Aficamten Meets Mark in Nonobstructive Hypertrophic Cardiomyopathy: ACACIA-HCM

The use of aficamten (Myqorzo; Cytokinetics), a selective cardiac myosin inhibitor, in patients with nonobstructive hypertrophic cardiomyopathy (HCM) improves physical limitations, symptoms, and peak exercise capacity, according to topline results from the  ACACIA-HCM trial announced today.

After 36 weeks, symptomatic patients randomized to aficamten versus placebo had a significant improvement in the dual primary endpoints of change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score and maximal exercise performance.

Aficamten, as well as mavacamten (Camzyos; Bristol Myers Squibb), are approved for the treatment of patients with obstructive HCM, but ACACIA-HCM marks the first successful trial in patients with nonobstructive disease. The ODYSSEY-HCM trial failed to show any significant improvement in the KCCQ clinical summary score and peak oxygen consumption with mavacamten in nonobstructive HCM patients.

ACACIA-HCM included 516 patients started with aficamten 5 mg once daily, with the potential for escalating the dose up to 20 mg if an echocardiogram showed no untoward effects on left ventricular ejection fraction. Both aficamten and mavacamten, when used in patients with obstructive HCM, carry a boxed warning stating that the drugs may cause systolic dysfunction and advising echo monitoring before starting and when on treatment.  

KCCQ clinical summary score, a measure of physical limitations and symptom frequency/burden, increased in both the aficamten-treated and placebo patients, but the improvement was significantly larger in the active treatment arm (least squares mean 11.4 vs 8.4; P = 0.021). Peak oxygen consumption, also expressed as least squares mean, increased by 0.64 mL/kg/min in the aficamten group but decreased by 0.03 mL/kg/min in the placebo group (P = 0.003). Significant improvements in other secondary endpoints, including NYHA functional class and NT-proBNP, were also observed.

In a conference call with investors, Cytokinetics leadership announced that the change in KCCQ clinical summary score occurred around 8 weeks, with the curves maintained through the extended 72-week follow-up. At study completion, most patients transitioned to an open-label registry study.

Nearly identical numbers of patients completed the planned dosing in the two study arms. LVEF < 50% occurred in 10% of patients treated with aficamten versus in 1% taking placebo. Two patients had serious heart failure events associated with the reduction in LVEF, while 3% of aficamten-treated patients stopped treatment due to LVEF < 40%.   

“The frequency of these findings is not surprising relative to those with aficamten in [obstructive] HCM given the strategy in nonobstructive HCM to dose to a maximally tolerated dose as opposed to a minimum effective dose,” said Cytokinetics Executive Vice President Fady Malik, MD, PhD, during the investor call.

If green-lit by regulators, aficamten would be the first drug approved for the treatment of nonobstructive HCM. Full ACACIA-HCM results will be presented at a major cardiology meeting at a later date.