VALOR-HCM: Mavacamten Decreases Need for Septal Reduction Therapy in Symptomatic Obstructive HCM

New pharmacological agent reduces need for septal reduction therapy in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM), according to new trial discussed at the 2022 American College of Cardiology Annual Scientific Session (ACC22).

HCM is a myocardial disease characterized by hypercontractility, dynamic left ventricular outflow tract (LVOT) obstruction and diastolic abnormalities due to underlying increased actin-myosin interactions.¹ Current pharmacological therapies focus on symptom modification with beta blockers or calcium channel blockers but don’t target underlying pathophysiology; meanwhile, invasive interventions such as alcohol septal ablation and septal myomectomy carry inherent procedural risks.^2,3 Thus, there remains a need for a disease-specific pharmacological agents for the treatment of symptomatic obstructive HCM.

Dr. Milind Desai, Professor of Medicine and Director of the Center for Hypertrophic Cardiomyopathy at the Cleveland Clinic, revealed the riveting results of VALOR-HCM at ACC22. The trial studied the safety and efficacy of mavacamten in patients with symptomatic obstructive HCM on maximally tolerated medical therapy considering septal reduction therapy (SRT).⁴ Mavacamten, an allosteric cardiac myosin-inhibitor, reduces actin-myosin cross-bridge formation hence reducing excessive cardiac contractility, a hallmark of HCM.

In this study, 112 patients were randomized in 1:1 fashion. The primary outcome of decision to proceed with SRT or guideline eligibility at week 16 was 17.9% vs 76.8% in mavacamten and placebo arms respectively (p <0.0001). Secondary outcomes revealed improvement in NYHA class by ≥ 1 class (63% vs 21%, p <0.05), resting LVOT gradient at 16 weeks (14 vs 46 mmHg, p <0.05), valsalva LVOT gradient at 16 weeks (28 vs 78 mmHg, p <0.05) and Kansas City Cardiomyopathy Questionnaire – 23 clinical summary score at 16 weeks (80 vs 67, p <0.05) all in favor of mavacamten.

These results are complementary to VALOR-HCM’s major predecessor, EXPLORER-HCM, which reported improvement in exercise capacity, NYHA functional class and LVOT obstruction in patients with obstructive HCM receiving mavacamten.¹

Although no major safety outcomes were observed, many continued to have concerns regarding long-term complications given short follow up duration of 16 weeks. The results of EXPLORER-LTE cohort of MAVA-LTE study were concurrently announced during ACC22 by Bristol Myers Squibb where outcomes of EXPLORER-HCM participants in the mavacamten arm at 48 and 84 weeks were released. Sustained improvement in LVOT gradient and NYHA class was reported without any major safety concerns.⁵

This data highlights the potential of the novel drug, mavacamten, to rapidly and safely modify disease pathophysiology and improve symptoms in patients with obstructive HCM, reducing the need for septal reduction therapy. However, further studies will be required to assess long-term safety profile and effect on clinical outcomes.

1. Olivotto I, Artur O, Barriales-Villa R, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomized, double-blind placebo-controlled, phase 3 trial. Lancet. 2020;396:759-769.
2. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011; 124: e783-e831
3. Authors/task force members, Elliot PM, Anastasakis A, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the diagnosis and management of hypertrophic cardiomyopathy of the European Society of Cardiology (ECS). Eur Heart J. 2014;35:2733-2779.
4. Desai, Milind. Mavacamten in adults with symptomatic obstructive HCM who are eligible for septal reduction therapy – VALOR-HCM. American College of Cardiology Annual Scientific Session (ACC 2022). Washington, DC, April 2, 2022.
5. Rader, Florian. Efficacy, safety of mavacamten in treating obstructive HCM holds up in EXPLORER-LTE cohort of MAVA-LTE study. American College of Cardiology Annual Scientific Session (ACC 2022). Washington, DC, April 3, 2022.