Abstract 18358: Preclinical Evaluation of the Safety and Activity of JK07, A Novel Bifunctional Neuregulin Antibody Fusion Which Selectively Activates ErbB4, for the Treatment of Heart Failure

Abstract

Background: Neuregulin (NRG) is a cardioregenerative growth factor that stimulates ErbB3 and ErbB4 signaling. NRG exhibited promising activity clinically in NYHA II/III heart failure (HF) patients, but concerns over cancer risk and GI tolerability limited development. Selective ErbB4 agonism might improve the tolerability and safety of NRG, but this hypothesis has not been evaluated previously due to lack of a selective ErbB4 agonist. JK07 is an ErbB3 antagonist antibody fused with the active domain of NRG-1, designed to selectively stimulate ErbB4. Methods: ErbB3 and ErbB4 activation by JK07 was evaluated in vitro in comparison to NRG-1. A left anterior descending (LAD) ligation model of HF in rats evaluated the ability of JK07 to improve left ventricular ejection fraction (LVEF) and alleviate symptoms of HF in comparison to control antibody-fused NRG-1. A rhesus macaque model of spontaneous heart failure was used to evaluate JK07’s ability to improve LVEF in animals with reduced LVEF (HFrEF) and to improve diastolic dysfunction in animals with preserved LVEF (HFpEF), in comparison to vehicle control and sacubitril/valsartan. Results: JK07 showed ErbB4 activation equivalent to NRG-1 in vitro, but significant attenuation of ErbB3 activation. In the LAD ligation model, JK07 induced dose-dependent increased LVEF, reverse remodeling, reduced collagen I deposition, reduced peripheral edema, increased exercise capacity and decreased infarct size. JK07 improvements were comparable to control NRG. In the rhesus model of HFrEF, both sacubitril/valsartan and JK07 treatment increased EF by at least 5% absolute in 7/10 animals, compared to 0/6 animals with placebo. In the rhesus model of HFpEF, diastolic dysfunction was improved by at least one grade in 6/10 animals receiving JK07, 1/10 animals receiving sacubitril/valsartan, and 0/6 animals receiving placebo. Conclusions: JK07 selectively activates ErbB4 in vitro. In a rodent LAD model of HF, selective ErbB4 activation was as effective as NRG-1 in improving LVEF and symptoms. In a spontaneous heart failure model in rhesus macaques, JK07 treatment was comparable to sacubitril/valsartan in the treatment of HFrEF and superior to sacubitril/valsartan in the treatment of HFpEF.