EDG-7500, a Novel Cardiac Sarcomere Regulator That Preserves Intrinsic Myosin-Motor Function, Improves Cardiac Function and Reserve in a Minipig Model of Hypertrophic Cardiomyopathy

Introduction: Hypertrophic Cardiomyopathy (HCM) is a myocardial disease characterized by LV hypertrophy, hyperdynamic contraction, and diastolic dysfunction that results in impaired exercise capacity. In HCM, excess acto-myosin crossbridge formation during diastole increases myocardial stiffness leading to hindered ventricular filling and limited cardiac reserve. EDG-7500, a novel sarcomere regulator that slows the rate of contraction but does not directly inhibit the myosin motor head, may offer salutary effects in HCM with minimal reduction in systolic performance. Here, this hypothesis was tested in the setting of the pathological HCM beta-myosin heavy chain (MYH7) R403Q mutation. Methods: In vitro, force dynamics were evaluated in human IPSC-derived engineered heart tissues (EHT) with the MYH7 R403Q mutation compared to isogenic controls (WT). The biomechanical effects of EDG-7500 were evaluated in permeabilized fibers from tissues isolated from minipigs carrying the MYH7 R403Q mutation. The in vivo cardiac responses to EDG-7500 were studied via echocardiography and invasive hemodynamics in the R403Q minipigs. In a subset of pigs, β-adrenergic receptor (β-AR) dependent cardiac output reserve was studied. Results: R403Q mutant EHT preserved peak force (PF) relative to WT but impaired relaxation kinetics (RT90: +19±4 ms, 171±4 vs. 152±2 ms in WT, P<0.05). EDG-7500 (0.3uM) accelerated relaxation kinetics in R403Q EHTs (RT90: -8±3ms, 180±4 to 172±2 ms, P<0.05) without affecting PF. RT90 improvement occurred at 6-fold lower concentrations than systolic inhibition (PF IC20: 1.95 ± 0.70 μM). In vivo, EDG-7500 improved early LV filling, accelerating e’ (6.9 ± 0.8 to 8.6 ± 0.6 cm/s, P < 0.05) and decreased atrial volume (-22%, P < 0.05) while enhancing β-AR dependent cardiac output recruitment; in R403Q pigs, EDG-7500 plus dobutamine led to higher cardiac outputs relative to only dobutamine (3.1±0.3 vs. 2.6±0.3 L/min, P<0.05). Conclusions: EDG-7500, a novel cardiac sarcomere regulator, improved diastolic function in EHT and animals with the HCM-pathogenic MYH7 R403Q mutation, improving β-AR dependent cardiac output reserve. This novel profile could be valuable for the treatment of patients with HCM and diseases of diastolic dysfunction.