Alnylam Pharmaceuticals, Inc. · NASDAQ:ALNY
Alnylam Pharmaceuticals — Technical Presentation (July 2018)
42 slides from Alnylam Pharmaceuticals's technical presentation, Jul 24, 2018
Slide 1: Givosiran, in Development for the Treatment of Acute Hepatic Porphyrias
Givosiran, in Development for the Treatment of Acute Hepatic Porphyrias July 24, 2018 © 2018 Alnylam Pharmaceuticals, Inc. 1
Slide 2: Agenda
Agenda Welcome • Christine Lindenboom, Vice President, Investor Relations & Corporate Communications Introduction • Akin Akinc, Ph.D., General Manager, Givosiran Disease Overview & Givosiran Phase 1/Open-Label Extension Results • Jae Kim, M.D., Vice President, Clinical Development Patient Perspectiv
Slide 3: Reminders
Reminders Event will run for approximately 60-75 minutes Q&A session at end of presentation • Questions may be submitted at any time via the ‘Ask a Question’ field on the webcast interface. Replay, slides and transcript available at www.alnylam.com/capella 3
Slide 4: 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 5: Agenda
Agenda Welcome • Christine Lindenboom, Vice President, Investor Relations & Corporate Communications Introduction • Akin Akinc, Ph.D., General Manager, Givosiran Disease Overview & Givosiran Phase 1/Open-Label Extension Results • Jae Kim, M.D., Vice President, Clinical Development Patient Perspectiv
Slide 6: 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 6
Slide 7: Alnylam Clinical Development Pipeline
Alnylam Clinical Development Pipeline Focused in 4 Strategic Therapeutic Areas (STArs): Genetic Medicines Cardio-Metabolic Diseases Hepatic Infectious Diseases CNS Diseases HUMAN BREAKTHROUGH EARLY STAGE LATE STAGE REGISTRATION/ COMMERCIAL POC1 DESIGNATION (IND or CTA Filed-Phase 2) (Phase 2-Phase 3
Slide 8: Alnylam Clinical Development Pipeline
Alnylam Clinical Development Pipeline Focused in 4 Strategic Therapeutic Areas (STArs): Genetic Medicines Cardio-Metabolic Diseases Hepatic Infectious Diseases CNS Diseases HUMAN BREAKTHROUGH EARLY STAGE LATE STAGE REGISTRATION/ COMMERCIAL POC1 DESIGNATION (IND or CTA Filed-Phase 2) (Phase 2-Phase 3
Slide 9: Givosiran for Acute Hepatic Porphyrias
Givosiran for Acute Hepatic Porphyrias Rationale for RNAi Therapeutic ALAS1 is the liver-expressed, initial enzyme of the heme Genetically biosynthesis pathway; it is upstream of the genetic enzyme validated, liver- deficiencies that are responsible for acute hepatic porphyrias 1 expressed target Up
Slide 10: Agenda
Agenda Welcome • Christine Lindenboom, Vice President, Investor Relations & Corporate Communications Introduction • Akin Akinc, Ph.D., General Manager, Givosiran Disease Overview & Givosiran Phase 1/Open-Label Extension Results • Jae Kim, M.D., Vice President, Clinical Development Patient Perspectiv
Slide 11: Disease Overview
Disease Overview Glycine Succinyl CoA ALA Synthase 1 Acute Hepatic Porphyrias (AHPs)1,2 (ALAS1) • Inborn errors of heme synthesis from liver enzyme Disease δ- Aminolevulinic acid (ALA) defects triggers • Acute Intermittent Porphyria (AIP) most common, ALAD ALAD Porphyria with a mutation in hydroxyme
Slide 12: AHPs: Acute Neurovisceral Crisis
AHPs: Acute Neurovisceral Crisis Autonomic neuropathy • Abdominal pain, nausea, vomiting, abdominal distension and constipation • Tachycardia, cardiac arrhythmia, labile hypertension, postural hypotension • Sweating, hoarse voice Acute peripheral neuropathy • Diffuse muscle weakness • Pain in back a
Slide 13: EXPLORE Natural History Study: Baseline Patient-Reported Chronic Symptoms
EXPLORE Natural History Study Baseline Patient-Reported Chronic Symptoms • 65% patients with chronic symptoms, most commonly pain, tiredness, anxiety and nausea, with 46% reporting daily symptoms Abdominal pain Arm/leg pain Pain Back pain Pain Muscle pain Headache Skin pain Other pain Tiredness Trou
Slide 14: EXPLORE Natural History Study: Baseline QoL Using EQ-5D-5L
EXPLORE Natural History Study Baseline QoL Using EQ-5D-5L Domains Percent of Patients Reporting Problem in Domain† 100 90 Currently on hemin prophylaxis Not known to be on hemin prophylaxis 80 70 Patients (%) 60 50 40 30 20 10 0 Mobility Self-care Usual activities Pain / discomfort Anxiety / depress
Slide 15: EXPLORE Natural History Study: Pain Characteristics on Study
EXPLORE Natural History Study Pain Characteristics on Study N=73 Non-attack pain: Overall N=61 baseline General N=51 N=73 Non-attack pain: Patients with Chronic N=34 month 6 chronic N=27 symptoms symptoms at N=23 Non-attack pain: baseline (n=34) N=34 month 12 Patients who N=60 Used opioids N=49 Mean
Slide 16: Therapeutic Hypothesis for Givosiran, an Investigational RNAi Therapeutic for AHPs
Therapeutic Hypothesis for Givosiran, an Investigational RNAi Therapeutic for AHPs Reduction of Liver ALAS1 Protein to Lower ALA and PBG ALAS1 protein ALA induces porphyria symptoms Givosiran results in reduction ALAS1 of ALAS1 and lowers ALA/PBG protein production to prevent attacks and disease sym
Slide 17: Phase 1 and Open-Label Extension (OLE) Study Design
Phase 1 and Open-Label Extension (OLE) Study Design Parts A & B in Chronic High Part A (Single Ascending Dose) Part B (Multiple Ascending Dose) Excreter (CHE) Patients† • Randomized 3:1 (givosiran:placebo), 0.035 mg/kg x 1, N=4 0.35 mg/kg qM x 2, N=4 single blind design 0.10 mg/kg x 1, N=4 1.0 mg/kg
Slide 18: Demographics and Baseline Characteristics
Demographics and Baseline Characteristics Parts A & B Part C Placebo Givosiran (N=23†) (N=4) (N=13) Age, years, median (range) 47 (30–64) 42 (27–60) 36 (21–59) Female, n (%) 18 (78) 2 (50) 13 (100) Weight, kg, mean (SD) 75.9 (15.9) 91.4 (20.8) 70.9 (14.5) Race, n (%) White/Caucasian 22 (96) 4 (100)
Slide 19: Safety and Tolerability
Safety and Tolerability Phase 1 Study Results Parts A & B Part C • 6 patients with SAEs, with none assessed Patients Reporting as related to study drug Adverse Event, N (%) Placebo Givosiran Placebo Givosiran – Part A: 2 patients (0.035 and 0.10 mg/kg) had (N=6) (N=20) (N=4) (N=13) abdominal pain re
Slide 20: Rapid, Dose-Dependent, and Durable ALAS1 mRNA Silencing After Givosiran Dosing
Rapid, Dose-Dependent, and Durable ALAS1 mRNA Silencing After Givosiran Dosing Phase 1 Study Results in Recurrent Attack Patients • Approximately 60-70% ALAS1 mRNA silencing with monthly dosing Normalized Serum ALAS1 mRNA*, mean (SEM) 1.2 1.1 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 20 40 60 80 100
Slide 21: Dose-Dependent Lowering of ALA and PBG After Givosiran Dosing
Dose-Dependent Lowering of ALA and PBG After Givosiran Dosing Phase 1 Study Results in Recurrent Attack Patients • Monthly dosing led to consistent and sustained lowering of ALA and PBG of >80% • Increasing monthly dose from 2.5 mg/kg to 5.0 mg/kg did not lead to further lowering Urine ALA Levels Ur
Slide 22: Givosiran Treatment Led to Decreased Annualized Attack Rates and Hemin Use
Givosiran Treatment Led to Decreased Annualized Attack Rates (AAR) and Decreased Hemin Use Phase 1 Study Results in Recurrent Attack Patients • Monthly dosing led to greater mean reductions in AAR (up to 83%) and annualized hemin use (up to 88%) relative to placebo Annualized Attack Rate† Annualized
Slide 23: ALA Lowering was Correlated with Reductions in AAR
ALA Lowering was Correlated with Reductions in AAR Phase 1 Study Results in Recurrent Attack Patients • Continuous relationship between AAR and ALA lowering 30 Annualized Attack Rate† (SEM) 25 20 21.2 15 10 11.8 9.4 5 7.0 4.6 0 ≤0% >0-25% >25-50% >50-75% >75% ALA Lowering Sardh et al. EASL Meeting,
Slide 24: Safety and Tolerability: Interim Phase 1/2 OLE
Safety and Tolerability Interim Phase 1/2 OLE Study Results* • 15/16 (94%) patients reported AEs • 2 patients with SAEs – 1 patient (5.0 mg/kg q3M) with upper extremity DVT, assessed as unlikely related to study drug due to prior indwelling central venous catheter and venous damage from chronic hemi
Slide 25: Clinical Activity Maintained in Givosiran Treated Patients with Extended Dosing in OLE
Clinical Activity Maintained in Givosiran Treated Patients with Extended Dosing in OLE Study Phase 1 and Interim OLE Study Results in Recurrent Attack Patients • Mean time in OLE of 10.6 months, with up to 22 months of total treatment in Phase 1 and OLE • Continuous dosing at 2.5 mg/kg monthly regim
Slide 26: Clinical Activity Demonstrated in Placebo Patients Crossing Over to Givosiran
Clinical Activity Demonstrated in Placebo Patients Crossing Over to Givosiran Treatment in OLE Phase 1 and Interim OLE Study Results in Recurrent Attack Patients • Upon crossing over to givosiran in OLE, prior Phase 1 placebo patients experienced >90% mean reduction in AAR and annualized hemin use r
Slide 27: Summary
Summary • In Phase 1 study, givosiran lowered induced ALAS1, with corresponding reductions in both ALA and PBG, and reduced attacks and hemin use in recurrent attack patients • Dose regimen of 2.5 mg/kg qM was selected for OLE and further clinical development • Interim Phase 1/2 OLE study results de
Slide 28: Agenda
Agenda Welcome • Christine Lindenboom, Vice President, Investor Relations & Corporate Communications Introduction • Akin Akinc, Ph.D., General Manager, Givosiran Disease Overview & Givosiran Phase 1/Open-Label Extension Results • Jae Kim, M.D., Vice President, Clinical Development Patient Perspectiv
Slide 29: A perfectly healthy child. My good health lasted through my college years.
• A perfectly healthy child. My good health lasted through my college years.
Slide 30: After college, and before my porphyria awoke at age 28, I indulged my wanderlust
• After college, and before my porphyria awoke at age 28, I indulged my wanderlust and visited 38 countries for business and pleasure. • For the last 23 years, my life has been reduced from the wide world to a 15x12 bedroom.
Slide 31: Thank goodness for pets!
• A rare, ‘invisible’ disease like porphyria can be extremely isolating. Patients can only turn down invitations from friends so many times before they stop calling. 5 • Thank goodness for pets! Without their unconditional love, porphyria would be very lonely.
Slide 32: Agenda
Agenda Welcome • Christine Lindenboom, Vice President, Investor Relations & Corporate Communications Introduction • Akin Akinc, Ph.D., General Manager, Givosiran Disease Overview & Givosiran Phase 1/Open-Label Extension Results • Jae Kim, M.D., Vice President, Clinical Development Patient Perspectiv
Slide 33: AHP Patient Population
AHP Patient Population • Consensus estimated prevalence of 2-5:100,000† • Predominantly female • ~5% of patients may be severely affected with frequent attacks (~1,000 patients with recurrent attacks in US/EU‡) • Many more have sporadic attacks and likely have chronic symptoms and impaired quality o
Slide 34: AHP Market Landscape
AHP Market Landscape No approved therapy for prevention of attacks Hemin is only available therapy; not approved for prophylactic use • Approved for treatment of acute attacks; has short duration of activity (half-life of 11 hours) – In EXPLORE study, mean of 4.0 attacks per year on hemin prophylaxi
Slide 35: Significant Economic Burden of AHPs
Significant Economic Burden of AHPs Healthcare Utilization and Cost Analysis* (EXPLORE Natural History Study) Hospitalizations as Costs Hospitalizations as Charges $141,738 $100,078 Hemin Acute Hospitalizations Attacks $141,738 (Costs) Hemin Acute $356,853 Attacks Hospitalizations $148,145 (Charges)
Slide 36: Opportunities for Facilitating Patient Identification and Improving Patient Care
Opportunities for Facilitating Patient Identification and Improving Patient Care Increase Disease Awareness & Knowledge Streamline Testing & Diagnosis Improve Care Networks & Support Current/New CoEs Redefine Expectations for Treatment of Patients Ensure Access 36
Slide 37: Alnylam Act
Alnylam ActTM • No-charge third-party genetic testing and counseling program* 123 16 Tests Positive • Recently expanded to include testing Submitted** Samples** and counseling for individuals who may carry a gene mutation known to be associated with the acute hepatic porphyrias • Blood or saliva sam
Slide 38: 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 39: Approval Timeline Assumptions
Approval Timeline Assumptions 2019 2020 2021+ * +ROW 39 *Assuming positive interim analysis results
Slide 40: Agenda
Agenda Welcome • Christine Lindenboom, Vice President, Investor Relations & Corporate Communications Introduction • Akin Akinc, Ph.D., General Manager, Givosiran Disease Overview & Givosiran Phase 1/Open-Label Extension Results • Jae Kim, M.D., Vice President, Clinical Development Patient Perspectiv
Slide 41: Upcoming RNAi Roundtables
Upcoming RNAi Roundtables Lumasiran, in Development for the Treatment of Primary Hyperoxaluria Type 1 • Wednesday, August 15th, 10:30 AM ET Patisiran & ALN-TTRsc02, for the Treatment of Transthyretin-Mediated Amyloidosis • Tuesday, September 11, time TBD Additional details for upcoming RNAi Roundtab
Slide 42: Thank You
Thank You © 2018 Alnylam Pharmaceuticals, Inc. 42
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