The Discovery of Ulacamten, a Cardiac Myosin Inhibitor for the Treatment of Heart Failure with Preserved Ejection Fraction
Luke W. Ashcraft, Chihyuan Chuang, Alfredo Garcia, Mark Vander Wal, Aroop Chandra, Justin Ho, Peadar Cremin, Jeanelle Zamora, Mark P. Grillo, Rajaa Sukhun, Darren T. Hwee, Anand Bat-Erdene, Leo H. Kim, James J. Hartman, Saswata Sankar Sarkar, Roshni V. Madhvani, Xiaolin Wang, Fady I. Malik, Scott Collibee, Bradley P. MorganAbstract
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%.