AUTHOR=Zhao Xue , Liu Hongzhong , Tian Wei , Fang Ligang , Yu Mengyang , Wu Xiaofei , Liu Aijing , Wan Ruijie , Li Li , Luo Jinghui , Li Yuqiong , Liu Bo , He Yu , Chen Xiaowen , Li Yuan , Xu Donghong , Wang Hongyun , Han Xiaohong 

TITLE=Safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of aficamten in healthy Chinese participants: a randomized, double-blind, placebo-controlled, phase 1 study

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1227470

DOI=10.3389/fphar.2023.1227470

ISSN=1663-9812

ABSTRACT=Objectives: Aficamten is a selective, small molecule allosteric inhibitor of cardiac sarcomere being developed as a chronic oral treatment for patients with symptomatic obstructive hypertrophic cardiomyopathy. This was the first-in-Chinese study aiming to investigate the safety, tolerability, pharmacokinetics of aficamten in healthy adults.Methods: This double-blind, randomized, placebo-controlled, Phase 1 study was conducted in 28 healthy male and female Chinese participants after single ascending dose (SAD) and one multiple doses (MD) of aficamten. In SAD cohort, 16 participants were randomized to receive single oral dose of aficamten 10mg, 20mg or placebo. In MD cohort, 12 participants were randomized to receive 2 This is a provisional file, not the final typeset article multiple doses of aficamten 5mg or placebo once daily for 14 days. Safety was monitored throughout the study with electrocardiograms, echocardiograms, clinical laboratory tests and adverse events (AE) reporting. Pharmacokinetic profiles of aficamten and metabolites, as well as CYP2D6 genetic impact were evaluated.Results: A total of 35 treatment-emergent AEs were reported by 14 (50%) participants with mild severity. There were no serious AEs or adverse decreases in left ventricular ejection fraction below 50% during the study. Aficamten was dose proportional over the dose range of 5-20mg and accumulated in MD dose cohort.Aficamten was safe and well tolerated in the healthy Chinese adults. The pharmacokinetics of aficamten in Chinese was comparable to those previously found in western participants. These Phase 1 data support progression of aficamten into future clinical studies in Chinese patients.