-MWT gait speed from basel
Slide 15: Recurrent Hospitalization and Death Events by Treatment Arm
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 Composite Rate of Cardiac Hospitalization and Mortality Hospitalization and All-Cause Mo
Slide 16: Encouraging Safety & Tolerability Profile
Phase 3 Study Results Encouraging Safety & Tolerability Profile Overall, 13 deaths in APOLLO study; no deaths considered related to study drug Type of Adverse Event, Placebo Patisiran • Lower percent deaths in patisiran vs. placebo treatment groups Number of patients (%) (N=77) (N=148) • Causes (e.g
Slide 17: hATTR Amyloidosis and APOLLO Assessments
hATTR Amyloidosis and APOLLO Assessments Patisiran Misfolded mutant & wild-type TTR amyloid fibrils in circulation Mutant & wild-type deposit in nerves and tissues TTR in liver of many organs Sensorimotor Nerves Autonomic Nerves Heart • Loss of sensation • Orthostatic hypotension • Heart failure Cli
Slide 18: ALN-TTRsc02 Opportunity
ALN-TTRsc02 Opportunity Advancing Continued Innovation for Patients with ATTR Amyloidosis Phase 1 Study – Healthy Volunteers -40 1.4 Mean [+/-SEM] TTR Knockdown Placebo (N=20) 5mg (N=6) -20 1.2 25mg (N=6) 50mg (N=6) Relative to Baseline (%) 100mg (N=6) 300mg (N=6) Mean max TTR KD of 97.1%; 1.00 ~80%
Slide 19: Agenda
Agenda • RNAi Therapeutics for hATTR Amyloidosis • RNAi Therapeutics for Other Rare and Common Diseases • New Frontiers for RNAi Therapeutics 19
Slide 20: Acute Hepatic Porphyrias
Acute Hepatic Porphyrias Givosiran Description Family of ultra-rare orphan diseases causing incapacitating and potentially fatal attacks, leading to frequent hospitalizations and chronic pain Severe, burning pain Weakness, in abdomen, chest, numbness, back respiratory failure Predominantly female, c
Slide 21: Givosiran: Investigational RNAi Therapeutic
Givosiran: Investigational RNAi Therapeutic Therapeutic Hypothesis Knockdown of Liver ALAS1 Protein to Reduce ALA/PBG ALA/PBG induce porphyria symptoms Givosiran (ALN-AS1) ALAS1 knockdown of ALAS1 protein reduces ALA/PBG production and prevents attacks Givosiran (ALN-AS1) 21
Slide 22: Givosiran Interim Phase 1 and OLE Study Results
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 83% Mean Decrease in AAR 93% Decrease in AAR Givosiran Compared to Placebo Givosiran Compared to Phase 1 Run-In 25 25 20 20 Mean (SEM) AAR Mea
Slide 23: Phase 3 Study Design
Phase 3 Study Design Randomized, Double-Blind, Placebo-Controlled Study in Acute Hepatic Porphyria Patients N ~ 75 Givosiran Primary Endpoint 1:1 RANDOMIZATION SC qM • Attacks requiring Patient Population 2.5 mg/kg hospitalization, urgent • Age ≥ 12 years care visit, home IV hemin at 6 months Open-L
Slide 24: Interim Analysis for Potential Accelerated Approval
Phase 3 Study Interim Analysis for Potential Accelerated Approval Alignment with FDA that reduction of urinary ALA is reasonably likely to predict clinical benefit • Interim analysis with ~30 patients after 3 mo dosing; expect topline data in mid-2018 • Expect NDA submission in late 2018 and potenti
Slide 25: PCSK9: Inclisiran
PCSK9 Inclisiran YAlnylan =~ t A
Slide 26: PCSK9 Therapeutic Hypothesis
PCSK9 Therapeutic Hypothesis RNAi vs. Mabs LDL LDLR Anti-PCSK9 Endosome Mabs Transiently block PCSK9 binding To LDL receptor Lysosomal (LDLR) degradation LDLR synthesis PCSK9 PCSK9 PCSK9 synthesis Synthesis Inhibitors inclisiran Durably block PCSK9 synthesis and all PCSK9 mRNA intracellular and extr
Slide 27: ORION-1 Phase 2 Clinical Study
ORION-1 Phase 2 Clinical Study 501 ASCVD subjects with elevated LDL-C on maximal lipid lowering therapy Primary objectives Secondary objectives • LDL-C levels at day 180 • Safety and tolerability, PCSK9 and LDL-C reduction and duration of effect qQ vs Bi-annual, proportion of patients reaching globa
Slide 28: Robust and Sustained LDL-C Reductions with Inclisiran
Robust and Sustained LDL-C Reductions with Inclisiran* Results to Day 360 Following One Dose *Phase 2 study results; Ray et al., ESC, Aug 2017 Inclisiran also known as “ALN-PCSsc” and “PCSK9si” The Medicines Company is leading and funding development of inclisiran from Phase 2 onward and will commer
Slide 29: Free from CVD for 100 Years?
Free from CVD for 100 Years? Hypothesis on Inclisiran Primary Prevention by E. Braunwald, ACC 2018 29
Slide 30: ORION-1 Phase 2 Study of Inclisiran: Safety Summary
ORION-1 Phase 2 Study of Inclisiran* Safety Summary Generally safe and well tolerated (N=501) • Overall incidence of treatment emergent adverse events (TEAE) 76% both in patients randomized to placebo and in patients randomized to inclisiran – No significant differences in TEAEs between inclisiran d
Slide 31: ORION Phase 3 Program
ORION Phase 3 Program • 3,660 patients (1:1 inclisiran or placebo) dosed across ORION-9, ORION-10 and ORION-11 – Baseline data and demographics consistent with ASCVD and ASCVD Risk Equivalents including HeFH • Encouraging safety results to date with >1000 patient years exposure – Including, ORION-3,
Slide 32: Agenda
Agenda • RNAi Therapeutics for hATTR Amyloidosis • RNAi Therapeutics for Other Rare and Common Diseases • New Frontiers for RNAi Therapeutics 32
Slide 33: UK Biobank Consortium
UK Biobank Consortium World-leading effort to connect genotype to full medical records for phenome-wide association studies • Goal to generate 500K exome sequences linked to medical records by end-2019 – 50K exomes sequenced to date • Consortium members receive broad, ongoing access to UK Biobank da
Slide 34: Nonalcoholic Steatohepatitis (NASH): HSD17B13 Target
Nonalcoholic Steatohepatitis (NASH) HSD17B13 Target Description HSD17B13 as a novel target1 Progressive disease characterized by hepatic fat buildup and inflammation, potentially leading to cirrhosis PATIENT POPULATION2 TA/TA (Variant) T/T (WT) Better Better >9 million adults in U.S. • Hepatocyte ex
Slide 35: RNAi Therapeutics for CNS Diseases
RNAi Therapeutics for CNS Diseases No Current Therapies to Prevent or Reverse Neurodegenerative Disease • Dominantly inherited neurodegenerative diseases include – Alzheimer’s disease – Parkinson’s disease – Frontotemporal dementia – Huntington’s disease – Amyotrophic lateral sclerosis (ALS) – Spino
Slide 36: Alnylam Advancements in Conjugate-Based Delivery
Alnylam Advancements in Conjugate-Based Delivery siRNA Linker Ligand design/chemistry Potency/duration/ Stability, optimal Efficient delivery specificity ligand orientation to target cells Evolution of conjugate potency (mouse, SD ED50) 100 Partially modified 10 STC ED50 (mg/kg) ESC 1 Advanced ESC E
Slide 37: Intrathecal Delivery of Novel siRNA Conjugates
Intrathecal Delivery of Novel siRNA Conjugates Single Dose Time Course in Rat Two targets tested to demonstrate sequence specificity siRNA conjugate dose of 0.9 mg Day 0 2 4 7 14 28 Tissue collection Tissues: Spinal cord: lumbar, thoracic and cervical Brain: prefrontal cortex, cerebellum and remaini
Slide 38: Robust, Durable CNS Silencing by Novel siRNA Conjugates
Robust, Durable CNS Silencing by Novel siRNA Conjugates Single Intrathecal Dose in Rats Sequence specific target knockdown across the brain and spinal cord for both targets • Confirmed siRNA uptake in several different cell types • Widespread distribution and knockdown in all key anatomical regions
Slide 39: Alnylam CNS Pipeline Strategy
Alnylam CNS Pipeline Strategy Expanding a Pipeline of Potentially Transformative Medicines GCCCCUGGAGGG Genetically validated, Biomarker for Definable path CNS-expressed POC in to approval and target gene Phase 1 patient access Alnylam CNS Objectives • 1st DC in 2018 • 1st IND in late ’19/early ’20
Slide 40: Summary
Summary • RNAi therapeutics are in advanced stages of clinical development and at cusp of commercialization – Patisiran poised to emerge as industry’s 1st RNAi therapeutic to reach market – RNAi therapeutics emerge as high impact, transformational medicines • Many RNAi therapeutic opportunities adva
Slide 41: Challenge Accepted
To those who say “impossible, impractical, unrealistic,” we say: CHALLENGE ACCEPTED © 2018 Alnylam Pharmaceuticals, Inc. 41