FDA Approves Mavcamten for the Treatment of Obstructive Hypertrophic Cardiomyopathy

The United States Food and Drug Administration (FDA) approved Mavacamten to treat patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) with class NYHA class II or III heart failure symptoms on April 28, 2022.1 The timing of the announcement coincidentally coincided with a well attended online Twitter journal club hosted by CardioNerds that featured the EXPLORER-HCM and VALOR-HCM trials, which assessed the role of Mavacamten in oHCM patients.

Mavacamten is a novel agent that is an elective allosteric inhibitor of cardiac myosin ATPase, which reduces the cross interaction of actin-myosin cross-bridges. This leads to decreased left ventricular outflow tract (LVOT) obstruction and increased left ventricle compliance resulting in improved functional capacity.2

The drug was approved after the results of EXPLORER-HCM trials. It enrolled 251 patients in a 1:1 fashion in a randomized double-blinded placebo-controlled trial and included oHCM patients with dynamic LVOT gradient of more than 50 mm Hg at rest or provocation, NYHA class II/III status, and normal LV systolic function.3 Upon 30 weeks of follow-up, Mavacamten arm patients showed improvement in the functional class (37% vs 17%, p<0.0001) and a decrease in the LVOT gradient at exercise, revealing increased exercise capacity.3

VALOR-HCM also evaluated the role of Mavacamten in patients with oHCM with NYHA functional class III/IV or NYHA class II functional class with exertional syncope or near sycncope and normal LV systolic function and and who qualified for septal reduction therapy (SRT) on maximally tolerated medical therapy. The study enrolled 112 patients in 1:1 fashion in a randomized double-blinded placebo-controlled trial.4 Upon 12 weeks follow-up, 17.9% of patients in the drug arm qualified for SRT vs. 76.8% in the placebo arm. The Mavacamten arm also showed significant improvement in functional capacity. VALOR-HCM trial was presented at the American College of Cardiology Conference, 2022, and the full manuscript is yet to be published.4

The incidence of HCM is about 0.16-0.29% of the general population.5 Traditionally, symptomatic oHCM patients are managed by beta-blocker, calcium channel blockers, and disopyramide for symptom relief. In the event of persistent symptoms despite medical therapy, septal reduction therapy with septal myectomy or alcohol septal ablation were potential options.5 Mavacamten is the first breakthrough medication specifically for oHCM, which can help delay or avoid septal reduction therapy and improve functional capacity.

It is noteworthy that, given the novelty of Mavacamten, the long-term safety, efficacy, and real-world experience are yet to be studied. Thus, FDA has guided Mavacamten prescription by specific Risk Evaluation and Mitigation Strategy and further guidelines regarding close follow-up and monitoring of the heart function and LVOT gradient by routine echocardiogram.1 Furthermore, prospectively DISCOVER-HCM registry plans to collect post-marketing safety and effectiveness of Mavacmten for oHCM and will be able to provide real-world data in the future.6

Prominent researcher, and expert in HCM from Cedar-Sinai Smidt Heart Institute Dr. Michelle Kittleson says “Mavacamten is exciting in principle as it’s the first therapy for HCM that targets the pathophysiology rather than just being a blunt instrument to target contractility (beta-blockers, calcium-channel blockers) or septal thickness (septal reduction therapies; SRT).  I’m optimistic that there is a reduction in symptoms and LVOT gradient based on EXPLORER-HCM with sustained improvement in the long-term extension trial.  I’m even more thrilled by the findings of VALOR-HCM because the most symptomatic patients– those contemplating invasive intervention solely to improve quality of life– feel better enough to reconsider SRT.


So what’s the catch (because there’s always a catch!).  I worry a little about safety as these are small trials- is there a safety signal for EF and/or arrhythmias that would be uncovered in larger cohorts?  I am also concerned about applicability- there were protocols for titrating dose to echo parameters and will this happen reliably in all centers?  Finally, is there risk of “indication creep,” where well-meaning clinicians offer the newest and most exciting medication to their patients who might not fit trial criteria, specifically using mavacamten first-line in patients who have not failed beta-blocker and/or calcium-channel blocker therapy?  (I had a Twitter poll about this on the day it was FDA-approved and there was a sizeable minority who selected mavacamten as first-line.)”


  1. FDA. FDA approves new drug to improve heart function in adults with rare heart condition. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-new-drug-improve-heart-function-adults-rare-heart-condition. Published 2022. Accessed May 2, 2022.
  2. Hegde SM, Lester SJ, Solomon SD, et al. Effect of Mavacamten on Echocardiographic Features in Symptomatic Patients With Obstructive Hypertrophic Cardiomyopathy. Journal of the American College of Cardiology. 2021;78(25):2518-2532.
  3. Olivotto I, Oreziak A, Barriales-Villa R, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. 2020;396(10253):759-769.
  4. Cardiology ACo. Mavacamten in Adults With Symptomatic Obstructive HCM Who Are Eligible for Septal Reduction Therapy – VALOR-HCM. https://www.acc.org/Latest-in-Cardiology/Clinical-Trials/2022/04/01/02/42/VALOR-HCM. Accessed May 2, 2022.
  5. Marian AJ, Braunwald E. Hypertrophic Cardiomyopathy. Circulation Research. 2017;121(7):749-770.
  6. MYOKARDIA. MyoKardia Collaborates with the American College of Cardiology and PINNACLE/Veradigm to Launch Patient Registry of Hypertrophic Cardiomyopathy. https://www.globenewswire.com/news-release/2020/11/11/2124742/37418/en/MyoKardia-Collaborates-with-the-American-College-of-Cardiology-and-PINNACLE-Veradigm-to-Launch-Patient-Registry-of-Hypertrophic-Cardiomyopathy.html. Accessed May 2, 2022.