Effects of Aficamten on cardiac contractility in a feline translational model of hypertrophic cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiac disease in humans and cats and lacks efficacious pharmacologic interventions in the preclinical phase of disease. LV outflow tract obstruction (LVOTO) is commonly observed in HCM-affected patients and is a primary driver of heart failure symptoms and reduced quality of life. Novel small-molecule cardiac myosin inhibitors target actin-myosin interactions to alleviate overactive protein interactions. A prospective, randomized, controlled cross-over study was performed to evaluate pharmacodynamic effects of two doses (0.3 and 1 mg/kg) of a next-in-class cardiac myosin inhibitor, aficamten (CK-3773274, CK-274), on cardiac function in cats with the A31P MYBPC3 mutation and oHCM. Dose-dependent reductions in LV systolic function, LVOT pressure gradient, and isovolumetric relaxation times compared to baseline were observed. Promising beneficial effects of reduced systolic function warrant further studies of this next-in-class therapeutic to evaluate the benefit of long-term administration in this patient population.

Figure 1

Left ventricular fractional shortening (LV FS) at 6-, 24-, and 48-h post administration of treatment. (A) Vehicle. (B) Aficamten (0.3 mg/kg). (C) Aficamten (1.0 mg/kg). The median is denoted at each time point and the whiskers represent the interquartile range The overall P value is denoted on the bottom left of each graph. Where pairwise comparisons were significant they are shown with their respective P values.

Figure 2

Left ventricular systolic internal dimension (LVIDs) at 6-, 24-, and 48-h post administration of treatment. (A) Vehicle. (B) Aficamten (0.3 mg/kg). (C) Aficamten (1.0 mg/kg). The median is denoted at each time point and the whiskers represent the interquartile range. The overall P value is denoted on the bottom left of each graph. Where pairwise comparisons were significant they are shown with their respective P values.

Figure 3

Left ventricular outflow tract peak pressure gradient (LVOT PG) at 6-, 24-, and 48-h post administration of treatment. (A) Vehicle. (B) Aficamten (0.3 mg/kg). (C) Aficamten (1.0 mg/kg). The median is denoted at each time point and the whiskers represent the interquartile range. The overall P value is denoted on the bottom left of each graph. Where pairwise comparisons were significant they are shown with their respective brackets and P values.