Date: 2017-03-22
Type of information: Publication of results in a medical journal
phase: 3
Announcement: results
Company: Novartis (Switzerland)
Product: serelaxin - RLX030
Action mechanism: protein. RLX030 (serelaxin) is a recombinant form of the human hormone relaxin-2 which occurs naturally in both men and women. In women, levels of relaxin-2 rise to support important physiological changes during pregnancy. Serelaxin acts by relaxing the blood vessels, leading to reduced stress on the heart and kidneys in both men and women.
Disease: acute heart failure
Therapeutic area: Cardiovascular diseases
Country:
Trial details: RELAX-AHF was an international randomized, double-blind study involving 1,161 patients and was designed to compare the efficacy and safety profile of RLX030 to placebo in addition to standard therapy for the treatment of AHF. RLX030 was given upon hospitalization in the form of an intravenous infusion (30 mcg per kg per day) for 48 hours in addition to conventional therapy for AHF, i.e. loop diuretics and other medicines. The study had two primary endpoints using different scales to measure reduction in dyspnea. The visual analog scale (VAS) showed a significant benefit up to day five (p=0.0075), whereas the Likert scale (a baseline-related short-term assessment of dyspnea relief) did not reach significance at 6, 12 and 24 hours (p=0.702). RELAX-AHF-2 is an event-driven, multicenter, randomized, double-blind, placebo-controlled, Phase III trial designed to evaluate the efficacy, safety and tolerability of RLX030 (serelaxin) when added to standard of care in patients with acute heart failure (AHF). The study has two primary endpoints; reduction of cardiovascular (CV) death through Day 180 and occurrence of worsening heart failure through Day five. The RELAX-AHF-2 study included 6,600 patients hospitalized for AHF and was initiated in October 2013. (NCT01870778)
Latest
news: • On March 22, 2017, Novartis announced results from the global Phase III RELAX-AHF-2 study investigating the efficacy, safety and tolerability of RLX030 (serelaxin) in patients with acute heart failure (AHF). The study did not meet its primary endpoints of reduction in cardiovascular death through Day 180 or reduced worsening heart failure through Day five when added to standard therapy in patients with AHF.
• On September 2, 2013, results from a new analysis of the Phase III RELAX-AHF study have been published in the European Heart Journal and presented as a late breaker at the European Society of Cardiology (ESC) congress in Amsterdam indicate that the investigational medicine RLX030 consistently improved symptoms and mortality across multiple subgroups of patients with acute heart failure (AHF) assessed in the trial. The addition of RLX030 to conventional treatment led to improvements in breathlessness (dyspnea) and mortality at 6 months across all pre-specified subgroups including those with renal impairment (eGFR<50ml/min), the elderly (>=75 years) and patients with atrial fibrillation, although the small numbers of patients in each group limit the statistical conclusions that can be drawn. AHF patients require urgent treatment so prompt decision-making to stop heart failure worsening is crucial in spite of patients often having diverse clinical profiles.
Results from RELAX-AHF previously presented in 2012 demonstrated that RLX030 reduced the risk of death by more than one-third (37%) compared with conventional treatment at six months (See below).
RLX030 is currently being assessed by health authorities around the world including the FDA and the European Medicines Agency (EMA) for the treatment of AHF. In June 2013 the FDA granted RLX030 Breakthrough Therapy designation status, recognizing its potential to address a serious unmet medical need.
Results from the full analysis of RELAX-AHF were presented at the American Heart Association congress in November 2012. The visual analog scale (VAS) showed a significant benefit up to day five (p=0.0075), whereas the Likert scale (a baseline-related short-term assessment of dyspnea relief) did not reach significance at 6, 12 and 24 hours (p=0.702). As one of the primary endpoints was met the study was positive according to protocol criteria.
Analysis of additional endpoints showed that patients who received RLX030 had a 37% reduction in the risk of mortality at 6 months after an AHF episode compared with those who received conventional treatment. RLX030 also significantly reduced heart failure worsening up to day 14 (p=0.026) thereby decreasing the need for intensified treatment, as well as reducing the mean length of stay in hospital by 0.9 days (p=0.039) and in the intensive/cardiac care unit by 0.4 days (p=0.029). The study did not meet secondary endpoints including days alive and out of hospital up to day 60 (p=0.438), and cardiovascular death or re-hospitalization due to heart or kidney failure up to day 60 (p=0.862). RELAX-AHF showed that the side effects of RLX030 were comparable to conventional therapy and the drug was generally well tolerated.
In this subgroup analysis the effects of RLX030 versus conventional treatment were similar across multiple pre-specified groups with respect to the primary dyspnea endpoints, 60-day composite outcomes, and 180-day mortality, although due to the small numbers of patients in each subgroup the study is underpowered to draw conclusions about individual groups. Subgroups included age, sex, race, geographic region, estimated glomerular filtration rate, time from presentation to randomization, baseline systolic blood pressure, history of diabetes, atrial fibrillation, ischemic heart disease, cardiac devices and intravenous nitrates at randomization.
• On November 7, 2012, Novartis has announced that the Phase III RELAX-AHF study has shown that investigational RLX030 (serelaxin) improved symptoms and reduced deaths by one-third at the end of six months in patients with acute heart failure (AHF). RELAX-AHF demonstrated that RLX030 significantly reduced dyspnea (i.e. shortness of breath), the most common symptom of AHF and the primary endpoint of the study. As one of two co-primary endpoints was met, the study achieved its primary objective based on pre-specified protocol criteria.
The study had two primary endpoints using different scales to measure reduction in dyspnea. The visual analog scale (VAS) showed a significant benefit up to day five (p=0.0075), whereas the Likert scale (a baseline-related short-term assessment of dyspnea relief) did not reach significance at 6, 12 and 24 hours (p=0.702). As one of the primary endpoints was met the study was positive according to protocol criteria.
The study did not meet its secondary efficacy endpoints, namely days alive and out of hospital up to day 60 (p=0.37), and cardiovascular death or re-hospitalization due to heart or kidney failure up to day 60 (p=0.89).
Results showed that 7.3% of patients died from all causes in the RLX030 group compared to 11.3% in the placebo group (p=0.02)at 180days of follow-up. All-cause mortality up to day 180 was a safety endpoint of the study. The number of deaths due to cardiovascular causes to day 180 (an additional pre-specified efficacy endpoint) was also significantly lower with RLX030 than placebo (6.1% vs. 9.6%, p=0.028). RLX030 was therefore associated with a 37% reduction in all-cause and cardiovascular mortality at the end of six months.
In addition to its effects on mortality and symptoms, RLX030 met several other efficacy endpoints including significantly reducing the worsening signs and symptoms of heart failure up to day 14 (p=0.024), thereby decreasing the need for intensified heart failure treatment. RLX030 also reduced the mean length of stay in hospital by 0.9 days (p=0.039) and in the intensive/cardiac care unit by 0.4 days (p=0.029).
RLX030 was well tolerated and adverse events (AEs), including low blood pressure (hypotension), were generally comparable between RLX030 and placebo. There was a lower incidence of adverse events related to renal impairment with RLX030 than placebo (4.6% vs. 8.6%). The most common AEs in both treatment groups were cardiac disorders, metabolism and nutrition disorders, and gastrointestinal disorders. No clinically significant differences in the incidence of serious adverse events were seen between treatment groups.
"This study with serelaxin is important because it may offer the prospect of a much-needed new medicine for acute heart failure, where the death rate remains high and there have been few new therapies for several decades," said Professor John R. Teerlink MD, of the Section of Cardiology, San Francisco Veterans Affairs Medical Center, University of California, San Francisco, the co-lead investigator of the RELAX-AHF study.
Professor Marco Metra, Director of the Institute of Cardiology at the University and Civil Hospital of Brescia, Italy, the other co-lead investigator of the study, said: "The reduction in mortality seen with serelaxin is supported by the decreases in episodes of worsening of heart failure, as well as by the biomarker data collected during the study, suggesting that the clinical effects of serelaxin may be linked to a beneficial effect on organs such as the heart and kidneys."
Novartis has begun discussing the results of this single Phase III study with health authorities worldwide.
(Teerlink JR, Cotter G, Davison BA et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial.
• On September 24, 2012, Novartis has announced that Phase III study results show that investigational RLX030 (serelaxin) reduced all-cause mortality in patients with acute heart failure (AHF). The six-month RELAX-AHF study shows that RLX030 reduces the number of deaths in patients with this disease, which has a higher mortality rate than most other cardiovascular diseases. The study had two primary endpoints using different scales to measure reduction in dyspnea, only one of which reached statistical significance. Dyspnea, or shortness of breath, is the most common symptom of AHF. RLX030 was well tolerated in the study.
The study will be presented at the American Heart Association (AHA) congress in Los Angeles in November, 2012. Novartis will initiate discussions of the results of this single Phase III study with health authorities worldwide shortly.
