Alnylam Pharmaceuticals, Inc. · NASDAQ:ALNY
Alnylam Pharmaceuticals — Technical Presentation (September 2016)
19 slides from Alnylam Pharmaceuticals's technical presentation, Sep 14, 2016
Slide 1: ALN-CC5 Interim Phase 1 Data and Efficacy in Preclinical Models of MG
ALN-CC5 An Investigational RNAI Therapeutic for the Treatment of Complement-Mediated Diseases: Interim Phase 1 Data in Healthy Volunteers and Efficacy in Pre- Clinical Animal Models of MG Anna Borodovsky, Linda L. Kusner, Jorg Taubel, Jim Bush, Noriyuki Kawahata, Helen Mclean, Angela Partisano, Jae
Slide 2: ALN-CC5 and Complement-Mediated Diseases
ALN-CC5 and Complement-Mediated Diseases Excessive complement activity drives disease pathophysiology in many indications Alternative Pathway Classical Pathway Lectin Pathway • Paroxysmal nocturnal hemoglobinuria (PNH) Initiation C3 C1 • Myasthenia gravis (MG) C3 • Atypical hemolytic uremic syndrome
Slide 3: RNAi Therapeutics
RNAi Therapeutics New Class of Innovative Medicines Harness natural pathway Catalytic mechanism Silence any gene in genome Upstream of today’s medicines Clinically proven approach 3
Slide 4: ALN-CC5: SC-Administered GalNAc-Conjugated siRNA Targeting C5
ALN-CC5: SC-Administered GalNAc- Conjugated siRNA Targeting C5 (GalNAc)3 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 Rec
Slide 5: Myasthenia Gravis (MG) Pathophysiology
Myasthenia Gravis (MG) Pathophysiology Complement has been known to play a significant role in AChR + MG for decades • Multi-modal combination therapy required to achieve optimal outcomes 5 Conti-Fine, J Clin Invest. 2006 Nov;116(11):2843-54
Slide 6: Evaluation of C5 Silencing in Rat EAMG
Evaluation of C5 Silencing in Rat EAMG Passive Model • Induced by injection of anti-AChR monoclonal antibody • Directed at the NMJ by a complement binding antibody ◦ Treatment with anti-C5 mAb blocks disease development • Very rapid course – animals show weakness in 24 hrs ◦ Pretreatment needed to e
Slide 7: Protection in Passive EAMG with C5 Silencing
Protection in Passive EAMG with C5 Silencing Anti-AChR D-10 D-7 D-3 D0 D1 D2 C5 siRNA Complement Activity Disease Activity Score S a lin e 3 .0 120 2 4 h rs c lin ic a l d is e a s e s c o r e 2 .5 m g /k g s iR N A 2 .5 4 8 h rs 100 5 m g /k g s iR N A % H e m o ly s is 2 .0 80 60 1 .5 40 1 .0 20 0
Slide 8: Reduction in MAC Deposition and AChR Preservation
Reduction in MAC Deposition and AChR Preservation Passive EAMG MAC A ChR MAC Staining AChR Staining *** * 50 60 * ** 40 M e a n In te n s ity M e a n In te n s ity 50 30 40 20 30 10 0 20 C o n tro l 2 .5 m g /k g 5 m g /k g C o n tro l 2 .5 m g /k g 5 m g /k g • Significant reduction in MAC depositi
Slide 9: Disease Reversal in the Active EAMG Model
Disease Reversal in the Active EAMG Model Complement Activity Disease Activity Score 140 2.5 PBS PBS 120 C5 siRNA 2.0 C5 siRNA Disease score % Hemolysis 100 control siRNA control siRNA 80 1.5 60 1.0 40 0.5 20 0 0.0 0 10 20 30 40 50 60 0 10 20 30 40 50 60 Days Days AChR/CFA 5 mg/kg 2xw AChR/CFA 5 mg/
Slide 10: C5 Silencing in EAMG Models Summary
C5 Silencing in EAMG Models Summary C5 silencing prevents or reverses disease development in rat EAMG models • Pre-treatment with C5 siRNA in PTMG blocks disease development ◦ Near complete prevention of disease with 70% hemolysis reduction – Effect similar to that observed with anti-C5 antibody tre
Slide 11: 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/cohort : dosing completed 50 mg x 1 SC Primary objectives 200 mg x 1 SC • Safety, tolerability Secondary objectives 40
Slide 12: 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 in-house sheep er
Slide 13: ALN-CC5 Phase 1/2: Part A – SAD
ALN-CC5 Phase 1/2: Part A – SAD* Blinded Safety and Tolerability Summary ALN-CC5 was generally well tolerated in healthy volunteers • No SAEs and no discontinuation due to adverse events (AE) • 14 healthy volunteers (70%) reported at least one AE; all were mild or moderate ◦ 2 healthy volunteers (10
Slide 14: ALN-CC5 Phase 1/2: Part B – MAD
ALN-CC5 Phase 1/2: Part B – MAD* Blinded Safety and Tolerability Summary ALN-CC5 was generally well tolerated in healthy volunteers • No SAEs and no discontinuation due to adverse events (AE) • 19 healthy volunteers (79%) reported at least one AE; all were mild or moderate ◦ 10 healthy volunteers (4
Slide 15: Pharmacodynamics: Serum C5 Knockdown, Part A SAD
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 (± SEM) C5 knockdown: 98 ± 0.9% • Mean (± SEM) C5 knockdown: ◦ Day 98 (600 mg): 97 ± 1.1% ◦ Day 1
Slide 16: Pharmacodynamics: Serum C5 Knockdown, Part B MAD
ALN-CC5 Phase 1/2: Part B – MAD* Pharmacodynamics and Clinical Activity: Serum C5 Serum C5 knockdown following multiple doses of ALN-CC5 • Maximum C5 knockdown relative to baseline up to 99% • Mean maximum (± SEM) C5 knockdown: 99 ± 0.2% • Mean (± SEM) C5 knockdown: 99 ± 0.2% at Day 112 (600mg, q2W)
Slide 17: Pharmacodynamics: CCP Inhibition, Part B MAD
ALN-CC5 Phase 1/2: Part B – MAD* Pharmacodynamics and Clinical Activity: CCP Complement Classical Pathway inhibition (CCP C5b-9 ELISA) • Multiple doses of ALN-CC5 • Maximum CCP inhibition relative to baseline up to 99.4% • Mean maximum (± SEM) CCP inhibition: 97.3 ± 1.0% • CCP activity comparable to
Slide 18: Pharmacodynamics: CH50 Reduction, Part B MAD
ALN-CC5 Phase 1/2: Part B – MAD* Pharmacodynamics and Clinical Activity: CH50 Reduction of CH50 activity • Multiple doses of ALN-CC5 • Maximum CH50 inhibition relative to baseline up to 100% • Mean maximum (± SEM) CH50 inhibition: 100 ± 0.2% -20 Mean (+/-SEM) CH50 Reduction 0 relative to baseline (%
Slide 19: ALN-CC5 Phase 1/2 Study Results Summary
ALN-CC5 Phase 1/2 Study Results* Summary ALN-CC5 represents a novel investigational approach for the potential treatment of complement-mediated diseases, such as myasthenia gravis • In an ongoing Phase 1/2 study in healthy volunteers (N=44), single and multi-dose subcutaneous administration of ALN-C
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