Alnylam Pharmaceuticals, Inc. · NASDAQ:ALNY
Alnylam Pharmaceuticals — SSIEM Annual Symposium 2016
16 slides from Alnylam Pharmaceuticals's conference presentation, Sep 7, 2016
Slide 1: A Randomized, Placebo Controlled, Phase 1 Study of ALN-AS1 in Acute Hepatic Porphyrias
A Randomized, Placebo Controlled, Phase 1 Study of ALN-AS1, an Investigational RNAi Therapeutic for the Treatment of Acute Hepatic Porphyrias Interim presentation of Safety and Pharmacodynamic Results SSIEM Annual Symposium 07 September 2016 Eliane Sardh1,2, Pauline Harper1,2, Nabil AL-Tawil1,3, Cra
Slide 2: Acute Hepatic Porphyrias Pathophysiology
Acute Hepatic Porphyrias Pathophysiology Glycine Succinyl CoA ALA Synthase 1 Acute Hepatic Porphyrias (AHP) Attack triggers (ALAS1) Inborn errors of heme synthesis resulting δ- Aminolevulinic acid (ALA) from enzyme defects in the liver ALAD ALAD Porphyria Porphobilinogen (PBG) • Acute Intermittent P
Slide 3: ALN-AS1: RNAi Therapeutic Hypothesis
ALN-AS1: RNAi Therapeutic Hypothesis Knockdown of Liver ALAS1 Protein to Reduce ALA/PBG ALAS1 protein ALN-AS1 knockdown of ALAS1 reduces ALA/PBG production and prevents attacks 3 Sardh: A Randomized, Placebo Controlled, Phase 1 Study of ALN-AS1, Sep 07 2016
Slide 4: ALN-AS1 Phase 1 Study: AIP patient populations
ALN-AS1 Phase 1 Study: AIP patient populations Asymptomatic High Excreters (ASHE) • Persistently elevated ALA/PBG • More clinically relevant than healthy volunteers • Ability to measure key biomarkers • Medically stable patient population for initial safety evaluation (studied in prior enzyme replac
Slide 5: ALN-AS1 Phase 1 Study: Design and Objectives
ALN-AS1 Phase 1 Study: Design and Objectives Parts A and B (SAD/MAD) in ASHE patients Study Design • Randomized, single-blind, placebo-controlled single and multiple ascending dose study in ASHE patients Primary Objective • Safety and tolerability of ALN-AS1 Secondary Objectives • Characterize ALN-A
Slide 6: ALN-AS1 Phase 1 Study: Key Eligibility Criteria
ALN-AS1 Phase 1 Study: Key Eligibility Criteria Part A and B Inclusion • Male or female, ages 18-65 years • Acute intermittent porphyria (AIP), with genetic diagnosis of HMBS mutation • Urine PBG > 4 mmol/mol creatinine at screening Part A and B Exclusion • Attack* within 6 months of screening • Hem
Slide 7: ALN-AS1 Phase 1 Study Progress
ALN-AS1 Phase 1 Study Progress Part A: Single-Ascending Dose (SAD) │ Randomized 3:1, Single-blind, Placebo-controlled in ASHE 0.035 mg/kg x 1 SC, N=4 *The 0.035 mg/kg SAD cohort was dosed after the 0.10 and 0.35 mg/kg cohorts 0.10 mg/kg x 1 SC, N=4 0.35 mg/kg x 1 SC, N=4 1.0 mg/kg x 1 SC, N=4 2.5 mg
Slide 8: ALN-AS1 Phase 1 Study Part A and Part B Demographics
ALN-AS1 Phase 1 Study Part A and Part B Demographics and Baseline Disease Characteristics Part A and B Characteristic Result Number of Patients N=23* (ALN-AS1:Placebo=21:7) Median Age (range) 47 years (30-64) Gender 18 Females, 5 Males Race n 22 White/Caucasian 1 Asian Genotype (n) 8 different mutat
Slide 9: Part A (SAD) and Part B (MAD) Safety and Tolerability
ALN-AS1 Phase 1 Study Interim Results Part A (SAD) and Part B (MAD) Safety and Tolerability ALN-AS1 was generally well-tolerated in Parts A and B of Study ALN-AS1-001 No drug-related SAEs or discontinuations due to AEs • Two SAD subjects (0.035 and 0.10 mg/kg dose groups) were hospitalized for SAE o
Slide 10: SAD Pharmacodynamic Data: Serum ALAS1 mRNA by cERD
ALN-AS1 Phase 1 Study Interim Results SAD Pharmacodynamic Data: Serum ALAS1 mRNA by cERD ALAS1 mRNA induced approximately 3-fold in ASHE compared to normal healthy volunteers Rapid, dose-dependent, and durable ALAS1 mRNA lowering after single dose • 64 ± 1% mean (SEM) maximal reduction in 2.5 mg/kg
Slide 11: SAD Pharmacodynamic Data: Urinary ALA and PBG
ALN-AS1 Phase 1 Study Interim Results SAD Pharmacodynamic Data: Urinary ALA and PBG Rapid, dose-dependent, and durable ALA and PBG lowering after single dose • Mean (SEM) maximal reduction in 2.5 mg/kg group: 86± 2% (ALA) and 95± 0.4% (PBG) • Prolonged ALA and PBG lowering with single dose supportin
Slide 12: SAD: Changes in Serum ALAS1 mRNA and Urinary ALA/PBG Highly Correlated
ALN-AS1 Phase 1 Study Interim Results SAD: Changes in Serum ALAS1 mRNA and Urinary ALA/PBG Highly Correlated ALAS1 mRNA vs ALA ALAS1 mRNA vs PBG 50 Percent Change PBG/Creatinine (mmol/mol) 60 Percent Change ALA/Creatinine (mmol/mol) Regression Line 40 Regression Line 50 SAD Placebo SAD Placebo 40 30
Slide 13: MAD Pharmacodynamic Data: Serum ALAS1 mRNA by cERD
ALN-AS1 Phase 1 Study Interim Results MAD Pharmacodynamic Data: Serum ALAS1 mRNA by cERD Rapid, dose-dependent, and durable ALAS1 mRNA lowering • 54 ± 2% mean (SEM) maximal reduction relative to baseline in 1.0 mg/kg dose group • ALAS1 mRNA reduction seen with 2 doses similar to single dose 1.5 1.4
Slide 14: MAD Pharmacodynamic Data: Urinary ALA and PBG
ALN-AS1 Phase 1 Study Interim Results MAD Pharmacodynamic Data: Urinary ALA and PBG Rapid, dose-dependent, and durable ALA and PBG lowering after multiple doses • Mean (SEM) maximal reduction in 1 mg/kg group: 84 ± 2% (ALA) and 89 ± 5% (PBG) • Multiple doses without additive effect in either dose gr
Slide 15: ALN-AS1 Phase 1 Study Initial Results Summary
ALN-AS1 Phase 1 Study Initial Results Summary ALN-AS1 generally well tolerated with single or multiple (2) doses • No drug-related SAEs or discontinuations due to AEs • No dose-dependent AEs or clinically significant changes in vital signs, EKG, clinical laboratory or physical examination Non-invasi
Slide 16: Acknowledgements
Acknowledgements Phase 1 Investigators Karolinska University Hospital Alnylam (Study Sponsor) Part A, B and C • Daphne Vassiliou • Külliki Saar • Amy Simon • Eliane Sardh • Nabil AL-Tawil • Oskar Fagerlund • Craig Penz • Pauline Harper • Ylva Floderus • Bill Querbes • Amy Chan • David Rees Karolinsk
Alnylam Pharmaceuticals — SSIEM Annual Symposium 2016 on 6ix