FDA panel votes against recommending approval for serelaxin

Issue: April 2014

The FDA’s Cardiovascular and Renal Drugs Advisory Committee voted unanimously against recommending approval of serelaxin for the improvement of acute HF symptoms via reduction of the rate of worsening of HF.

If approved, serelaxin would be sold by Novartis under the brand name Reasanz.

In explaining the 0-11 vote, panel members said that the drug shows promise for improvement of worsening of HF and might even favorably impact mortality, but that the data from the phase 3 RELAX-AHF trial, which had primary endpoints related to dyspnea, were not convincing.

“I think this was more of a failure of trial design than it was of the drug itself,” panel member Stuart Rich, MD, of the University of Chicago Pritzker School of Medicine, said. “[RELAX-AHF] was designed to measure dyspnea … and [the investigators] tried to refashion it to measure worsening HF. I share the sponsor’s enthusiasm. A drug that can reduce morbidity and mortality in acute HF is really needed. Hopefully [RELAX-AHF] will be a learning study where the hypotheses can be better thought-out and then proven in a subsequent trial.”

Novartis sought approval for serelaxin based only on RELAX-AHF, which evaluated the safety and efficacy of intravenous serelaxin for 48 hours compared with placebo in 1,161 patients with acute HF (mean age, 72 years; 62% men; 94% white).

There were two primary endpoints. One, the area under the curve for change in dyspnea through day 5 as measured by a 100-mm visual analog scale, was met (placebo group, 2,308 mm-h; serelaxin group, 2,756 mm-h; ∆=448 mm-h; 95% CI, 120-775 mm-h; P=.007). The other, moderately to markedly improved dyspnea at 6, 12 and 24 hours as measured by a seven-point Likert scale, was not (placebo group, 26%; serelaxin group, 27%; OR=1.05; 95% CI, 0.8-1.4).

However, the data showed that those assigned serelaxin had a reduced rate of worsening of HF, and Novartis sought approval for that indication.

Panel member Philip Sager, MD, of Stanford University School of Medicine, agreed. “I do want to applaud the sponsor for working to develop this drug for acute HF,” he said. “This is a difficult area to develop drugs in and is an unmet medical need. I think that the data we looked at today show that there’s real potential for helping patients with harder endpoints — such as reduced worsening of congestive HF, reduced time in the hospital and [reduced] time in the ICU — and potentially improving cardiac as well as renal biomarkers. I hope that this disappointing vote and meeting today won’t preclude the sponsor from continuing to develop the drug.”

During the meeting, members of the advisory panel questioned whether worsening of HF was adequately defined in the study protocol, and whether it was appropriate to seek an indication for worsening of HF when the pivotal trial was designed to measure dyspnea.

A. Michael Lincoff

“I think it’s clear that the drug does have an effect on worsening HF, but given the limitations of how that was not rigorously defined … we need better data on understanding the magnitude of benefit in a rigorous fashion,” A. Michael Lincoff, MD, chairperson of the advisory committee, said. “The data that we have here don’t stand alone for proof.”

In a briefing document prepared for advisory panel members, FDA staff argued that the results were driven by mild episodes of worsening HF that could be managed with diuretics.

However, the reviewers did not observe any major safety concerns that would preclude approval. According to the document, serelaxin had a favorable mortality profile in RELAX-AHF and the dose-finding study Pre-RELAX-AHF, and Novartis is currently conducting a large outcome trial to verify the finding.

The FDA is not required to follow the recommendations of its advisory panels, but it usually does.

For more information:

CRDAC Briefing Document. BLA 125468.

Disclosure: The members of the FDA’s Cardiovascular and Renal Drugs Advisory Committee report no relevant financial disclosures.