Treatment with aficamten significantly improves patient-reported health status and exercise capacity in patients with symptomatic nonobstructive hypertrophic cardiomyopathy (nHCM), according to the ACACIA-HCM trial presented at ESC 2026.
“Patients with nHCM experience limiting symptoms that affect their daily lives. However, despite this being a relatively common disorder, there are no effective therapies,” said lead investigator Dr Ahmad Masri from Oregon Health & Science University in Portland, Oregon, US.
“Building on our experience with the cardiac myosin inhibitor, aficamten, in obstructive HCM, we conducted the ACACIA-HCM trial to investigate its effects on symptom burden and exercise capacity in patients with nHCM,” he added.
ACACIA-HCM was a double-blind, placebo-controlled, phase III trial involving 517 adults (mean age 55 years, 54 percent female) with symptomatic nHCM and baseline left ventricular ejection fraction (LVEF) of 68 percent. Participants were randomized 1:1 to receive either aficamten 5–20 mg (n=258) or placebo (n=259) for up to 72 weeks, followed by a 4-week washout period, with the aficamten dose titrated based on LVEF.
At week 36, patients receiving aficamten demonstrated a significant improvement in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), the first primary endpoint of the study, compared with those receiving placebo (least squares mean [LSM] difference from baseline, 3 points; p=0.021). [ESC 2026, Hot Line Session 1]
Notably, this advantage in KCCQ-CSS was evident at all other timepoints (weeks 24, 48, 60, and 72) and at the end of treatment, with LSM differences ranging from 4.8–7 points, favouring aficamten over placebo (p≤0.005 for all).
The second primary endpoint was the change in maximal exercise performance, which significantly improved by 0.67 mL/kg/min (p=0.003) in peak oxygen uptake from baseline to week 36 with aficamten compared with placebo.
Furthermore, the benefit observed with aficamten over placebo was consistent across multiple prespecified subgroups, including beta-blocker use, presence of intracavitary obstruction, and genotype status.
Taken together, the results showed that “in patients with symptomatic nHCM, aficamten was superior to placebo on both the dual primary endpoints,” said Masri, during the ESC press conference.
Secondary endpoints
At week 36, a significantly higher proportion of patients on aficamten achieved ≥1 improvement in the NYHA* functional class than those on placebo (44 percent vs 29 percent; common rate difference, 14.1 percent; p<0.001).
Aficamten treatment was also associated with improved comprehensive exercise performance compared with placebo (mean difference in composite z-score, 0.14; p<0.001).
In addition, N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations were lower in the aficamten group than in the placebo group (geometric LSM ratio, 0.43; p<0.001), but the time to the first composite cardiovascular event did not differ between the treatment groups (hazard ratio, 1.13; p=0.678).
Safety
Serious adverse events occurred at a slightly higher rate in the aficamten group than in the placebo group (20.2 percent vs 14.7 percent). However, three deaths were reported in the placebo group and none in the aficamten group.
In terms of LVEF, there was a higher incidence of LVEF <50 percent among patients on aficamten than those on placebo (10.5 percent vs 0.8 percent), but Masri noted that the majority of the reductions of LVEF <50 percent were managed by simple down titration.
The incidence of new-onset atrial fibrillation was similar between the aficamten and placebo groups (1.6 percent vs 1.2 percent).
“Aficamten was generally well tolerated … and safe without new emergent safety signals,” noted Masri.
Aficamten is a reversible cardiac myosin inhibitor approved for obstructive HCM, with favourable effects on diastolic function—a primary issue in nHCM—and favourable pharmacological properties that allow for rapid titration, dose adjustment, and good tolerability, making it a promising option for nHCM.
Overall, the ACACIA-HCM trial showed that aficamten improved exercise capacity, patient-reported health status, symptoms, and NT-proBNP compared with placebo in patients with symptomatic nHCM,” said Masri.
“These findings show that aficamten is an effective treatment for patients with nHCM,” he added.