ACACIA-HCM Analysis Underscores Aficamten’s Effect on nHCM Outcome Measures

Aficamten has successfully improved exercise capacity, NT-proBNP, and diastolic function, among other outcome measures of nonobstructive hypertrophic cardiomyopathy (nHCM), based on an analysis of the ACACIA-HCM trial.1

These data were presented at the Heart Failure Society of America (HFSA) Annual Scientific Meeting 2026 in Phoenix, Arizona, by Martin Maron, MD, medical director of the Lahey Hospital & Medical Center. In an exclusive interview with HCPLive, Maron discussed the implications of these findings – and the path forward for aficamten following the conclusion of this trial.1,2

“The premise here is that aficamten was able to improve on measures of diastolic function, which then translated into the improvement in some clinical outcomes that we saw, making patients feel and function better with non-obstructive HCM,” Maron told HCPLive. “In addition, NT-proBNP itself is a prognostic marker of outcome in HCM, and so the idea that we could lower it could be associated with longer-term benefit.”

ACACIA-HCM was a phase 3, randomized, multinational, double-blind trial comparing aficamten’s efficacy and safety to placebo in nHCM. Patients were eligible for enrollment if they had a body mass index (BMI) <40 kg/m2, were diagnosed with nHCM, and had a screening echocardiogram showing end-diastolic left ventricular (LV) wall thickness ≥15 mm in ≥1 myocardial segment, or ≥13 mm in ≥1 wall segment, and a known disease-causing gene mutation or family history of HCM, among other criteria.3

Patients were randomly assigned in a 1:1 ratio to receive either aficamten at 5 mg with a maximum dose of 20 mg or placebo for ≥72 weeks. The 2 primary endpoints were change in Kansas City Cardiomyopathy Questionnaire – Clinical Summary Score (KCCQ-CSS) from baseline to week 36 and change in peak oxygen uptake (pVO2) from baseline to week 36. Secondary endpoints included the proportion of patients with ≥1 class improvement in New York Heart Association (NYHA) functional class, change in NT-proBNP, and change in left atrial volume index (LAVI) at week 36.2,3

A total of 258 patients were ultimately enrolled into the aficamten arm, while 259 were assigned to placebo. Mean age among these patients was 55.1 years. By week 36, KCCQ-CSS had improved by 11.4 points (95% CI, 9.6-13.2) among those receiving aficamten versus 8.4 points (least squares mean difference, 3 points; 95% CI, 0.5 to 5.5; P = 0.2) in the placebo arm. Mean change in pVO2 was 0.64 mL/kg/min (95% CI, 0.32 to 0.95) in the aficamten group and -0.03 mL/kg/min in the placebo group (95% CI, -0.35 to 0.28), with a least-squares mean difference of 0.67 mL/kg/min (95% CI, 0.22 to 1.11; P = .003).2

In the present study, Maron and colleagues conducted a responder analysis integrating several alternative endpoints. These included improvements in the following categories:

• Relief of limiting symptoms, measured as ≥1 change in NYHA class
• Enhanced exercise capacity, measured as ≥0.5 mL/kg/min increases in pVO2
• Diastolic function, measured as >10% decrease in LAVI or similar magnitude changes associated with lower risk of adverse cardiovascular outcomes
• Diastolic function, measured separately as a >10% increase in septal e’ or a similar magnitude change associated with enhanced survival
• Cardiac biomarker, measured as a ≥50% reduction in NT-proBNP.1

Through this analysis, Maron and colleagues found that 13% of placebo recipients (n = 33) saw ≥0.5 mL/kg/min increases in pVO2 and ≥1 NYHA class improvement, compared to 21% (n = 54) of the aficamten recipients (risk difference, 8.1%; 95% CI, 1.7 to 14.5%; P = .013). 10% (n = 26) of patients in the placebo arm achieved ≥1 mL/kg/min increases in pVO2 and ≥1 NYHA class improvements, while 17% (n = 44) among the aficamten arm saw the same (risk difference, 7%; 95% CI, 1.1 to 13%; P = .019). Another 21% (N = 54) of placebo patients and 29% (n = 74) of aficamten recipients saw improvements of ≥1.5 mL/kg/min in pVO2 and no worsening of NYHA class (risk difference, 7.8%; 95% CI, 0.4 to 15%; P = .038).1

Ultimately, Maron and colleagues determined that 53% of patients with nHCM receiving aficamten experienced a clinically meaningful improvement in ≥3 clinically relevant outcome measures. Additionally, the number needed to treat for aficamten ranged from 1.7 for NT-proBNP to 14 in pVO2 improvements versus placebo.1

“We’ve gone 60 years without a proven medical therapy for patients with symptomatic nHCM. For that reason, it’s represented the greatest unmet treatment need that we’ve had in HCM,” Maron said. “This is the first time that we’ve ever been able to demonstrate that a drug can improve how patients feel and function. I think this is a transformative moment for HCM.”

Editors’ Note: Maron reports disclosures with Imbria, Alexion, Edgewise, Cytokinetics, Braveheart, and Pacegenix.

References

1. Maron M, Masri A, Bhatia A, et al. Global Efficacy of Aficamten in Nonobstructive Hypertrophic Cardiomyopathy: Results From ACACIA-HCM. Presented at the Heart Failure Society of America (HFSA) Annual Scientific Meeting, Phoenix, AZ. October 9-12, 2026.

2. Masri A, Maron MS, Bhatia A, et al. Aficamten for symptomatic nonobstructive hypertrophic cardiomyopathy. New England Journal of Medicine. Published online August 28, 2026. doi:10.1056/nejmoa2603021

3. Cytokinetics. A Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy (nHCM) (ACACIA-HCM). ClinicalTrials.gov Identifier: NCT06081894. Updated September 22, 2026. Accessed October 13, 2026. https://clinicaltrials.gov/study/NCT06081894