ION775, a long-acting siRNA targeting APOC3: single-dose, 12-month results in participants with moderate hypertriglyceridemia

Background Reduction in apolipoprotein C-III (apoC-III) is an established strategy to lower plasma triglycerides (TGs) and TG-rich lipoproteins. Purpose To evaluate the safety, tolerability, and pharmacodynamics of ION775, an investigational GalNAc-conjugated small interfering RNA targeting APOC3 messenger RNA, in otherwise healthy adults with elevated TGs, and to characterize its effects on plasma apoC-III, fasting TGs, and atherogenic lipoproteins. Methods This was a Phase 1, randomized, double-blind, placebo-controlled, single-ascending-dose study in adults with fasting TGs 150–500 mg/dL. Forty participants (30 ION775, 10 placebo) received a single subcutaneous dose of ION775 (10, 30, 100, 300, or 600 mg) or placebo and were followed for up to 12 months; 12-month follow-up is ongoing for the 600-mg cohort. The primary endpoint was safety. Prespecified pharmacodynamic endpoints included percent change from baseline in apoC-III, TGs, and other lipid parameters at 6 months versus placebo (Wilcoxon rank-sum test). This analysis reports safety and efficacy at 6 months, including mean percent change from baseline versus pooled placebo in apoC-III, TGs, non–HDL cholesterol (non–HDL-C), remnant cholesterol, and apolipoprotein B (apoB). Results Baseline mean (SD) apoC-III and TGs were 13.0 (3.4) mg/dL and 224.0 (69.2) mg/dL, respectively. ION775 was well tolerated, with no serious or severe adverse events and no injection-site reactions. ION775 produced rapid, sustained, dose-dependent reductions in apoC-III and TGs. At 6 months, mean percent changes in apoC-III from baseline were −54%, −74%, and −82% for the 30-, 100-, and 300-mg dose groups (p=0.0007 for all) versus +10% with placebo. Corresponding mean changes in TGs were −52% (p=0.005), −68% (p=0.0007), and −68% (p=0.0007) for 30, 100, and 300 mg, respectively, versus +0.2% with pooled placebo. At 6 months, ION775 100 and 300 mg reduced apoB by −20% (p=0.0013) and −29% (p=0.0007), non–HDL-C by −22% (p=0.0007) and −31% (p=0.0007), and remnant cholesterol by −69% (p=0.003) and −73% (p=0.003), respectively. At 6 months, 100% of ION775-treated participants across all dose groups achieved TG levels <150 mg/dL. At 12 months, mean reductions from baseline in apoC-III were −46% and −62%, and in TGs were −46% and −65%, in the 100- and 300-mg groups, respectively. Conclusion(s) Single subcutaneous doses of ION775 produced rapid, significant, dose-dependent, and durable reductions in apoC-III and TGs, with favorable effects on atherogenic lipoprotein measures and an acceptable safety profile through up to 12 months of follow-up. Phase 2 studies will evaluate ION775 in patients with more severe forms of hypertriglyceridemia.