HRS-7249, a small interfering RNA targeting apolipoprotein C3, in healthy subjects
L Zhu, T Luo, X Ren, D Yang, W Zhang, C Deng, K Zi, Y Zhu, X Wang, C Shu, L Diao, B JiangAbstract
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.