Hospitalization for acute heart failure (AHF) is one of the most important predictors of post-discharge mortality. While most AHF patients respond well to initial therapies, mortality and rehospitalization rates reach 20% to 30% within 3 to 6 months of hospital discharge. New therapies are needed to help keep these patients out of the hospital where their care has become a growing financial burden. However, the high attrition rate of drugs in development for AHF means no new therapies have launched since 2002.

Relaxin is a naturally occurring peptide that may be best known as a hormone of pregnancy. So, what lessons for HF can be gleaned from pregnancy?

The body's adaptions to pregnancy are many and varied: cardiac output is increased (about 20%), systemic vascular resistance is decreased (~30%), global arterial compliance is increased (~30%), renal blood flow is increased (50-85%), as is creatinine clearance (40-65%). Relaxin mediates all these adaptions, plus it has anti-ischemic, anti-inflammatory, and antifibrotic effects.

Relaxin and its signaling systems are present in both men and women, but it's elevated to pharmacologic levels during 9 months of pregnancy.

Current research interest includes serelaxin (recombinant human relaxin-2), to determine if it produce these beneficial effects in patients with AHF.

Pre-RELAX-AHF

The Pre-RELAX-AHF study compared various doses of relaxin with placebo to assess symptom relief, clinical endpoints, and safety.¹ In this dose-finding study, 234 patients with AHF were randomly assigned, in a double-blind manner, to standard care plus 48 hours of intravenous placebo or relaxin at doses of 10, 30, 100, or 250 mcg/kg per day.

The 30 mcg/kg per day dose was the most efficacious, leading to rapid and significant improvement in dyspnea. Specifically, in the relaxin-30 group, 41% of patients showed moderate or marked improvements in dyspnea at 6, 12 and 24 hours compared to 23% of patients assigned to placebo (p = 0.04). While all doses showed sustained improvement in dyspnea at day 5 and day 14, only relaxin-30 was significantly better compared to placebo at the end of 2 weeks.

Active treatment also was associated with improvement of in-hospital measures of AHF signs and symptoms. For example, there were trends indicating greater fluid and weight loss, less need for intravenous diuretics, and less deterioration of heart failure in the hospital among the patients receiving relaxin. Moreover, more patients receiving active treatment had complete resolution of signs of congestion.

Relaxin-treated patients showed fewer adverse long-term clinical outcomes than controls. However, again, only relaxin-30 was associated with significantly less risk of cardiovascular death or heart or renal failure rehospitalization at 60 days compared to placebo, as well as significantly fewer cardiovascular deaths to day 180. During an average follow-up of 4.5 months, no patients in the relaxin-30 group died of CV causes compared to 14% of the placebo group (p = 0.046).

It had a good safety profile, including no apparent adverse renal effects.

RELAX-AHF

Based on these results, RELAX-AHF was launched as an international, double-blind, placebo-controlled trial, enrolling patients admitted to hospital for AHF and randomly assigned to standard care plus 48-hour intravenous infusions of placebo (n=580) or serelaxin (30 μg/kg per day, n=581) within 16 hours of presentation. All patients had dyspnea, congestion on chest radiograph, increased brain natriuretic peptide (BNP) or N-terminal proBNP, mild-to-moderate renal insufficiency, and systolic blood pressure >125 mm Hg. The primary endpoints assessing dyspnea improvement were changed from baseline in the visual analogue scale area under the curve (VAS AUC) to day 5 and the proportion of patients with moderate or marked dyspnea improvement as measured with the Likert scale during the first 24 hours.

In RELAX-AHF, a 48-hour infusion of serelaxin was associated with an improvement in VAS AUC, the primary dyspnea endpoint, but had no significant effect on the other primary endpoint (Likert scale).² No significant effects were recorded for the secondary endpoints of CV death or readmission for HF or renal failure, or days alive out of the hospital up to 60 days (TABLE). Serelaxin treatment was associated with significant changes in other prespecified endpoints, including fewer deaths at 180 days.

A 37% reduction in CV and all-cause mortality (p = 0.028) was also noted with active therapy. Serelaxin mildly reduced BP, and was well tolerated with no notable difference in the overall adverse event profile and a lower rate of renal adverse events compared with placebo.

Subsequent to the final results, published in Lancet, Metra et al. analyzed the effects of serelaxin on serum biomarkers of organ damage, as well as signs and symptoms of congestion resolution. This paper, published in the JACC, showed that changes in markers of cardiac (hs-TnT), renal (creatinine and cystatin-C) and hepatic (AST and ALT) damage, and of decongestion (NT-pro-BNP), were all associated with 180-day mortality and improved with serelaxin administration.³

The post hoc exploratory nature of these findings regarding the association between early biomarkers changes and 6-month mortality means that the results should be considered hypotheses generating and that further studies will be required to further explore the effects of serelaxin.

"Breakthrough" Status

On June 21, 2013, US regulators gave breakthrough therapy status to this investigational treatment for patients with AHF, potentially fast-tracking its development and approval. The US Food and Drug Administration (FDA) created the "breakthrough therapy" designation earlier in 2013 for medicines deemed likely to demonstrate "substantial improvement" over existing drugs.

Novartis, the drug's developer, said the FDA's decision was supported by efficacy and safety results from RELAX-AHF, which showed serelaxin reduced patient deaths by 37% at 6 months after AHF compared to those who received standard therapy.

One month later, Decision Resources, a research and advisory firm for pharmaceutical and healthcare issues, reported that based on clinical trial data and thought leader opinion, serelaxin has the potential to gain acceptance among cardiologists for the treatment of AHF given that it is predicted to reduce mortality and prevent worsening renal function. The report noted that while cardiologists are most compelled by drugs that reduce patient mortality, the high price of novel AHF treatments could offset cardiologist receptivity to such agents. Payers also indicate that they would only accommodate such high price premiums in the presence of substantial improvements in efficacy.

Cardiorentis's ularitide is similarly predicted to reduce mortality as well as offer other improvements in efficacy and safety compared to current therapies.

"In the last 20 years, many of the therapies in development for acute heart failure resulted in disappointment," said Decision Resources Analyst Joseph Dwyer, MRes, PhD. "The high attrition rate for drugs in the acute heart failure pipeline is largely accounted for by improper trial design stemming from poor understanding of the disease and the lack of identification of an ideal therapeutic window. The biologic vasodilator serelaxin is set to address some of the previous failures of acute heart failure therapies, and this new agent has the potential to fulfill the largest unmet needs in this patient population and could emerge as a truly breakthrough therapy."

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References

1. Teerlink JR, Metra M, Felker GM, et al. Lancet. 2009;373:1429-39.
2. Metra M, Cotter G, Davison BA, et al. J Am Coll Cardiol 2013;61:196-206. http://content.onlinejacc.org/article.aspx?articleid=1500202
3. FDA grants Breakthrough Therapy designation to Novartis' serelaxin (RLX030) for acute heart failure. Press release, June 21, 2013. http://www.novartis.com/newsroom/media-releases/en/2013/1711047.shtml

	Serelaxin	Placebo	p Value
Primary Endpoints Dyspnea relief (VAS AUC)	2756 ± 2588	2308 ± 3082	0.0075
Dyspnea relief (Likert)	27%	26%	0.70
Secondary Endpoint Rehospitalization (60 days)	48.3 days	47.7	0.37
CV death or readmission for HF	13.2%	13.0%	0.89
Other prespecified endpoints CV deaths (180 days)	35 days	55 days	0.028
Other prespecified endpoints Deaths (180 days)	42 days	65 days	0.019

Keywords: Renal Insufficiency, Area Under Curve, United States Food and Drug Administration, Heart Failure, Vascular Resistance, Creatinine, Infusions, Intravenous, Natriuretic Peptide, Brain

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