Dataset Information

Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial.

ABSTRACT:

Background

Chronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal vasoconstriction characterizes hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury in patients with advanced cirrhosis, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients and is limited by ischemic adverse events. Serelaxin (recombinant human relaxin-2) is a peptide molecule with anti-fibrotic and vasoprotective properties that binds to relaxin family peptide receptor-1 (RXFP1) and has been shown to increase renal perfusion in healthy human volunteers. We hypothesized that serelaxin could ameliorate renal vasoconstriction and renal dysfunction in patients with cirrhosis and portal hypertension.

Methods and findings

To establish preclinical proof of concept, we developed two independent rat models of cirrhosis that were characterized by progressive reduction in renal blood flow and glomerular filtration rate and showed evidence of renal endothelial dysfunction. We then set out to further explore and validate our hypothesis in a phase 2 randomized open-label parallel-group study in male and female patients with alcohol-related cirrhosis and portal hypertension. Forty patients were randomized 1:1 to treatment with serelaxin intravenous (i.v.) infusion (for 60 min at 80 ?g/kg/d and then 60 min at 30 ?g/kg/d) or terlipressin (single 2-mg i.v. bolus), and the regional hemodynamic effects were quantified by phase contrast magnetic resonance angiography at baseline and after 120 min. The primary endpoint was the change from baseline in total renal artery blood flow. Therapeutic targeting of renal vasoconstriction with serelaxin in the rat models increased kidney perfusion, oxygenation, and function through reduction in renal vascular resistance, reversal of endothelial dysfunction, and increased activation of the AKT/eNOS/NO signaling pathway in the kidney. In the randomized clinical study, infusion of serelaxin for 120 min increased total renal arterial blood flow by 65% (95% CI 40%, 95%; p < 0.001) from baseline. Administration of serelaxin was safe and well tolerated, with no detrimental effect on systemic blood pressure or hepatic perfusion. The clinical study's main limitations were the relatively small sample size and stable, well-compensated population.

Conclusions

Our mechanistic findings in rat models and exploratory study in human cirrhosis suggest the therapeutic potential of selective renal vasodilation using serelaxin as a new treatment for renal dysfunction in cirrhosis, although further validation in patients with more advanced cirrhosis and renal dysfunction is required.

Trial registration

ClinicalTrials.gov NCT01640964.

SUBMITTER: Snowdon VK

PROVIDER: S-EPMC5330452 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Publications

Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial.

Snowdon Victoria K VK Lachlan Neil J NJ Hoy Anna M AM Hadoke Patrick W F PW Semple Scott I SI Patel Dilip D Mungall Will W Kendall Timothy J TJ Thomson Adrian A Lennen Ross J RJ Jansen Maurits A MA Moran Carmel M CM Pellicoro Antonella A Ramachandran Prakash P Shaw Isaac I Aucott Rebecca L RL Severin Thomas T Saini Rajnish R Pak Judy J Yates Denise D Dongre Neelesh N Duffield Jeremy S JS Webb David J DJ Iredale John P JP Hayes Peter C PC Fallowfield Jonathan A JA

PLoS medicine 20170228 2

<h4>Background</h4>Chronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal vasoconstriction characterizes hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury in patients with advanced cirrhosis, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients and is limited by ischemic adverse events. Serelaxin (reco ...[more]

PMID: 28245243

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Project description:BACKGROUND:In preclinical models, recombinant human relaxin-2 (serelaxin) had anti-fibrotic effects and ameliorated portal hypertension (PH). A small exploratory study in patients with cirrhosis also suggested that serelaxin could reduce portal pressure. METHODS:In a phase 2, double-blind, randomised controlled study conducted in a single centre (Royal Infirmary of Edinburgh, UK), male and female adult participants with cirrhosis and clinically significant PH (CSPH; hepatic venous pressure gradient (HVPG) >?10?mmHg) were enrolled. Participants were allocated to serelaxin or placebo in a 3:1 ratio. The placebo was matched to serelaxin on appearance and administration protocol to create and maintain blinding. The primary endpoint was the change from baseline in fasting HVPG after 2?h of peripheral i.v. serelaxin infusion (80??g/kg/day for 60?min followed by 30??g/kg/day for at least 60?min). Secondary endpoints included the change from baseline in hepatic blood flow and systemic haemodynamics (cardiac index, systemic vascular resistance index and aortic pulse wave velocity). Short-term safety and tolerability of serelaxin were assessed. RESULTS:A total of 17 participants were screened, 15 were randomised and 11 completed the study (n =?9 serelaxin, n =?2 placebo). Reasons for withdrawal were baseline HVPG <?10?mmHg (n =?2) and technical failure (n =?2). The trial ended early due to manufacturer discontinuation of the study drug. The median age was 56 (range 43-69) years and 73% of participants were male. Alcohol was the commonest cirrhosis aetiology (n =?10). Participants had a median Model for End-Stage Liver Disease score of 10 (range 6-14). The mean baseline HVPG was 16.3?(range 10.3-21.7) mmHg. Individual responses were variable, but overall there was no statistically significant change in HVPG after 2?h of i.v. serelaxin (arithmetic mean of difference?±?SD was 0.4?±?3.5?mmHg (95% CI -2.3, 3.1; p =?0.76)). There were also no substantial changes from baseline in hepatic or systemic haemodynamics. We recorded 12 adverse events in 7 participants treated with serelaxin; none were significant, and most were unrelated to the investigational medicinal product. There were no serious adverse events. CONCLUSION:In a small randomised, phase 2, proof-of-concept study in patients with cirrhosis and CSPH, serelaxin infusion was safe and well-tolerated but had a neutral effect on HVPG. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02669875. Registered on 1 February 2016.

Dataset Information

Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial.

Background

Methods and findings

Conclusions

Trial registration

Publications

Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial.

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