Aficamten is a next-in-class cardiac myosin inhibitor designed to target the myocardial hypercontractility and impaired relaxation that is responsible for the pathophysiology of nHCM, resulting in generation of symptoms and function impairment. This was the rationale to explore aficamten in cohort 4 of the REDWOOD-HCM trial (NCT04219826) as a potential novel therapy for nHCM. Ahmad Masri, MD, presented the results.

In cohort 4, 41 patients with symptomatic nHCM (New York Heart Association [NYHA] class II/III) with a left ventricular ejection fraction (LVEF) 60% or greater and NT-proBNP concentrations of more than 300 pg/mL were screened and treated with aficamten in addition to standard of care. Aficamten in available doses of 5 mg, 10 mg, and 15 mg was up-titrated if LVEF was 55% or greater, maintained if LVEF was 50% to 54%, down-titrated if LVEF was less than 50%, and discontinued if LVEF was less than 40%.

At 10 weeks, dose titration of the myosin inhibitor led to a modest and reversible reduction in LVEF from baseline of -5.5%. No treatment interruptions or down-titration events according to the protocol were necessary. The participants showed a mean improvement in the Kansas City Cardiomyopathy Questionnaire of 10.6 points (P<0.0001 for change from baseline to 10 weeks). Also, 58% of participants had clinical reduction in symptom burden, with almost half of them reporting moderate to very large improvements. “This far exceeds what you expect from placebo,” Dr. Masri said. Moreover, 56% of all patients demonstrated function improvement of  NYHA class 1 or greater, and 28% of participants achieved NYHA class 1 and became asymptomatic by week 10. In addition, the frequency of angina was reduced from daily or weekly to weekly or monthly upon treatment.

The improvement of symptoms was accompanied by distinct reductions in cardiac biomarkers. Significant improvement in NT-proBNP was seen with an average decrease of 66% (P<0.0001).

At 10 weeks, three (7.3%) participants experienced LVEF less than 50%, but all LVEF returned to baseline levels after 2 weeks of washout. In addition, there were no serious adverse events attributed to aficamten therapy. A subgroup analysis showed a consistent treatment effect across multiple subgroups independent of responder definition. Notably, seven patients with mid-cavitary obstruction, who are often excluded from other studies but experience substantially from limiting symptoms, also showed reductions in both biomarkers and symptom improvement. A phase 3 study is planned to further evaluate aficamten in nHCM.

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