FDA approves cardiac myosin inhibitor for treatment of obstructive HCM

News - May 2, 2022

The FDA has approved mavacamten for the treatment of adults with symptomatic NYHA class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve functional capacity and symptoms.

Mechanism of action of mavacamten

Mavacamten is a selective cardiac myosin inhibitor that targets the underlying pathophysiology of obstructive HCM. It reduces cardiac muscle contractility by inhibiting excessive myosin-actin cross-bridge formation.

Approval is based on the EXPLORER-HCM trial

The approval is based on data from the EXPLORER-HCM trial, a phase 3, double-blind, randomized, placebo-controlled, parallel group trial. EXPLORER-HCM enrolled a total of 251 adults with NYHA class II or III obstructive HCM with LVEF ≥55% and left ventricular outflow tract (LVOT) peak gradient ≥50 mmHg at baseline. Patients were randomized (1:1) to receive either mavacamten or placebo once daily for 30 weeks. The dose was periodically adjusted to optimize the decrease in LVOT gradient and maintain LVEF ≥50%. The primary composite endpoint for EXPLORER-HCM was the proportion of patients who achieved either improvement of mixed venous oxygen tension (pVO2) by ≥1.5 mL/kg/min plus improvement in NYHA class by at least 1 or improvement of pVO2 by ≥3.0 mL/kg/min plus no worsening in NYHA class.

Results of the EXPLORER-HCM trial

At week 30, a greater proportion of patients met the primary endpoint in the mavacamten group compared with the placebo group (37% vs. 17%, difference of 19%, 95% CI 9-30, P=0.0005).
Patients in the mavacamten group also showed greater improvement in all secondary endpoints compared to patients in the placebo group at week 30, including mean change from baseline post-exercise LVOT peak gradient (-47 mmHg vs. -10 mmHg, difference of -35, 95% CI -43 to -28, P<0.0001), mean change from baseline in pVO2 (1.4 mL/kg/min vs. -0.1 mL/kg/min, difference of 1.4, 95% CI 0.6 to 2.1, P<0.0006), number (%) of patients with improvement of NYHA class ≥ 1 (80 (65%) vs. 40 (31%), difference of 34%, 95% CI 22% to 45%, P<0.0001), and mean change from baseline in KCCQ-23 CSS (14 vs. 4, difference of 9, 95% CI 5 to 13, P<0.0001).
Mavacamten reduced LVEF. Mean absolute change from baseline in LVEF was -4% (SD 8) in the mavacamten group and 0% (SD 7) in the placebo group. After a 8-week interruption of the trial drug, mean LVEF was similar to baseline in both treatment groups.

Safety information

The U.S. Prescribing Information for mavacamten includes a warning for the risk of heart failure due to systolic dysfunction.

Initiation of mavacamten in patients with LVEF<55% is not recommended, and mavacamten should be interrupted if LVEF is <50% at any visit or if the patient experiences heart failure symptoms or worsening clinical status. In addition, use of mavacamten is contraindicated with moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors and moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers.

Because of the risk of heart failure, mavacamten is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS).

Source: Press release Bristol Myers Squibb, April 28, 2022