Mavacamten: a novel small molecule modulator of β-cardiac myosin for treatment of hypertrophic cardiomyopathy

ABSTRACT

Introduction

Hypertrophic cardiomyopathy (HCM) is a common known monogenetic cardiovascular disorder which frequently leads to symptoms such as dyspnea and exercise intolerance. Current guideline-recommended pharmacotherapies have variable therapeutic responses. Mavacamten, a small molecule modulator of β-cardiac myosin, reduces hypercontractility, a central mechanism in the pathogenesis of HCM. Mavacamten has recently been evaluated in Phase 2 and 3 clinic trials for obstructive and nonobstructive symptomatic HCM

Areas covered

This article reviews available preclinical and clinical trials assessing the efficacy and safety of Mavacamten for the treatment of symptomatic obstructive and nonobstructive HCM

Expert opinion

Findings from Phase 2 and 3 trials suggest that Mavacamten represents a very promising new therapy for the treatment of symptomatic patients with HCM. Treatment leads to an improvement in symptomatic and physiologic metrics for symptomatic patients with HCM with minimal adverse events. Patients with obstructive HCM demonstrated a significant improvement in LVOT gradient, NYHA functional class, Kansas City Cardiomyopathy Questionnaire (KCCQ), Overall Summary Score (OSS), and numerical rating scale (NRS) dyspnea scores; and patients with both obstructive and nonobstructive HCM had significant improvement in serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations.

KEYWORDS:

• Mavacamten
• myosin
• hypertrophic cardiomyopathy

Article highlights

• Various sarcomeric mutations in HCM lead to a hypercontractile sarcomere and secondarily, impaired myocardial compliance

• Mavacamten is a small molecule, selective allosteric inhibitor of cardiac myosin ATPase developed to specifically target the underlying pathophysiology of hypertrophic cardiomyopathy by reducing actin–myosin cross-bridge formation, thereby reducing contractility

• Treatment with mavacamten improves exercise capacity, LVOT obstruction, NYHA functional class in patients with obstructive hypertrophic cardiomyopathy.

• In patients with nonobstructive hypertrophic cardiomyopathy, Phase 2 data indicate that there is significant reduction in NT-proBNP and cTnI, suggesting improvement in myocardial wall stress

• Further studies are underway to evaluate the efficacy of mavacamten to reduce the need for septal reduction therapies

This box summarizes key points contained in the article.

Declaration of interest

M Desai and S Nissen are on the executive steering committee for VALOR-HCM, and M Desai is the national principal investigator of VALOR-HCM, investigating Mavacamten in obstructive hypertrophic cardiomyopathy patients (NCT04349072). The Cleveland Clinic has a research agreement with Myokardia, Inc. However, M Desai and S. Nissen have no financial conflicts of interests with Myokardia, Inc. A Tower-Rader is a site investigator of REDWOOD-HCM, investigating CK-274 in obstructive hypertrophic cardiomyopathy patients (NCT04219826). M Desai holds the Haslam Family endowed chair in cardiovascular medicine. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One peer reviewer sits on a steering committee for a Phase 2 study with Cytokinetics evaluating novel myosin inhibitor for obstructive HCM. One peer reviewer provides consulting and collaborative research studies to the Leducq Foundation (CURE-PLAN), Red Saree Inc., Greater Cincinnati Tamil Sangam, AstraZeneca, MyoKardia, Merck, and Amgen. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose

Box 1. Drug summary

Additional information

Funding

This paper was not funded