First-in-class cardiac myosin inhibitor effective in obstructive hypertrophic cardiomyopathy

 

Recent results from the multicentre, phase 3 EXPLORER-­HCM trial highlight the benefits of a disease-specific treatment for patients with obstructive hypertrophic cardiomyopathy. Mavacamten, a first-in-class cardiac myosin inhibitor, improved exercise capacity, left ventricular outflow tract (LVOT) obstruction, NYHA functional class, and health status in this patient population [1,2].

Hypertrophic cardiomyopathy is characterised by primary left ventricular hypertrophy. Core pathophysiological features include hypercontractility, diastolic dysfunction, and dynamic LVOT obstruction. Patients with obstructive hypertrophic cardiomyopathy are often symptomatic and can have atrial fibrillation, heart failure, and malignant ventricular arrhythmias.

Current treatment for obstructive hypertrophic cardiomyopathy is symptomatic and includes β-blockers, non­-dihydropyridine calcium channel blockers, and disopyramide. However, these drugs do not address the underlying molecular mechanisms of hypertrophic cardiomyopathy and do not modify its natural history. In addition, they are often inadequate or poorly tolerated. Invasive septal reduction therapy, such as surgical septal myectomy and alcohol septal ablation, can effectively help patients with drug­refractory symptoms. However, these invasive procedures carry inherent risks and require expertise that is not universally available. So, effective pharmacological treatments for obstructive hypertrophic cardiomyopathy are urgently needed.

To this aim, the randomised, double-blind, placebo-controlled EXPLORER­-HCM trial evaluated the efficacy and safety of mavacamten in patients with hypertrophic cardiomyopathy with an LVOT gradient of ≥50 mmHg and NYHA class II-III symptoms. Participants from 68 centres in 13 countries were randomly assigned to mavacamten (n=123) or placebo (n=128). The primary endpoint was a composite functional endpoint designed to specifically demonstrate benefit both in symptoms and function, namely a ≥1.5 mL/kg/min increase in peak oxygen consumption (pVO₂) and at least 1 NYHA class reduction or a ≥3.0 mL/kg/min pVO₂ increase without NYHA class worsening.

Prof. Iacopo Olivotto (Azienda Ospedaliera Universitaria Careggi, Italy) presented the results, showing that 37% of patients in the mavacamten group versus 17% in the placebo group met the primary endpoint (difference +19.4; 95% CI 8.7-30.1; P=0.0005) after 30 weeks. Safety was similar between groups, and treatment-emergent adverse events were generally mild.

In this first randomised phase 3 trial with positive results in patients with obstructive hypertrophic cardiomyopathy, mavacamten not only improved functional capacity and LVOT gradient but also symptoms and key aspects of health status (secondary endpoints). These results highlight the benefits of disease­specific treatment in hypertrophic cardiomyopathy.

 

1. 
   
   1. Olivotto I. EXPLORER-HCM: Efficacy and safety of mavacamten in adults with symptomatic obstructive hypertrophic cardiomyopathy. Hot Line 1, ESC Congress 2020, 29 Aug.
   
   
   2. Olivotto I, et al. Lancet 2020, August 29. Doi.org/10.1016/S0140-6736(20)31792-X.

 

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Posted on 5 November, 202023 February, 2021