ACACIA-HCM: Aficamten Beats Placebo in Non-Obstructive Hypertrophic Cardiomyopathy

Aficamten has outperformed placebo among patients with symptomatic non-obstructive hypertrophic cardiomyopathy (nHCM), according to topline data from ACACIA-HCM.1

These data were announced by parent company Cytokinetics on May 5, 2026, highlighting improvements in both Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and maximal exercise performance (pVO2). These results highlight aficamten’s potential as a treatment for the underlying hypercontractility associated with nHCM.1

“Traditionally, we have placed more weight on peak oxygen consumption – it is a very hard endpoint to move,” Ahmad Masri, MD, cardiomyopathy section head at Oregon Health & Science University, director of the OHSU hypertrophic cardiomyopathy center and OHSU Knight Cardiovascular Institute Cardiac Amyloidosis Program, and co-author of the study, told HCPLive in an exclusive interview. “We’ve shown that the minimal change in peak VO2 that patients perceive as clinically significant is 0.5. Most of the heart failure therapies we use don’t even hit on pVO2, even when they improve mortality and heart failure hospitalizations.”

Trial Structure

ACACIA-HCM is a multicenter, randomized, double-blind phase 3 trial comparing aficamten to placebo in adults with symptomatic nHCM. The trial itself was conducted across 180 locations worldwide and included patients with a body mass index (BMI) <40 kg/m2 who had been diagnosed with nHCM and had a screening echocardiogram with end-diastolic left ventricular wall thickness ≥15 mm in ≥1 myocardial segment. Additionally, patients were required to have NYHA class II or III, a respiratory exchange rate of ≥1 at screening, and a KCCQ-CSS score of ≤85, among other criteria.2

Patients were excluded from ACACIA-HCM if they presented with significant valvular heart disease, known or suspected infiltrative, genetic, or storage disorders causing cardiac hypertrophy, or a history of LV systolic dysfunction, syncope, symptomatic ventricular arrhythmia, resistant hypertension, or sustained ventricular tachyarrhythmia with exercise, among other criteria.2

The study consisted of 2 primary endpoints – change in KCCQ-CSS and change in pVO2 from baseline to week 36. Secondary endpoints included the proportion of patients with ≥1 class improvement in NYHA functional class and changes in the composite z-score of 2 cardiopulmonary exercise testing parameters of sub-maximal exercise performance, NT-proBNP, and left atrial volume index.1

A total of 516 patients were enrolled in the trial and randomly assigned in a 1:1 ratio to either aficamten or placebo. Each patient was administered ≤4 escalating doses of aficamten or placebo based on echocardiographic guidance – those in the treatment arm began with 5 mg daily. Echocardiograms were performed at weeks 2, 4, and 6 to determine the safety of up-titrating to doses of 10, 15, or 20 mg. Escalation only occurred in the presence of LVEF ≥60%.1

Trial Results

By week 36, patients in the aficamten arm saw improvements in KCCQ-CSS of 11.4 points (95% CI, 9.6 to 13.2) and of 0.64 mL/kg/min in pVO2 (95% CI, 0.32 to 0.95), compared to 8.4 points (95% CI, 6.6 to 10.2) and -0.03 mL/kg/min (95% CI, 0.22 to 1.1), respectively, in the placebo arm (P = .021 and .003, respectively). The improvement in KCCQ was robust and consistent throughout treatment; however, following washout, it decreased among the aficamten arm to match placebo. pVO2 remained unchanged for patients on placebo despite increasing for those on aficamten, consistent with previous research.1

Investigators also reported statistically significant improvements in NYHA functional class, the composite z-score of ventilatory efficiency and pVO2, and NT-proBNP. No new safety signals were identified, and only 2 participants receiving aficamten experienced serious adverse events of heart failure associated with LVEF <50%.1

“What we are looking at here is symptom improvement as a continuous variable. You’re looking at the mean average population change,” Masri said. “We all know that there are some patients who might report feeling better, some who report feeling worse, and so you will have to understand, who are the patients who felt better? What is the categorical change of having 5 or more points of improvement in KCCQ? That’s where we don’t have the data yet, and I think that data will help us understand the symptom perspective.”

Editors’ Note: Masri reports disclosures with Pfizer, Attralus, Eidos, Ionis, Cytokinetics, BioMarin, and others.

References

1. Cytokinetics. Cytokinetics Announces Positive Topline Results from ACACIA-HCM, the Pivotal Phase 3 Clinical Trial of Aficamten in Patients with Non-Obstructive Hypertrophic Cardiomyopathy. May 5, 2026. Accessed May 8, 2026. https://ir.cytokinetics.com/press-releases/press-release-details/2026/Cytokinetics-Announces-Positive-Topline-Results-from-ACACIA-HCM-the-Pivotal-Phase-3-Clinical-Trial-of-Aficamten-in-Patients-with-Non-Obstructive-Hypertrophic-Cardiomyopathy/default.aspx

2. Cytokinetics. Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic nHCM (ACACIA-HCM). ClinicalTrials.gov Identifier: NCT06081894. Updated February 2, 2026. Accessed May 8, 2026. https://clinicaltrials.gov/study/NCT06081894