Mavacamten for Treatment of Symptomatic Obstructive HCM (the EXPLORER-HCM Trial)

Hypertrophic cardiomyopathy (HCM), the most common inherited cardiomyopathy, is present in ~1 in 500 people in the general population1 and can be broadly divided into obstructive and nonobstructive forms depending on the presence of left ventricular outflow tract (LVOT) obstruction.2 A third of patients with HCM have obstruction (LVOT gradient ≥30 mmHg) at rest, and another third have physiologically provoked gradients. Marked gradients ≥50 mmHg at rest or with provocation, in the presence of symptoms that cannot be controlled by medications, represent the conventional threshold for surgical or percutaneous intervention.2 Although surgical and percutaneous therapies are effective in reducing LVOT gradient and symptoms, the outcomes of these procedures are highly dependent on operator experience.3 There is a clear, unmet need for an efficacious medical/pharmacologic therapy for patients with obstructive HCM and debilitating symptoms. Surgical management of HCM is not a widely performed operation and is currently performed at designated high-volume centers.

The American College of Cardiology guidelines recommend that septal myectomy be performed by an experienced operator, which is defined as an individual with a cumulative case volume of at least 20 procedures or an individual who is working in a dedicated HCM program with a cumulative total of at least 50 procedures.2 These guidelines help improve the quality of care provided to patients, but they also limit availability of the procedure to many patients who do not have access to large tertiary care academic centers. Additionally, both surgical myectomy and percutaneous alcohol septal ablation are invasive procedures that require necessary expertise and have known complications. This is the gap that the investigators of the EXPLORER-HCM (Mavacamten for Treatment of Symptomatic Obstructive Hypertrophic Cardiomyopathy) trial aimed to address.4 EXPLORER-HCM was a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial that evaluated the safety and efficacy of mavacamten—a first-in-class, small molecule allosteric inhibitor of cardiac myosin ATPase—in patients with symptomatic HCM with LVOT obstruction (peak LVOT gradient ≥50 mmHg). Other inclusion criteria were age ≥18 years, left ventricular ejection fraction (LVEF) ≥55%, New York Heart Association (NYHA) Class II-III symptoms, and the ability to safely perform cardiopulmonary exercise testing.4 Key exclusion criteria included a history of syncope or sustained ventricular tachycardia with exercise within 6 m before screening, QT interval >500 ms, paroxysmal or intermittent atrial fibrillation (AF) on the screening electrocardiograph, and persistent/permanent AF not on adequate rate control or anticoagulation.

Mavacamten has been previously evaluated in the double-blind, phase 2, randomized MAVERICK-HCM (Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy) trial for patients with symptomatic nonobstructive HCM. This study revealed that mavacamten was well tolerated in most patients and resulted in reduction of N-terminal pro-B-type natriuretic peptide and cardiac troponin I, suggesting an improvement in myocardial wall stress.5 Another study evaluating this drug, PIONEER-HCM (A Phase 2 Open-label Pilot Study Evaluating MYK-461 in Subjects With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction), was an open-label non-randomized trial that investigated the effect of mavacamten on LVOT gradient in symptomatic patients with obstructive HCM and found that it resulted in a significant reduction in gradient among patients in the high-dose (10 or 15 mg/d) cohort. Taking this to the next step, the EXPLORER-HCM trial randomized 251 patients with symptomatic obstructive HCM to mavacamten or placebo. The starting dose was 5 mg with a 2-step dose titration to achieve target reduction in LVOT gradient <30 mmHg and a plasma concentration between 350 and 700 ng/mL. The primary outcome of this study was a composite endpoint to assess clinical response at week 30 compared with baseline. It was defined as either

  • a ≥1.5 mL/kg per min increase in peak oxygen consumption (pVO2) and at least 1 NYHA class reduction or
  • a ≥3.0 mL/kg per min improvement in pVO2 and no worsening of NYHA class.

At the end of treatment, 37% of patients on mavacamten (vs. 17% on placebo) met the primary outcome (+19.4%; 95% confidence interval, 8.7-30.1; p = 0.0005). Additionally, 20% of patients on mavacamten had both a ≥3.0 mL/kg per min increase in pVO2 and ≥1 improvement in NYHA class (vs. 8% on placebo). Mavacamten treatment was associated with a significant improvement in LVOT gradient, increased pVO2, and improved symptoms; 50% of patients receiving mavacamten were NYHA Class I at completion (vs. 21% of placebo). One of the most fascinating observations was that 27% of patients receiving the study drug had a complete response (as defined by reduction in all LVOT gradients to <30 mmHg and reaching NYHA Class I). Only 1% of placebo achieved complete response.

These promising endpoint results were reposted in the setting of a very favorable side-effect profile. Mean reduction in LVEF was -3.9% (vs. -0.01% with placebo). The study achieved a 97% completion rate with only 2 discontinuations secondary to adverse events in the mavacamten arm (AF and syncope). Additionally, 2 patients were found to have stress cardiomyopathy in the mavacamten arm. Overall, 7 patients on mavacamten (and 2 on placebo) had a drop in LVEF, and of these, 3 (and 2 in the placebo arm) required protocol-driven temporary discontinuation of the drug. Importantly, there were no incident heart failure events associated with mavacamten.

This trial is the first phase 3 study to evaluate the role of mavacamten in treating symptomatic obstructive HCM. The drug showed significant improvements across all primary and secondary outcomes with a very favorable side-effect profile compared with placebo. These improvements were seen in the presence of comprehensive background medical therapy with beta-blockers or calcium channel blockers in patients with prior failed septal ablation. Some limitations of this study are relative lack of diversity, with a predominantly older, white (~90%) cohort, as well as exclusion of patients on disopyramide and those with NYHA Class IV symptoms. Longer-term follow-up data on mavacamten relating to safety and efficacy will follow. MAVA-LTE (A Long-Term Safety Extension Study of Mavacamten in Adults Who Have Completed MAVERICK-HCM or EXPLORER-HCM; NCT03723655), a long-term extension study that will include all patients who completed the MAVERICK-HCM and EXPLORER-HCM trials, is in progress, as is VALOR-HCM (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive HCM Who Are Eligible for Septal Reduction Therapy; NCT04349072), which is exploring the use of this drug as an alternative to septal reduction therapy.

The future will tell if this drug reduces the referrals for surgical and percutaneous management of obstructive HCM. Mavacamten may improve access to HCM treatment for many patients and provide many others with a noninvasive alternative to surgery; this promises to be a huge milestone in the management of this form of inherited cardiomyopathy.


  1. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation 1995;92:785-9.
  2. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2011;58:e212-60.
  3. Kim LK, Swaminathan RV, Looser P, et al. Hospital Volume Outcomes After Septal Myectomy and Alcohol Septal Ablation for Treatment of Obstructive Hypertrophic Cardiomyopathy: US Nationwide Inpatient Database, 2003-2011. JAMA Cardiol 2016;1:324-32.
  4. Olivotto I, Oreziak A, Barriales-Villa R, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2020;396:759-69.
  5. Ho CY, Mealiffe ME, Bach RG, et al. Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy. J Am Coll Cardiol 2020;75:2649-60.

Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Atrial Fibrillation/Supraventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Cardiac Surgical Procedures, Disopyramide, Atrial Fibrillation, Calcium Channel Blockers, Troponin I, Takotsubo Cardiomyopathy, Stroke Volume, Natriuretic Peptide, Brain, Double-Blind Method, Follow-Up Studies, Pilot Projects

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