Safety, tolerability, pharmacokinetics, pharmacodynamics and food effect of HRS‐1893, a cardiac myosin inhibitor, in healthy subjects

Abstract Aim This first‐in‐human study assessed the safety, tolerability, pharmacokinetics (PK), effect of food on PK and pharmacodynamics of HRS‐1893, a cardiac myosin inhibitor, in healthy subjects. Methods In the single ascending dose part, eight subjects in each of the 5‐, 15‐, 50‐, 75‐ and 100‐mg (optional) cohort and 10 subjects in the 30‐mg cohort were randomized in 6:2 and 8:2 ratios, respectively, to receive HRS‐1893 or placebo. Participants from the 30‐mg cohort then entered a food effect study where they received HRS‐1893 or placebo after a high‐fat meal. In the multiple ascending dose part, eight subjects in each of the 10‐, 20‐, 40‐ and 60‐mg (optional) cohorts were randomized (6:2) to receive HRS‐1893 or placebo twice daily for 14 days. Results HRS‐1893 was well tolerated within the tested dose range. Following single dosing, the median (5th and 95th percentile) maximum plasma concentration of HRS‐1893 ranged from 343 (241 and 436) to 1090 (990 and 1430) ng/ml and was reached within 1.0‐ to 2.0‐h post‐administration. Drug exposure increased in a less‐than‐dose‐proportional manner with dose escalation. AUC 0− t ranged from 1890 (1710 and 2520) to 10 100 (7710 and 11 600) h·ng/ml, and AUC 0‐∞ ranged from 1960 (1820 and 2660) to 11 900 (9260 and 13 100) h·ng/ml. A steady‐state was attained by Day 8 following continuous administration. Food intake had no obvious effect on the PK profile of HRS‐1893 at 30 mg. HRS‐1893 also resulted in favourable changes in cardiac indicators. Conclusion HRS‐1893 demonstrated favourable safety and PK profiles, with potential therapeutic efficacy among healthy subjects. Clinical trial registration ClinicalTrials.gov , NCT05879523.