Key result
HRS-7249 cuts APOC3 up to ~97% with mostly mild adverse events in healthy subjects.
Why the study?
APOC3 is a novel target for treating hypertriglyceridemia, and the safety, tolerability, pharmacokinetics, and pharmacodynamics of HRS-7249, a small interfering RNA targeting APOC3, needed assessment in healthy subjects.
Does subcutaneous HRS-7249 demonstrate acceptable safety and tolerability while lowering APOC3 and triglyceride levels in healthy subjects?
RCT (n=48)
Double-blind
Randomized in a 6:2 ratio
Does subcutaneous HRS-7249 demonstrate acceptable safety and tolerability while lowering APOC3 and triglyceride levels in healthy subjects?
Answers are grounded in this paper and cite their sources.
In this phase 1 study of healthy subjects, single ascending doses of the APOC3-targeting siRNA HRS-7249 demonstrated acceptable safety and tolerability while producing substantial, dose-dependent reductions in serum APOC3 and triglyceride levels.
Background Apolipoprotein C3 (APOC3) is involved in the metabolism of triglyceride (TG) and is a novel target for the treatment of hypertriglyceridemia. HRS-7249 is a small interfering RNA designed to disrupt and inhibit the expression of APOC3 and consequently lower TG level. Purpose This phase 1 study aimed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of HRS-7249 in healthy subjects. Methods In this randomized, double-blind, placebo-controlled single ascending dose study, 6 dose cohorts were planned (10, 50, 100, 200, 400, and 600 mg). Each cohort planned to enroll 8 healthy subjects, randomized in a 6:2 ratio to receive subcutaneous HRS-7249 or placebo. The primary endpoint was safety and tolerability. Results 48 subjects were enrolled and treated (HRS-7249, n = 36; placebo, n = 12). Treatment-emergent adverse events (AE) were reported by 34 (94.4%) subjects in the HRS-7249 group and 8 (66.7%) subjects in the placebo group, most of which were mild in severity. The most common AE related to HRS-7249 was increased alanine aminotransferase (19.4%). Serum APOC3 concentrations considerably decreased following HRS-7249 treatment, while that in the placebo group fluctuated around the baseline (Figure). APOC3 in the HRS-7249 group decreased in a roughly dose-dependent manner across 10 to 600 mg, with the largest mean percent change ranging from -71.3% to -97.0%. TG reduction showed similar trends, ranging from -62.2% to -74.7%. Conclusion HRS-7249 showed acceptable safety and tolerability and can effectively lower APOC3 and TG in healthy subjects.
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Zhu et al. (2026) conducted an RCT in Healthy subjects (targeting hypertriglyceridemia) (n=48). HRS-7249 vs. Placebo was evaluated on Safety and tolerability (treatment-emergent adverse events). HRS-7249 had mostly mild adverse events (94.4% vs 66.7% with placebo) and reduced APOC3 by up to 71.3%-97.0% and triglycerides by 62.2%-74.7% in healthy subjects.
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