Single-dose ION775, a GalNAc-conjugated siRNA targeting APOC3, lowers triglycerides for up to 12 months in moderate hypertriglyceridemia

BACKGROUND: Apolipoprotein C-III (apoC-III) regulates triglyceride-rich lipoprotein metabolism. ION775 is a GalNAc-conjugated small interfering RNA designed to silence APOC3 mRNA and enable infrequent dosing. OBJECTIVE: To evaluate the safety, tolerability, and lipid effects of single-dose ION775 in adults with moderate hypertriglyceridemia. METHODS: In this phase 1 randomized, double-blind, placebo-controlled, single-ascending-dose study, adults with fasting triglycerides of 150 to 500 mg/dL received a single subcutaneous dose of ION775 (10-600 mg) or placebo and were followed for up to 12 months. The primary endpoint was safety and tolerability; pharmacodynamic endpoints included changes in apoC-III, triglycerides, and related lipid parameters. RESULTS: Forty participants were treated (ION775, n = 30; placebo, n = 10). ION775 was generally well tolerated, with no serious adverse events, severe treatment-emergent adverse events, or injection-site reactions. At 6 months, mean apoC-III changes ranged from -35.3% to -86.8% across active doses (all P ≤ .0047 vs placebo), and triglyceride changes ranged from -26.2% to -68.4%, with significant reductions at doses ≥30 mg (P ≤ .0017). Across the 30- to 600-mg groups, calculated remnant cholesterol, non-high-density lipoprotein cholesterol, and apoB were reduced by 61.4% to 72.7%, 21.8% to 33.9%, and 20.0% to 29.1%, respectively (P ≤ .0075, P = .0002, and P ≤ .0047 vs placebo, respectively). In the 300- and 600-mg cohorts, apoC-III and triglyceride reductions were sustained through 12 months. CONCLUSION: Single-dose ION775 was generally well tolerated and produced rapid, dose-dependent, durable reductions in apoC-III and triglycerides sustained through 12 months, supporting further development as an infrequently dosed therapy for triglyceride-rich lipoprotein disorders.