Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial

Summary

Background

Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy.

Methods

In this phase 3, randomised, double-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II–III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks. Visits for assessment of patient status occurred every 2–4 weeks. Serial evaluations included echocardiogram, electrocardiogram, and blood collection for laboratory tests and mavacamten plasma concentration. The primary endpoint was a 1·5 mL/kg per min or greater increase in peak oxygen consumption (pVO₂) and at least one NYHA class reduction or a 3·0 mL/kg per min or greater pVO₂ increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO₂, NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). This study is registered with ClinicalTrials.gov, NCT03470545.

Findings

Between May 30, 2018, and July 12, 2019, 429 adults were assessed for eligibility, of whom 251 (59%) were enrolled and randomly assigned to mavacamten (n=123 [49%]) or placebo (n=128 [51%]). 45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met the primary endpoint (difference +19·4%, 95% CI 8·7 to 30·1; p=0·0005). Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient (−36 mm Hg, 95% CI −43·2 to −28·1; p<0·0001), greater increase in pVO₂ (+1·4 mL/kg per min, 0·6 to 2·1; p=0·0006), and improved symptom scores (KCCQ-CSS +9·1, 5·5 to 12·7; HCMSQ-SoB −1·8, −2·4 to −1·2; p<0·0001). 34% more patients in the mavacamten group improved by at least one NYHA class (80 of 123 patients in the mavacamten group vs 40 of 128 patients in the placebo group; 95% CI 22·2 to 45·4; p<0·0001). Safety and tolerability were similar to placebo. Treatment-emergent adverse events were generally mild. One patient died by sudden death in the placebo group.

Interpretation

Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy. The results of this pivotal trial highlight the benefits of disease-specific treatment for this condition.

Funding

MyoKardia.

Introduction

Hypertrophic cardiomyopathy is a myocardial disorder characterised by primary left ventricular hypertrophy.1, 2 This complex disease can be broadly defined by pathologically enhanced cardiac actin–myosin interactions, with core pathophysiological features that include hypercontractility, diastolic abnormalities, and dynamic left ventricular outflow tract (LVOT) obstruction.2, 3, 4 Patients with obstructive hypertrophic cardiomyopathy are often symptomatic and can have atrial fibrillation, heart failure, and malignant ventricular arrhythmias.2, 5 Current treatment for obstructive hypertrophic cardiomyopathy focuses on symptomatic relief with β blockers, non-dihydropyridine calcium channel blockers, and disopyramide.6, 7, 8, 9 However, these non-specific agents are often inadequate or poorly tolerated,¹⁰ do not address the underlying molecular mechanisms of hypertrophic cardiomyopathy, and do not modify its natural history. Invasive septal reduction therapy, including surgical septal myectomy and alcohol septal ablation, can effectively help patients with drug-refractory symptoms,6, 7 but carries risks inherent to invasive procedures and requires expertise that is not universally available.11, 12, 13 Thus, developing effective pharmacological therapy for obstructive hypertrophic cardiomyopathy is an important unmet need.

Research in context

Evidence before this study

The gaps in therapeutic options for hypertrophic cardiomyopathy are well recognised, and no pharmacological agent is indicated for treatment of the condition (only propranolol carries a US Food and Drug Administration indication for improving New York Heart Association functional class in symptomatic hypertrophic subaortic stenosis based on an uncontrolled series of 13 patients). In the absence of randomised trials, guideline-recommended pharmacological therapy is administered on an empirical basis and includes β blockers or non-dihydropyridine calcium channel blockers, as well as disopyramide for individuals refractory to first-line therapy. Although beneficial for some patients, use of these drugs is limited by side-effects, and often does not provide optimal control of left ventricular outflow tract (LVOT) gradients and symptoms, leaving an unmet burden of disease in many patients. We searched PubMed for research articles published between database inception and Aug 14, 2020, using the terms “hypertrophic cardiomyopathy”, “hypertrophic subaortic stenosis”, and “phase 3”, with no language restrictions applied. We did not identify any published phase 3 clinical trial for pharmacological agents. Several agents, such as perhexiline, trimetazidine, ranolazine, eleclazine, spironolactone, valsartan, and losartan, have shown no or limited efficacy in other prospective trials. In the published phase 2 PIONEER-HCM trial in patients with obstructive hypertrophic cardiomyopathy, treatment with mavacamten led to improvements in post-exercise LVOT gradients, exercise capacity, and symptoms, and was generally well tolerated, with most adverse effects being mild or moderate, self-limiting, and unrelated to the study drug.

Added value of this study

This pivotal phase 3 EXPLORER-HCM trial is the largest placebo-controlled randomised clinical trial to date in hypertrophic cardiomyopathy, to our knowledge. Most patients in the active treatment and placebo groups continued to receive currently available background hypertrophic cardiomyopathy therapy except disopyramide (ie, monotherapy with β blockers or non-dihydropyridine calcium channel blockers). The primary composite functional endpoint and sequential secondary endpoints were designed and discussed with hypertrophic cardiomyopathy experts, patients, and regulatory authorities to comprehensively assess treatment benefits for obstructive hypertrophic cardiomyopathy. The endpoints comprised measures of symptoms and functional capacity as well as LVOT obstruction and health status. After 30 weeks of treatment with mavacamten, there was a significant benefit across the composite primary endpoint, its components, and all secondary endpoints, as well as relevant improvements in patient-reported measures and reductions in biomarkers of cardiac wall stress and injury. Treatment with mavacamten was generally well tolerated and the safety profile was similar to placebo. Seven patients on mavacamten (three patients during the 30-week treatment and four patients at the end of treatment) and two on placebo had a transient decrease in left ventricular ejection fraction to less than 50%.

Implications of all the available evidence

Results from this phase 3 trial show significant efficacy of the first targeted pharmacological therapy designed specifically to address the primary underlying pathophysiological basis of obstructive hypertrophic cardiomyopathy. Treatment with mavacamten led to clinically meaningful improvements in haemodynamic status, functional capacity, and subjective wellbeing. An ongoing, long-term extension of the study will provide further evidence for clinical benefit and safety of mavacamten over 5 years.

Mavacamten is a first-in-class, small molecule, selective allosteric inhibitor of cardiac myosin ATPase specifically developed to target the underlying pathophysiology of hypertrophic cardiomyopathy by reducing actin–myosin cross-bridge formation,14, 15 thereby reducing contractility and improving myocardial energetics.¹⁶ In preclinical and early clinical studies, treatment with mavacamten successfully relieved LVOT gradients and improved parameters of left ventricular filling.15, 17, 18, 19, 20 In the phase 2, open-label PIONEER-HCM study (NCT02842242), mavacamten was well tolerated and significantly reduced post-exercise LVOT gradients in obstructive hypertrophic cardiomyopathy.¹⁹ Treatment was also associated with improvements in exercise capacity and New York Heart Association (NYHA) functional class. On the basis of these results, the pivotal EXPLORER-HCM trial aimed to assess the efficacy and safety of mavacamten for targeted medical treatment of obstructive hypertrophic cardiomyopathy.