Abstract
BACKGROUND: Plozasiran (VSA001, ARO-APOC3) is an RNA interference therapy that targets Apolipoprotein C3 (APOC3), a key regulator of lipoprotein metabolism. The study aimed at assessing the safety, tolerability, pharmacokinetics (PK), and pharmacodynamic (PD) profiles of plozasiran in Chinese healthy volunteers (HVs). METHODS: In this double-blind, placebo-controlled, phase I clinical study, a total of 24 Chinese adult HVs received single subcutaneous (SC) injection of 25 mg, 50 mg plozasiran or placebo on day 1. Safety, tolerability, PK and PD profiles were accessed during a follow-up period of 85 days. RESULTS: Eighteen HVs received plozasiran (25 mg: n = 9; 50 mg: n = 9) and 6 HVs received placebo. Plozasiran was well tolerated in Chinese HVs. No death, no severe adverse events or treatment-emergent adverse events (TEAEs) leading to discontinuation were observed. TEAEs were reported in 9 of 18 HVs from plozasiran group and in 1 of 6 HVs from placebo group. All TEAEs were transient and recovered autonomously, except for 2 subjects with 4 TEAEs from plozasiran group needed concomitant medications. After SC injection, plozasiran was rapidly absorbed and quickly eliminated in the plasma. Maximum geomean serum concentration was 102 ng/mL (CV%:36.4%) and 216 ng/mL (58.1%) for 25 mg and 50 mg group, respectively. The median T(max) of the 25 mg and 50 mg groups was 3 h (2.00, 6.02) and 6 h (1.00, 6.00), respectively. The geomean AUC(0-t) was 971 ng*h/mL (21.1%) and 2016 ng*h/mL (29.5%), and AUC(0-∞) was 999 ng*h/mL (20.80%) and 2148 ng*h/mL (27.0%), respectively. The geomean CL/F, V(z)/F and t(1/2) of plozasiran 25 and 50 mg groups were 25.0 L/h (20.80%) and 23.3 L/h (27.0%), 120 L (41.8%) and 100 L (41.8%), 3.33 h (27.0%) and 2.99 h (22.0%), respectively. After subcutaneous injection of plozasiran, the concentrations of APOC3 and triglyceride (TG) decreased substantially in both treatment groups, reaching a steady-state level simultaneously (Days 8-29), which persisted until the end of the study (EOS). Maximum mean decreases in APOC3 were observed on day 29; 79.0% and 95.1% from baseline for 25 mg and 50 mg group, respectively, with corresponding reductions of TG of 64.5% and 71.3%. In addition, increase in HDL-C, and decreases in non-HDL-C, ApoB, LDL-C and VLDL-C were observed in plozasiran group. No noticeable change of PD parameters was observed in placebo group. CONCLUSIONS: Plozasiran at 25 and 50 mg was well tolerated with acceptable safety profile in Chinese HVs. Safety, PK and PD profiles observed in the present study were consistent with the data reported from clinical studies conducted outside China.