MAPLE-HCM: CPET Data Support Aficamten over Metoprolol as Monotherapy

Information from a prespecified analysis of the MAPLE-HCM trial offers evidence positioning aficamten as a more effective monotherapy than metoprolol for patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM).

Presented at the Heart Failure Society of America (HFSA) Annual Scientific Meeting 2025, the prespecified CPET analysis shed new light on the effects of the cardiac myosin inhibitor on exercise capacity among patients from the trial as aficamten approaches its December 2025 PDUFA date.^1,2

“This pre-specified analysis from MAPLE-HCM provides novel comparative data for both aficamten and metoprolol treatment in oHCM,” wrote investigators.¹ “Treatment with aficamten was superior to metoprolol in improving all measures of physiologic adaptation exercise.”

MAPLE-HCM was an international, double-blind, double-dummy trial of 175 adult participants with symptomatic obstructive HCM. The study population had a mean age of 58 years and a mean left ventricular outflow tract gradient of 47 mmHg at rest and 74 mmHg after the Valsalva maneuver.^1,2

After 1:1 randomization assignment, 88 patients were included in the aficamten group and 87 in the metoprolol group. In May 2025, Cytokinetics announced the trial met its primary endpoint of a statistically significant improvement in peak oxygen uptake (pVO₂) from baseline to Week 24 for aficamten compared to metoprolol.^1,2

The trial’s 24 weeks results indicated pVO₂ had improved by 1.1 ml per kilogram of body weight per minute (95% CI, 0.5 to 1.7) in the aficamten group and fell by 1.2 ml per kilogram per minute (95% CI, -1.7 to -0.8) in the metoprolol group (least-squares mean between-group difference, 2.3 ml per kilogram per minute; 95% CI, 1.5 to 3.1; P <.001). Additionally, patients receiving aficamten also had significantly greater improvements in New York Heart Association (NYHA) functional class, KCCQ-Clinical Summary Score (KCCQ-CSS), left ventricular outflow tract gradient (LVOT), NT-proBNP level, and left atrial volume index than patients given metoprolol.^1,2

In this CPET substudy, patients were required to achieve a peak respiratory exchange ratio >1.05 to ensure maximal effort, with invalid tests excluded for technical deviations or serious adverse events. The primary endpoint was change in exercise capacity, with secondary endpoints including changes in Valsalva LVOT gradients, NYHA functional class, KCCQ-CSS, NT-proBNP, and echocardiographic parameters.¹

Treatment with aficamten led to significant improvements in both submaximal and maximal exercise parameters compared with metoprolol. Improvements were seen across ventilatory efficiency, pVO₂, and other physiologic markers, reflecting more efficient cardiovascular performance.¹

Importantly, aficamten-treated patients also demonstrated faster post-exercise VO₂ recovery, a parameter strongly correlated with LVOT gradient reduction (r=0.37; P <.001) and functional status improvements, suggesting a more favorable hemodynamic adaptation to exercise.¹

Integrative Z-score analysis, incorporating multiple CPET endpoints, showed a mean change of +0.23 (SD, 0.57) with aficamten compared with a decline of –0.24 (SD, 0.38) in the metoprolol arm, resulting in a significant between-group difference of +0.45 (95% CI, +0.31 to +0.59; P <.001). Responder analyses revealed a higher proportion of patients with any degree of exercise improvement on aficamten, whereas metoprolol recipients were more likely to experience deterioration.¹

Correlative analyses confirmed improvements in NYHA class, LVOT gradient reduction, and NT-proBNP were all associated with gains in pVO₂, reinforcing the clinical relevance of these physiologic benefits. Of note, investigators pointed out metoprolol treatment was associated with neutral or even detrimental effects on several exercise metrics.¹

“These findings support the use of aficamten over metoprolol as monotherapy in patients with symptomatic oHCM,” investigators concluded.¹

References:

1. Lewis G. Divergent Effect of Aficamten Versus Metoprolol on Exercise Performance in Obstructive Hypertrophic Cardiomyopathy: A Prespecified Analysis of MAPLE-HCM. Presented at the Heart Failure Society of America (HFSA) Annual Scientific Meeting 2025. Minneapolis, MN. September 26-29, 2025.

2. Cytokinetics. Cytokinetics Announces Positive Topline Results From MAPLE-HCM. Cytokinetics.com. Published May 13, 2025. Accessed September 28, 2025. https://ir.cytokinetics.com/press-releases/press-release-details/2025/Cytokinetics-Announces-Positive-Topline-Results-From-MAPLE-HCM-05-13-2025/default.aspx