Development of a long‐acting relaxin analogue, LY3540378, for treatment of chronic heart failure

• DOI: 10.1111/bph.16055
• Publication Date: 2023-02-13T23:39:05Z
• Authors: Petra Verdino; Stacey L. Lee; Fariba N. Cooper; Steven R. Cottle; Patrick F. Grealish; Charlie C. Hu; Catalina M. Meyer; Joanne Lin; Victoria Copeland; Gina Porter; Richard L. Schroeder; Tyran D. Thompson; Leah L. Porras; Asim Dey; Hong Y. Zhang; Emily C. Beebe; Scot J. Matkovich; Tamer Coskun; Aldona M. Balciunas; Andrea Ferrante; Robert Siegel; Laurent Malherbe; Nicoletta Bivi; Chad D. Paavola; Ryan J. Hansen; Matthew M. Abernathy; Sylvia O. Nwosu; Molly C. Carr; Josef G. Heuer; Xiaojun Wang
• Keywords: Relaxin

Chronic heart failure, a progressive disease with limited treatment options currently available, especially in failure preserved ejection fraction (HFpEF), represents an unmet medical need as well economic burden. The development of novel therapeutic to slow or reverse progression would be highly impactful patients and society. Relaxin-2 (relaxin) is human hormone regulating cardiovascular, renal, pulmonary adaptations during pregnancy. A short-acting recombinant relaxin, Serelaxin, demonstrated short-term symptom relief biomarker improvement acute trials. Here, we present the long-acting relaxin analogue tested chronic failure.LY3540378 protein composed serum albumin-binding VHH domain.LY3540378 potent agonist family peptide receptor 1 (RXFP1) maintains selectivity against RXFP2/3/4 comparable native relaxin. half-life LY3540378 preclinical species extended through high affinity binding domain albumin. When single dose administration, elicited relaxin-mediated pharmacodynamic responses, such reduced osmolality increased renal blood flow rats. In isoproterenol-induced cardiac hypertrophy mouse model, significantly improved isovolumetric relaxation time. monkey cardiovascular safety study, there were no adverse observations from administration LY3540378.LY3540378 suitable clinical candidate, progressing