ESC Congress 2026 Abstract · Oct 26, 2026

Safety, tolerability, pharmacokinetics and pharmacodynamics of HRS-1301, an oral PCSK9 inhibitor, in healthy participants: a first-in-human, randomized, double-blind, placebo-controlled phase I trial

By Zhong SL, Wang X, Wang P et al.

Background/Introduction: Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) is a proven therapeutic strategy for reducing plasma low density lipoprotein-cholesterol (LDL-C). HRS-1301 is an oral small molecule PCSK9 inhibitor designed to prevent LDL receptor degradation, representing a novel therapeutic approach for dyslipidemia. Purpose: This first-in-human study aimed to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of HRS-1301 in healthy volunteers with or without elevated LDL-C. Methods: This randomized, double-blind, placebo-controlled phase I study comprised a single ascending dose (SAD) part and a multiple ascending dose (MAD) part. In SAD, 42 healthy volunteers received single oral doses of HRS-1301 at 20, 50 (fed and fasted), 100, 200, and 300 mg or placebo, with a randomization ratio of 6:2 (HRS-1301: placebo) for the 20, 100, 200, and 300 mg cohorts and 8:2 for the 50 mg cohorts. In MAD, 40 healthy volunteers with LDL-C ≥ 2.60 to < 4.90 mmol/L and triglyceride < 5.60 mmol/L were randomized (6:2) to HRS-1301 at 20, 50, 100, 200 mg or placebo once daily for 14 days. The primary endpoints were safety and tolerability. Results: A total of 83 participants were treated. All treatment-emergent adverse events (TEAEs) were mild, with no serious adverse events reported. Following 14 days of once-daily dosing, incidence of TEAEs was similar between pooled HRS-1301 group (60.6%) and placebo (62.5%), with no dose-dependent increase observed. The most common TEAEs in HRS-1301 group were increased white blood cell count (9.4%) and white blood cells urine positive (9.4%) in SAD, and decreased blood fibrinogen (12.1%), increased white blood cell count (9.1%) and increased bilirubin conjugated (9.1%) in MAD. HRS-1301 exhibited linear PK characteristics. After single dose, median Tmax was 1.0-2.0 hours and geometric mean t1/2 ranged from 9.8–13.5 hours. Approximately 50% to 60% of administered dose was excreted unchanged in urine. Plasma concentrations reached steady state on Day 3 after once-daily dosing, with an accumulation ratio of 1.04 to 1.55. Compared to the fasted state, administration with a high-fat meal reduced Cmax and AUC by approximately 20% and 5%, respectively. Treatment with HRS-1301 for 14 days resulted in a dose-dependent reduction in LDL-C. Placebo-adjusted mean reductions from baseline on Day 14 were 30.1%, 31.9%, 35.6% and 41.8% for the 20, 50, 100, and 200 mg doses, respectively (Figure 1 and 2). Notably, a continued downward trend was observed in LDL-C lowering for the 100 mg and 200 mg doses after 14-days administration. Similar dose-dependent reductions were observed in total cholesterol, non-high-density lipoprotein cholesterol and apolipoprotein B. Conclusion(s): HRS-1301 was well tolerated and demonstrated favorable PK profiles and dose-dependent reductions in LDL-C, supporting its further clinical development as a potential oral therapy for dyslipidemia.Figure 1.Plasma LDL-C after administrationFigure 2.LDL-C change on Day 14

doi.org/10.1093/eurheartj/ehag785.4122Open accessInterventions