CT-002 - EFFECT OF MODERATE HEPATIC IMPAIRMENT ON THE PHARMACOKINETICS OF AFICAMTEN AND ITS METABOLITES.

D. Xu¹, P. Divanji², E. Kim², J. Li², Y. Benattia², A. Griffith², S. Kupfer², P. German²; ¹Cytokinetics, Incorporated, South San Francisco, CA, ²Cytokinetics, Incorporated.

Background: Aficamten is a next-in-class small molecule, selective cardiac myosin inhibitor in phase 3 development for potential treatment of hypertrophic cardiomyopathy. In a human mass balance study, aficamten was predominantly cleared by metabolism with minimal parent drug recovery from urine. Aficamten metabolites account for approximately 80% of the recovered aficamten dose. CK-3834282 and CK-3834283 (pharmacologically inactive) are the main circulating metabolites in plasma. Because aficamten was anticipated to undergo hepatic metabolism and biliary excretion, this study evaluated the impact of moderate hepatic impairment (HI) on the pharmacokinetics (PK) of aficamten and its metabolites to inform dosing recommendations in patients with mild and moderate HI.

Methods: This was a single-dose, open-label, parallel-group study in participants with moderate HI (Child-Pugh class B, total score of 7 to 9 points; n=8) and participants with normal hepatic function (n=8). Participants in the HI and normal hepatic function groups were matched for age (±10 years), sex, race, and body mass index (±20%). Participants received aficamten 20 mg as a single oral dose under fasting conditions. Safety was monitored throughout the study.

Results: Sixteen participants received treatment and completed the study. Aficamten PK parameters in participants with moderate HI and normal hepatic function were generally comparable; the maximum aficamten concentration (Cmax) was numerically higher (38%) in participants with moderate HI with 90% confidence intervals overlapping 100%. There was no statistically significant difference in terminal elimination half-life and oral clearance of aficamten in participants with moderate HI and normal hepatic function. Similar metabolite:parent ratios were observed between participants with moderate HI and normal hepatic function (Table). Exploratory analyses indicated no relevant relationship between aficamten exposure and Child-Pugh score or its individual components. No serious or severe treatment-emergent adverse events or clinically significant laboratory abnormalities were reported.

Conclusion: The PK of aficamten and its metabolites was not meaningfully affected by moderate HI. Study treatments were well tolerated.
No dose adjustment of aficamten in moderate or mild HI is warranted based on these data.