Key result
Ulacamten reduces LV contractility in rats with a ~16-hour half-life in Phase 1 humans.
Why the study?
Cardiac myosin inhibition is an emerging modality for treating heart diseases with supranormal myocardial contractility, motivating the discovery of an oral allosteric inhibitor for HFpEF with a different binding site and biochemical phenotype from mavacamten and aficamten.
Reports the discovery and preclinical/Phase 1 profile of ulacamten, a novel oral allosteric cardiac myosin inhibitor with a distinct binding site from mavacamten and aficamten, now entering Phase II testing for HFpEF.
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Supports Phase II evaluation in HFpEF; leaves open differentiation from other myosin inhibitors via distinct binding site.
Cardiac myosin inhibition is an emerging and innovative modality for the treatment of heart diseases associated with supranormal myocardial contractility. The discovery of ulacamten, an oral allosteric cardiac myosin inhibitor with a different binding site compared to the FDA approved cardiac myosin inhibitors mavacamten and aficamten, is reported here. Ulacamten resulted from the optimization of a diketopiperazine screening hit with a differentiated biochemical phenotype from mavacamten and aficamten. Ulacamten reduces left ventricular fractional shortening in healthy Sprague–Dawley rats and obese ZSF1 rats, and the human half-life from a Phase 1 study was determined to be 14–17 h with steady state being reached in 1 week. Ulacamten is currently being studied in a Phase II clinical trial (AMBER-HFpEF, NCT06793371) in symptomatic HFpEF patients with ejection fractions ≥60%.
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Ashcraft et al. (2026) studied Heart Failure with Preserved Ejection Fraction (HFpEF). Ulacamten was evaluated on Left ventricular fractional shortening (rats) and human pharmacokinetic half-life (Phase 1). Ulacamten reduced left ventricular fractional shortening in rats and demonstrated a human half-life of 14-17 hours in a Phase 1 study, reaching steady state in 1 week.
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