Alnylam Pharmaceuticals, Inc. · NASDAQ:ALNY
Alnylam Pharmaceuticals — Technical Presentation (July 2017)
12 slides from Alnylam Pharmaceuticals's technical presentation, July 2017
Slide 1: Reduction of Hepatic Factor XII Expression in Mice by ALN-F12 Inhibits Thrombosis without Increasing Bleeding Risk
Reduction of Hepatic Factor XII Expression in Mice by ALN-F12 Inhibits Thrombosis without Increasing Bleeding Risk Jingxuan Liu1, June Qin1, Brian C. Cooley2, Akin Akinc1 , James Butler1 1Alnylam Pharmaceuticals, Cambridge, MA USA 2Animal Surgery Core Lab, University of North Carolina, Chapel Hill,
Slide 2: Acknowledgements
Acknowledgements Alnylam Pharmaceuticals UNC Chapel Hill • June Qin • Dr. Brian C. Cooley • Akin Akinc, PhD • James Butler, PhD • Daniel Freedman, PhD • Eoin Coakley, MD • Anna Borodovsky, PhD • Tracy Zimmerman, PhD • Kevin Fitzgerald, PhD 2
Slide 3: Investigational RNAi Therapeutics
Investigational RNAi Therapeutics A Potential New Class of Innovative Medicines Harness natural pathway of RNAi • RNAi = RNA interference • Catalytic mechanism • Mediated by small interfering RNA or “siRNA” Therapeutic gene silencing • Any gene in genome • Distinct mechanism of action vs. other drug
Slide 4: ALN-F12: An Investigational RNAi Therapeutic Targeting FXII
ALN-F12: An Investigational RNAi Therapeutic Targeting FXII • siRNA conjugated to N-acetylgalactosamine (GalNAc) ligand • Efficient delivery to hepatocytes following subcutaneous (SC) administration • Targets the F12 gene encoding for FXII • Robust activity in NHPs • ED50 < 1 mg/kg; ED80 < 3 mg/kg •
Slide 5: FXII: A Potential Target for the Treatment of Thrombosis
FXII: A Potential Target for the Treatment of Thrombosis • Serine protease, auto-activated by contact with negatively charged surfaces ◦ PolyP, protein aggregates, DNA, RNA, etc. • FXIIa activates FXI and triggers fibrin formation (intrinsic coagulation) • FXII deficiency (Hageman trait) is not asso
Slide 6: Preclinical Evaluation of ALN-F12 for Thromboprophylaxis
Preclinical Evaluation of ALN-F12 for Thromboprophylaxis Overview of Mouse Thrombosis and Hemostasis Models Thrombosis Models • Venous Electrolytic Injury ◦ Electrolytic “shock” injury allows precise control of thrombosis initiation ◦ Fluorescently labeled platelets & fibrin enable real time imaging
Slide 7: ALN-F12 Inhibits Venous Thrombosis in Mice
ALN-F12 Inhibits Venous Thrombosis in Mice Venous Electrolytic Injury Model Liver mRNA 100% F12 (Control) 48% F12 25% F12 3% F12 Liver F12 mRNA levels 1.2 Ratio to PBS Average 1.0 • Single SC Dose 0.8 • 10 days post dosing 0.6 • N=8 per group 0.4 0.2 0.0 7 PBS 0.3 mpk 0.75 mpk 10 mpk
Slide 8: F11-siRNA Inhibits Venous Thrombosis in Mice
F11-siRNA Inhibits Venous Thrombosis in Mice Venous Electrolytic Injury Model Liver mRNA Control (100% F11) 33% F11 22% F11 4% F11 2.0 Liver F11 mRNA levels Ratio to PBS Average 1.5 • Single SC Dose 1.0 • 10 days post dosing • N=8 per group 0.5 0.0 8 PBS 0.3 mpk 0.75 mpk 10 mpk
Slide 9: ALN-F12, F11-siRNA Inhibit Venous Thrombosis in Mice
ALN-F12, F11-siRNA Inhibit Venous Thrombosis in Mice Real Time Images of Fibrin and Platelet Deposition in Electrolytic Injury Model Control ALN-F12 F11-siRNA Red: Fibrin Green: Platelet 9
Slide 10: ALN-F12 Inhibits Arterial Thrombosis in Mice
ALN-F12 Inhibits Arterial Thrombosis in Mice FeCl3-induced Arterial Thrombosis Model Liver F12 mRNA levels 1.2 0.8 0.4 > 97% K/D 0.0 PBS ALN-F12 Liver F11 mRNA levels 1.5 1.0 0.5 > 98% K/D 0.0 PBS FXI-siRNA • Single SC Dose • 10 days post dosing • N=8 per group 10
Slide 11: ALN-F12 Does NOT Impair Hemostasis
ALN-F12 Does NOT Impair Hemostasis No Bleeding Phenotype at > 95% FXII or FXI Reduction • Single SC Dose • 10 days post dosing One-way ANOVA: n.s., not significant; ***, p<0.001 • N=8 per group 11
Slide 12: Summary
Summary Reduction of FXII by ALN-F12 Prevented Thrombosis Without Increased Bleeding Risk in Rodent Models of Thrombosis and Hemostasis • ALN-F12 reduced liver F12 mRNA and plasma FXII in a dose dependent manner in rodents and NHPs • ALN-F12 mediated reduction of FXII prevented platelet and fibrin a
Alnylam Pharmaceuticals — Technical Presentation (July 2017) on 6ix