FDA Panel Supports Weekly Rezafungin for Candidemia and Invasive Candidiasis

On Tuesday, an FDA advisory committee overwhelmingly recommended approval, with a “limited use” indication, of long-acting rezafungin for the treatment of candidemia and invasive candidiasis (IC) in adults.

By a vote of 14-1, the Antimicrobial Drugs Advisory Committee (AMDAC) said the benefit-risk profile supports weekly echinocandin injection when patients have limited options or no alternatives.

The FDA’s limited-use indication allows for a more flexible development program for antifungal drugs that can potentially treat serious infections in people with few available options. In the case of rezafungin, the main support for the application of Cidara Therapeutics came in the form of a single phase III non-inferiority study (ReSTORE) along with a dose finding phase II study (STRIVE).

“Overall, the ‘yes’ were largely in favor of a limited-use indication; the paradox of this comment is that the population that would be recommended [for] limited use is largely unstudied,” said AMDAC President Lindsey Baden, MD, of Harvard Medical School in Boston, in his summary of the committee’s discussion after the vote. “So follow-up data in this population would be very important .”

Still, “the agent is guaranteed to be available to those patients without other alternatives to treat their fungal infection, whether it is a side effect of toxicity or a logistical issue,” he added.

In explaining his “yes” vote, George Siberry, MD, MPH, of the United States Agency for International Development in Washington, DC, said “there are sufficient efficacy and safety data to justify use in patients with these life-threatening diseases. who have no alternative treatment available to them,” but added that the data were not sufficient to recommend routine use.

Committee members noted that rezafungin injections offered several potential benefits when compared to other echinocandins, the most notable being that it can be given weekly, whereas echinocandins currently approved for the treatment of candidemia/HF require daily dosing.

“The ability to be at home and potentially without a central line through the use of infusion centers, this would be even more relevant for those needing chronic or suppressive therapy,” said Michael Green, MD, MPH, Children’s Hospital of Pittsburgh.

Patients in whom continuous catheter use is contraindicated, people with a history of injecting drug use, and those who fail other therapies may be suitable candidates for less frequent dosing, indicated panelist Richard Murphy, MD, MPH, Veterans Affairs White River Junction Medical Center in Vermont. For these patients, “I would find this drug helpful,” he said.

The only “no” vote came from Joan Hilton, ScD, MPH, a professor of biostatistics at the University of California, San Francisco, who stated that while the drug showed promise, she didn’t feel the entire body of evidence met the approval criteria. from the FDA.

ReSTORE was a phase III trial that randomized 187 subjects with candidemia or HF to either weekly rezafungin or daily caspofungin. The 30-day all-cause mortality, the study’s primary endpoint, was 23.7% with rezafungin versus 21.3% with caspofungin (difference 2.4%, 95% CI -9.7 to 14, 4). With the upper limit of the non-inferiority margin below 20%, the study met the criteria for FDA limited use designation.

During the discussion, Nimish Patel, PharmD, PhD, University of California San Diego, pointed out that if four fewer deaths had occurred in the rezafungin arm, a non-inferiority margin of 10% would have been achieved, which the FDA indicated that would have allowed the company to seek standard approval.

“Four deaths seems too extreme to add a downside to this treatment, which has the potential to help a lot of people,” said Patel, who noted that rezafungin’s advantages may not just be clinical.

“The hospitalization burden of invasive candidiasis is quite high,” he said. “I think this offers a really exciting approach to treating patients and facilitating early discharge from hospitalizations, and I think there’s a really elegant economic story that is likely to emerge from potential approval.”

In ReSTORE, rezafungin was administered intravenously with a loading dose of 400 mg followed by weekly doses of 200 mg for up to 4 weeks – the proposed dosage. Cidara Therapeutics maintained that this loading dose was advantageous, particularly for more rapid clearance of infection, and presented data showing numerically higher mycological eradication with rezafungin on day 5 (68.8% vs 61.7% for caspofungin), although the difference was not statistically different and narrowed considerably by day 14 (67.7% vs 66%).

“The potential antifungal superiority achieved by greater drug exposure or better in vitro activity, in my opinion, is unproved at this time,” Green said.

Prior to the meeting, the FDA team highlighted a safety signal for tremor with rezafungin that was first seen in non-human primate studies and later in clinical trials. The pooled safety data included 151 rezafungin-treated patients from the phase II and III studies. In these, tremor was identified in four patients receiving rezafungin (2.6%) compared to none of those assigned to caspofungin.

For committee members, however, neurotoxicity was not cited as a reason to block approval of the drug.

Although the FDA is not required to follow the recommendations of its advisory committees, it generally does.

  • Ingrid Hein is a writer for MedPage Today, covering infectious diseases. She has been a medical reporter for over a decade. follow

Disclosures

Advisory committee participants had nothing to disclose.

FDA Panel Supports Weekly Rezafungin for Candidemia and Invasive Candidiasis

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