Hypertrophic cardiomyopathy: an up-to-date snapshot of the clinical drug development pipeline

ABSTRACT

Introduction

Hypertrophic cardiomyopathy (HCM) is a complex cardiac disease with highly variable phenotypic expression and clinical course most often caused by sarcomeric gene mutations resulting in left ventricular hypertrophy, fibrosis, hypercontractility, and diastolic dysfunction. For almost 60 years, HCM has remained an orphan disease and still lacks a disease-specific treatment.

Areas covered

This review summarizes recent preclinical and clinical trials with repurposed drugs and new emerging pharmacological and gene-based therapies for the treatment of HCM.

Expert opinion

The off-label drugs routinely used alleviate symptoms but do not target the core pathophysiology of HCM or prevent or revert the phenotype. Recent advances in the genetics and pathophysiology of HCM led to the development of cardiac myosin adenosine triphosphatase inhibitors specifically directed to counteract the hypercontractility associated with HCM-causing mutations. Mavacamten, the first drug specifically developed for HCM successfully tested in a phase 3 trial, represents the major advance for the treatment of HCM. This opens new horizons for the development of novel drugs targeting HCM molecular substrates which hopefully modify the natural history of the disease. The role of current drugs in development and genetic-based approaches for the treatment of HCM are also discussed.

KEYWORDS:

• Hypertrophic cardiomyopathy
• drug trials
• mavacamten
• myosin inhibitors
• new drugs
• gene-based therapy

Declaration of interest

The authors have no 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

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by Grants from the Institute of Health Carlos III (CB16/11/00303), Ministerio de Ciencia e Innovación (PID2021-118694RB-I00) and Comunidad de Madrid (B2017/BMD-3738).