Novartis insisted yesterday it will continue its development of the experimental drug serelaxin despite an FDA advisory panel’s unanimous recommendation against agency approval—the acute heart failure (AHF) treatment’s third regulatory setback already this year.
FDA’s Cardiovascular and Renal Drugs Advisory Committee (CRDAC) voted 11–0 to recommend that FDA reject serelaxin, also known as RLX030 and by the trade name Reasanz. The panel echoed concerns raised in a report by agency staff that was made public earlier this week.
FDA typically abides by advisory recommendations such as those of CRDAC and the staff report, written by FDA’s Melanie Blank and Tzu-Yun McDowell. The agency is reviewing a BLA submitted by Novartis, and is set to make a decision by May 17.
CRDAC’s vote followed a hearing at which Novartis presented Phase II and III efficacy and safety data from serelaxin’s clinical development program, including the 1,161-patient Phase III RELAX-AHF study. For months, the company has highlighted results from RELAX-AHF showing that patients who received serelaxin had a 37% reduction in mortality at six months after an AHF episode compared to those who received conventional treatment.
“Reducing rate of in-hospital worsening heart failure is important for patients and physicians,” Novartis added in a string of Twitter tweets during and after the CRDAC hearing, adding: “Consistency of results across and within our Phase II and III trials supports our acute heart failure treatment”
Novartis has since been recruiting patients for a follow-up Phase III study, RELAX-AHF-2, designed to replicate the first trial’s key findings in a different primary endpopint, cardiovascular mortality. More than 6,300 patients will be assessed in the second study, of which approximately 1,000 will be from the U.S., Novartis said. The study is expected to generate results in 2016.
After CRDAC’s hearing, Novartis declared it would continue development of serelaxin – the same stance the company took in January following a negative recommendation for the drug by a key advisory panel of the European Medicines Agency (EMA).
“We'll continue to drive our robust clinical trial program and build upon the already established body of evidence," Wright, global head of development, Novartis Pharmaceuticals, said in a company statement.
Wright added that Novartis will address specific concerns raised at the CRDAC hearing: “The discussion provided important information that we will address with the FDA as it completes its review.”
The staff report raised three concerns: One was Novartis’ reliance on one clinical trial to assess serelaxin’s effect on dyspnea rather than at least two, or one trial with data for multiple studies.
Another concern raised by Blank and McDowell was the single trial’s focus on serelaxin’s beneficial effect on dyspnea, dismissed by FDA as an exploratory finding that did not address the AHF indication of the experimental drug. In its recommendation against serelaxin, the EMA’s Committee for Medicinal Products for Human Use (CHMP)—recommended against commission approval of serelaxin. CHMP said Novartis’ study results did not demonstrate a benefit for short-term relief of dyspnoea over up to 24 hours—and said the clinical relevance was unclear for serelaxin’s showing some benefit over five days.
The FDA staffers also questioned whether the trial’s primary endpoint would have been achieved if it hadn’t assigned the worst reported score to patients who died or had worsening heart failure during the first five days. The company assigned a zero score from the time of occurrence of the event to patients who died or experienced worsening heart failure.