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FDA Committee Gives ‘Thumbs Down’ to Serelaxin for Acute Heart Failure

Advisors question efficacy data

The FDA’s Cardiovascular and Renal Drugs Advisory Committee has ruled that serelaxin (Novartis), a new treatment for acute heart failure, should not be approved because there is insufficient evidence to show it improves the symptoms of the disease.

The committee’s statement comes 2 days before a meeting of outside advisors who will make their own recommendation on whether the drug should be approved. The FDA is not obligated to follow the advice of its advisory panels, but it usually does so.

The panel expressed two primary concerns regarding the evidence supporting the proposed indication for serelaxin.

First, support for the drug’s efficacy comes from a single trial, RELAX-AHF, whose primary objective was to demonstrate that the administration of serelaxin to patients with acute heart failure causes improvement in dyspnea. For symptomatic claims, the FDA generally requires evidence of efficacy equivalent to two independent trials, both successful at a P value of < 0.05.

Second, while the pivotal trial was designed to assess dyspnea, the applicant (Novartis) is seeking a somewhat different claim. The proposed claim is to improve the symptoms of acute heart failure through reduction of the rate of worsening of heart failure.

The advisory committee does not believe that the pivotal trial data support the claim “to improve the symptoms of acute heart failure” for the following reasons:

  • The primary endpoint measures — the Likert dyspnea score and the Area Under the Curve–Visual Analog Scale (AUC-VAS) dyspnea score — did not capture symptoms other than dyspnea. The other symptoms of acute heart failure (e.g., cough, edema, choking, fatigue, and anxiety) were not systematically measured in the study. “Therefore, the current evidence does not support a broad claim related to the symptoms of acute heart failure,” the committee concluded.
  • The advisors also feel that a dyspnea indication is a more reasonable consideration because of the dyspnea endpoint measures that were used in the RELAX-AHF trial. However, the trial results do not provide persuasive evidence of an effect on dyspnea.
  • Further, because the pre-specified imputation method treated all episodes of worsening heart failure equally, relatively mild episodes that were easily managed with small increases in intravenous diuretics drove the results of the trial.
  • Finally, the committee points out that even if the results of the RELAX-AHF study were accepted at face value with the pre-specified worsening heart failure imputation method, the clinical relevance of the difference in VAS dyspnea scores is questionable. A 447.7-mm/hr mean difference in the change in AUC-VAS from baseline between treatment groups translates into an average difference between groups of approximately 4 mm on the 100-mm VAS scale.

“We recommend that serelaxin not be approved at this time because there is insufficient evidence to support the proposed indication to ‘improve the symptoms of acute heart failure through reduction of the rate of worsening of heart failure,’” the committee said. “We did not identify any significant safety concerns precluding approval.”

Serelaxin is a recombinant human protein that is identical to the naturally occurring peptide hormone relaxin. Relaxin is involved in the hemodynamic and renovascular adaptive changes that occur during pregnancy. On a cellular level, the proposed mechanism of action is that serelaxin binds to the G-protein–coupled receptor RXFP1 and signals mainly via the second messenger cyclic AMP.

Sources: Reuters; March 25, 2014; and FDA Briefing Document; March 25, 2014.

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