Acute administration of EDG-15400, a novel cardiac sarcomere modulator, improves left ventricular compliance and cardiac reserve in a genetic mini-pig model of HCM with relevance to HFpEF
C E Craig Emter, M H Marcus Henze, S R Steve Roof, S F Shane Falero, N H Natalie Hawryluk, E D Emy Dinatale, A R Alan RussellAbstract
Introduction
Diastolic dysfunction characterized by increased left ventricular (LV) filling pressures and decreased cardiac reserve under stress are hallmarks of heart failure with preserved ejection fraction (HFpEF). EDG-15400 is a selective cardiac sarcomere modulator, specifically designed to accelerate ventricular relaxation without affecting overall systolic function currently under evaluation in a Phase 1 study.
Purpose
To determine if EDG-15400 improves diastolic function and cardiac reserve under stress without impairing systolic function in a mini-pig model of non-obstructive hypertrophic cardiomyopathy (nHCM) with translational relevance to HFpEF.
Methods
Acute cardiac responses to EDG-15400 were studied via echocardiography (N=7) and invasive pressure-volume hemodynamics (N=6) in isoflurane/fentanyl-anesthetized Yucatan mini-pigs carrying the MYH7 R403Q mutation (5-7 months old). EDG-15400 was administered over a 1-5 min IV bolus, and data were collected both at resting baseline and following β-adrenergic (β-AR) stress (dobutamine, 2 ug/kg/min IV). Plasma samples were collected immediately after imaging/hemodynamic assessment via the jugular or femoral artery. Statistical significance was set at P ≤ 0.05 (*denotes vs. baseline) using independent/paired samples t-test, repeated measures ANOVA, or linear regression with data reported as mean ± SE.
Results
EDG-15400 (0.3 mg/kg) improved LV filling by accelerating early diastolic filling velocity (e’; +15%, *9.8 ± 0.7 vs. 8.5 ± 0.3 cm/sec) from baseline with no change in LV fractional shortening (39 ± 2 vs. 37 ± 2%) or mean arterial pressure (73 ± 3 vs. 68 ± 2 mmHg). Diastolic compliance was improved, reflected by a decrease in the end diastolic pressure-volume relationship (-34%; *4.7 ± 0.7 vs. 3.1 ± 0.6 mmHg/mL) and dose-dependent (0.1-0.5 mg/kg) decrease in LV end diastolic pressure. Acute EDG-15400 increased stroke volume reserve (SVR) under β-AR stimulation (SVR via thermodilution: *6.6 ± 1.9 vs. 1.6 ± 1.0 mL). Contractility-exposure pharmacokinetic/pharmacodynamic relationships showed neither the LV end systolic pressure-volume relationship nor preload recruitable stroke work was altered by EDG-15400 with no dose-dependence.
Conclusion
Acute EDG-15400 treatment demonstrated potent improvement in LV diastolic function and cardiac reserve without impairing systolic performance in a mini-pig model of nHCM with translational relevance to HFpEF. These beneficial cardiac effects were observed without a parallel decrease in LV contractility, contrasting with current cardiac myosin inhibitors and providing support for clinical investigation of EDG-15400 in HFpEF beyond supranormal LV ejection fractions.