Alnylam Pharmaceuticals, Inc. · NASDAQ:ALNY
Alnylam Pharmaceuticals — WFH 2016 World Congress, Orlando
20 slides from Alnylam Pharmaceuticals's conference presentation, Jul 25, 2016
Slide 1: Fitusiran Interim Weekly and Monthly Dosing Results in Hemophilia A or B
A Subcutaneously Administered Investigational RNAi Therapeutic (Fitusiran) Targeting Antithrombin for Treatment of Hemophilia: Interim Weekly and Monthly Dosing Results in Patients with Hemophilia A or B K John Pasi1, Pencho Georgiev2, Tim Mant3, Michael Desmond Creagh4, Toshko Lissitchkov5, David B
Slide 2: Fitusiran: Investigational RNAi Therapeutic for Treatment of Hemophilia
Fitusiran Investigational RNAi Therapeutic for Treatment of Hemophilia Fitusiran (ALN-AT3) • SC-administered small interfering RNA (siRNA) therapeutic targeting antithrombin (AT) ◦ Non-biologic, chemically-synthesized, with targeting ligand to specifically deliver to liver—site of AT synthesis Hemop
Slide 3: Fitusiran Phase 1 Study
Fitusiran Phase 1 Study Dose-Escalation Study in Four Parts Part A: Single-Ascending Dose (SAD) │Randomized 3:1, Single-blind, Placebo-controlled, Healthy volunteers 30 mcg/kg x 1 SC, N=4 Part B: Multiple-Ascending Dose (MAD) – Weekly dosing │ Open-label, Patients with Hemophilia A or B 15 mcg/kg qW
Slide 4: Demographics & Baseline Characteristics, Parts B, C & D
Interim Fitusiran Phase 1 Study Results* Demographics & Baseline Characteristics, Parts B, C & D Part B Part C Part D Subcutaneous Subcutaneous Subcutaneous Weekly × 3 Monthly × 3 Monthly × 3 15 45 75 225 450 900 1800 80 50 mcg/kg mcg/kg mcg/kg mcg/kg mcg/kg mcg/kg mcg/kg mg mg N=3 N=6 N=3 N=3 N=3 N
Slide 5: Safety/Tolerability, Parts B, C, & D
Interim Fitusiran Phase 1 Study Results* Safety/Tolerability†, Parts B, C, & D • No SAEs related to study drug • Majority of AEs mild or moderate in severity ◦ AEs (excluding ISRs) in ≥10% of patients – Upper respiratory tract infection (10%), arthralgia (10%) • 11 (35%) patients reported drug-relat
Slide 6: AT Lowering, Part C
Interim Fitusiran Phase 1 Study Results* AT Lowering, Part C AT lowering after monthly dosing in patients with hemophilia A and B 125 Cohort 1 225 mcg/kg (N=3) Cohort 2 450 mcg/kg (N=3) Cohort 3 900 mcg/kg (N=3) Cohort 4 1800 mcg/kg (N=3) Cohort 5 80 mg (N=6) 100 % Mean (+/- SEM) AT Activity Relativ
Slide 7: AT Lowering, Parts A, B & C
Interim Fitusiran Phase 1 Study Results* AT Lowering, Parts A, B & C Dose-dependent AT lowering • Mean maximal AT lowering of 87 ± 1% at 80 mg fixed dose 100 Relative Nadir AT Level (Mean +/- SEM, %) 90 80 70 60 50 40 30 20 10 0 30 15 45 75 225 450 900 1800 80 mg mcg/kg mcg/kg mcg/kg mcg/kg mcg/kg m
Slide 8: Thrombin Generation, Part B & C
Interim Fitusiran Phase 1 Study Results* Thrombin Generation, Part B & C Post hoc analysis of thrombin generation by AT lowering quartiles • Mean thrombin generation increase of 289% relative to baseline at AT lowering >75% (p<0.001†) 250 Boxes denote median and interquartile range 200 Peak Thrombin
Slide 9: Exploratory Analysis of Factor Equivalence
Interim Fitusiran Phase 1 Study Results* Exploratory Analysis of Factor Equivalence Fitusiran achieved peak thrombin generation values equivalent to >40% Factor VIII • Pre-dose factor administration used to establish individualized factor-peak thrombin relationship (in all 3 patients with pre-dose f
Slide 10: Exploratory Analysis of Bleed Events, Parts B & C
Interim Fitusiran Phase 1 Study Results* Exploratory Analysis of Bleed Events, Parts B & C Post hoc analysis of bleed events by AT lowering quartiles • Includes more than 1100 cumulative days with AT lowering >75% in 16 patients 30 ABR Estimate, Mean (SEM) 20 10 0 AT Lowering AT Lowering AT Lowering
Slide 11: Exploratory Analysis of Bleed Events
Interim Fitusiran Phase 1 Study Results* Exploratory Analysis of Bleed Events Post hoc analysis of bleed events during Onset and Observation periods • Prospectively collected bleed events during Onset (Day 0-28) and Observation periods (Day 29 to last available, to maximum of Day 112) -20 350 AT % L
Slide 12: Exploratory Analysis of Bleed Events, Part C
Interim Fitusiran Phase 1 Study Results* Exploratory Analysis of Bleed Events, Part C† Observation Period Pre-study Onset Spontaneous Dose Patient Prior Tx ABR‡ ABR All Bleeds, n ABR Bleeds, n AsBR C1-1 PPx 2 13 1 4 1 4 225 C1-2 PPx 0 0 1 4 0 0 mcg/kg C1-3 PPx 0 50 4 17 0 0 C2-1 PPx 4 25 4 17 3 13 4
Slide 13: Exploratory Analysis of Bleed Events, Part C: Median ABR
Interim Fitusiran Phase 1 Study Results* Exploratory Analysis of Bleed Events, Part C† Summary of Median ABR (All Cohorts) Summary of Median ABR (80 mg) 30 28 15 13 25 20 10 ABR 15 ABR 13 6 10 5 5 2 0 0 0 0 PPx OD PPx Onset Observation ‡ Onset Observation Pre-study‡ Onset Observation Pre-Study Pre-s
Slide 14: ABR Results in Select Prospective Studies
ABR Results in Select Prospective Studies* Median ABRs for Prophylaxis Therapy 9 7.9 8 7 6 Median ABR 5 4 4 3.1 3 1.9 2 2 2 1.6 1.6 1.4 1.1 1 0 0 Eloctate1 Adynovate 2 Novoeight 3 Kovaltry 4 Kogenate Advate 6 Alprolix 7 Idelvion 8 Benefix 9 Rixubis 10 FEIBA 11 5 FS Hemophilia A Hemophilia B Inhibito
Slide 15: Inhibitor Patients, Part D
Fitusiran Phase 1 Study Inhibitor Patients, Part D Study population • Hemophilia A and Hemophilia B patients with inhibitors, utilizing bypassing agents (BPAs) for bleed management Exploratory pre-dose evaluation of response to BPAs • BPA administered prior to fitusiran dosing to explore peak thromb
Slide 16: AT, Peak Thrombin, Part D (Cohort 1, 50 mg)
Interim Fitusiran Phase 1 Study Results* AT, Peak Thrombin, Part D (Cohort 1, 50 mg) Initial AT lowering and thrombin generation results in patients with inhibitors • Comparable AT lowering and thrombin generation as observed with similar doses in non-inhibitor patients • Thrombin generation with fi
Slide 17: Exploratory Analysis of Bleed Events, Part D (Cohort 1, 50 mg)
Interim Fitusiran Phase 1 Study Results* Exploratory Analysis of Bleed Events, Part D (Cohort 1, 50 mg)† Observation Period Prescribed Pre-study Onset Days in Bleeds, Dose Patient Hemophilia Prior Tx BPA ABR‡ ABR Obs Period n ABR D1-1 HA w/ inh OD aPCC 40 13 57 0 0 D1-2 HB w/ inh OD rFVIIa/aPCC 26 1
Slide 18: Summary of Interim Results
Fitusiran Phase 1 Study* Summary of Interim Results Fitusiran generally well tolerated in hemophilia A and B patients with and without inhibitors • No SAEs related to study drug; no thromboembolic events • AEs (excluding ISRs) in ≥10% of patients: upper respiratory tract infection (10%) and arthralg
Slide 19: Next Steps
Fitusiran Next Steps 21 patients now enrolled in open-label extension (OLE) study, including inhibitor patients • To date, patients have received up to 13 monthly doses of fitusiran Additional data expected to be shared in late 2016 • Including updated results from Part D inhibitor patients and init
Slide 20: Acknowledgements
Acknowledgements Thank you to the Healthy Volunteers, Patients and Investigators who participated in this Phase 1 Study Country PI Name Location United Kingdom Steve Austin London – St. George’s Healthcare NHS Trust Haemophilia Centre David Bevan London – The Centre for Haemostasis and Thrombosis Gu
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