PII-132 - PHARMACOKINETICS AND SAFETY OF MAVACAMTEN IN HEALTHY CHINESE SUBJECTS WITH DIFFERENT CYP2C19 PHENOTYPES

X. Wu¹, N. Chen¹, P. Hsu², J. Sun³, W. Li⁴, Q. Wang³, Q. Wei¹, J. Yu¹, G. Gao¹, H. Yang¹, L. Wang¹, J. Wang¹, Y. Jin¹, W. Liu¹, J. Wu¹, J. He¹, C. Lyu², J. Zhang¹; ¹Phase 1 Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, China, ²Shanghai LianBio Development Co., Ltd,, ³Shanghai LianBio Development Co., Ltd, Shanghai, China, ⁴dMed Biopharmaceutical Co., Ltd. Shanghai, China.

Background: Obstructive hypertrophic cardiomyopathy (oHCM) is a subtype of HCM characterized with left ventricular outflow tract obstruction resulting from the hypertrophy of cardiac muscle and anatomic alterations in the mitral valve and apparatus. Mavacamten, a cardiac myosin inhibitor, it is metabolized primarily by CYP2C19 in the liver, is the first and only targeted medication recently approved for the treatment of symptomatic oHCM NYHA class II-III. Previous pharmacokinetic (PK) results of mavacamten in healthy Caucasian, Japanese and Asian subjects demonstrated that mavacamten exposure was affected by CYP2C19 metabolism status. This study was aimed to determine the PK and safety of mavacamten in healthy adult Chinese subjects.

Methods: This is an open-label, parallel-group, phase 1 trial aimed to determine the pharmacokinetics and safety of mavacamten in healthy Chinese subjects with different CYP2C19 genotypes. The primary outcome was to define the pharmacokinetics of mavacamten in healthy Chinese subjects, the secondary outcome was to examine safety and tolerability.

Results: After a single oral dose of 15 or 25 mg mavacamten in fasted healthy adult Chinese individuals, Cmax was reached within a median Tmax of 0.6-1.5 hours, indicating rapid absorption. Interindividual variability was moderate, and individuals carrying non-functional CYP2C19 alleles (*2/*2, *3/*3, or *2/*3) exhibited longer half-life and increased total exposure. After stratification of CYP2C19 genotypes, total mavacamten exposures were similar among different ethnic groups when compared to prior PK studies, with geometric mean ratios of Cmax ranged from 0.9 to 1.7, and both AUC0-last and AUC0-inf ranged from 1.1 to 1.2. PK parameters after single dose of mavacamten are presented in Table 1. There were no significant adverse events observed in this study. Single oral administration of mavacamten up to 25 mg was well-tolerated across all dose groups.

Conclusion: The PK profile of mavacamten in the healthy Chinese population was consistent with that of other healthy populations reported from prior studies.