Aficamten is associated with improvements in cardiac mechanics in obstructive hypertrophic cardiomyopathy: Results from FOREST-HCM

BACKGROUND: Aficamten is a next-in-class, selective cardiac myosin inhibitor (CMI) that relieves left ventricular outflow tract (LVOT) obstruction in obstructive hypertrophic cardiomyopathy (oHCM) by addressing underlying myocardial hypercontractility. The long-term impact of aficamten on myocardial mechanics as measured by global longitudinal strain (GLS) is unknown. METHODS: FOREST-HCM (NCT04219826) is an ongoing open-label extension trial for eligible patients with HCM who completed a parent study of aficamten. Here we report echocardiographic parameters (LVOT gradient and myocardial GLS) obtained from baseline up to week 48 from oHCM patients (N = 27) included in the FOREST-HCM study. RESULTS: From baseline to 38 ± 4.8 weeks, aficamten reduced LVOT gradients at rest (mean difference - 32.7 ± 24 mmHg, p < 0.0001 vs. baseline) and with Valsalva (mean difference - 62.44 ± 34.5 mmHg, p < 0.0001 vs. baseline). Compared to baseline, strain analysis revealed similar GLS at week 12 (-13.9 ± 3.2 vs. -14.3 ± 3.0, p = 0.316) but a significant improvement at weeks 36-48 (-13.9 ± 3.2 vs. -15.1 ± 2.7, p = 0.0093). These improvements were only seen in patients who achieved a hemodynamic response (resting LVOT-G < 30 mmHg, n = 24, p = 0.0009; or complete response with rest <30 mmHg and Valsalva <50 mmHg, n = 21, p = 0.0023). CONCLUSIONS: Aficamten therapy improves myocardial mechanics after long-term treatment, which may indicate functional myocardial improvement incremental to relief of outflow obstruction. The potential mechanisms underlying this improvement warrant further investigation. REGISTRATION: https://clinicaltrials.gov/study/NCT04848506; Clinical trial identifier: NCT04848506.