An FDA advisory committee on Tuesday 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 risk-benefit profile supports the weekly echinocandin injection when patients have limited or no alternative options.
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 primary support for Cidara Therapeutics’ application came in the form of a single phase III non-inferiority trial (ReSTORE), along with a dose-finding phase II study (STRIVE).
“Overall, the ‘yeses’ were largely in favor of a limited-use indication; the paradox in that comment is that the population that would be recommended [for] the limited use is largely unstudied,” said AMDAC chair Lindsey Baden, MD, of Harvard Medical School in Boston, in his roundup of the committee’s discussion following the vote. “Ergo, follow-up data in this population would be very important.”
Still, “the agent warrants being available to those patients with no other alternatives for treating their fungal infection, be it a toxicity side effect or logistic issue,” he added.
In explaining his “yes” vote, George Siberry, MD, MPH, of the U.S. Agency for International Development in Washington, D.C., said “there are enough efficacy and safety data to justify the use in patients with these life-threatening illnesses who have no alternative treatments available to them,” but added that the data were not sufficient to recommend routine use.
Committee members observed that rezafungin injections offered several potential benefits when compared to other echinocandins, the most notable being that it can be dosed weekly, whereas currently approved echinocandins for treating candidemia/IC require daily dosing.
“The ability to be at home, and potentially without a central line by use of infusion centers, this would be even more relevant for those who require chronic or suppressive therapy,” said Michael Green, MD, MPH, of the Children’s Hospital of Pittsburgh.
Patients in whom ongoing catheter use is contraindicated, people with a history of injection drug use, and those who fail other therapies may be suitable candidates for the less-frequent dosing, indicated panelist Richard Murphy, MD, MPH, of Veterans Affairs White River Junction Medical Center in Vermont. For these patients, “I would find this drug useful,” he said.
The single “no” vote came from Joan Hilton, ScD, MPH, a professor of biostatistics at the University of California San Francisco, who held that while the drug had promise, she did not feel the full body of evidence met FDA’s approval criteria.
ReSTORE was a phase III trial that randomized 187 subjects with candidemia or IC to weekly rezafungin or daily caspofungin. All-cause mortality at 30 days, the study’s primary endpoint, was 23.7% with rezafungin versus 21.3% caspofungin (2.4% difference, 95% CI -9.7 to 14.4). With the upper limit of the non-inferiority margin landing under 20%, the trial met criteria for FDA’s limited-use designation.
During discussion, Nimish Patel, PharmD, PhD, of University of California San Diego, pointed out that if four fewer deaths had occurred in the rezafungin arm, a 10% non-inferiority margin would have been attained, which the FDA had indicated would have allowed the company to seek a standard approval.
“Four deaths just seems pretty extreme to add a handicap to this treatment, which has the potential to help a lot of people,” said Patel, who noted that the advantages of rezafungin may not just be clinical.
“The inpatient burden of invasive candidiasis is quite high,” he said. “I think this offers a very exciting approach to treating patients and facilitating earlier discharge from inpatient settings, and I think there is a really elegant economic story that will likely emerge from the potential approval.”
In ReSTORE, rezafungin was given intravenously with a 400-mg loading dose followed by 200-mg weekly doses for up to 4 weeks — the proposed dosing. Cidara Therapeutics maintained that this loading dose was advantageous, particularly for faster clearance of infection, and presented data showing numerically higher mycological eradication with rezafungin at day 5 (68.8% vs 61.7% for caspofungin), though the difference was not statistically different and narrowed considerably by day 14 (67.7% vs 66%).
“The potential antifungal superiority achieved by higher drug exposure or better in vitro activity to my mind is unproven at this time,” said Green.
Ahead of the meeting, FDA staff highlighted a safety signal for tremor with rezafungin that was initially observed in nonhuman primate studies and later in clinical trials. Pooled safety data included 151 rezafungin-treated patients from the phase II and III trials. In these, tremor was identified in four patients on rezafungin (2.6%) compared with none of those assigned to caspofungin.
For committee members, however, the neurotoxicity was not highlighted as a reason to block the drug’s approval.
While the FDA is not bound to follow the recommendations of its advisory committees, it usually does.
The advisory committee participants had nothing to disclose.