CardioExchange Archive

European regulators have dealt a setback to a novel heart failure drug under development by Novartis.

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recommended against giving market approval to serelaxin (Reasanz) for the treatment of acute heart failure. The recommendation is based largely on the committee’s analysis of the RELAX-AHF trial, which was published in the Lancet in 2012. Here is CHMP’s explanation for their decision:

The Committee noted that the study results did not demonstrate a benefit for short-term relief of dyspnoea over up to 24 hours, and although some benefit was shown over 5 days it was not clear how this was of clinical relevance. Furthermore, the Committee had concerns about the way the effectiveness of the medicine in the study had been analysed. The results included calculated values for a number of patients who had died or had required additional treatment for worsening symptoms and whose actual data were not used. In addition, the CHMP questioned whether differences in the background treatment given to patients in the two study groups may have influenced the results. Since only one main study was included in the application, further studies would be needed to confirm the effectiveness of Reasanz in the treatment of acute heart failure.

CHMP did acknowledge that it had found no safety concerns with the drug.

The same drug received a “breakthrough therapy” designation from the FDA last year and will be the subject of a meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Committee on February 13.

In response to the recommendation, Novartis said it would  submit a revised application and request “conditional approval” for the drug. (Conditional approval means that a drug for an “unmet medical need” is allowed on the marketplace with “less complete data than is normally required.” In such cases, CHMP may require the company to complete additional studies.) Last year enrollment began in RELAX-AHF-2, a 6,000 patient study with cardiovascular mortality as the primary endpoint.

“With the results from RELAX-AHF showing significant mortality benefits with RLX030 in patients with AHF and recognizing that there had been no treatment breakthroughs in this area for 20 years, Novartis took a decision to file for regulatory approval,” said a Novartis executive in a press release. “It has become apparent through the review process and in accordance with advice we’ve received that the current evidence package may be more compatible with an application for conditional approval in the EU. We look forward to providing a revised package for review to the CHMP shortly.”

The mortality finding in RELAX-AHF has been the subject of considerable controversy. Although treatment with serelaxin in the trial had no effect on hospital readmission there was a surprising reduction in mortality at six months, though the trial was not designed to test an effect on mortality. As I reported at the time, the trial investigators acknowledged that the findings of a six-month survival benefit “for a drug given for 48 h with a moderate number of death events (107 total) raises the question of whether this benefit is due to chance and whether another, confirmatory trial should be done.” Heart failure expert Milton Packer said that “if the mortality effect is true then this trial changes the way we do things.” But, he emphasized, ”the real question is whether the mortality difference seen in this trial is true and replicable.”