Alnylam Pharmaceuticals, Inc. · NASDAQ:ALNY
Alnylam Pharmaceuticals — Technical Presentation (August 2015)
24 slides from Alnylam Pharmaceuticals's technical presentation, Aug 30, 2015
Slide 1: Subcutaneous RNAi Therapeutic ALN-PCSsc Targeting PCSK9: Initial Phase 1 Results
A Subcutaneously Administered Investigational RNAi Therapeutic (ALN-PCSsc), Targeting PCSK9 for the Treatment of Hypercholesterolemia: Initial Phase 1 Study Results Kevin Fitzgerald, PhD Co-authors: Amy Simon1, Suellen White1, Anna Borodovsky1, Nirav Patel1, Brian Bettencourt1, Valerie Clausen1, Jay
Slide 2: RNAi Therapeutics: A New Class of Innovative Medicines
RNAi Therapeutics A New Class of Innovative Medicines • 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 for innovative medicines
Slide 3: 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 GCCCCUGGAGGG ◦ e.g., Serum TTR, thrombin generation, hemolytic activity, LDL-C, HBsAg levels 3. Definable path to approval an
Slide 4: Alnylam Development Pipeline
WZAlnylam, Development Pipeline GENETIC MEDICINES TTR-Mediated Amyloidosis Hemophilia and Rare Bleeding Disorders Complement-Mediated Diseases Hepatic Porphyrias Alpha-1 Antitrypsin Deficiency Primary Hyperoxaluria Type 1 TTR-Mediated Amyloidosis Beta-Thalassemia/Iron-Overload Disorders Additional G
Slide 5: Alnylam Development Pipeline
ZLAlnylam’. Development Pipeline GENETIC MEDICINES TTR-Mediated Amyloidosis Hemophilia and Rare Bleeding Disorders Complement-Mediated Diseases Hepatic Porphyrias Alpha-1 Antitrypsin Deficiency Primary Hyperoxaluria Type 1 TTR-Mediated Amyloidosis Beta-Thalassemia/Iron-Overload Disorders Additional
Slide 6: GalNAc-siRNA Conjugates: Subcutaneous RNAi Therapeutics
GalNAc-siRNA Conjugates Subcutaneous RNAi Therapeutics GalNAc-siRNA GalNAc3 conjugate ASGPR (pH>5) Asialoglycoprotein Receptor (ASGPR) Clathrin-coated pit Highly expressed in hepatocytes High rate of uptake Recycling time ~15 minutes protein Conserved across species Recycling ASGPR Clathrin-
Slide 7: PCSK9 and ALN-PCSsc Program
PCSK9 and ALN-PCSsc Program WT PCSK9 Unmet need in hypercholesterolemia 30 20 • Elevated LDL-C validated risk factor for CVD 10 • 34 million Americans have hypercholesterolemia Frequency (%) 0 (> 240 mg/dL) 30 LOF PCSK9 • Recent clinical studies 20 - Many patients on statins do not meet LDL-C goal 1
Slide 8: PCSK9 Therapeutic Hypothesis
PCSK9 Therapeutic Hypothesis LDL LDLR Anti-PCSK9 Endosome MAbs Transiently block PCSK9 binding to LDL receptor Lysosomal (LDLR) degradation LDLR synthesis PCSK9 PCSK9 PCSK9 synthesis Synthesis ALN-PCS Inhibitors Durably block PCSK9 PCSK9 mRNA synthesis and all intracellular and extracellular PCSK9 N
Slide 9: Potent PCSK9 Knockdown and LDL-C Lowering: Single Dose Data in NHP
Potent PCSK9 Knockdown and LDL-C Lowering Single Dose Data in NHP 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, supports once-monthly or possibly once
Slide 10: ALN-PCSsc Phase 1 Study
ALN-PCSsc Phase 1 Study Healthy Subjects with LDL-C >100mg/dl, On or Off Statins Primary objectives Secondary objectives • PK, PCSK9 and LDL-C reduction • Safety, tolerability Part A: Single Dose (SAD) │Randomized 3:1, Single blind, Placebo controlled 25 mg x 1 SC 100 mg x 1 SC 300 mg x 1 SC = dose
Slide 11: SAD Cohort Demographics and Baseline Characteristics
Initial ALN-PCSsc Phase 1 Study Results SAD Cohort Demographics and Baseline Characteristics 24 SAD subjects dosed with ALN-PCSsc or placebo (3:1) Total (excluding Placebo 25 mg 100 mg 300 mg 500 mg 800 mg placebo) N=6 N=3 N=3 N=3 N=3 N=6 N = 18 Age (years), Mean 47.5 47.3 48.0 48.3 39.3 48.7 46.7 (
Slide 12: MD Cohort Demographics and Baseline Characteristics
Initial ALN-PCSsc Phase 1 Study Results MD Cohort Demographics and Baseline Characteristics 45 MD subjects dosed with ALN-PCSsc or placebo (3:1) 300 mg 500 mg 125mg 250mg 300 mg qM x2 500 mg qM x2 Total (excluding Placebo qW x4 q2W x2 qM x2 S^ qM x2 S^ placebo) N=12 N=6 N=6 N=6 N=4 N=6 N=5 N = 33 Ag
Slide 13: Baseline Values for PCSK9 and LDL-C
Initial ALN-PCSsc Phase 1 Study Results Baseline Values for PCSK9 and LDL-C SAD phase Treatment Placebo 25mg 100 mg 300 mg 500 mg 800 mg Overall (N) (6) (3) (3) (3) (3) (6) (24) 278.9 342.7 233.8 253.8 263.2 279.6 276.3 Mean (SEM) PCSK9 (ng/mL) (40.6) (39.2) (22.6) (12.9) (14.4) (27.3) (13.9) 142.2
Slide 14: SAD Safety and Tolerability
Initial ALN-PCSsc Phase 1 Study Results SAD Safety and Tolerability ALN-PCSsc generally well tolerated • No SAEs and no discontinuations due to AEs • All AEs mild or moderate in severity - At highest dose group (800 mg), one subject with mild localized injection site reaction - No clinically signifi
Slide 15: MD Safety and Tolerability
Initial ALN-PCSsc Phase 1 Study Results MD Safety and Tolerability ALN-PCSsc generally well tolerated • No SAEs and no discontinuations due to AEs • All AEs mild or moderate in severity - AE profile generally similar with or without statins - At higher drug exposures 3 subjects with mild, localized
Slide 16: SAD PCSK9 Knockdown Relative to Baseline
Initial ALN-PCSsc Phase 1 Study Results SAD PCSK9 Knockdown Relative to Baseline Treatment Placebo 300 mg -40 25 mg 500 mg Mean (SEM) % PCSK9 Knockdown 100 mg 800 mg -20 (Change from Baseline) 0 20 40 60 80 100 0 1 2 3 4 5 Day/Treatment combinations where N=1 not displayed Months 24 SAD subjects dos
Slide 17: SAD PCSK9 Knockdown Relative to Baseline
Initial ALN-PCSsc Phase 1 Study Results SAD PCSK9 Knockdown Relative to Baseline PCSK9 % Knockdown (KD) SAD Phase Mean Max Mean % KD Mean % KD % KD Day 84 N at Day 140 N at Dose Group (+/- SEM)@ Max % KD (+/- SEM)@ Day 84# (+/- SEM)^ Day 140@ Placebo 29.4 (3.9) 38.4 0.1 (6.4) 5 NA 0 25 mg 54.3 (2.7)
Slide 18: SAD LDL-C Lowering Relative to Baseline
Initial ALN-PCSsc Phase 1 Study Results SAD LDL-C Lowering Relative to Baseline Treatment 0 Placebo 300 mg 25 mg 500 mg 100 mg 800 mg Mean (SEM) % LDL-C Lowering 20 (Change from Baseline) 40 60 80 0 1 2 3 4 5 Days/Treatments where N=1 not displayed 24 SAD subjects dosed with ALN-PCSsc or placebo (3:
Slide 19: SAD LDL-C Lowering Relative to Baseline
Initial ALN-PCSsc Phase 1 Study Results SAD LDL-C Lowering Relative to Baseline LDL-C % Reduction SAD Phase Mean Max % Mean % Mean % Reduction Max % Reduction Day N at Reduction Day N at Dose Group (+/- SEM)@ Reduction 84 (+/- SEM)@ Day 84# 140 (+/- SEM)^ Day 140# Placebo 18.6 (2.3) 25.1 7.4 (7.0) 5
Slide 20: MD PCSK9 Knockdown Relative to Baseline
Initial ALN-PCSsc Phase 1 Study Results MD PCSK9 Knockdown Relative to Baseline Treatment -60 Placebo 300 mg qMX2 125 mg qWX4 300 mg S^qMX2 Mean (SEM) % PCSK9 Knockdown 250 mg q2WX2 500 mg qMX2 -40 500 mg S^qMX2 (Change from Baseline) -20 0 20 40 60 80 100 0 1 2 3 4 5 qW, q2W, or qM Months S ^ =On s
Slide 21: MD PCSK9 Knockdown Relative to Baseline
Initial ALN-PCSsc Phase 1 Study Results MD PCSK9 Knockdown Relative to Baseline PCSK9 % KD MD Phase Mean Max Dose Group % KD (SEM)@ Max % KD Placebo 29.6 (5.3) 63.2 125 mg qwX4 82.3 (1.1)*** 85.7 250 mg q2wX2 80.9 (1.4)*** 84.6 300 mg qMX2 78.6 (3.1)*** 86.9 300 mg S^ qMX2 83.0 (3.2)*** 88.1 500 mg
Slide 22: MD LDL-C Lowering Relative to Baseline
Initial ALN-PCSsc Phase 1 Study Results MD LDL-C Lowering Relative to Baseline 0 Mean (SEM) % LDL-C Lowering (Change from Baseline) 20 40 Treatment 60 Placebo 300 mg S ^ qMX2 125 mg qWX4 500 mg qMX2 250 mg q2WX2 500 mg S ^ qMX2 300 mg qMX2 80 0 1 2 3 4 5 qW, q2W, or qM Month S ^ =On a stable dose of
Slide 23: MD LDL-C Lowering Relative to Baseline
Initial ALN-PCSsc Phase 1 Study Results MD LDL-C Lowering Relative to Baseline LDL-C % KD MD Phase Mean Max Dose Group % Reduction (+/- SEM)@ Max % Reduction Placebo 21.5 (3.26) 42.6 125 mg qwX4 51.2 (1.91) 59.6 250 mg q2wX2 60.4 (4.51)*** 70.3 300 mg qMX2 64.4 (5.41)*** 79.3 300 mg S^ qMX2 51.8 (10
Slide 24: Summary and Next Steps
Summary and Next Steps ALN-PCSsc is promising first-in-class PCSK9 synthesis inhibitor • Generally well tolerated - No SAEs and no discontinuations due to AEs - All AEs mild or moderate in severity • Similar LDL-C reduction to published data reported for anti-PCSK9 MAbs* in subjects with and without
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