Relaxin

Relaxin-2 (Human Relaxin-2 / Serelaxin)

Evidence & Status

  • Moderate Evidence
  • Moderate

At a Glance

A two-chain insulin-superfamily peptide hormone that remodels connective tissue, reduces fibrosis, and dilates blood vessels. Studied in acute heart failure (Phase III trial failed primary endpoint), renal protection, and anti-fibrotic applications. Produced naturally in pregnancy.

Plain English

Relaxin is a hormone best known for its role in pregnancy, where it helps soften connective tissue and prepare the body for childbirth. Scientists study it because those same tissue-remodelling properties make it a candidate for treating conditions where connective tissue becomes too stiff or fibrotic — such as in heart failure, kidney disease, and certain lung conditions. Recombinant serelaxin, a lab-made version of human relaxin, was tested in large clinical trials for acute heart failure. An early trial produced promising results, including a reduction in short-term deaths, but a large confirmatory study failed to reproduce the survival benefit, and clinical development for heart failure was discontinued. Research interest in relaxin continues in areas like anti-fibrosis, kidney protection, and connective tissue remodelling, where its mechanism of promoting normal tissue turnover and inhibiting excessive scar formation remains scientifically compelling.

Overview

A peptide hormone of the insulin/relaxin superfamily encoded by the RLN2 gene. Relaxin-2 is the predominant circulating form of relaxin in humans, produced by the corpus luteum during pregnancy but also expressed in the heart, kidney, and other tissues. Signals through the RXFP1 (relaxin family peptide receptor 1) and RXFP2 G-protein coupled receptors. Primary biological actions include connective tissue remodeling via matrix metalloproteinase induction and collagen remodeling, vasodilation through NO/cGMP pathways, anti-fibrotic signalling, and cervical softening during pregnancy. Recombinant serelaxin (rhRLX-2) was extensively studied for acute decompensated heart failure — the Phase II RELAX-AHF trial showed significant reductions in dyspnoea and promising mortality signals, but the confirmatory Phase III RELAX-AHF-2 trial (n=6,600) did not meet its primary or key secondary endpoints. Research continues in fibrotic diseases, renal protection, and connective tissue applications.

Research Summary

Relaxin-2 has a moderate human evidence base, primarily from the serelaxin heart failure clinical program. The Phase II RELAX-AHF trial (n=1,161) demonstrated improvements in dyspnoea relief and a striking 37% reduction in 180-day cardiovascular mortality (exploratory endpoint), generating significant interest in relaxin as a cardioprotective and vasodilatory agent. However, the confirmatory Phase III RELAX-AHF-2 trial did not meet its primary endpoint of 180-day cardiovascular mortality, and clinical development for acute heart failure was discontinued. The anti-fibrotic evidence base is largely preclinical — animal models of renal, hepatic, pulmonary, and cardiac fibrosis show consistent reversal with relaxin, mediated through MMP induction and inhibition of TGF-β profibrotic signalling. Connective tissue and reproductive biology research provides strong mechanistic context. The gap between compelling preclinical anti-fibrotic data and clinical trial outcomes reflects a recurring challenge in translational peptide research.

Research Areas

  • Connective tissue remodeling
  • Anti-fibrotic signalling
  • Cardiovascular protection
  • Renal protection
  • Reproductive biology & cervical remodeling
  • Wound healing & collagen turnover

Safety & Risks

Serious Risks

  • Clinically significant hypotension — particularly relevant with IV administration; blood pressure monitoring required in clinical settings
  • No FDA-approved indication; use outside clinical trial context is without established safety profile
  • Long-term connective tissue effects of repeated exogenous relaxin administration are not characterized
  • Phase III trial failure for acute heart failure primary endpoint; clinical development discontinued by Novartis for this indication

Reported Side Effects

  • Hypotension (vasodilatory mechanism; dose-dependent)
  • Injection site reactions
  • Headache
  • Flushing
  • Nausea (uncommon)
United States
Research only; no FDA-approved indication; serelaxin (recombinant H2 relaxin) was in Phase III trials for acute heart failure but did not receive regulatory approval
United Kingdom
Research only; no EMA approval
Australia
Research only
Canada
Research only

Citations & Sources