Alnylam Pharmaceuticals, Inc. · NASDAQ:ALNY
Alnylam Pharmaceuticals — ESPN 2015
11 slides from Alnylam Pharmaceuticals's conference presentation, Sep 5, 2015
Slide 1: Development of an Investigational RNAi Therapeutic Targeting Glycolate Oxidase for PH1
Development of an Investigational RNAi Therapeutic Targeting Glycolate Oxidase for the Treatment of Primary Hyperoxaluria Type 1 David V. Erbe, PhD September 5, 2015 1 CONFIDENTIAL
Slide 2: Statement of Conflict of Interest
Statement of Conflict of Interest: The speaker is an employee of Alnylam Pharmaceuticals. 2 CONFIDENTIAL
Slide 3: RNAi Therapeutics: A New Class of Innovative Medicines
RNAi Therapeutics A New Class of Innovative Medicines GalNAc-siRNA conjugate • Harness the natural pathway, mediated by small interfering RNA or “siRNA”, to ASGPR therapeutically silence any gene (pH>5) ◦ Distinct mechanism of action vs. other drug Clathrin-coated pit classes – Catalytic gene silenc
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 DISCOVERY DEVELOPMENT Primary Hyperoxaluria Type 1 ALN-GO1 TTR-Mediated Amyloidosis Beta-Thalassemia/Iron-O
Slide 5: Primary Hyperoxaluria Type 1 (PH1)
Primary Hyperoxaluria Type 1 (PH1) Summary • Rare, devastating disease due to excessive overproduction of oxalate by the liver ◦ Deficiency of alanine-glyoxlyate aminotransferase (AGT) ◦ Prevalence of 6-7 per million, higher in some populations globally ◦ Calcium oxalate crystals deposit in kidneys,
Slide 6: Glycolate Oxidase Knockdown to Starve Substrate for Oxalate Synthesis in PH1
Glycolate Oxidase (GO) Knockdown to Starve Substrate for Oxalate Synthesis in PH1 PH1 PH1 ALN-GO1 Urinary Oxalate (Uox) • Human GO deficiency well tolerated provides validation through increased glycolate excretion ◦ 8-yr old boy with homozygous GO loss-of-function identified by Dr. Yaacov Umol/24
Slide 7: Potent mRNA Silencing, Substantial Efficacy with Durability in Normal and Diseased Mice
ALN-GO1 in Normal and Diseased Mice Potent mRNA Silencing, Substantial Efficacy with Durability Normal mice (single dose) PH1 mice (single dose) 1 .5 M ouse HAO 1 m RNA, BS=1 to PPBS) HAO1 mRNA (mg/g Creatinine/24 hr) 1 .0 Urine Oxalate e la t iv e to R(relative day 10 sac 0 .5 0 .0 .3 .1 0 3 1 S 1
Slide 8: Substantially Lowered Urinary Oxalate in Rat PH1 Model
ALN-GO1 Substantially Lowered Urinary Oxalate in Rat PH1 Model Oxalate decreased up to 98% following weekly dosing 1500 VehEG + AGXT LNP + PBS 1% 3 mg/kg 1% ALN-GO1 EG + AGXT LNP + 3mg/kg (mg/g Creatinine/24 hr) 1 mg/kg 1% ALN-GO1 EG + AGXT LNP + 1mg/kg Urine Oxalate 1% 0.3EG + AGXT mg/kg LNP + 0.3m
Slide 9: Single, Low Dose ALN-GO1 in PH1 Rats
Single, Low Dose ALN-GO1 in PH1 Rats 1:1 Relationship of Oxalate Lowering to HAO1 mRNA Silencing Demonstrates substantial potential for efficacy 1800 1600 1400 (mg/g Creatinine/24 hr) PBS Urine Oxalate 1200 1000 0.01 mg/Kg 800 0.03 mg/Kg 600 400 0.1 mg/Kg 200 0.3 mg/Kg 0 -1 1 3 5 7 9 11 13 15 ALN-GO
Slide 10: ALN-GO1 in Non-human Primates (ongoing)
ALN-GO1 in Non-human Primates (ongoing) Potent mRNA Silencing, Expected Increases in Serum Glycolate Dose 80 Grou Dose p# Level Frequency G r. 1 (mg/kg) S e r u m G ly c o la t e , M G r. 2 1 Veh qMx6 60 G r. 3 2 0.25 qWx8 G r. 4 3 1 40 G r. 5 4 1 G r. 6 5 2 qMx6 20 G r. 7 6 4 7 2→1 qWx4 → qMx5 0
Slide 11: Summary, Next Steps, & Acknowledgments
ALN-GO1 Summary, Next Steps, & Acknowledgments • Pre-clinical data summary ◦ Potent, durable silencing of HAO1 mRNA across species – Translates into expected increases in serum glycolate in healthy animals ◦ Profound lowering of urinary oxalate in animal models of PH1 – 1:1 relationship of oxalate l