Nonobstructive Heart Enlargement Responds to Aficamten

Treatment with aficamten (Myqorzo) improved exercise capacity as well as health status and symptoms in patients with symptomatic nonobstructive hypertrophic cardiomyopathy (HCM) in a large, double-blind, placebo-controlled trial.

The 517-patient phase III trial, ACACIA-HCM, met both dual primary endpoints, including change from baseline to week 36 in peak oxygen uptake and patient-reported health status on the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), according to Ahmad Masri, MD, of Oregon Health & Science University Medical Group in Portland, Oregon, speaking at the European Society of Cardiology’s annual meeting. Results were published simultaneously in the New England Journal of Medicine (NEJM).

At 36 weeks, the mean change in peak oxygen uptake was 0.64 mL/kg/min in the aficamten group, versus -0.03 mL/kg/min in the placebo group, for a least-squares mean difference of 0.67 mL/kg/min (P=0.003).

KCCQ-CSS values rose an average of 11.4 points in the aficamten group versus 8.4 points with placebo, for a least-squares mean difference of 3.0 points (P=0.02).

Aficamten, a cardiac myosin inhibitor, was approved by the FDA last December to improve functional capacity and symptoms in patients with symptomatic obstructive HCM, on the strength of data from the SEQUOIA-HCM trial. This new trial extends those findings to patients with symptomatic nonobstructive HCM.

Secondary endpoints, including improvement in New York Heart Association functional class, a comprehensive exercise metric (Z-score), and wall stress measured using N-terminal pro-B-type natriuretic peptide (NT-proBNP), all favored aficamten treatment over placebo.

Masri also presented data from a responder analysis, showing treatment was effective across several measures, including symptom burden and diastolic function. That analysis was published separately in Circulation.

“You have multiple domains of benefit that are reflecting on the patients, from symptoms, to patient-reported health status, exercise, biomarkers,” Masri said, “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.”

Discussant for the trial, Nosheen Reza, MD, of the University of Pennsylvania in Philadelphia, congratulated the researchers “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.”

She pointed out, however, that the magnitude of benefit in the nonobstructive group was more modest than that seen in previous trials of cardiac myosin inhibitors in obstructive HCM, and pointed to several research priorities to better define patients who might benefit.

“ACACIA-HCM is an important step forward,” 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.”

Aficamten treatment was generally safe, Masri said, with no emerging safety signals. Serious adverse events occurred in 20.2% of patients on aficamten and 14.7% on placebo. Heart failure occurred in 4.7% of patients on treatment versus 1.2% of those on placebo. All heart failure events were treated with diuretics and all occurred during the 12-week titration period, Masri noted.

Reversible reductions in left ventricular ejection fraction (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%.”

Labeling for aficamten in obstructive HCM currently includes a boxed warning about LVEF reductions and that the drug can cause heart failure due to systolic dysfunction; aficamten is available only through a restricted program under a Risk Evaluation and Mitigation Strategy, the company noted at the time of the drug’s approval. LVEF assessment on echocardiogram is required prior to and during treatment.

Patients were included in ACACIA-HCM if they had symptomatic nonobstructive HCM, with LV end-diastolic wall thickness of at least 15 mm, or at least 13 mm in the presence of a known disease-causing genetic mutation or family history of HCM; a resting LV outflow tract gradient of less than 30 mm Hg, and less than 50 mm Hg with a Valsalva maneuver; and LVEF of 60% or higher.

They were randomized to placebo (n=259) or aficamten (n=258) starting at a dose of 5 mg, titrated to a maximum of 20 mg. The patients were followed for 72 weeks, with a 4-week washout period to end the study. Primary results were taken at week 36. The NEJM report included a graph showing change in KCCQ-CSS values through week 72, indicating that aficamten’s advantage over placebo continued to grow, but only about 100 patients completed all 72 weeks of follow-up and efficacy after week 36 wasn’t formally analyzed.

Thus, the durability of benefit beyond 36 weeks is “uncertain, pending results from the ongoing FOREST-HCM open-label extension trial,” Masri’s group observed in their NEJM report.