Alnylam Pharmaceuticals, Inc. · NASDAQ:ALNY
Alnylam Pharmaceuticals — ASH 2015
23 slides from Alnylam Pharmaceuticals's conference presentation, Dec 6, 2015
Slide 1: Subcutaneous RNAi Therapeutic ALN-CC5 Targeting Complement C5: Interim Phase 1 Results
A Subcutaneously Administered Investigational RNAi Therapeutic (ALN-CC5) Targeting Complement C5 for Treatment of PNH and Complement-Mediated Diseases: Interim Phase 1 Study Results Anita Hill1, Jorg Taubel2, Jim Bush3, Anna Borodovsky4, Noriyuki Kawahata4, Helen Mclean4, Christine Powell4, Prasoon
Slide 2: ALN-CC5 and Complement-Mediated Diseases
ALN-CC5 and Complement-Mediated Diseases Excessive complement activity drives disease pathophysiology in many Alternative Pathway Classical Pathway Lectin Pathway indications Initiation C3 C1 • Paroxysmal nocturnal hemoglobinuria (PNH) C3 • Atypical hemolytic uremic syndrome (aHUS) C4 and C2 • Neuro
Slide 3: Paroxysmal Nocturnal Hemoglobinuria (PNH)
Paroxysmal Nocturnal Hemoglobinuria (PNH) Background • Bone marrow defect due to acquired PIG-A gene mutation leading to deficiency of GPI-anchored surface proteins that protect red blood cells against complement mediated cell lysis • Concomitant quantitative bone marrow failure in ~50% of patients
Slide 4: ALN-CC5: SC-Administered GalNAc-Conjugated siRNA Targeting C5
ALN-CC5: SC-Administered GalNAc- Conjugated siRNA Targeting C5 GalNAc3 ALN-CC5 ASGPR ALN-CC5 (pH>5) • siRNA conjugated to N-acetylgalactosamine Clathrin-coated pit (GalNAc) ligand • Efficient delivery to hepatocytes following subcutaneous (SC) administration C5 protein • Wide therapeutic index Recyc
Slide 5: ALN-CC5 Phase 1/2 Study Design
ALN-CC5 Phase 1/2 Study Design Healthy Volunteers and Patients with PNH Part A: Single-Ascending Dose (SAD): Healthy Volunteers Randomized 3:1, double blind, placebo controlled, N=4 50 mg x 1 SC 200 mg x 1 SC 400 mg x 1 SC 600 mg x 1 SC 900 mg x 1 SC Part B: Multiple-Ascending Dose (MAD): Healthy Vo
Slide 6: Materials and Methods
Materials and Methods Pharmacodynamic (PD) assays • Serum concentrations of C5 assayed using validated LCMS assay • Complement activity ◦ Serum samples assessed using CAP and CCP Wieslab ELISA assays (alternative and classical pathways respectively) ◦ Serum samples assessed using sheep erythrocyte
Slide 7: Complement Assays Benchmarks from Select Published Literature
Complement Assays Benchmarks from Select Published Literature Assay Disease Values reported Notes in literature Free C5 aHUS 93.5%1 Results from clinical study of aHUS patients (Electrohemiluminescence (patients treated (Max % C5 inhibition) treated with eculizumab at 900 mg (4xqW) and immunoassay)
Slide 8: ALN-CC5 Phase 1/2 Part A - SAD Demographics
ALN-CC5 Phase 1/2 Part A - SAD Demographics and Baseline Characteristics 20 healthy volunteers dosed with ALN-CC5 or placebo (3:1) Part A: Single Ascending Dose (SAD) Single subcutaneous injection 50 mg 200 mg 400 mg 600 mg 900 mg N=4 N=4 N=4 N=4 N=4 Age (years), Mean 23.8 22.5 22.0 28.5 26.8 (Min,
Slide 9: ALN-CC5 Phase 1/2 Part B - MAD Demographics
ALN-CC5 Phase 1/2 Part B - MAD Demographics and Baseline Characteristics 12 healthy volunteers dosed with ALN-CC5 or placebo (3:1) Part B: Multiple Ascending Dose (MAD) Weekly × 5 subcutaneous injections 100 mg 200 mg 400 mg q1w x 5 q1w x 5 q1w x 5 N=4 N=4 N=4 Age (years), Mean 33.8 28.0 25.0 (Min,
Slide 10: Blinded Safety and Tolerability Summary – Part A
Initial ALN-CC5 Phase 1 Study Results Blinded Safety and Tolerability Summary – Part A (SAD) ALN-CC5 appears generally well tolerated in healthy volunteers • No SAEs and no discontinuation due to AEs • Total of 29 AEs observed ◦ All reported AEs mild or moderate in severity; 3 possibly drug-related‡
Slide 11: Blinded Safety and Tolerability Summary – Part B
Initial ALN-CC5 Phase 1 Study Results Blinded Safety and Tolerability Summary – Part B (MAD) ALN-CC5 is generally well tolerated in healthy volunteers after multiple doses • No SAEs and no discontinuation due to AEs • Total of 30 AEs observed ◦ All reported AEs mild or moderate in severity; 12 possi
Slide 12: Part A SAD: Serum C5 Knockdown
ALN-CC5 Phase 1/2: Part A – SAD Pharmacodynamics and Clinical Activity: Serum C5 Serum C5 knockdown following single dose of ALN-CC5 • Maximum C5 knockdown relative to baseline up to 99% • Mean maximum C5 knockdown of 98 ± 0.9% (mean ± SEM) • Mean C5 knockdown of 96 ± 1.0% (mean ± SEM) at Day 98 (90
Slide 13: Part A SAD: Complement Inhibition
ALN-CC5 Phase 1/2: Part A – SAD Pharmacodynamics and Clinical Activity: Complement Inhibition Mean (+/- SEM) CAP Reduction -20 Complement alternative 0 pathway inhibition (CAP Relative to Baseline C5b-9 ELISA) 20 • Single dose of ALN-CC5 40 60 • Maximum CAP reduction relative to baseline up to 95% 8
Slide 14: Part A SAD: Hemolysis Inhibition
ALN-CC5 Phase 1/2: Part A – SAD Pharmacodynamics and Clinical Activity: Hemolysis Inhibition Inhibition of sheep erythrocyte hemolysis • Following single dose of ALN-CC5 • Maximum serum hemolysis inhibition relative to baseline up to 79% • Mean maximum hemolysis inhibition of 74 ± 4.2% (mean ± SEM)
Slide 15: Part A SAD Summary of Preliminary Results
ALN-CC5 Phase 1/2 Part A – SAD Summary of Preliminary Results Part A : Single Ascending Dose (SAD) Single subcutaneous injection 50 mg 200 mg 400 mg 600 mg 900 mg Placebo Residual C5 Mean nadir; mcg/mL ± SEM 15.3 ± 2.5 5.2 ± 0.5 3.8 ± 1.0 2.2 ± 0.8 1.8 ± 0.2 60.5 ± 3.3 Nadir; mcg/mL 10.8 4.3 1.8 1.1
Slide 16: Part B MAD: Serum C5 Knockdown
ALN-CC5 Phase 1/2: Part B – MAD Pharmacodynamics and Clinical Activity: Serum C5 Serum C5 knockdown following 5 weekly doses of ALN-CC5 • Maximum C5 knockdown relative to baseline up to 99% • Mean maximum C5 knockdown of 98 ± 0.5% (mean ± SEM) • Mean C5 knockdown of 98 ± 0.3% (mean ± SEM) at Day 112
Slide 17: Part B MAD: Complement Inhibition
ALN-CC5 Phase 1/2: Part B – MAD Pharmacodynamics and Clinical Activity: Complement Inhibition Complement Alternative Pathway -20 Mean (+/- SEM) CAP Reduction inhibition (CAP C5b-9 ELISA) 0 Relative to Baseline • 5 weekly doses of ALN-CC5 20 • Maximum CAP inhibition relative to 40 baseline up to 97%
Slide 18: Part B MAD: Hemolysis Inhibition
ALN-CC5 Phase 1/2 Part B – MAD Pharmacodynamics and Clinical Activity: Hemolysis Inhibition Inhibition of sheep erythrocyte hemolysis • 5 weekly doses of ALN-CC5 • Maximum serum hemolysis inhibition relative to baseline up to 98% • Mean maximum serum hemolysis inhibition of 84 ± 7.6% (mean ± SEM) 0
Slide 19: Part B MAD Summary of Preliminary Results
ALN-CC5 Phase 1/2 Part B – MAD Summary of Preliminary Results Part B: Multiple Ascending Dose (MAD) Weekly × 5 subcutaneous injections 100 mg 200 mg 400 mg Placebo Residual C5 levels Mean nadir; mcg/mL ± SEM 4.2 ± 0.5 1.3 ± 0.3 1.3 ± 0.2 67.5 ± 2.1 Nadir; mcg/mL 3.5 0.6 1.0 63.2 C5 knockdown Mean ma
Slide 20: Free and Residual C5
Free and Residual C5 Eculizumab and free C5 levels (μg/mL)1 ALN-CC5 and residual C5 levels (μg/mL)* • Eculizumab concentration-effect relationship for • Serum C5 levels after multiple doses of ALN-CC5 reduction in free C5 in aHUS patients in healthy human volunteers • Free C5 measured using validate
Slide 21: Summary and Next Steps
ALN-CC5 Phase 1/2 Study Results* Summary and Next Steps • ALN-CC5 represents novel investigational approach for potential treatment of complement-mediated diseases, including PNH • In ongoing Phase 1/2 study in healthy volunteers (N=32), single and multi-dose subcutaneous administration of ALN-CC5 g
Slide 22: Acknowledgements
Acknowledgements Trial participants Principal investigators Country PI Name Location United Jorg Taubel Richmond Pharmacology Ltd, Tooting, UK Kingdom Jim Bush Covance Clinical Research Unit Limited, Leeds, UK Anita Hill Department of Haematology, Leeds Teaching Hospitals, Leeds, UK Spain Alvaro Urb
Slide 23: Thank You
Thank You ZL Alnylan.