Serelaxin a novel treatment for acute heart failure

Abstract

Acute heart failure (AHF) represents a major healthcare burden with a high risk of in-hospital and post-discharge mortality, which remained almost unchanged in the last few decades, underscoring the need of new treatments. Relaxin is a naturally occurring human peptide initially identified as a reproductive hormone and has been shown to play a key role in the maternal hemodynamic and renal adjustments that accommodate pregnancy. Recently, the new molecule serelaxin, a recombinant form of the naturally occurring hormone relaxin has been studied in patients hospitalized for AHF. In addition to vasodilation, serelaxin has anti-oxidative, anti-inflammatory and connective tissue regulating properties. In preclinical studies, it reduced both systemic and renal vascular resistance and, in the clinical trials Pre-RELAX-AHF and RELAX-AHF, it improved dyspnea and signs of congestion. In addition, serelaxin was associated with a reduction of 180-day mortality. The aim of this review is to summarize the pharmacological properties of serelaxin and the results of the preclinical and clinical studies.

Keywords:

• acute heart failure
• heart failure
• serelaxin
• treatment
• vasodilator

Financial & competing interests disclosure

M Metra has received consulting honoraria from Novartis and Bayer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Relaxin is a naturally occurring human peptide initially identified as a reproductive hormone. Recently, the new molecule serelaxin, a recombinant form of the naturally occurring hormone relaxin, released during pregnancy, has been studied in patients hospitalized for acute heart failure (AHF).

• Relaxin is synthesized in the corpus luteum of the ovary and women are exposed to monthly elevation of relaxin during the luteal phase. In men, relaxin is synthesized and is present in the prostate and very low levels may be present in the circulation although little is known about the physiology of relaxin in male subjects [9]. Serelaxin (RLX030, Novartis) is the recombinant form of human relaxin-2.

• Serelaxin is cleared in the body via catabolism by proteases/peptidases, which are not affected by cytochrome P450 enzyme. Serelaxin has two G-protein coupled receptors, relaxin family peptide 1 (RXFP-1) and RXFP2. Activation of nitric oxide synthase appears to be central in the vascular modulation effects of serelaxin. The serelaxin-induced sustained vasodilator pathway utilizes the endogenous ET system, which regulates vascular tone via a balance between vasodilation and vasoconstriction.

• In the dose-finding, Pre-RELAX-AHF trial serelaxin provided the most notable beneficial effects in five of seven primary treatment targets, with some nominal improvement in dyspnea relief, cardiovascular death or readmission at 60 days, and cardiovascular death at 180 days, as well as non-significant improvement in length of hospital stay and days alive out of hospital at 60 days.

• In the clinical trials designed to evaluate systemic and renal hemodynamic response, serelaxin reduced pulmonary capillary wedge pressure and improved renal plasma flow respectively.

• In the RELAX-AHF study, in patients hospitalized for AHF serelaxin significantly reduced dyspnea over the first 24 hours and showed a significant reduction of 180-day all-cause and cardiovascular mortality.

• Several clinical trials in patients with AHF demonstrated that serelaxin improves symptoms and hemodynamics with an excellent safety profile.

Notes