The U.S. Food and Drug Administration (FDA) has approved mavacamten (Camzyos) for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (HCM).
HCM is a genetic cardiovascular disease characterized by an increased thickness of the left ventricular wall not solely explained by abnormal loading conditions. HCM has a variable presentation which can include, dyspnea, sudden cardiac death, syncope, presyncope, angina, palpitations, orthopnea, paroxysmal nocturnal dyspnea, and congestive heart failure. HCM can be inherited and caused by mutations in several genes (most commonly, MYH7, MYBPC3, TNNT2, and TNNI3.)
Mavacamten is an allosteric and reversible inhibitor selective for cardiac myosin. Mavacamten modulates the number of myosin heads that can enter on actin states, thus reducing the probability of systolic and diastolic cross-bridge formation. Excess myosin actin cross-bridge formation and dysregulation of the super relaxed state are mechanistic hallmarks of HCM. Mavacamten shifts the overall myosin population towards an energy sparing, recruitable, super relaxed state. In HCM patients, myosin inhibition with mavacamten reduces dynamic left ventricular outflow tract (LVOT) obstruction and improves cardiac filling pressures.
The approval of mavacamten is largely based on data from the phase 3 EXPLORER-HCM trial. At baseline, the mean left ventricular ejection fraction (LVEF) was 74%, and the mean LVOT gradient was 73 mmHg. The baseline mean Kansas City Cardiomyopathy Questionnaire-23 Clinical Summary Score was 71.
At Week 30, 37% (n=45/123) of patients taking mavacamten achieved the composite primary endpoint, defined as 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. In the control group, on v17% (n=22/128) treated with placebo reached the primary endpoint. Additionally at Week 30, patients receiving mavacamten had greater improvement compared to placebo group across all secondary endpoints.
Adverse reactions occurring in >5% of patients and more commonly in the mavacamten group than in the placebo group were dizziness (27% vs 18%) and syncope (6% vs 2%). Mean resting LVEF was 74% at baseline in both treatment groups. Mean absolute change from baseline in LVEF was -4% in the mavacamten group and 0% in the placebo group over the 30-week treatment period. At Week 38, following an 8-week interruption of trial drug, mean LVEF was similar to baseline for both treatment groups. Additionally, 7 (6%) patients in the mavacamten group and 2 (2%) patients in the placebo group experienced reversible reductions in LVEF to <50% (median 48%) while on treatment. In all 7 patients treated with mavacamten, LVEF recovered following interruption of mavacamten.
Boxed WARNING. Mavacamten reduces left ventricular ejection fraction (LVEF) and can cause heart failure due to systolic dysfunction. Because of that, the medication will only be available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS).
The cost of mavacamten is expected to be about $90,000 per year, according to the Hypertrophic Cardiomyopathy Association, but patient assistance programs are in place to reduce the costs to less $20 for most U.S. patients.
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