Novel cardiac myosin inhibitor helps with exercise capacity in obstructive HCM

Treatment with the oral selective cardiac myosin inhibitor aficamten produced improvements in peak oxygen uptake in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM), as shown in the phase III SEQUOIA-HCM trial.

After 24 weeks of treatment, the primary endpoint of peak oxygen uptake increased by a mean of 1.8 ml/kg/min with aficamten but remained unchanged with placebo (between-group difference, 1.7 ml/kg/min, 95 percent confidence interval [CI], 1.0–2.4; p<0.001). [N Engl J Med 2024;390:1849-1861]

“The effect of aficamten on exercise capacity appeared to be similar across a variety of prespecified subgroups, including patients who had been severely symptomatic (NYHA class III or IV heart failure) and functionally limited (peak oxygen uptake of ≤18 ml per kilogram per minute) at baseline,” the investigators noted.

Additionally, unlike with mavacamten in the EXPLORER-HCM trial, which suggested that beta-blockers might interfere with the positive effects of the drug, the treatment effects of aficamten did not appear to be influenced by background beta-blocker use and the presence of a pathogenic sarcomere gene variant, they added. [Lancet 2020;396:759-769]

Easing of blockage

Results for all 10 secondary endpoints also favoured aficamten, including the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; between-group difference, 7 points), proportion of patients achieving an improvement of at least one NYHA class (between-group difference, 34.2 percent), left ventricular outflow tract gradient after the Valsalva maneuver (between-group difference, –50 mm Hg), and total duration of septal reduction therapy eligibility during treatment period (between-group difference, −78 days), among others.

“The effect of aficamten on the left ventricular outflow tract gradient after the Valsalva maneuver was relatively rapid, with a least-squares mean difference between the groups of −20 mm Hg after 2 weeks,” the investigators said.

“These changes in haemodynamics and symptoms were also reflected in the significantly less amount of time that patients in the aficamten group were eligible (according to professional guidelines) for septal reduction therapy, with a least-squares mean difference of 78 fewer days with aficamten than with placebo,” they added.

The investigators postulated that the increase in exercise capacity with aficamten may be attributed to the rapid and sustained reduction in left ventricular outflow tract gradients throughout the treatment period.

Few low EF events

At week 24, the left ventricular ejection fraction (LVEF) among aficamten-treated patients was “modestly lower” than among those who received placebo (mean difference, –4.8 percentage points), with the difference disappearing after the 4-week washout period at the end of the trial. A transient reduction of <50 percent in LVEF was reported in five patients (3.5 percent) in the aficamten group, but none of them required treatment interruption or experienced heart failure exacerbation.

Serious adverse events (AEs) occurred in 5.6 percent of patients in the aficamten group and in 9.3 percent in the placebo group. AEs such as paranoia with aficamten and syncope and lymphocytic leukaemia with placebo led to early treatment discontinuation. Commonly reported AEs in the aficamten group were palpitations (7.0 percent vs 2.9 percent) and hypertension (7.7 percent vs 2.1 percent).

The investigators noted that all changes in the left ventricular outflow tract gradient, symptoms, and LVEF with aficamten returned to baseline after the washout period, indicating rapid reversibility of the drug’s pharmacodynamic effects.

SEQUOIA-HCM included 282 adult patients (mean age 59.1 years, 59.2 percent men) with symptomatic obstructive HCM. At baseline, the mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8 percent.

The patients were randomly assigned to receive treatment with aficamten (n=142) or placebo (n=140) for 24 weeks. Aficamten was initially dosed at 5 mg, with dose adjustments up to a maximum of 20 mg based on echocardiography results.

“The outcomes observed in this trial with aficamten appear to be generalizable to the broad, global population of patients with obstructive HCM encountered in clinical practice. Women were well represented (40.8 percent). Although ethnic diversity was rather limited, the patients in the trial were from North America, Europe, Israel, and China,” the investigators said.

“The clinical profile of the population included patients with typical characteristics of obstructive HCM, including those with a range of left ventricular outflow tract gradients and left ventricular wall thicknesses, and was inclusive of all conventional HCM background therapy use,” they added.