Aficamten improved symptoms and exercise capacity in patients with symptomatic non-obstructive hypertrophic cardiomyopathy in the ACACIA-HCM phase III trial. Results of the ACACIA-HCM trial were presented in a Hot Line session at ESC Congress 2026 on August 28, 2026, and published simultaneously in the New England Journal of Medicine.

The ACACIA-HCM trial was a double-blind, phase III study conducted at 182 international sites. A total of 517 adults with symptomatic non-obstructive hypertrophic cardiomyopathy were randomized 1:1 to receive aficamten or placebo for up to 72 weeks. The mean age of participants was 55 years, and 54% were women.

The baseline left ventricular ejection fraction (LVEF) was 68%. The dual primary endpoints were the change in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and the change in maximal exercise performance (pVO2) from baseline to week 36.

At 36 weeks, the KCCQ-CSS improved by 11.4 points in the aficamten group and 8.4 points in the placebo group (p=0.02). At 36 weeks, pVO2 improved by 0.64 mL/kg/min in the aficamten group and changed by -0.03 mL/kg/min in the placebo group (p=0.003). Aficamten treatment resulted in improvements in secondary endpoints including New York Heart Association functional class, submaximal exercise performance, and NT-proBNP levels.

Nosheen Reza is a discussant for the ACACIA-HCM trial and is affiliated with the University of Pennsylvania in Philadelphia. "Congratulations on this milestone; the first definitively positive trial in this population, in which complementary primary efficacy endpoints, objective exercise capacity, and patient-reported health status were met," Reza said. "The opportunity now for us is to understand how treating nonobstructive HCM is basically not a single phenotype, and move towards better defining the mechanisms, patients, and therapeutic targets that determine clinical response," she said.

The ACACIA-HCM trial included patients with a resting LV outflow tract gradient of less than 30 mm Hg and less than 50 mm Hg with a Valsalva maneuver. The trial included patients with an LVEF of 60% or higher. Patients started aficamten at a dose of 5 mg, titrated to a maximum of 20 mg.

Only about 100 patients completed all 72 weeks of follow-up. Efficacy after week 36 was not formally analyzed.

Serious adverse events occurred in 20.2% of patients on aficamten and 14.7% of patients on placebo. Heart failure occurred in 4.7% of patients on aficamten versus 1.2% of patients on placebo. All heart failure events occurred during the 12-week titration period and were treated with diuretics.

Reversible reductions in LVEF to less than 50% were seen in 27 patients (10.5%) on aficamten and 2 patients (0.8%) on placebo. "Aficamten works by modulating heart contractility, so that's why we pay attention to ejection fraction," Masri said. "However, the majority of these patients actually continued on either the same dose or a lower dose of aficamten, because per protocol, we just down-titrate the aficamten dose for an [ejection fraction] between 40% and 50%," he said.

Aficamten is a cardiac myosin inhibitor approved by the FDA in December 2025 for symptomatic obstructive HCM based on the SEQUOIA-HCM trial. Aficamten labeling for obstructive HCM includes a boxed warning about LVEF reductions and risk of heart failure due to systolic dysfunction. Aficamten is available only through a restricted program under a Risk Evaluation and Mitigation Strategy.

Aficamten is approved in the U.S. China, and the European Union for obstructive HCM, but not for non-obstructive HCM. Most of the eligible patients from the ACACIA-HCM trial are continuing treatment with aficamten in the FOREST-HCM study. The ACACIA-HCM trial was registered under NCT06081894 on ClinicalTrials.gov. A responder analysis from the ACACIA-HCM trial was published separately in Circulation.

Timeline

In December 2025, aficamten was approved by the FDA as a cardiac myosin inhibitor for symptomatic obstructive HCM based on the SEQUOIA-HCM trial. On August 28, 2026, results of the ACACIA-HCM trial were presented in a Hot Line session at ESC Congress 2026. Also on August 28, 2026, Ahmad Masri, the Principal Investigator of the ACACIA-HCM trial affiliated with Oregon Health & Science University in Portland, USA, stated that building on experience with the cardiac myosin inhibitor in obstructive HCM, the trial investigated its effects on symptom burden and exercise capacity in patients with non-obstructive HCM.

On August 28, 2026, Masri said results from the ACACIA-HCM trial provide really positive news for patients with symptomatic non-obstructive HCM. He noted that improvements were seen as early as 12 weeks and there was a pronounced return of symptoms after aficamten treatment was stopped. Masri also stated that you have multiple domains of benefit that are reflecting on the patients, from symptoms, to patient-reported health status, exercise, biomarkers, and so every way, shape, or form you look at this, there was benefit from aficamten in a disease that has no treatments available right now. Regarding safety management, he said on August 28, 2026, that however, the majority of these patients actually continued on either the same dose or a lower dose of aficamten, because per protocol, we just down-titrate the aficamten dose for an [ejection fraction] between 40% and 50%.

What's New

Additional reporting indicates that a study titled 'Global Efficacy of Aficamten in Nonobstructive Hypertrophic Cardiomyopathy: Results From ACACIA-HCM' was published in Circulation in 2026. Earlier studies provided context, including a study titled "Efficacy and Safety of Aficamten in Symptomatic Nonobstructive Hypertrophic Cardiomyopathy: Results From the REDWOOD-HCM Trial, Cohort 4" published in 2024 in Journal of Cardiac Failure. Two other studies were published in 2024 in Journal of the American College of Cardiology: one titled "Impact of Aficamten on Disease and Symptom Burden in Obstructive Hypertrophic Cardiomyopathy" and another titled "Effect of Aficamten on Cardiac Structure and Function in Obstructive Hypertrophic Cardiomyopathy". At ESC Congress 2026, Cytokinetics presented the ACACIA-HCM results in a Hot Line session, signaling the importance of the trial in the cardiology community.

How Sources Differ

Sources differ on trial inclusion criteria regarding left ventricular ejection fraction. One source states that the ACACIA-HCM trial had a 10.5% incidence of LVEF <50% in the aficamten group, compared to 0.8% in the placebo group, showing the risk profile associated with the drug. Another source states that the ACACIA-HCM trial included patients with an LVEF of 60% or higher.

Why It Matters

The ACACIA-HCM trial represents the first definitively positive trial in the population of patients with symptomatic non-obstructive hypertrophic cardiomyopathy, a condition that currently has no available treatments. The results demonstrate clinically meaningful improvements in symptoms and exercise capacity with a treatment that targets the cause of the disease. This is particularly relevant because aficamten is already approved in the U.S. China, and the European Union for obstructive HCM, but not for non-obstructive HCM, indicating that the ACACIA-HCM results may influence future regulatory decisions.

The trial's findings are supported by benefits across multiple domains, including symptoms, patient-reported health status, exercise, and biomarkers. However, the safety profile requires careful monitoring, as evidenced by a higher rate of serious adverse events in the treatment group compared to placebo. The fact that most eligible patients from the ACACIA-HCM trial are continuing treatment with aficamten in the FOREST-HCM study suggests ongoing interest in evaluating long-term outcomes and further defining the mechanisms and therapeutic targets for this patient population.