EXPLORER-HCM and MAVERICK-HCM for evaluating Mavacamten in hypertrophic cardiomyopathy

EXPLORER-HCM and MAVERICK-HCM for evaluating Mavacamten in hypertrophic cardiomyopathy

Mavacamten is a first-in-class reversible cardiac myosin inhibitor which has been evaluated in the EXPLORER-HCM trial for symptomatic hypertrophic obstructive cardiomyopathy [1]. Conventionally the medications used for treatment of hypertrophic cardiomyopathy were beta blockers, verapamil and sometimes disopyramide. These drugs are sometimes inadequate or poorly tolerated and are not disease-specific.

EXPLORER-HCM  was a randomized, double-blind, placebo-controlled, phase 3 trial of mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy. The trial was conducted at 68 centres across 13 countries in patients hypertrophic cardiomyopathy and left ventricular outflow tract (LVOT) gradient of 50 mm Hg or more and New York Heart Association (NYHA) class II-III symptoms. Assignment was 1:1 to either mavacamten or placebo, for a period of 30 weeks.

The primary endpoint of the study was a 1·5 mL/kg per min or greater increase in peak oxygen consumption (VO₂) and reduction in at least one NYHA class or greater than 3·0 mL/kg per min or greater increase in peak VO₂ without worsening of NYHA class. Post exercise LVOT gradient, peak VO₂, NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score, and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath sub score were the secondary end points.

45 of the 123 patients on mavacamten versus 22 of the 128 patients on placebo met the primary endpoint. Adverse events related to treatment were generally mild, with similar safety and tolerability in both groups. Mean fall in post exercise LVOT gradient was 36 mm Hg in mavacamten group while it was 28.1 mm Hg in the placebo group. Greater increases in peak VO₂ and improved Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score, and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath sub score were noted in the mavacamten group. 80 patients in the mavacamten group had at least one NYHA class improvement while the corresponding number in the placebo group was 40. There was one death by sudden cardiac death in the placebo group.

An earlier phase 2 trial evaluated 21 patients in an open-label, nonrandomized manner [2]. That study had documented that mavacamten can reduce LVOT obstruction and improve exercise capacity and symptoms in patients with hypertrophic obstructive cardiomyopathy.

MAVERICK-HCM (Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy) trial evaluated mavacamten in nonobstructive hypertrophic cardiomyopathy [3]. It was a multicenter, double-blind, placebo-controlled, dose-ranging phase II study in adults with symptomatic non obstructive hypertrophic cardiomyopathy. They were in functional class II or III and had left ventricular ejection fraction of 55% or more and N-terminal pro-B-type natriuretic peptide (NT-proBNP) 300 pg/ml or more. 59 participants were randomized to either two different doses of mavacamten or placebo in a 1:1:1 pattern. Reversible reduction in left ventricular ejection fraction to 45% or less was noted in 5 patients on mavacamten. Geometric mean of NT-proBNP decreased by 53% in the pooled mavacamten group versus 1% in the placebo group. Cardiac troponin I showed 34% reduction of geometric mean in the pooled mavacamten group compared to 4% increase in the placebo group. The results suggested improvement in myocardial wall stress.

References

1. Olivotto I, Oreziak A, Barriales-Villa R, Abraham TP, Masri A, Garcia-Pavia P, Saberi S, Lakdawala NK, Wheeler MT, Owens A, Kubanek M, Wojakowski W, Jensen MK, Gimeno-Blanes J, Afshar K, Myers J, Hegde SM, Solomon SD, Sehnert AJ, Zhang D, Li W, Bhattacharya M, Edelberg JM, Waldman CB, Lester SJ, Wang A, Ho CY, Jacoby D; EXPLORER-HCM study investigators. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020 Sep 12;396(10253):759-769. doi: 10.1016/S0140-6736(20)31792-X. Epub 2020 Aug 29. Erratum in: Lancet. 2020 Sep 12;396(10253):758. PMID: 32871100.
2. Heitner SB, Jacoby D, Lester SJ, Owens A, Wang A, Zhang D, Lambing J, Lee J, Semigran M, Sehnert AJ. Mavacamten Treatment for Obstructive Hypertrophic Cardiomyopathy: A Clinical Trial. Ann Intern Med. 2019 Jun 4;170(11):741-748. doi: 10.7326/M18-3016. Epub 2019 Apr 30. PMID: 31035291.
3. Ho CY, Mealiffe ME, Bach RG, Bhattacharya M, Choudhury L, Edelberg JM, Hegde SM, Jacoby D, Lakdawala NK, Lester SJ, Ma Y, Marian AJ, Nagueh SF, Owens A, Rader F, Saberi S, Sehnert AJ, Sherrid MV, Solomon SD, Wang A, Wever-Pinzon O, Wong TC, Heitner SB. Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy. J Am Coll Cardiol. 2020 Jun 2;75(21):2649-2660. doi: 10.1016/j.jacc.2020.03.064. PMID: 32466879.