New Era: Mavacamten for Obstructive Hypertrophic Cardiomyopathy

Abstract

Obstructive hypertrophic cardiomyopathy results from asymmetric septal hypertrophy which eventually obstructs the outflow of the left ventricle. Obstructive hypertrophic cardiomyopathy is linked to mutations in genes that encode for sarcomere proteins including actin, &#946:myosin heavy chain, titin, and troponin. The mutations lead to structural abnormalities in myocytes and myofibrils causing conduction irregularities and abnormal force generation. Obstructive hypertrophic cardiomyopathy is a chronic disease that worsens over time and patients become at higher risk to develop atrial fibrillation, heart failure, and stroke. Up until recently, there were no disease-specific medications for obstructive hypertrophic cardiomyopathy. Nevertheless, the US Food and Drug Administration approved mavacamten on April 28, 2022, for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (New York Heart Association class II to III) in adults to improve functional capacity and symptoms. Its approval was based on data from EXPLORER-HCM and EXPLORER-LTE (NCT03723655). Mavacamten is a novel, first-in-class, orally active, allosteric inhibitor of cardiac myosin ATPase, which decreases the formation of actin-myosin cross-bridges, and thus, it reduces myocardial contractility, and it improves myocardial energetics. It represents a paradigm-shifting pharmacological treatment of obstructive hypertrophic cardiomyopathy. In this review, we describe its chemical and mechanistic aspects as well as its pharmacokinetics, adverse effects and warnings, potential drug-drug interactions, and contraindications.

Cardiac myosin inhibitor, CK-586, minimally reduces systolic function and ameliorates obstruction in feline hypertrophic cardiomyopathy

“…However, the availability of such pharmaceuticals is limited in both human and veterinary patients. In addition to the use of surgical or interventional procedures (e.g., surgery and alcohol septal ablation), where incomplete response and risk of in-hospital morbidity and mortality is relatively high 21 – 23 , mavacamten is currently the only FDA-approved cardiac sarcomere inhibitor treatment option for symptomatic oHCM. The drug’s mechanism of action is to bind to the cardiac sarcomere myosin heads and reduce sarcomeric ATPase activity, consequently decreasing the myocardial hypercontractility that leads to outflow tract pressure gradients and LVOTO 24 .…”