Danicamtiv, a Selective Agonist of Cardiac Myosin, for Dilated Cardiomyopathy

作者：Neal K. Lakdawala, Ray E. Hershberger, Pablo García‐Pavía, Perry Elliott, Jonathan Ginns, Benjamin Meder, Scott Solomon, Jonathan W. Cunningham, Juan R. Gimeno, Roberto Barriales‐Villa, Eric Adler, Brenda Gerull, Naveen L. Pereira, Brian P. Halliday, Wanying Li, Praneeth Jarugula, Sonomi Maruyama, Saffie Mohran, Maria A. Papadaki, Anu Anto, Robert L. Anderson, Héctor M. Rodrı́guez, Carlos del Río, Jay M. Edelberg, Gregory Kurio, Juan Diego Maya, James L. Januzzi · 发表于：Journal of the American College of Cardiology · 年份：2025 · DOI：10.1016/j.jacc.2025.09.1511 · 被引用次数：6 · 研究领域：Cardiomyopathy and Myosin Studies、Cardiovascular Effects of Exercise、Viral Infections and Immunology Research

BACKGROUND: Precision therapies for dilated cardiomyopathy (DCM) are lacking despite diverse manifestations and clinical trajectories based on underlying etiology. DCM-associated pathogenic variants in cardiac beta-myosin heavy chain (MYH7) and titin (TTN) can impair the function/availability of cardiac myosin. Danicamtiv is a novel investigational small molecule that selectively enhances cardiac myosin function. OBJECTIVES: The study sought to translationally evaluate danicamtiv in the setting of myosin dysfunction, from in vitro assessments to a clinical trial exploring its safety and efficacy in DCM due to MYH7 or TTN variants, or other causes (either positive or negative genetic results). METHODS: The danicamtiv effects on DCM-variant cardiac myosin enzyme activity and skinned left ventricular (LV) fiber force generation were assessed in vitro. A phase 2a, baseline-controlled, open-label trial enrolled individuals with DCM into cohorts by variants (MYH7 or TTN) or other causes. In the week of treatment period (TP)1, participants received oral danicamtiv 25 mg twice daily with dose adjustment in TP2 to 10 or 50 mg twice daily. The primary endpoint was safety/tolerability; secondary endpoints included echocardiography-assessed changes in cardiac structure/function. RESULTS: In vitro, danicamtiv increased the activity of wild-type and DCM myosin, increasing force production in cardiac fibers. Forty-one participants were enrolled in the trial (mean age 49.6 ± 13 years; mean b...