Advisory committee unanimously recommends Cresemba for invasive aspergillosis, less certain for mucormycosis

The FDA’s Anti-Infective Drug Advisory committee voted 11-0 today that isavuconazonium demonstrated safety and efficacy for the treatment of invasive aspergillosis.

For the treatment of mucormycosis, it voted 8-2, with one abstention, that isavuconazonium was safe and efficacious, although all members expressed hesitancy about the recommendation, based on the lack of robust data.

“I don’t think anyone would argue whether isavuconazole is better than placebo,” Michael N. Neely, MD, MSc, associate professor of pediatrics at the University of Southern California, said during the meeting. “Is it better than the comparator, amphotericin? We don’t know. But we have to take into consideration the absolute unmet need for therapy.”

Neely, who voted yes, said that if isavuconazonium (Cresemba, Astellas) is approved for mucormycosis, the label will need to make clear that the drug has never been tested in a head-to-head trial against amphotericin in humans, and the approval is based on historical controls. Isavuconazonium is a prodrug that contains the active moiety isavuconazole.

John Bennett, MD, chief of the clinical mycology section at the National Institute of Allergy and Infectious Diseases (NIAID) voted no, as did Dean Follmann, PhD, assistant director for biostatistics at the NIAID.

“I’m concerned that if the drug is approved for this indication, the FDA has set the bar very low for the future,” Bennett said.

Marc H. Scheetz, PharmD, MSc, associate professor of pharmacy practice at Midwestern University Chicago College of Pharmacy, abstained, saying that statistically, the drug would probably not demonstrate noninferiority.

“Should the physicians have this in their armamentarium? The answer is wholeheartedly yes,” Scheetz said. “There should be options, especially for a disease that is this dire and this rare. But should it be labeled for this indication? I’m not sure how to answer that.”

The committee based its decisions primarily on the results of two phase 3 studies. For invasive aspergillosis, data from a randomized, double blind, multicenter, noninferiority study included 516 patients randomly assigned to isavuconazole or voriconazole. The trial demonstrated similarity in all-cause mortality between the two drugs at day 42: 18.6% in the isavuconazole group vs. 20.2% in the voriconazole group. It also demonstrated similar success rates for overall response at end of treatment in a modified intention-to-treat analysis: 35% for isavuconazole and 36.4% for voriconazole.

For invasive mucormycosis, the committee considered data from a study of patients with proven invasive fungal disease caused by rare molds, yeast or dimorphic fungi. The study included 37 patients whose disease was attributed to the Mucorales order, and 21 patients received isavuconazole. The all-cause mortality in this population was 37.8%, and the success rate for overall response at end of treatment was 31.4% in the modified intention-to-treat population. Other data included demonstrations of superiority to placebo and noninferiority to amphotericin in animal models of mucormycosis, and a mortality rate (37.8%) similar to that reported in the literature (37.8%) for amphotericin.