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.