Aficamten Shows Multidomain Response in Nonobstructive HCM

Key Takeaways

• Among patients with symptomatic nonobstructive HCM in the randomized ACACIA-HCM trial, multidomain response favored aficamten over placebo.
• An NT-proBNP reduction of at least 50% occurred in 63% of aficamten recipients versus 5% of placebo recipients.
• The peak-VO2 threshold responder comparison favored aficamten numerically, but differing reported P values leave its statistical significance unclear.

Symptomatic nonobstructive hypertrophic cardiomyopathy (nHCM) can limit activity and cause breathlessness. Improvement in how a patient feels may not coincide with changes in exercise capacity, cardiac physiology, and a circulating biomarker. For patients receiving aficamten, the question is whether favorable changes across these dimensions occur together. Investigators assessed these responses among patients enrolled in ACACIA-HCM.

Investigators assessed patients already randomized in the Assessment Comparing Aficamten to Placebo on Cardiac Endpoints in Adults With Non-Obstructive Hypertrophic Cardiomyopathy (ACACIA-HCM) trial, as described in the ACACIA-HCM responder analysis in Circulation. Of 517 patients, 258 received daily aficamten and 259 received placebo; responses were assessed at week 36. This was an analysis of the existing trial, not another randomized trial. Symptom response meant improvement by at least one New York Heart Association (NYHA) class or improvement on the Patient Global Impression of Change. Other favorable responses were an increase in peak oxygen uptake (peak VO2) of at least 0.5 mL/kg/min; a decrease in left atrial volume index of more than 10%; an increase in septal early diastolic mitral annular velocity (septal e′) of more than 10%; and a decrease in N-terminal pro-B-type natriuretic peptide (NT-proBNP) of at least 50%. Patients were classified as nonresponders with no favorable domains, limited responders with one or two, partial responders with three or four, and complete responders with all five.

At week 36, partial or complete response—favorable changes in at least three domains—occurred in 53% of aficamten recipients versus 14% of placebo recipients. Symptom, septal e′, and left atrial volume index responses also favored aficamten. The multidomain finding captured patient-reported symptoms alongside measures of cardiac physiology.

The peak VO2 threshold was reached by 45% of aficamten recipients versus 37% of placebo recipients; reported P values differ, so the statistical significance of this responder comparison is unclear. The biomarker response also favored aficamten, as reflected in the NT-proBNP result above.

These response categories describe changes measured after treatment, not evidence that aficamten improves survival or prevents later clinical events in symptomatic nHCM. The peak VO2 comparison asks whether an individual crossed a 0.5 mL/kg/min threshold rather than describing exercise-capacity changes across their full range.

According to the authors, aficamten was associated with improvement across symptoms and physiological measures in symptomatic nHCM. Reported P values differ for the peak VO2 threshold responder comparison, leaving its statistical significance unclear; these findings did not demonstrate a survival benefit.

Clinician Questions

What biological target does aficamten address in nonobstructive hypertrophic cardiomyopathy?

Aficamten is a cardiac myosin inhibitor intended to address excess contractility and impaired diastolic function in nonobstructive hypertrophic cardiomyopathy, as the ACACIA-HCM investigators explain.

Was an approved treatment available for symptomatic nonobstructive hypertrophic cardiomyopathy when aficamten was evaluated?

When aficamten was evaluated, the ACACIA-HCM researchers described symptomatic nonobstructive hypertrophic cardiomyopathy as having no approved treatment.