Mavacamten effective in symptomatic obstructive HCM regardless of sex

In a secondary analysis of VALOR-HCM among patients with severely symptomatic obstructive hypertrophic cardiomyopathy (HCM) treated with mavacamten for 128 weeks, there were no sex differences in need for septal reduction therapy or clinical, echocardiographic, and safety outcomes.

This summary is based on the publication of Desai MY, Saberi S, Geske JB, et al. - Long-Term Response of Obstructive Hypertrophic Cardiomyopathy Patients to Mavacamten Based on Sex: Insights From the VALOR-HCM Trial. JACC Heart Fail. 2025 Mar 3:S2213-1779(25)00155-6 [Online ahead of print]. doi: 10.1016/j.jchf.2025.02.005.

Introduction and methods

Background

Female patients with hypertrophic cardiomyopathy (HCM) are thought to have a more severe disease course and worse survival than men [1]. The VALOR-HCM (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive HCM Who Are Eligible for Septal Reduction Therapy) trial recently showed that the cardiac myosin inhibitor mavacamten reduced the need for septal reduction therapy (SRT) at 128 weeks in 9 out of 10 severely symptomatic patients with obstructive HCM [2]. However, it is unknown whether there are sex differences in the response to medical therapies such as mavacamten.

Aim of the study

In a secondary analysis of the VALOR-HCM trial, the authors evaluated sex-associated differences in the efficacy and safety of 128-week treatment with mavacamten in patients with severely symptomatic obstructive HCM eligible for SRT.

Methods

In the VALOR-HCM trial, a multicenter, double-blind, placebo-controlled, parallel-group, phase 3 RCT conducted in the US, 112 patients with severely symptomatic obstructive HCM (left ventricular outflow tract (LVOT) gradient ≥50 mmHg; LVEF ≥60%) who were referred for SRT were randomized to mavacamten or placebo, in addition to maximum-tolerated medical therapy. At 16 weeks, patients assigned to placebo were crossed over to mavacamten. Of the total study population, 108 patients (54 women (50%)) were followed for 128 weeks (end of treatment).

Outcomes

The primary efficacy endpoint was a composite outcome of a decision to proceed with SRT or eligibility for SRT. Additional efficacy endpoints were changes from baseline to 128 weeks in resting, post-Valsalva, and postexercise LVOT gradients, NYHA functional class, KCCQ – Clinical Summary Score (CSS), and levels of NT-proBNP and cTnI. Echocardiographic endpoints included changes from baseline to 128 weeks in interventricular septal wall thickness, LV systolic and diastolic volume index, and markers of favorable cardiac remodeling (LV mass index, left atrial volume index, and medial ratio of early diastolic transmitral velocity to early diastolic mitral annular velocity (E/e’)).

Safety assessment comprised new-onset AF, treatment-emergent adverse events, and interruption or permanent discontinuation of the study drug.

Main results

• At 128 weeks, the proportion of patients proceeding with SRT or who remained guideline-eligible (i.e., primary endpoint) did not differ between men and women (16.7% vs. 14.8%; P>0.05).
• Men and women showed similar changes in NYHA class HF symptoms (decrease ≥1 NYHA classes: 93.6% vs. 87.8%; decrease ≥2 NYHA classes: 55.3% vs. 53.1%) and equal improvement of the mean ± SD KCCQ-CSS (14.2 ± 16 vs. 14.2 ± 18) (all P>0.05) from baseline to 128 weeks.
• In both sexes, reductions in the LVOT gradient, LVEF, biomarker levels, and markers of cardiac remodeling were observed (all P>0.05).
• In addition, there were no sex differences in the safety outcomes (all P>0.05).

Conclusion

In this secondary analysis of the VALOR-HCM trial among patients with severely symptomatic obstructive HCM referred for SRT, mavacamten treatment for 128 weeks resulted in reduced long-term need for SRT, fewer symptoms and better quality of life, improved LVOT gradient, lower biomarker levels, and favorable cardiac remodeling, regardless of sex. There were also no sex differences in the safety outcomes.

Find this article online at JACC Heart Fail.

References

1. Geske JB, Ong KC, Siontis KC, et al. Women with hypertrophic cardiomyopathy have worse survival. Eur Heart J. 2017;38: 3434–3440. https://doi.org/10.1093/eurheartj/ehx527
2. Desai MY, Wolski K, Owens A, et al. Mavacamten in patients with hypertrophic cardiomyopathy referred for septal reduction: week 128 results from VALOR-HCM. Circulation. Published online November 18, 2024. https://doi.org/10.1161/CIRCULATIONAHA.124.072445