Mavacamten: treatment aspirations in hypertrophic cardiomyopathy

Abstract

Managing dynamic left ventricular outflow tract (LVOT) obstruction remains one of the most challenging therapeutic aspects of hypertrophic cardiomyopathy. Individuals who are affected frequently present with disabling symptoms, which can be ameliorated following reduction of LVOT obstruction. Pharmacological treatment currently comprises non-disease specific therapies such as β blockers, negatively inotropic calcium channel blockers, and disopyramide, which offer a variable degree of symptomatic relief and are often limited by side-effects. 1 Ammirati E Contri R Coppini R Cecchi F Frigerio M Olivotto I Pharmacological treatment of hypertrophic cardiomyopathy: current practice and novel perspectives. Eur J Heart Fail. 2016; 18: 1106-1118 Crossref PubMed Scopus (57) Google Scholar Enhanced myocardial contractility is a key factor in the pathophysiology of LVOT obstruction. 2 Anderson RL Trivedi DV Sarkar SS et al. Deciphering the super relaxed state of human β-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers. Proc Natl Acad Sci USA. 2018; 115: e8143-e8152 Crossref PubMed Scopus (93) Google Scholar Mavacamten is a first-in-class, selective allosteric inhibitor of cardiac myosin ATPase, which reduces actin-myosin cross-bridge formation, thereby reducing myocardial contractility and improving myocardial energetics. 3 Rohde JA Roopnarine O Thomas DD Muretta JM Mavacamten stabilizes an autoinhibited state of two-headed cardiac myosin. Proc Natl Acad Sci USA. 2018; 115: e7486-e7494 Crossref PubMed Google Scholar Animal studies showed that mavacamten reduced myocardial contraction in a dose-dependent manner and relieved LVOT obstruction. 4 Stern JA Markova S Ueda Y et al. A small molecule inhibitor of sarcomere contractility acutely relieves left ventricular outflow tract obstruction in feline hypertrophic cardiomyopathy. PLoS One. 2016; 11e0168407 Crossref PubMed Scopus (46) Google Scholar These findings were replicated in a phase 2 trial (PIONEER-HCM), in which mavacamten reduced the post-exercise LVOT gradient, increased peak oxygen consumption (pVO2), and improved symptoms in patients with the condition. 5 Heitner SB Jacoby D Lester SJ et al. Mavacamten treatment for obstructive hypertrophic cardiomyopathy: a clinical trial. Ann Intern Med. 2019; 170: 741-748 Crossref PubMed Scopus (67) Google Scholar Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trialTreatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy. The results of this pivotal trial highlight the benefits of disease-specific treatment for this condition. Full-Text PDF