The peptide hormone relaxin has numerous roles both within and independent of pregnancy and is often thought of as a “pleiotropic hormone.” Relaxin targets several tissues throughout the body, and has many functions associated with extracellular matrix remodeling and the vasculature. This review considers the potential therapeutic applications of relaxin in cervical ripening, in vitro fertilization, preeclampsia, acute heart failure, ischemia-reperfusion, and cirrhosis. We first outline the animal models used in preclinical studies to progress relaxin into clinical trials and then discuss the findings from these studies. In many cases, the positive outcomes from preclinical animal studies were not replicated in human clinical trials. Therefore, the focus of this review is to evaluate the various animal models used to develop relaxin as a potential therapeutic and consider the limitations that must be addressed in future studies. These include the use of human relaxin in animals, duration of relaxin treatment, and the appropriateness of the clinical conditions being considered for relaxin therapy.

The availability of highly purified recombinant human relaxin, serelaxin, has allowed clinical trials to be conducted in several indications and the elucidation of its pharmacology in human subjects. These studies have demonstrated that serelaxin has unique haemodynamic properties that are likely to contribute to organ protection and long‐term outcome benefits in acute heart failure. Clinical observations support its consideration for therapeutic use in other patient populations, including those with chronic heart failure, coronary artery disease, portal hypertension and acute renal failure.

The availability of highly purified recombinant human relaxin, serelaxin, has allowed clinical trials to be conducted in several indications and the elucidation of its pharmacology in human subjects. These studies have demonstrated that serelaxin has unique haemodynamic properties that are likely to contribute to organ protection and long-term outcome benefits in acute heart failure. Clinical observations support its consideration for therapeutic use in other patient populations, including those with chronic heart failure, coronary artery disease, portal hypertension and acute renal failure.

Extensive uterine adaptations, including angiogenesis, occur prior to implantation in early pregnancy and are potentially regulated by the peptide hormone relaxin. This was investigated in two studies. First, we took a microarray approach using human endometrial stromal (HES) cells treated with relaxin in vitro to screen for target genes. Then we aimed to investigate whether or not relaxin deficiency in mice affected uterine expression of representative genes associated with angiogenesis and uterine remodeling, and also blood vessel proliferation in the pre-implantation mouse endometrium.

Background: Nearly 30% of patients (pts) are rehospitalized within 60–90 days of discharge after an episode of acute heart failure (AHF). Serelaxin, currently in Phase III AHF trials, has been shown to reduce in-hospital worsening HF and mortality in AHF pts. As serelaxin may be repeatedly administered, the RELAX-REPEAT study assessed the safety and immumogenicity of repeat serelaxin doses in pts with compensated chronic HF. Methods: In this multicenter, double-blind, Phase IIb study (NCT01982292), pts received 3 sequential 48 hour IV infusions of serelaxin 30 µg/kg/day or placebo (2:1) at randomization, Week (Wk) 4, and 8, in addition to standard of care. Primary objective was to assess proportion of pts developing anti serelaxin antibodies at any time following serelaxin infusions. Secondary objectives included other assessments of possible serelaxin immunogenicity and safety and tolerability of repeat infusions. Exploratory assessments included effects on renal function and other biomarkers. Results: Of the 323 pts randomized, 320 (serelaxin, n = 212; placebo, n = 108) were included in the safety set. Twelve pts from the serelaxin group were excluded as they did not meet prespecified antibody analysis criteria. One of 200 pts (0.5%) who received serelaxin had anti serelaxin antibody positive results (non neutralizing) at Wk 2 through Wk 12 that were undetectable at Wk 16 and not associated with any AEs. There is 95% confidence that the true proportion of pts who develop antibodies following repeat serelaxin doses is less than 2.4% (upper limit of the exact 1-sided CI). There were no confirmed hypersensitivity or infusion related reactions following adjudication in either treatment groups; overall incidence of all treatment-emergent AEs was comparable. There were statistically significant decreases in cystatin-C and increases in eGFR following each serelaxin infusion compared with placebo (Figure), and decreases in plasma aldosterone that were significant after the 3rd infusion. Conclusion: Overall, data showed that repeat doses of serelaxin were safe and well tolerated in pts with chronic HF. The immunogenicity profile of serelaxin was favorable and there were no confirmed hyperensitivity or infusion related reactions. There were notable improvements in renal function following each 48 hour serelaxin infusion.

Nonclinical studies indicate that the hormone relaxin is a good candidate for a safe cervical ripening agent that does not cause uterine contractions.

Background: Nearly 30% of patients (pts) admitted for acute heart failure (AHF) are rehospitalized within 60–90 days of discharge. Currently in Phase III trials for AHF, serelaxin has reduced in-hospital worsening HF and mortality in prior AHF studies. As pts are rehospitalized for AHF, serelaxin may be repeatedly administered, so the RELAX-REPEAT study assessed the safety and immunogenicity of repeat doses of serelaxin in pts with compensated chronic HF (CHF). Methods: In this multicenter, double-blind, placebo-controlled, Phase IIb study (NCT01982292), pts received 3 sequential 48-hour IV infusions of serelaxin 30 µg/kg/day or placebo (2:1) at randomization, Week (Wk) 4 and 8, in addition to standard of care, with final follow-up at Wk 16. The primary objective was to assess development of anti-serelaxin antibodies at any time following the serelaxin infusions. Results: Of 323 randomized, 320 (serelaxin, n = 212; placebo, n = 108) were included in the safety set. Twelve pts from the serelaxin group were excluded from the primary analysis as they did not meet prespecified criteria for antibody analysis. One of 200 pts (0.5%) who received serelaxin had anti-serelaxin antibody positive results (non-neutralizing) at Wk 2 through Wk 12 that were undetectable at Wk 16 and not associated with any adverse events (AEs). There is 95% confidence that the true proportion of patients who develop antibodies following repeat doses of serelaxin is less than 2.4%. There were no confirmed hypersensitivity or infusion-related reactions following adjudication in either treatment group; incidence of treatment-emergent AEs was comparable. There were statistically significant decreases in cystatin-C and increases in estimated glomerular filtration rate (eGFR) following each serelaxin infusion compared with placebo (Figure), as well as decreases in plasma aldosterone that were significant after the third infusion. Conclusion: These data show that repeat doses of serelaxin were safe and well tolerated in pts with CHF. The immunogenicity profile of serelaxin was favorable and there were notable improvements in renal function following completion of each 48-hour serelaxin infusion.

Background: Elevated plasma concentrations of liver function tests are prevalent in patients with chronic heart failure (HF). Little is known about liver function in patients with acute HF. We aimed to assess the prevalence and prognostic value of serial measurements of liver function tests in patients admitted with acute decompensated HF.Methods: We investigated liver function tests from all 234 patients from the Relaxin for the Treatment of Patients With Acute Heart Failure study at baseline and during hospitalization. The end points were worsening HF through day 5, 60-day mortality or rehospitalization, and 180-day mortality.Results: Mean age was 70 +/- 10 years, 56% were male, and most patients were in New York Heart Association functional class III/IV (73%). Abnormal liver function tests were frequently found. for alanine transaminase (ALT; 12%), aspartate transaminase (AST; 21%), alkaline phosphatase (12%), and total bilirubin (19%), and serum albumin (25%) and total protein (9%) were decreased. In-hospital changes were very small. On a continuous scale, baseline ALT and AST were associated with 180-day mortality (hazard ratios [HRs; per doubling] 1.52 [P = .030] and 1.97 [P = .013], respectively) and worsening HF through day 5 (HRs [per doubling] 1.72 [P = .005] and 1.95 [P = .008], respectively). Albumin was associated with 180-day mortality (HR 0.86; P = .001) but not with worsening HF (HR 0.95; P = .248). Total protein was associated with only worsening HF (HR 0.91; P = .004).Conclusions: Abnormal liver function tests are often present in patients with acute HF and are associated with an increased risk for mortality, rehospitalization, and in-hospital worsening HF.

Background\r\nLittle is known about mode of death after acute heart failure (AHF) hospitalization. In the RELAX-AHF (Efficacy and Safety of Relaxin for the Treatment of Acute Heart Failure) study, serelaxin, the recombinant form of human relaxin-2, reduced post-discharge mortality at 180 days in selected patients with AHF.

BACKGROUND Little is known about mode of death after acute heart failure (AHF) hospitalization. In the RELAX-AHF (Efficacy and Safety of Relaxin for the Treatment of Acute Heart Failure) study, serelaxin, the recombinant form of human relaxin-2, reduced post-discharge mortality at 180 days in selected patients with AHF.OBJECTIVES The goal of this study was to assess the effect of serelaxin on specific modes of death in patients with AHF.METHODS The RELAX-AHF study randomized 1,161 patients with AHF to 48 h of therapy with intravenous serelaxin or placebo. Patients were followed for vital status through 180 days. A blinded clinical events committee reviewed all deaths and adjudicated a cause of death on the basis of pre-specified criteria. Cox proportional hazard models were used to assess the effect of serelaxin on each mode of death, on the basis of pre-specified groupings of mode of death.RESULTS There were 107 deaths (9.3%): 37 (35%) due to HF, 25 (23%) due to sudden death, 15 (14%) due to other cardiovascular (CV) causes, 19 (18%) due to non-CV causes, and 11 (10%) classified as unknown. The treatment effect of serelaxin was most pronounced on other CV deaths (hazard ratio [HR]: 0.29; 95% CI: 0.12 to 0.73; p = 0.005) and sudden death (HR: 0.46; 95% CI: 0.20 to 1.07; p = 0.065). There was no apparent impact of serelaxin treatment on HF deaths or non-CV deaths.CONCLUSIONS In the RELAX-AHF study, the effects of serelaxin on mortality were primarily driven by reduction in mortality from other CV causes and sudden death, without apparent impact on HF deaths. (Efficacy and Safety of Relaxin for the Treatment of Acute Heart Failure [RELAX-AHF];

AIM:Patients hospitalized for acute heart failure (AHF) differ with respect of many clinical characteristics which may influence their prognosis and response to treatment. We have assessed possible differences in the effects of serelaxin on dyspnoea relief, 60 Day outcomes and 180 Day mortality across patient subgroups in the RELAX-AHF trial.METHODS AND RESULTS:Subgroups were based on pre-specified covariates (age, sex, race, geographic region, estimated glomerular filtration rate, time from presentation to randomization, baseline systolic blood pressure, history of diabetes, atrial fibrillation, ischaemic heart disease, cardiac devices, i.v. nitrates at randomization). Other covariates which may modify the efficacy of AHF treatment were also analysed. Subgroup analyses did not show any difference in the effects of serelaxin vs. placebo on dyspnoea relief or on the incidence of cardiovascular death or rehospitalizations for heart failure or renal failure at 60 days. Nominally significant interactions between some patient subgroups and the effects of serelaxin on 180 days cardiovascular and all-cause mortality were noted but should be interpreted cautiously due to the number of comparisons and the low incidence of deaths in the subgroups at lower risk.CONCLUSION:The effects of serelaxin vs. placebo appeared to be similar across subgroups of patients in RELAX-AHF.

Aims Serelaxin is effective in relieving dyspnoea and improving multiple outcomes in acute heart failure (AHF). Many AHF patients have preserved ejection fraction (HFpEF). Given the lack of evidence-based therapies in this population, we evaluated the effects of serelaxin according to EF in RELAX-AHF trial.Methods and results RELAX-AHF randomized 1161 AHF patients to 48-h serelaxin (30 mu g/kg/day) or placebo within 16 h from presentation. We compared the effects of serelaxin on efficacy endpoints, safety endpoints, and biomarkers of organ damage between preserved (a parts per thousand yen50%) and reduced (< 50%, HFrEF) EF. HFpEF was present in 26% of patients. Serelaxin induced a similar dyspnoea relief in HFpEF vs. HFrEF patients by visual analogue scale-area under the curve (VAS-AUC) through Day 5 [mean change, 461 (-195, 1117) vs. 397 (10, 783) mm h, P = 0.87], but had possibly different effects on the proportion of patients with moderately or markedly dyspnoea improvement by Likert scale at 6, 12, and 24 h [odds ratio for favourable response, 1.70 (0.98, 2.95) vs. 0.85 (0.62, 1.15), interaction P = 0.030]. No differences were encountered in the effect of serelaxin on short- or long-term outcome between HFpEF and HFrEF patients including cardiovascular death or hospitalization for heart/renal failure through Day 60, cardiovascular death through Day 180, and all-cause death through Day 180. Similar safety and changes in biomarkers (high-sensitivity troponin T, cystatin-C, and alanine/aspartate aminotransferases) were found in both groups.Conclusions In AHF patients with HFpEF compared with those with HFrEF, serelaxin was well tolerated and effective in relieving dyspnoea and had a similar effect on short- and long-term outcome, including survival improvement.

Objectives The aim of this study was to assess the effects of serelaxin on short-term changes in markers of organ damage and congestion and relate them to 180-day mortality in patients with acute heart failure.Background Hospitalization for acute heart failure is associated with high post-discharge mortality, and this may be related to organ damage.Methods The Pre-RELAX-AHF (Relaxin in Acute Heart Failure) phase II study and RELAX-AHF phase III study were international, multicenter, double-blind, placebo-controlled trials in which patients hospitalized for acute heart failure were randomized within 16 h to intravenous placebo or serelaxin. Each patient was followed daily to day 5 or discharge and at days 5, 14, and 60 after enrollment. Vital status was assessed through 180 days. In RELAX-AHF, laboratory evaluations were performed daily to day 5 and at day 14. Plasma levels of biomarkers were measured at baseline and days 2, 5, and 14. All-cause mortality was assessed as a safety endpoint in both studies.Results Serelaxin reduced 180-day mortality, with similar effects in the phase II and phase III studies (combined studies: N = 1,395; hazard ratio: 0.62; 95% confidence interval: 0.43 to 0.88; p = 0.0076). In RELAX-AHF, changes in markers of cardiac (high-sensitivity cardiac troponin T), renal (creatinine and cystatin-C), and hepatic (aspartate transaminase and alanine transaminase) damage and of decongestion (N-terminal pro-brain natriuretic peptide) at day 2 and worsening heart failure during admission were associated with 180-day mortality. Serelaxin administration improved these markers, consistent with the prevention of organ damage and faster decongestion.Conclusions Early administration of serelaxin was associated with a reduction of 180-day mortality, and this occurred with fewer signs of organ damage and more rapid relief of congestion during the first days after admission. (J Am Coll Cardiol 2013; 61: 196-206) (C) 2013 by the American College of Cardiology Foundation

Background Acute heart failure (AHF) remains a major public health burden with a high prevalence and poor prognosis. Relaxin is a naturally occurring peptide hormone that increases cardiac output, arterial compliance, and renal blood flow during pregnancy. The RELAX-AHF-1 study will evaluate the effect of RLX030 (recombinant form of human relaxin 2) on symptom relief and clinical outcomes in patients with AHF.Methods The protocol includes a completed phase 2 234-patient dose-finding study (Pre-RELAX-AHF) and an ongoing phase 3 1,160-patient trial (RELAX-AHF-1). Patients with AHF and systolic blood pressure >125 mm Hg are randomized within 16 hours of presentation to a 48-hour IV infusion of RLX030 or placebo. The 30 mu g/kg per day dose of RLX030 was chosen for RELAX-AHF-1 based on effects on dyspnea, clinical outcomes, and safety observed in Pre-RELAX-AHF. Primary efficacy end points in RELAX-AHF-1 are (1) the area under the curve of change of the dyspnea Visual Analog Scale from baseline through day 5 and (2) whether the patient reports moderately to markedly better dyspnea at 6, 12, and 24 hours. Secondary efficacy end points include days alive and out of the hospital through day 60 and cardiovascular death or rehospitalization for heart failure or renal failure through day 60. Patients will be followed up through day 180 for mortality. As of September 19, 2011, 978 patients have been enrolled.Conclusions Pre-RELAX-AHF results suggested that infusion of RLX030 may accelerate dyspnea relief and improve prognosis in patients hospitalized with AHF. RELAX-AHF-1 will further evaluate these effects. (Am Heart J 2012;163:149-155.e1.)