CardioExchange Archive

Ahead of an important advisory panel FDA reviewers have recommended against approval of a novel drug for acute heart failure from Novartis. The once highly promising drug, which received a “breakthrough therapy” designation from the FDA last year, was turned down for approval in Europe earlier this year.

On Thursday, the FDA’s Cardiovascular and Renal Drugs Advisory Committee will discuss the biologics license application (BLA) for serelaxin injection (proposed trade name Reasanz) from Novartis. The indication is for the improvement of the symptoms of acute heart failure through reduction of the rate of worsening of heart failure. (The meeting was originally scheduled for February but was postponed due to weather.) Serelaxin is a recombinant form of the naturally occurring human hormone relaxin-2, which has been found to help women adjust to the cardiovascular changes that occur during pregnancy.

The FDA reviewers raised critical questions and concerns about the pivotal RELAX-AHF trial, which was published in the Lancet in 2012. The reviewers did not raise any safety concerns about the drug but stated that “there is insufficient evidence to support the proposed indication.”

Generally, the reviewer notes, the FDA requires two independent trials to demonstrate a drug’s efficacy. But the RELAX-AHF trial, the single trial in support of the BLA, was further hampered because it successfully met only one of its two primary endpoints. Further, although the trial “was designed to assess dyspnea… the proposed claim is to improve the symptoms of acute heart failure.” Acute heart failure symptoms other than dyspnea “were not systematically measured in this study,” wrote the reviewer, who went on to then question the reliability and relevance of the dyspnea findings.

The FDA reviewer also cast doubt on the reliability of the surprising finding of a mortality reduction at 180 days in the serelaxin group. Although the result adds confidence to the safety of the compound, the endpoint was not prespecified and needs to be confirmed in a follow up study before gaining acceptance. The reviewer also thought that additional doubt was raised because the mortality benefit had not been observed at an earlier time point, despite the fact that the drug is used acutely. (Novartis is currently conducting a large outcomes trial to confirm the mortality result.)