FLORENCE, ITALY — The vasoactive peptide hormone serelaxin (Novartis) is both safe and tolerable for patients with chronic heart failure (CHF), suggests new research from some of the same investigators who conducted the phase 3 RELAX-AHF trial of 1161 patients with acute heart failure (AHF).
In RELAX-REPEAT, a placebo-controlled, phase 2, repeat-dosing trial of 320 patients with CHF, only one participant developed antiserelaxin antibodies up to 16 weeks after receiving three sequential 48-hour IV infusions of the drug (the primary end point.)
In addition, 15.1% of the serelaxin group reported adverse events (AEs) potentially indicative of hypersensitivity or infusion reactions vs 13% of the placebo groups. However, after the AEs were submitted for adjudication, none were confirmed, Dr John Teerlink (San Francisco Veterans Affairs Medical Center/University of California, San Francisco) told attendees at a late-breaking clinical-trial session here at the European Society of Cardiology (ESC) Heart Failure 2016 Congress. And overall treatment-emergent AEs did not differ significantly between the groups.
Teerlink later told heartwire from Medscape that the results were as expected. "We already knew about the immunogenetic properties of this drug since we'd administered it in a large group previously," he said. "But we were also pleased to see beneficial effects on renal function in this smaller study."
"This study validates past research on serelaxin and is clinically relevant to patients with chronic heart failure," said Dr Javed Butler (Emory University, Atlanta, GA).
"There's a lot of interest in developing outpatient therapies for heart failure and for outpatient IV diuretic clinics. No matter what, the idea was that safety data on recurrent use would be helpful in this population. So in that sense, these results are very important," said Butler.
Building on RELAX-AHF
As reported by heartwire , the original RELAX-AHF was presented at the American Heart Association 2012 Scientific Sessions, showing significant relief of dyspnea and decreased CV mortality, but no significant lowering of HF hospital readmissions. Teerlink reported that the large RELAX-AHF2 trial is currently targeting an enrollment of 6800 acute-HF patients. Results for that trial, including for its primary end points of CV mortality at 6 months and worsening HF through day 5, are expected to be released next year.
For RELAX-REPEAT, the investigators wanted to examine whether serelaxin could be given serially/sequentially to patients with CHF.
"People with heart failure have frequent and recurrent heart-failure hospitalizations. If serelaxin were approved for acute heart failure, we would anticipate that it would be quite likely that an [HF] patient would be receiving multiple doses of serelaxin throughout their lifetime," said Teerlink.
"There's also the possibility of giving this as a chronic outpatient therapy, although we'll need to do more studies. Still, we wanted to examine this patient group."
The study participants were randomized 2:1 to receive three 30-µg/kg/day IV infusions of serelaxin at weeks 0, 4, and 8 (n=212, 79% men, 97% white, mean age 66.7 years) or matching placebo (n=108, 76% men, 93% white, mean age 65.2 years). All had stable NYHA class 2–3 CHF with N-terminal pro-B-type natriuretic peptide (NT-proBNP) >300 pg/L, and systolic blood pressure >125 mm Hg.
"Intriguing" Aldosterone Effect
In the one patient who tested positive for antiserelaxin antibodies, there were no adverse events. Plus, "antibodies detected after the first infusion became undetectable at week 16. And there were low titers at all study visits," said Teerlink. "These antibodies were nonneutralizing."
When researchers examined systolic blood pressure at the end of each infusion through week 16, there were no significant differences between the treatment arms. However, plasma cystatin C levels were significantly lower for the serelaxin group after infusion 1 (P=0.02), infusion 2 (P=0.004), and infusion 3 (P=004), and improvements in estimated glomerular filtration rate (eGFR) were greater (P=0.0009, P<0.0001, and P=0.0007, respectively).
"Intriguingly, we also noted a 5% to 10% decrease in aldosterone levels at the end of each infusion, suggesting that serelaxin may also have some neurohormonal modulating properties—which we observed in the RELAX-AHF trial as well," Teerlink told meeting attendees.
"Overall, RELAX-REPEAT provided encouraging information as we look to the future direction of serelaxin in acute and chronic heart failure," he added. "It speaks to the question surrounding the serelaxin program: is it possible for a 48-hour infusion of an acute therapy to actually have long-term benefits?"
Session discussant Butler said the results "aren't surprising," but it was important to see validation of other data. "It was good to see the safety demonstration for serelaxin in this patient population while we wait for the more definitive outcomes results from RELAX-AHF2."
The study was funded by Novartis. Teerlink reported receiving research contracts from Novartis for RELAX-REPEAT, RELAX-AHF-ASIA and RELAX-AHF-2 and consulting fees from the company.
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Heartwire from Medscape © 2016 Medscape, LLC
Cite this: RELAX-REPEAT: Multiple Doses of Serelaxin Safe, Tolerable for Chronic Heart Failure - Medscape - May 27, 2016.