Mavacamten’s Benefits Are Not Sex-Dependent and Include Sustained Cardiac Remodeling

Two analyses of final 128-week results of the multicenter VALOR-HCM trial of mavacamten for symptomatic obstructive hypertrophic cardiomyopathy (HCM) show that it provides similar sustained benefits to both women and men and demonstrates favorable cardiac remodeling through 2.5 years.

So report the VALOR-HCM investigators in recent publications in JACC: Heart Failure (2025;13[6]:1037-1040) and in JACC: Cardiovascular Imaging (2025 Epub 17 Sep), respectively. The findings, recapped below, address important clinical questions about possible sex-based differences in response to mavacamten and the drug’s potential for inducing disease-modifying effects.

“Compared with men, women derived similar and sustained long-term benefit from mavacamten, including reduced need for septal reduction therapy, improvements in symptoms and quality of life, and favorable cardiac remodeling,” says VALOR-HCM lead investigator Milind Desai, MD, MBA, Medical Director of Cleveland Clinic’s Hypertrophic Cardiomyopathy Center. “Moreover, women derived these benefits without additional safety concerns. Our other analysis showed that, across the overall study sample, sustained improvements were achieved in a range of structural and functional cardiac measures and occurred in association with meaningful improvements in quality of life.”

VALOR-HCM in brief

Mavacamten, an oral cardiac myosin inhibitor, is the first medication approved for treatment of obstructive HCM. Key to its approval were initial results of the VALOR-HCM trial, which enrolled 112 adults with severely symptomatic obstructive HCM who had been referred for septal reduction therapy (SRT).

Trial participants were initially randomized to receive either mavacamten (128-week exposure) or placebo. Those in the placebo group were switched to mavacamten after 16 weeks (112-week exposure). The primary endpoint was the proportion of patients who proceeded with SRT or remained guideline-eligible for SRT at final evaluation at week 128. Final results, published in Circulation (2025;151:1378-1390), showed that mavacamten was associated with sustained freedom from the need for SRT in at least 84% of patients, with 88% of patients remaining on long-term use of the drug.

Analysis of long-term response by sex

The analysis to assess for any sex-based differences in mavacamten response (JACC Heart Fail. 2025;13[6]:1037-1040) was prompted by earlier observational studies indicating that women with HCM often present at more advanced ages with worse symptoms, poorer cardiopulmonary exercise tolerance and unfavorable hemodynamics compared with men — all factors associated with worse survival despite similar rates of surgical myectomy.

Cohort profile by sex

Of the 108 VALOR-HCM enrollees who qualified for final evaluation, 54 were women and 54 were men. At baseline, women were older (mean age of 63 vs. 58 years) with a shorter duration since HCM diagnosis (6 vs. 9 years) and lower rates of atrial fibrillation history (5.5% vs. 26.3%) compared with men. However, the two groups showed similar rates of New York Heart Association (NYHA) class III or higher symptoms (89% vs. 93%) and similar use of beta-blocker therapy.

Women also showed slightly higher left ventricular ejection fraction (LVEF; 69% vs. 68%), higher post-Valsalva left ventricular outflow tract (LVOT) gradients (84 vs. 71 mm Hg) and higher LV filling pressures as measured by medial E/e' ratio.

Key findings

At 128 weeks of follow-up, women and men showed comparable improvements across multiple parameters:

• Reductions in SRT eligibility (14.8% of women remained eligible vs. 16.7% of men)
• Improvement by at least one NYHA functional class (87.8% vs. 93.6%, respectively)
• Improvement by at least two NYHA functional classes (53.1% vs. 55.3%, respectively)
• Increases in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-23 CSS) (14.2 points for both groups)
• Reductions in resting, post-Valsalva and postexercise LVOT gradients
• Improvements in cardiac biomarkers (NT-proBNP and cardiac troponin I)
• Favorable cardiac remodeling, including reductions in left atrial (LA) volume index, LV mass index and LV filling pressures

The researchers found no significant differences in safety parameters between women and men, including in rates of treatment interruption due to reduced LVEF (11.1% in women vs. 16.7% in men) and serious treatment-emergent adverse events (18.5% vs. 20.4%, respectively).

Clinical implications

“These findings build on results from the EXPLORER-HCM trial, in which women had greater improvements in quality-of-life scores after mavacamten therapy despite being older and having higher baseline filling pressures and NT-proBNP levels,” Dr. Desai notes.

“Evidence to date demonstrates that mavacamten provides sustained improvements for patients with obstructive HCM regardless of sex,” he adds. “These findings underscore the importance of developing strategies for earlier diagnosis, especially in women, and further evaluating novel therapies for this condition.”

Analysis of long-term cardiac remodeling

The VALOR-HCM protocol included serial echocardiographic assessment by a core laboratory, including LVEF and LVOT gradient, as well as LA global longitudinal strain (GLS) measurements at baseline and week 128 using vendor-neutral software.

Key findings

At week 128, the cardiac remodeling analysis (JACC Cardiovasc Imag. 2025 Epub 17 Sep) demonstrated sustained and statistically significant improvements (all P < .05) across multiple echocardiographic parameters:

• Hemodynamics. Significant reductions were achieved in LVOT gradients, including at rest (–61%), post-Valsalva (–72%) and postexercise (–53%).
• Reverse hypertrophy. LV mass index decreased by 11% from baseline.
• Diastolic function. Septal E/e' improved by 18%, suggesting a reduction in LV filling pressure.
• Strain and remodeling. Sustained and significant improvement was observed in advanced markers of remodeling. LV-GLS improved by 4.5%. LA volume index decreased by 6%, and all LA strain components significantly improved, including LA reservoir strain (32% improvement), LA contraction strain (35% improvement) and LA conduit strain (15.5% improvement).

“The significant improvements in LV-GLS and LA strain are particularly relevant because abnormal strain values are linked to histopathological changes in HCM,” Dr. Desai observes.

Notably, patients who experienced meaningful clinical improvement (≥ 5 points in KCCQ-23 CSS) demonstrated significant improvements in LV and LA strain, supporting the link between symptomatic relief and favorable physiologic change. Patients with minimal clinical improvement (< 5 points) showed no significant improvement in most strain values.

The analysis also addressed the clinical challenge of identifying patients who might experience a decline in LVEF. Among the 15 patients who required temporary mavacamten interruption due to LVEF dropping below 50% at any point during the study, mean baseline LV and LA strain values were significantly lower (worse) relative to the remaining patients. “This hypothesis-generating result suggests that a lower baseline strain value, even with preserved LVEF, may help identify patients at higher risk for systolic dysfunction while receiving cardiac myosin inhibitor therapy,” Dr. Desai notes.

Clinical implications

The finding of sustained favorable cardiac remodeling, including improvements in key LV and LA strain markers, reinforces the concept that mavacamten provides disease modification in obstructive HCM, the investigators conclude.

“While more research is needed to definitively determine whether specific baseline LV and LA strain thresholds can guide mavacamten dosing or predict long-term prognosis,” Dr. Desai says, “clinicians should consider how baseline strain data might be used clinically. There is potential that it could identify a subset of patients who require lower starting or maintenance doses or who may be less likely to respond favorably to myosin inhibitor therapy without developing LV systolic dysfunction or atrial fibrillation.”

“These cardiac remodeling findings are very interesting and suggest that this agent could potentially change the trajectory of this disease in addition to providing symptom benefit,” adds Cleveland Clinic staff cardiologist Maran Thamilarasan, MD, who wasn’t involved in the study. “We eagerly await even longer-term data on these agents.”