Novartis said today it will continue to pursue approvals for its drug candidate RLX030 or Reasanz (serelaxin) in Europe, despite a key advisory panel recommending against the acute heart failure (AHF) treatment’s approval by the European Commission (EC).
Novartis said it will submit a new filing package, including new data analyses, to obtain conditional approval during the second quarter of this year, then submit a revised marketing approval application to the European Medicines Agency (EMA).
"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 European Union. We look forward to providing a revised package for review to the CHMP shortly," David Epstein, division head of Novartis Pharmaceuticals, said in a statement. “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."
Epstein told reporters on a conference call Novartis had been advised by members of the EMA's Committee for Medicinal Products for Human Use (CHMP) that a conditional approval would have a greater likelihood of success.
Serelaxin is a relaxin receptor agonist designed to relax the blood vessels, reduce fluid buildup, and protect the heart and vital organs from damage wrought by an acute heart failure episode.
Novartis has trumpeted results from its Phase III RELAX-AHF study, in which patients who received serelaxin had a 37% reduction in mortality at six months after an AHF episode compared to those who received conventional treatment. In September, Novartis started recruiting the first of more than 6,000 patients expected to participate in RELAX-AHF-2, its second Phase III study, with the goal of replicating the key findings of RELAX-AHF. Cardiovascular mortality will be RELAX-AHF-2’s primary endpoint.
However, the CHMP—whose guidance is usually accepted by the EC—recommended against approval of serelaxin. The CHMP said Novartis’ study results did not demonstrate a benefit for short-term relief of dyspnoea over up to 24 hours. While acknowledging that some benefit was shown over five days, the panel said the clinical relevance of that finding was unclear.
The CHMP also said it had concerns about the analysis of serelaxin’s effectiveness, since 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. The CHMP additionally 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,” the CHMP wrote in a statement. Although the safety of Reasanz seemed acceptable, in view of the uncertainties about the benefits of treatment, the CHMP was of the opinion at that point in time that the benefits of Reasanz did not outweigh its risks and recommended that it be refused marketing authorization.
Novartis’ revised roadmap for pursuing serelaxin approval will likely delay a final decision in Europe, but will also likely bring the timing of that decision closer to May as expected in the United States, where the drug candidate is under FDA review. The agency granted serelaxin breakthrough therapy status in June.
U.S. approval is arguably more crucial for serelaxin, with one analyst estimating that American sales will likely account for 70% of the $1.1 billion in annual global sales he’s projecting for the heart failure treatment. Novartis is counting on strong sales from serelaxin and other candidates to recoup patent-cliff losses for Diovan—a factor in the shutdown of its Suffern, NY, manufacturing plant announced earlier this week, the company told GEN—and cancer drug Gleevec.
“The company has generally been more bullish than investors on this drug’s prospects, and while Eurpoean Union regulators may have issued a negative opinion, in the United States approval seems more likely,” analyst Tim Anderson of Sanford C. Bernstein wrote in a note to investors, according to Bloomberg News.