Currently available medical treatments for obstructive HCM focus on symptom relief, fail to address the underlying causes and are associated with modest efficacy or substantial adverse events. While surgical septal myectomy and alcohol septal ablation are efficacious, they carry the risks inherent to invasive procedures and require specific expertise. An effective pharmacological therapy for obstructive HCM is therefore an unmet need for those patients with HCM who suffer debilitating and life-changing symptoms.
Mavacamten is a first-in-class cardiac myosin inhibitor that directly targets the underlying pathophysiology of HCM. In early clinical trials, mavacamten led to significant improvements of symptoms, physical function, exercise capacity, and quality of life, and reduced left ventricular outflow tract (LVOT) obstruction in patients with obstructive HCM.
In the EXPLORER-HCM global phase 3 trial, 251 patients with symptomatic obstructive HCM were randomised to once-daily mavacamten (5 mg initially with a two-step dose titration) or placebo for 30 weeks. The primary endpoint was the treatment effect of mavacamten at week 30 relative to placebo on both symptoms and cardiac function, defined as achieving 1) ≥1.5 mL/kg/min improvement in peak oxygen consumption (peak VO2) and ≥1 New York Heart Association (NYHA) class reduction or 2) ≥3.0 mL/kg/min improvement in peak VO2 and no worsening of NYHA class.
Secondary endpoints included change from baseline to week 30 in post-exercise LVOT gradient and patient-reported outcomes such as the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) and HCM Symptom Questionnaire-Shortness-of-Breath (HCMSQ-SoB) subscore.
At week 30, 45 (36.6%) patients on mavacamten met the primary endpoint vs. 22 (17.2%) patients on placebo (p=0.0005). All secondary endpoints, including post-exercise LVOT gradient and patient-reported outcomes, also demonstrated significant improvements for mavacamten as compared with placebo (all p<0.0006).
Safety and tolerability with mavacamten were similar to placebo. Some 11 serious adverse events were reported in 8.1% of patients on mavacamten vs. 20 events in 8.6% of patients on placebo. Serious cardiac adverse events occurred in 4 patients treated with mavacamten (atrial fibrillation [AF], n=2; stress cardiomyopathy, n=2) and 4 in the placebo group (AF, n=3; AF and congestive heart failure, n=1).
“The results of this pivotal trial support a role for disease-specific therapy for HCM, which treats the cause instead of just managing symptoms,” said Principal Investigator, Professor Iacopo Olivotto (Careggi University Hospital, Florence, Italy). He noted, “The totality and consistency of the results showed benefit of mavacamten treatment compared with placebo in patients on background HCM therapy. Mavacamten improved functional capacity, LVOT gradient, symptoms, and key aspects of quality of life in patients with obstructive HCM and was generally well tolerated.” Results from EXPLORER-HCM provide hope for the first specific treatment for obstructive HCM.