New Targeted Inhibitor Offers Promise for Patients with Symptomatic Obstructive HCM


Current therapies focus on relief of symptoms, but there is still an unmet need to address and target the molecular defects of hypertrophic cardiomyopathy.

Iacopo Olivotto, MD

Iacopo Olivotto, MD

Mavacamten, a first of its kind drug that targets cardiac myosin, has shown to be efficacious and safe in adult patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM).

These findings were presented at the European Society of Cardiology (ESC 2020) Congress.

Although there are ways to medically manage obstructive HCM, there still remains a great need to develop effective pharmacological therapies in this domain.

A team led by Iacopo Olivotto, MD, of the University of Florence, Italy, conducted the EXPLORER-HCM study, a phase 3, multicenter, randomized, double-blind, placebo-controlled trial that enrolled patients with obstructive HCM.

The investigators examined a total of 251 patients, thus making the study the largest randomized, controlled trial for HCM.

Screening occurred for 35 days, followed by a 30-week treatment period and an 8-week washout period.

Patients were randomized 1:1 to receive either mavacamten (n = 123) or placebo (n = 128). Starting dose was 5 mg, with titrations at weeks 8 and 14.

The mean age of both populations was 58.5; additionally, 46.3% were female in the mavacamten group and 35.2% in the placebo group.

Of the entire patient population, 92% were allowed to continue with their background therapy of either beta-blockers or calcium channel antagonists.

At baseline, the mean left ventricle ejection fraction (LVEF) was 74%, and the mean maximum left ventricle wall thickness was 20 mm. The population also had a mean elevated left ventricular outflow tract (LVOT) gradient of 85 mmHg.

For their primary endpoints, the investigators developed two criteria. If patients met one of them, they were considered to have achieved endpoint.

The first was a composite of pVO2 ≥ 1.4 mL/kg/min and a New York Heart Association (NYHA) Classification reduction of ≥1 class by week 30.

The second criterion was a composite of pVO2 ≥ 3.0 mL/kg/min in addition to no worsening of NYHA class.

They also sought several secondary endpoints, which included change in baseline in post-exercise LVOT gradient.

Following 30 weeks of treatment, 36.6% of patients in the mavacamten cohort achieved either one of the two primary endpoints—versus only 17.2% with placebo (difference, 19.4; 95% CI, 8.7-30.1; P<.0005).

The investigators also noted that 20.3% and 7.8% of patients in the investigative drug and placebo groups, respectively, achieved both pVO2 ≥ 3.0 mL/kg/min and a ≥1 improvement in NYHA class (12.5; 95% CI, 4.0-21.0; P = .0005).

Further, there was a greater reduction in post-exercise LVOT gradient for those receiving mavacamten (-47 mmHg) than for those taking placebo (-10 mmHg; [difference, -36; 95% CI -43.2 to -28.1; P<.0001).

Adverse events of 1 of more during treatment occurred in 87.8% of mavacamten users and 78.9% of placebo users. Only 11 in the mavacamten group and 20 in the placebo experienced serious adverse events.

The most common serious events associated with the investigative drug were atrial fibrillation, syncope, and stress cardiomyopathy.

Overall, a total of 97% of participants completed the study, and 3 discontinued due to treatment emergent events (2 on mavacamten, and 1 on placebo).

In a follow-up Q&A of the study’s presentation, Olivotto provided further comments on the potential of the novel drug.

“Surgical expertise and interventional expertise for this disease is limited,” he said. “We know from real-world trials and registries that, aside from very few centers, these patients don’t get good treatment by intervention. So, having a drug that can do that makes it a bit more democratic to treat obstruction worldwide.”

The study, “Efficacy and Safety of Mavacamten in Adults with Symptomatic Obstructive Hypertrophic Cardiomyopathy: Results of the EXPLORER-HCM Study,” was presented at ESC 2020.

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