Abstract We094: Acute Administration of The Novel Cardiac Sarcomere Modulator EDG-7500, Improves Ventricular Filling While Preserving LVEF In Dogs with Pacing Induced Left-Ventricular Systolic Dysfunction

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Introduction: EDG-7500 is a cardiac sarcomere modulator that has been shown to slow early LV contraction and to improve diastolic filling, without directly inhibiting cardiac myosin. To assess the acute hemodynamic effects of EDG-7500 in a model of depressed systolic and diastolic LV function, we studied dogs with pacing-induced LV dysfunction before and after EDG-7500 administration. Methods: Beagle dogs (n = 7) underwent chronic RV pacing (180 to 240 ppm), and were studied, in sinus rhythm, at two levels of induced-dysfunction: mid-range EF (mEF, targeting 50%), and reduced EF (rEF, targeting 40%). At each level, animals were evaluated by echocardiography before and after administration of 0.3 mg/kg IV EDG-7500. Healthy beagle dogs served as disease controls (n = 7). Results: Post-pacing (Paced) dogs had depressed EF (mEF: 50 ± 4 and rEF: 40 ± 4 vs. 74 ± 1%, P < 0.05) and short-axis global circumferential strain (mEF: -23 ± 2 and rEF: -14 ± 2 vs. -33 ± 1%, P < 0.05), and elevated NT-proBNPs (mEF: 1,049 ± 319 and rEF: 4,236 ± 722 vs. 302 ± 27 pmol/L, P < 0.05) when compared vs. healthy dogs. Paced dogs had slower early diastolic mitral annular velocity (mean e’, mEF: 11.0 ± 0.9 and rEF: 8.4 ± 0.8 vs. 14.2 ± 0.7 cm/s, P < 0.05) and elevated E/e’ (mEF: 7.4 ± 0.7 and rEF: 8.4 ± 0.9 vs. 6.0 ± 0.2 n/u, P < 0.05), at similar heart rates. Acute EDG-7500 increased e’ (mean e’, mEF: +9 ± 2 and rEF: +12 ± 3%, P<0.05) and decreased E/e’ (mEF: -7 ± 2% and rEF: -9 ± 2%, P<0.05), with no detectable effects on EF (mEF: +3 ± 6% and rEF: -5 ± 3%, P=NS). There were no adverse clinical observations. Conclusions: Treatment with EDG-7500 was well tolerated in dogs with tachycardia-induced mid-range (mEF) and reduced LV systolic function (rEF). In both cases, EDG-7500 improved echocardiographic indices of early ventricular filling and filling pressures, without observable effect on systolic performance. This data supports exploration of the effects of EDG-7500 in patient populations with LV diastolic dysfunction and mild to moderately reduced cardiac systolic performance.