Aficamten improves clinical outcomes in obstructive HCM

Patients with obstructive hypertrophic cardiomyopathy (oHCM) can derive broad clinical benefits from treatment with aficamten, which include complete haemodynamic response and improved exercise capacity among others, as shown by the results of the SEQUOIA-HCM study.

“Over a relatively short treatment period, nearly all patients (97 percent) on aficamten experienced a clinically meaningful improvement in one or more clinically relevant outcome measures, including complete haemodynamic response, relief in limiting symptoms, enhanced exercise capacity, and significant decrease in NT-proBNP,” said lead author Dr Martin S Maron from Lahey Hospital and Medical Centre, Burlington, Massachusetts, US.

In the study, Maron and his team randomized symptomatic oHCM patients in a 1:1 ratio to receive either aficamten (n=142) or placebo (n=140) daily for 24 weeks.

The following outcomes were assessed at 24 weeks and compared with baseline: (1) improvement in the burden of limiting symptoms with ≥1 change in NYHA class and/or ≥10-point increase in the Kansas City Cardiomyopathy Questionnaire-Clinical Summary score (KCCQ-CCS), (2) complete haemodynamic response (resting and Valsalva gradient of <30 and <50 mm Hg, respectively), (3) ≥1.5 mL/kg/min change in peak oxygen consumption (pVO2), and (4) ≥50-percent decrease in serum NT-proBNP levels.

In addition, the research team also evaluated the eligibility of patients with oHCM for septal reduction therapy (SRT). [Maron MS, et al, HFSA 2024]

Of the patients randomly allocated to aficamten, 84 percent achieved a ≥50-percent reduction in NT-proBNP levels, 71 percent showed improvements in limiting symptoms, 68 percent had a complete haemodynamic response, and 47 percent exhibited better exercise capacity at week 24. Of note, all these improvements were markedly greater than those seen with placebo (p≤0.002).

Moreover, 97 percent of patients who received aficamten demonstrated improvements in one or more of the above clinically relevant outcome measures, which included 23 percent who had improvements in all four measures. These rates were significantly higher than those seen in the placebo group (59 percent and 0 percent, respectively; p<0.001 for both comparisons).

SRT eligibility

Notably, 88 percent of patients in the aficamten group who were initially eligible for SRT no longer met the criteria for such therapy at week 24. In comparison, this rate was significantly higher than the 52 percent in the placebo group (p=0.002).

“The combined effect of aficamten on improving symptomatic status and haemodynamics converted most of those patients who were guideline eligible for SRT at baseline to no longer meeting those criteria at week 24,” Maron said.

“These findings underscore the broad clinical efficacy of aficamten for the treatment of patients with symptomatic oHCM, including those eligible for SRT,” he added.

Aficamten is a novel cardiac myosin inhibitor that reduces outflow gradients and improves functional capacity in oHCM. [N Engl J Med 2024;390:1849-1861]

In patients with oHCM, “left ventricular outflow tract obstruction is the predominant mechanism responsible for limiting symptoms and other adverse consequences,” according to Maron.