The Lancet August 29, 2020

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

Iacopo Olivotto et al.

Bottom Line

In patients with symptomatic obstructive hypertrophic cardiomyopathy, the first-in-class cardiac myosin inhibitor mavacamten significantly improved exercise capacity, LVOT obstruction, NYHA functional class, and health status compared with placebo.

Key Findings

1. At 30 weeks, the primary composite endpoint (≥1.5 mL/kg/min increase in peak VO2 and ≥1 NYHA class reduction, OR ≥3.0 mL/kg/min increase in peak VO2 without NYHA class worsening) was achieved by 37% (45/123) of patients receiving mavacamten compared to 17% (22/128) receiving placebo (absolute difference 19.4%, 95% CI 8.7-30.1; p=0.0005).

2. 20% of patients on mavacamten achieved both a ≥3.0 mL/kg/min increase in pVO2 and ≥1 NYHA class improvement, compared with 8% on placebo (difference 12.5%, 95% CI 4.0-21.0).

3. Mavacamten administration led to clinically profound and significant reductions in post-exercise left ventricular outflow tract (LVOT) gradients, with nearly 75% of patients in the treatment arm falling below the standard threshold for septal reduction therapy (<50 mmHg).

4. Mavacamten demonstrated significant improvements in secondary endpoints, including Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) and the Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath (HCMSQ-SoB) subscore.

5. The drug was generally well-tolerated with mild-to-moderate adverse effects; however, mavacamten's negative inotropic mechanism requires monitoring, as transient decreases in left ventricular ejection fraction (LVEF) were noted and necessitate dose adjustment.

Study Design

Design

RCT

Double-Blind

Sample

251

Patients

Duration

30 wk

Median

Setting

13 countries

Population Adults with symptomatic (NYHA class II-III) obstructive hypertrophic cardiomyopathy, a peak LVOT gradient ≥50 mmHg (at rest or provoked), and a preserved left ventricular ejection fraction (LVEF) ≥55%.

Intervention Mavacamten starting at 5 mg orally once daily. Doses were periodically titrated (from 2.5 mg up to 15 mg) over 30 weeks to optimize patient response (decreased LVOT gradient) while maintaining LVEF ≥50%.

Comparator Matching oral placebo administered once daily.

Outcome A composite endpoint defined as either a ≥1.5 mL/kg/min increase in peak oxygen consumption (pVO2) and at least a 1-class reduction in NYHA functional class, OR a ≥3.0 mL/kg/min increase in pVO2 without worsening of NYHA class.

Study Limitations

• The 30-week duration was relatively short, necessitating longer-term extension data to fully establish durability, long-term safety, and survival benefits.

• The study excluded patients with a baseline LVEF <55%, meaning the safety and efficacy of mavacamten in obstructive HCM patients with borderline or reduced systolic function remains unknown.

• The rigorous individual dose titration required during the trial—based on serial echocardiograms, LVOT gradients, and LVEF monitoring—implies a high monitoring burden that may be challenging to replicate in routine real-world clinical practice.

• The study enrolled a largely white patient population, limiting the generalizability of the findings across diverse racial and ethnic groups.

Clinical Significance

EXPLORER-HCM represents a paradigm shift in the management of obstructive hypertrophic cardiomyopathy. By demonstrating that targeted inhibition of cardiac myosin can directly mitigate the underlying pathophysiology of hypercontractility, mavacamten provides a highly effective pharmacological alternative to invasive septal reduction therapies (surgical myectomy or alcohol septal ablation) for heavily symptomatic patients.

Historical Context

For nearly 60 years following the initial description of hypertrophic cardiomyopathy, medical therapy has relied on non-specific negative inotropes and chronotropes (such as beta-blockers, verapamil, and disopyramide). These conventional therapies often fail to completely alleviate symptoms and do not directly address the molecular basis of the disease. The development of mavacamten, which specifically limits excess myosin-actin cross-bridge formation, marked the first targeted, disease-modifying pharmacologic treatment for HCM.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the mechanism of action of mavacamten directly target the underlying pathophysiology of obstructive hypertrophic cardiomyopathy at the sarcomere level, and why does this represent a shift from traditional therapies like beta-blockers?

Key Response

Students need to understand that oHCM is driven by sarcomere mutations causing hypercontractility and impaired relaxation. Traditional therapies like beta-blockers just slow heart rate and increase filling time. Mavacamten is a first-in-class cardiac myosin inhibitor that directly reduces actin-myosin cross-bridge formation, specifically targeting the hypercontractile state and improving diastolic compliance.

Resident

Given that mavacamten reduces left ventricular contractility to relieve LVOT obstruction, what is the most critical safety parameter to monitor during initiation and titration, and how should a transient drop in this parameter be managed clinically?

Key Response

The key risk of a myosin inhibitor is systolic heart failure due to over-inhibition. LVEF must be closely monitored via serial echocardiograms. If LVEF drops below 50 percent, the drug must be temporarily interrupted, highlighting the narrow therapeutic index and the need for strict monitoring protocols in clinical practice.

Fellow

The EXPLORER-HCM trial used a composite primary endpoint involving both pVO2 and NYHA class improvements. Why is combining objective cardiopulmonary exercise testing metrics with subjective functional class particularly important in the oHCM population, and how do mavacamten effects on resting versus provoked LVOT gradients influence this endpoint?

Key Response

Fellows should grasp the discordance often seen between symptoms and resting hemodynamics in oHCM. Provocable gradients are key drivers of symptoms. Using both objective pVO2 and subjective NYHA metrics prevents bias and captures true clinical benefit, as mavacamten significantly reduced post-exercise gradients which strongly correlates with improved functional capacity.

Attending

With the approval of mavacamten, how should we re-evaluate the timing and selection criteria for septal reduction therapies such as myectomy or alcohol septal ablation in patients with highly symptomatic, drug-refractory oHCM?

Key Response

Attendings must integrate new drugs into the treatment algorithm. Mavacamten offers a potent medical alternative to invasive septal reduction therapy for patients failing first-line medical therapy. The discussion centers on whether mavacamten should universally precede surgical consideration, weighing the burden of lifelong monitoring and cost against the upfront risks of surgery.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The EXPLORER-HCM trial utilized a sequential testing procedure for its secondary endpoints to control for Type I error. How does this hierarchical statistical design impact the interpretation of exploratory endpoints like the KCCQ clinical summary score, and what are the limitations of this approach?

Key Response

Sequential testing ensures rigorous alpha control where if one test fails, subsequent ones are exploratory. While it strengthens the validity of the highest-ranked secondary endpoints like post-exercise LVOT gradient, it limits formal statistical claims on lower-ranked endpoints if the hierarchy breaks, necessitating careful interpretation of patient-reported outcomes.

Journal Editor

Despite the rigorous double-blind design of EXPLORER-HCM, the profound reduction in LVOT gradients and subsequent symptom relief might effectively unblind patients and investigators. How might this functional unblinding bias the subjective components of the primary endpoint, and how can trialists mitigate this?

Key Response

In oHCM, patients on placebo remain symptomatic while those on active drug experience noticeable relief. This functional unblinding can inflate subjective outcomes like NYHA class. Mitigation requires heavy reliance on objective measures like pVO2 and independent blinded outcome assessors who do not have access to treatment-related hemodynamic data.

Guideline Committee

Based on the EXPLORER-HCM results, how should the AHA/ACC guidelines for the diagnosis and treatment of HCM be updated regarding the stepwise pharmacological management of symptomatic oHCM, specifically regarding the placement of mavacamten relative to disopyramide or septal reduction therapy?

Key Response

Current guidelines recommend beta-blockers or non-DHP CCBs as first-line, and historically disopyramide or septal reduction for refractory symptoms. EXPLORER-HCM provides strong RCT evidence to insert mavacamten as a second-line option. The committee must debate whether it replaces disopyramide and if a trial of mavacamten should be a mandatory Class 2a prerequisite before referring a patient for septal myectomy.

Clinical Landscape

Noteworthy Related Trials

2021

REDWOOD-HCM

n = 41 · JACC

Tested

Aficamten

Population

Symptomatic obstructive hypertrophic cardiomyopathy

Comparator

Placebo

Endpoint

Safety, tolerability, and change in LVOT gradient

Key result: Treatment resulted in safe, significant, and dose-dependent reductions in resting and provoked LVOT gradients.

2022

VALOR-HCM

n = 112 · JACC

Tested

Mavacamten

Population

Symptomatic obstructive HCM patients referred for septal reduction therapy

Comparator

Placebo

Endpoint

Composite of patient decision to proceed with SRT or remaining eligible for SRT at week 16

Key result: Mavacamten significantly reduced the proportion of patients meeting guideline criteria for or choosing to undergo septal reduction therapy.

2024

SEQUOIA-HCM

n = 282 · NEJM

Tested

Aficamten

Population

Symptomatic obstructive hypertrophic cardiomyopathy

Comparator

Placebo

Endpoint

Change in peak oxygen uptake (pVO2) by cardiopulmonary exercise testing

Key result: Aficamten significantly improved exercise capacity, symptoms, and dynamic outflow gradients compared to placebo.

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