Mavacamten’s Effects Against Obstructive Hypertrophic Cardiomyopathy Persist Through 32 Weeks in VALOR-HCM

Mavacamten’s effects in reducing the need for septal reduction therapy (SRT) in patients with highly symptomatic obstructive hypertrophic cardiomyopathy (HCM) persist through 32 weeks of treatment, according to the latest data from the multicenter VALOR-HCM trial.

Trial participants initially randomized to mavacamten showed sustained reduction in the percentage proceeding to SRT or remaining guideline-eligible for SRT, and those initially randomized to placebo for the study’s first 16 weeks showed significant reductions in eligibility for SRT after being crossed over to mavacamten for weeks 16 to 32.

The 32-week results of the double-blind, randomized, placebo-controlled crossover trial were presented Nov. 6 in a featured science session at the at the American Heart Association Scientific Sessions by VALOR-HCM principal investigator Milind Desai, MD, MBA, Director of the Hypertrophic Cardiomyopathy Center at Cleveland Clinic. The study was simultaneously published online in Circulation.

“These latest results show that patients were able to safely remain on mavacamten for an extended period and collectively showed continued improvement, with even fewer meeting guideline criteria for septal reduction therapy at 32 weeks compared with 16 weeks,” says Dr. Desai. “These data provide further support for mavacamten’s potential to address an unmet need for noninvasive treatment of severe symptomatic obstructive HCM. We also observed important favorable changes in terms of cardiac remodeling that could have long-term implications in management of these patients.”

Mavacamten essentials

Mavacamten (Camzyos®) was approved by the FDA in April 2022 for treatment of adults with symptomatic obstructive HCM based on 16-week results of the VALOR-HCM trial, which Dr. Desai presented at the American College of Cardiology Scientific Session earlier this year.

No medication had previously been approved for this indication. While beta-blockers, calcium channel blockers and/or disopyramide may improve symptoms in patients with moderate left ventricular outflow tract (LVOT) obstruction, these drugs are typically inadequate when patients progress to severe symptomatic obstructive HCM. In such cases, SRT — surgical myectomy or alcohol septal ablation — is recommended and has been shown to improve long-term survival and quality of life.

Mavacamten is a targeted inhibitor of cardiac myosin designed to reduce the excessive contractility characteristic of obstructive HCM. It had previously been shown to improve LVOT gradient, quality of life and physical function in patients with obstructive HCM. “We undertook VALOR-HCM to determine mavacamten’s potential to serve as an alternative to septal reduction therapy in patients with severely symptomatic and refractory obstructive HCM,” Dr. Desai explains.

Study design and crossover details

The study involved 112 enrollees at 19 U.S. sites, including Cleveland Clinic. All had documented HCM with maximum septal wall thickness of ≥ 15 mm (≥ 13 mm in those with a family history of HCM). Other key inclusion criteria were:

• Severe symptoms (New York Heart Association [NYHA] class III/IV or class II with exertional syncope/near syncope) despite maximally tolerated medical therapy (disopyramide, beta blocker or calcium channel blocker alone or in various combinations)
• Dynamic LVOT gradient ≥ 50 mmHg at rest or with provocation
• Documented left ventricular ejection fraction (LVEF) ≥ 60%
• Referral for SRT within the prior 12 months and active consideration of scheduling SRT

Patients could choose to proceed to SRT at any time.

Enrollees initially were randomized 1:1 to mavacamten 5 mg or placebo once daily by mouth. Randomization was stratified by type of SRT recommended (surgical myectomy or alcohol ablation) and by NYHA class. After assessment at the initial prespecified 16-week endpoint, the original mavacamten group continued the drug for 32 weeks and the placebo group was crossed over to dose-blinded mavacamten for weeks 16 to 32.

Mavacamten dosage was titrated throughout the study based on echocardiographic assessment of LVOT and LVEF every four weeks. The 5-mg daily dose could be reduced to 2.5 mg or increased up to 10 mg or eventually to 15 mg. Echo assessments were done by the study’s core lab at Cleveland Clinic.

The primary endpoint was a composite of the patient’s decision to proceed with SRT by week 32 or continued eligibility for SRT (according to 2011 ACC/AHA guidelines) at week 32. Patients and study staff were blinded to patients’ original assignment, mavacamten dose and echo data until week 32.

The study was coordinated by the Cleveland Clinic Coordinating Center for Clinical Research (C5Research) and Medpace (Cincinnati, Ohio).

Results bolster 16-week data

As reported previously (and detailed at J Am Coll Cardiol. 2022;80:95-108), results at 16 weeks showed a significant reduction in the proportion of patients meeting SRT guideline criteria in the mavacamten group versus the placebo group.

Of the study’s 112 enrollees, 108 qualified for assessment at 32 weeks: 56 initially randomized to mavacamten and 52 initially randomized to placebo. The four patients excluded from the original placebo group included two who underwent SRT in the first 16 weeks and two who discontinued the study.

On the primary endpoint, results at week 32 were as follows:

• In the original mavacamten group, 50 of 56 patients (89.3%) no longer met guideline criteria for SRT and elected not to undergo SRT, a further improvement from the 82.1% rate at 16 weeks. Of the other six patients, three (5.4%) elected to undergo SRT.
• In the placebo crossover group, 45 of 52 patients (86.5%) no longer met guideline criteria for SRT and elected not to undergo SRT, compared with a 23.2% rate in this group at 16 weeks. Of the other seven patients, two (3.8%) elected to undergo SRT.

The original mavacamten group showed a sustained reduction from baseline to week 32 in mean resting LVOT gradient (–33.0 mmHg) and mean provoked LVOT gradient (–43.0 mmHg), and similar mean reductions in LVOT gradients (–33.7 mmHg and –52.9 mmHg, respectively) were seen in the placebo crossover group after 16 weeks of mavacamten therapy.

“The reduction in the crossover group replicated the effects seen after 16 weeks of mavacamten therapy in the double-blind phase of the study,” Dr. Desai notes.

An improvement of at least 1 NYHA class was achieved by 90.6% of patients in the mavacamten group at 32 weeks and by 70% of patients in the placebo crossover group after 16 weeks of active therapy; additionally, mean Kansas City Cardiomyopathy Questionnaire score improved by 13.1 points in the original mavacamten group and by 8.0 points in the placebo crossover group.

These improvements were accompanied by favorable changes in cardiac remodeling as suggested by significant improvements in left ventricular mass index, left atrial volume index and markers of diastolic function in both groups.

There were no serious safety events, and no patients in the original mavacamten group met criteria for permanent discontinuation. Nine patients in the overall cohort temporarily discontinued therapy due to reduction of LVEF during mavacamten treatment; all remained asymptomatic, resumed treatment at a lower dose and continued in the study. “The study’s strategy of monthly echo monitoring to guide dosing and avoid excessive LVEF reduction due to mavacamten’s mechanism of action appears to be effective,” says Dr. Desai.

Further follow-up ahead

The investigators reported that 95% of patients had chosen not to undergo SRT and now remain in the study’s long-term extension phase. “This implies strong patient preference for a medical therapy option that may allow avoidance of an invasive procedure,” Dr. Desai observes.

“There is an encouraging similarity between the findings at 32 weeks in the crossover group and the 16-week findings in the mavacamten group from the initial analysis,” adds co-author Steven Nissen, MD, Chief Academic Officer of Cleveland Clinic’s Heart, Vascular & Thoracic Institute and chair of the VALOR-HCM executive steering committee. “These results show that patients are able to stay on mavacamten and improve sufficiently that they don’t need surgery or alcohol septal ablation. We will continue to follow them and assess whether that effect safely persists out to a year and beyond.”

The investigators note that the study carries significant potential implications for practice, in view of the limited number of high-volume centers for SRT and the association between SRT volumes and optimal outcomes.

“An effective noninvasive alternative to septal reduction therapy would provide a much-needed option for highly symptomatic patients and would expand our toolbox of offerings to these patients,” says VALOR-HCM co-author Nicholas Smedira, MD, MBA, Surgical Director of Cleveland Clinic’s Hypertrophic Cardiomyopathy Center. “Now that we have this evidence of improvement in symptoms with mavacamten, we are eager to learn whether long-term use of this agent reduces life-threatening arrhythmias and sudden death.”

Disclosure: The study was funded by MyoKardia, Inc., which markets mavacamten. Dr. Desai reports that he serves as a consultant for Myokardia.