Abstract 4142919: Chronic administration of EDG-7500, a novel sarcomere modulator, prevents increases in cardiac mass, T1 relaxation time, and left ventricular end diastolic pressure in a Yucatan mini-pig model of genetic non-obstructive hypertrophic

Introduction: Pathologic cardiac remodeling is a hallmark of hypertrophic cardiomyopathy (HCM). EDG-7500 is a novel oral, selective cardiac sarcomere modulator designed to slow the rate of contraction and speed the rate of relaxation without directly inhibiting myosin motor-head function. EDG-7500 is currently in a phase 2 clinical trial in HCM patients. Aims: To determine if EDG-7500 can prevent pathologic cardiac remodeling and disease progression in a mini-pig model of non-obstructive HCM (nHCM) caused by heterozygous MYH7 R403Q mutation. Approach: R403Q pigs were assigned to 2 groups; placebo control (CTRL; n=7-11) and EDG-7500 treated for 5-6 months (n=5-9), with untreated wild-type (WT; n=6-11) as reference. Cardiac magnetic resonance imaging (CMR) and terminal tissue collection occurred at 7-8 months of age. CMR sequences were collected in 12-16 parallel, short-axis views using a 3T scanner for calculation of left ventricular (LV) EF, volumes, T1-time, and LV mass. LV and left atrial (LA) mass also were measured postmortem. LV end diastolic pressure (EDP) and the end diastolic pressure-volume relationship (EDPVR) were measured in vivo via catheter. Myocardial atrial and brain natriuretic peptide (ANP and BNP) mRNA and α and β myosin heavy chain (MYHC) proteins were evaluated. Statistical significance was set at P≤0.05 (*denotes vs. CTRL) using one way ANOVA or linear regression with data reported as mean±SE. Results: EDG-7500 prevented increases in LV mass both in vivo (CMR; *45±3 vs. 61±6 in CTRL; WT, 46±3g) and postmortem without affecting LV end diastolic volume and EF. EDG-7500 attenuated: 1) increased LV EDP (*10±1 vs. 25±3 in CTRL; WT, 8±1mmHg); 2) decreased LV compliance (EDPVR *1.6±0.2 vs. 3.9±0.4 in CTRL; WT, 1.0±0.1mmHg/mL); and 3) increased LA mass (*12±1 vs. 22±2 in CTRL; WT, 7±1g). EDG-7500 also prevented increased T1-time (*971±31 vs. 1107±26 in CTRL; WT, 925±33msec), which was positively correlated to LV EDP (R=0.75). EDG-7500 prevented HCM-mediated increases in LV BNP (*16±6 vs. 46±13 in CTRL; WT, 1±0.2) and LA ANP mRNA (*3±1 vs.15±4 in CTRL; WT, 1±3), while preventing a pathologic isoform shift to more LA β-MYHC protein (*89%α:11%β vs. 75%α:25%β in CTRL; WT, 92%α:8%β). Conclusion: In a mini-pig model of nHCM, chronic EDG-7500 therapy prevents pathologic cardiac remodeling, decreased LV compliance, and disease progression without impairing resting systolic function. These findings support clinical investigation of EDG-7500 in nHCM.