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

Autor: Verdino P; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Lee SL; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Cooper FN; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Cottle SR; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Grealish PF; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Hu CC; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Meyer CM; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Lin J; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Copeland V; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Porter G; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Schroeder RL; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Thompson TD; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Porras LL; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Dey A; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Zhang HY; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Beebe EC; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Matkovich SJ; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Coskun T; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Balciunas AM; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Ferrante A; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Siegel R; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Malherbe L; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Bivi N; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Paavola CD; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Hansen RJ; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Abernathy MM; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Nwosu SO; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Carr MC; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Heuer JG; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA., Wang X; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2023 Aug; Vol. 180 (15), pp. 1965-1980. Date of Electronic Publication: 2023 Mar 08.
DOI: 10.1111/bph.16055
Abstrakt: Background and Purpose: Chronic heart failure, a progressive disease with limited treatment options currently available, especially in heart failure with preserved ejection fraction (HFpEF), represents an unmet medical need as well as an economic burden. The development of a novel therapeutic to slow or reverse disease progression would be highly impactful to patients and society. Relaxin-2 (relaxin) is a human hormone regulating cardiovascular, renal, and pulmonary adaptations during pregnancy. A short-acting recombinant relaxin, Serelaxin, demonstrated short-term heart failure symptom relief and biomarker improvement in acute heart failure trials. Here, we present the development of a long-acting relaxin analogue to be tested in the treatment of chronic heart failure.
Experimental Approach: LY3540378 is a long-acting protein therapeutic composed of a human relaxin analogue and a serum albumin-binding VHH domain.
Key Results: LY3540378 is a potent agonist of the relaxin family peptide receptor 1 (RXFP1) and maintains selectivity against RXFP2/3/4 comparable to native relaxin. The half-life of LY3540378 in preclinical species is extended through high affinity binding of the albumin-binding VHH domain to serum albumin. When tested in a single dose administration, LY3540378 elicited relaxin-mediated pharmacodynamic responses, such as reduced serum osmolality and increased renal blood flow in rats. In an isoproterenol-induced cardiac hypertrophy mouse model, treatment with LY3540378 significantly reduced cardiac hypertrophy and improved isovolumetric relaxation time. In a monkey cardiovascular safety study, there were no adverse observations from administration of LY3540378.
Conclusion and Implications: LY3540378 demonstrated to be a suitable clinical development candidate, and is progressing in clinical trials.
(© 2023 Eli Lilly and Company. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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