Development of a long‐acting relaxin for the treatment of pulmonary hypertension

Background and Purpose Relaxin is a naturally occurring peptide hormone with significant cardiovascular effects, particularly during the adaptation to pregnancy. A short‐acting peptide therapeutic previously demonstrated pharmacological effects in acute heart failure. TX000045 (‘TX45’) is a long‐acting relaxin being developed for the treatment of pulmonary hypertension. Experimental Approach TX45 is human relaxin‐2 fused to the C‐terminus of the Fc domain of human IgG1, wherein the B and A chains of human relaxin are connected by a peptide linker. Protein engineering optimized the biophysical properties through adjustment of the isoelectric point. Preclinical animal models confirmed extended half‐life and known pharmacodynamic (PD) vasodilator effects on renal plasma flow. TX45 decreased inflammation, cardiac hypertrophy and pulmonary arterial muscularization in a monocrotaline (MCT) rat pulmonary hypertension model. First‐in‐human studies evaluated pharmacokinetic (PK) and PD in a double‐blind, placebo‐controlled, single ascending dose study in healthy subjects. Key Results TX45 significantly improved biophysical and PK/PD properties, relative to unmodified versions. TX45 clearly decreased pulmonary hypertension in the MCT rat model. In healthy human subjects, TX45 was well‐tolerated with a terminal elimination half‐life of 2–3 weeks and increased renal plasma flow. Repeated measures of renal plasma flow after single doses of TX45 were used to create an exposure–response model that enabled Phase 2 dose selection. Conclusions and Implications TX45 is an extended half‐life relaxin with PK and PD properties consistent with a relaxin mimetic. TX45 was well tolerated in early clinical studies. Preclinical PK/PD data predicted human PK/PD.