Abstract 4363704: YOSEMITE Rationale and Design: Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Zodasiran Efficacy and Safety in Adolescents and Adults with Homozygous Familial Hypercholesterolemia

Background/Synopsis: HoFH is a rare autosomal condition caused by mutations in the LDLR pathway resulting in impaired LDL-C clearance. Patients with HoFH have severe hypercholesterolemia, conferring early risk of CAD and struggle to achieve target LDL-C levels. Zodasiran, an investigational siRNA inhibits hepatic production of ANGPTL3, a key regulator of Lipoprotein and Endothelial lipase mediated LDL-C, HDL-C and TG metabolism and clearance. Zodasiran doses to 300 mg Q3M demonstrated durable reductions in LDL-C and have been well tolerated. Methods: YOSEMITE is a phase 3, randomized, double-blind, placebo-controlled trial. Key inclusion criteria are genetically confirmed HoFH or a clinical diagnosis (total cholesterol >500 mg/dL OR treated LDL-C concentration of ≥300 mg/dL either accompanied by TGs <300 mg/dL AND both parents with documented total cholesterol >250 mg/dL OR xanthomas before 10 years of age), LDL-C ≥70 mg/dL and on maximally tolerated LLT. Key exclusion criteria include use of any hepatocyte targeted siRNA treatments within 1-year. Results: 60 HoFH subjects > 12-years randomized 2:1 will receive quarterly subcutaneous zodasiran 200 mg or matching placebo over 1-year, followed by a 1-year open-label extension. The randomization will be stratified by apheresis treatment. The primary efficacy endpoint is percent change from baseline in fasting LDL-C. Secondary endpoints include percent change from baseline in fasting ApoB, non-HDL-C, TGs, ANGPTL3, total cholesterol, Lp(a) and HDL-C; change from baseline and AUC in fasting LDL-C to 1-year. Safety and tolerability will be assessed. Conclusions: YOSEMITE is designed to determine whether quarterly-dosed zodasiran safely reduces LDL-C levels in patients with HoFH.