American College of Cardiology

American College of Cardiology

March 30, 2020
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Mavacamten shows promise in nonobstructive hypertrophic cardiomyopathy

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Carolyn Y. Ho

In patients with nonobstructive hypertrophic cardiomyopathy, treatment with mavacamten was well tolerated and reduced biomarkers of cardiac injury and wall stress, according to results of the phase 2 MAVERICK-HCM study.

MAVERICK-HCM is “the first study to show an improvement in serum biomarkers of hemodynamic stress and myocardial injury in patients with nonobstructive [hypertrophic cardiomyopathy],” Carolyn Y. Ho, MD, medical director of the cardiovascular genetics center at Brigham and Women’s Hospital and associate professor at Harvard Medical School, said during a virtual presentation at the American College of Cardiology Scientific Session. “There’s also a suggestion that patients with more severe disease may benefit the most from mavacamten.”

Nonobstructive hypertrophic cardiomyopathy benefit

“Mavacamten is best known as a novel drug being developed to treat obstructive hypertrophic cardiomyopathy,” Ho said during the presentation.

Mavacamten (MyoKardia) is a first-in-class, selective allosteric inhibitor of cardiac myosin, which reduces the number of myosin-actin cross bridges and, thus, decreases the excessive contractility that is characteristic of hypertrophic cardiomyopathy (HCM), she said.

“This results in improving obstructive physiology. However, there’s also experimental evidence that mavacamten may have properties that help to improve myocardial relaxation and myocardial energetics — two other hallmarks of hypertrophic cardiomyopathy pathophysiology that may be particularly relevant to patients without obstruction. Therefore, it may be beneficial for those with nonobstructive hypertrophic cardiomyopathy.”

For the MAVERICK-HCM study, researchers analyzed data from 59 patients with symptomatic nonobstructive HCM. After a 28-day screening period, patients were assigned to one of three groups: once-daily mavacamten with a drug concentration target of 200 ng/mL (n = 19; mean age, 58 years; 47%), once-daily mavacamten with a drug concentration target of 500 ng/mL (n = 21; mean age, 50 years; 57%) or once-daily placebo (n = 19; mean age, 54 years; 68% women). Patients assigned mavacamten were also pooled together (n = 40; mean age, 54 years; 53% women). Treatment was administered for 16 weeks, with monitoring for another 8 weeks after treatment.

Mavacamten was generally well tolerated, Ho reported. The key safety endpoint was severity and frequency of treatment-emergent adverse events, serious adverse events, and adverse events of special interest. The researchers observed at least one serious adverse event in 10.3% of patients in the mavacamten group vs. 21.1% of those in the placebo group.

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Ho reported that serious adverse events were predominantly CV in origin, and included recurrent atrial fibrillation and atrial flutter.

Left ventricular ejection fraction was also reduced in the pooled mavacamten group. From baseline to 16 weeks, the mean LVEF reduction was −2.3% among patients assigned to the low mavacamten concentration group, −5.6% among those assigned to the higher concentration mavacamten group, −4.1% in the pooled mavacamten group and −2.3% in those assigned placebo.

The researchers also reported results of several exploratory efficacy outcomes.

Mavacamten reduced NT-proBNP by 53% vs. 1% with placebo (P = .0005). The drug also decreased cardiac troponin I by 34% vs. a 4% increase with placebo (P = .009).

“These results were notable because BNP has been shown to be an independent predictor of morbidity and mortality in hypertrophic cardiomyopathy,” Ho said during the presentation. “These promising results are the first demonstration of medical therapy improving NT-proBNP levels in patients with nonobstructive HCM and suggests physiologic benefit from mavacamten potentially in improving hemodynamic stress.”

“These results were also notable because troponin levels have additionally been correlated with prognosis in myocardial fibrosis in hypertrophic cardiomyopathy,” Ho said.

Nonobstructive focus

Martin S. Maron

During a panel discussion following presentation of the results, Martin S. Maron, MD, director of the Hypertrophic Cardiomyopathy Center, co-director of cardiac CT and MRI and assistant professor at Tufts University School of Medicine, said, “it is great to see clinical trial work of a new drug applied to the nonobstructive cohort of patients with this disease.

“Most of the attention over the last several decades has been really focused on improvement of outcomes in obstructive HCM,” Maron said. “The substantial decrease in biomarkers with mavacamten in nonobstructive HCM patients is encouraging, although tempered at this preliminary stage by evidence for a clinical benefit and uncertain consequences related to significant decreases in ejection fraction in some patients.” by Darlene Dobkowski

Reference:

Ho CY, et al. Featured Clinical Research III. Presented at: American College of Cardiology Scientific Session; March 28-30, 2020 (virtual meeting).

Disclosures: The study was funded by MyoKardia. Ho reports she is a consultant for MyoKardia, is the lead investigator of the SHaRe Registry funded by MyoKardia, and serves on the advisory board for Ambry Genetics and Novartis. Healio could not confirm relevant financial disclosures for Maron at the time of publication. Edelberg is an employee of MyoKardia.