A First-in-Human Study of Ulacamten, a Novel Cardiac Myosin Inhibitor for HFpEF

Background and Objectives: Ulacamten (CK‐4021586) is a small molecule allosteric inhibitor of cardiac myosin in development for treating heart failure with preserved ejection fraction. This first‐in‐human study evaluated safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and food effect (FE) of ulacamten in healthy adult participants. Methods: This was a phase I, double‐blind, randomized, placebo‐controlled, single and multiple ascending dose escalation (SAD, MAD) and FE study. Seven SAD cohorts (n = 10; eight active, two placebo) received oral doses of 10−600 mg, two MAD cohorts received 100 and 200 mg once daily for 7 days, and one FE cohort received a single 150‐mg dose. Participants were required to have left ventricular ejection fraction (LVEF) ≥ 60% or ≥ 65% at screening. Intensive PK plasma sampling was conducted (Days 1, 7 [MAD only] for 168 h post dose). Safety was monitored throughout the study. Multiple echocardiographic measurements were collected (for 24 h post dose) for PD assessment. Results: Ulacamten was steadily absorbed, with median plasma half‐life of 14−18 h, median tmax of 1.5−5 h, and generally dose‐proportional exposure. Following multiple‐dose administration, PK was linear with time, steady state was achieved by Day 4, and mean accumulation of exposure at steady state was 37−69%, consistent with the half‐life. Ulacamten plasma concentrations demonstrated a modest and predictable PK/PD relationship with change from baseline in systolic function measures. All adverse events were mild or moderate in severity. Stopping criteria were not met in this study. Conclusions: Ulacamten demonstrated dose‐proportional exposure, a predictable PK/PD relationship with respect to LVEF, and good tolerability, supporting its further clinical development. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT05877053, registered May 23, 2023