Cardiac myosin inhibitor, CK-586, minimally reduces systolic function and ameliorates obstruction in feline hypertrophic cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) remains the most common cardiomyopathy in humans and cats with few preclinical pharmacologic interventional studies. Small-molecule sarcomere inhibitors are promising novel therapeutics for the management of obstructive HCM (oHCM) patients and have shown efficacy in left ventricular outflow tract obstruction (LVOTO) relief. The objective of this study was to explore the 6-, 24-, and 48-hour (h) pharmacodynamic effects of the cardiac myosin inhibitor, CK-586, in six purpose-bred cats with naturally occurring oHCM. A blinded, randomized, five-treatment group, crossover preclinical trial was conducted to assess the pharmacodynamic effects of CK-586 in this oHCM model. Dose assessments and select echocardiographic variables were assessed five times over a 48-h period. Treatment with oral CK-586 safely ameliorated LVOTO in oHCM cats. CK-586 treatment dose-dependently eliminated obstruction (reduced LVOTOmaxPG), increased measures of systolic chamber size (LVIDs Sx), and decreased select measures of heart function (LV FS% and LV EF%) in the absence of impact on heart rate. At all tested doses, a single oral CK-586 dose resulted in improved or resolved LVOTO with well-tolerated, dose-dependent, reductions in LV systolic function. The results from this study pave the way for the potential use of CK-586 in both the veterinary and human clinical setting.

Keywords: Cat; Left ventricular outflow tract obstruction (LVOTO); Myosin-inhibitor; Obstructive hypertrophic cardiomyopathy (oHCM); Pharmacodynamics.

Figure 1

Study design and timepoints. Visual representation of study design and timepoints for the pharmacokinetic/dose-finding (top green) and pharmacodynamic (bottom gray) phases of the study is presented. h hour.

Figure 2

Plasma [CK-586] pharmacokinetic/dose-finding analysis. Mean total plasma [CK-586] values across four cats in the 3- and in the 10 mg/kg dose groups, as well as a single cat in the 4.8-, 10.5-, 15.9-, and 16.2 mg/kg dose groups spanning a 24 h period immediately following a single oral dose delivered as an API in capsule are illustrated. h hour, API active pharmaceutical ingredient.

Figure 3

Changes in measures of LV systolic chamber size across timepoints. Median LVIDs Sx values in six cats across Vehicle and four CK-586 oral doses (2-, 5-, 10-, and 15 mg/kg) spanning a 48 h time period are illustrated. Dashed line represents lower-bound cut-off for normal feline LVIDs Sx measurement (3.7 mm). LVIDs Sx systolic left ventricular internal diameter in short-axis, h hour.

Figure 4

Changes in measures of LV function and LV pressure gradient across timepoints. Median LV FS% (A), LV EF% (B), LVOTmaxPG (C), and LV IVRT (D) values in six cats across Vehicle and four CK-586 oral doses (2-, 5-, 10-, and 15 mg/kg) spanning a 48 h time period are illustrated. Dashed line represents the lower-bound cut-off for normal feline LV FS% measurements (35%) and the upper-bound cut-off LVOTmaxPG (14.5 mmHg)^,,. LV left ventricular, FS% percent fractional shortening, EF% percent ejection fraction, LVOTmaxPG left ventricular outflow tract maximum pressure gradient, IVRT isovolumetric relaxation time, h hour.

Figure 5

Observed incidence of LVOTO across timepoints. The total number of observed LVOTO incidences defined by an LVOT velocity > 1.9 m/s (LVOTmaxPG ≥ 14.5 mmHg)^, in six cats across Vehicle and four doses of CK-586 (2-, 5-, 10-, and 15 mg/kg). LVOTO left ventricular outflow tract obstruction, LVOT left ventricular outflow tract, LVOTmaxPG left ventricular outflow tract maximum pressure gradient, h hour.