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: 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.