Breakthrough therapy designation for Mavacamten in HOCM

Breakthrough therapy designation for Mavacamten in HOCM

USFDA has approved Mavacamten for the treatment of adults with symptomatic NYHA class II-III hypertrophic obstructive cardiomyopathy (HOCM) to improve exercise capacity and symptoms [1]. So far HOCM was being treated with beta blockers, non-dihydropyridine calcium channel antagonists and disopyramide with negative inotropic effects. Mavacamten is a first-in-class reversible cardiac myosin inhibitor.

EXPLORER-HCM [2] and MAVERICK-HCM [3] were the two important clinical trials on mavacamten. EXPLORER-HCM was in obstructive HCM while MAVERICK-HCM was in non-obstructive HCM. The medication has been designated as breakthrough therapy for the specified indication.

An important safety information mentioned by USFDA is the possibility of heart failure, which is more likely in those with intercurrent infection or arrhythmias like atrial fibrillation with fast ventricular rate. They suggested monitoring with echocardiogram to assess cardiac function. Possibility of drug interactions with certain prescription and over the counter drugs which interfere with the metabolism of mavacamten have also been highlighted. Due to the risk of heart failure, the mavacamten is available only through a Risk Evaluation and Mitigation Strategy (REMS) to ensure safe use by lowering the risk of heart failure.

Concomitant use with certain cytochrome P450 inhibitors or discontinuation of certain cytochrome P450 inducers may increase the risk of heart failure due to systolic dysfunction. Use along with moderate to strong inhibitors and inducers are contraindicated. Close monitoring and dose reduction have been recommended if mild to moderate inhibitors are being co-prescribed.

Close medical supervision and monitoring of left ventricular ejection fraction is needed when either a negative inotropic drug is added or escalated. It has been advised to avoid concomitant use with disopyramide in combination with verapamil or diltiazem as it has been associated with left ventricular systolic dysfunction heart failure symptoms in clinical trial [4].

References

1. FDA approves new drug to improve heart function in adults with rare heart condition. Available at: https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-new-drug-improve-heart-function-adults-rare-heart-condition. Accessed on 3 May 2022.
2. 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.
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.
4. Full prescribing information on FDA website is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214998s000lbl.pdf. Accessed on 3 May 2022.