Agency reviewers highlight limited clinical trial data, neurotoxicity concerns

Ahead of an advisory committee meeting on Tuesdayopens in a new tab or window, FDA staff raised concerns over whether the potential benefits of weekly rezafungin injections for adults with candidemia and invasive candidiasis (IC) outweigh any potential risks, including neurotoxicity.

According to an agency briefing documentopens in a new tab or window for the Antimicrobial Drugs Advisory Committee, potential approval of the investigational, long-acting echinocandin for candidemia and IC caused by susceptible Candida species hinges on a single phase III non-inferiority study (ReSTORE), along with data from the dose-finding phase II STRIVE study.

“The key issues for consideration in the benefit-risk assessment of rezafungin include the presumed ability to meet an unmet need in the context of generally similar (to current treatment options) effects on survival, the ability to mitigate any identified risks such as neurotoxicity, and the acceptable tradeoffs between the benefits and risks to patients,” FDA staff wrote.

Candidemia and IC affect about 25,000 people per year in the U.S., according to the CDCopens in a new tab or window. The in-hospital all-cause mortality rate among people with candidemia is approximately 25%.

“There are three FDA-approved echinocandins, all of which are available only as intravenous (IV) formulations dosed once daily,” FDA staff noted. “Antifungal therapy is usually continued for 2 weeks after documented clearance of Candida spp. from the blood in the case of candidemia or following adequate source control and clinical response in IC.”

In the ReSTORE trial, which involved 187 subjects, rezafungin was found to be noninferior to caspofungin in the primary endpoint of all-cause mortality at 30 days in the modified intention-to-treat population, with rates of 23.7% in the rezafungin group versus 21.3% in the caspofungin group. Rezafungin was given as a 400-mg IV loading dose followed by weekly 200-mg IV doses for up to 4 weeks — the proposed clinical dose.

The safety dataset for rezafungin, submitted by sponsor Cidara Therapeutics, included 151 patients from ReSTORE who were given the proposed clinical dose and 81 patients from STRIVE given a higher dose (400 mg administered weekly).

In this dataset, tremor was observed in 2.6% of those receiving the proposed rezafungin dose compared with zero patients receiving caspofungin. Tremor was also reported in early nonhuman primate studies.

While the ReSTORE/STRIVE data “show a similar safety profile to the FDA-approved echinocandins, the size of the dataset limits the ability to identify rare adverse reactions that may be unique to rezafungin,” according to agency staff.

Although tremor has been reported to be an uncommon adverse reaction in the labeling of other echinocandins for candidemia/IC, the FDA noted that the trial data need further scrutiny.

“The review team’s assessment is that the Applicant has not provided sufficient data to support the position that rezafungin provides improved activity against Candida spp. with reduced susceptibility to FDA-approved echinocandins or provides improved tissue penetration,” the FDA wrote in its briefing document. “Overall, the review team finds that rezafungin is primarily distinguished from FDA-approved echinocandins by its extended half-life but welcomes the committee’s input on whether rezafungin may have additional benefits that would extend treatment options for patients with candidemia/IC to address an unmet need.”

All of the currently approved echinocandins, including caspofungin, anidulafungin, and micafungin, come with warnings for hypersensitivity reactions and hepatic adverse reactions in their labeling. Micafungin also has a warning for hematologic effects, renal effects, and infusion and injection site reactions, and anidulafungin has warnings related to risks associated with two of the inactive ingredients in its formulation.

“None of the echinocandins have warning statements related to neurotoxicity, and the only nervous system adverse reaction reported in >5% of patients in clinical trials was headache,” the FDA wrote.

Tremor was reported as an adverse reaction occurring in less than 5% of 68 pediatric patients in an open-label non-comparative study of anidulafungin, and in the pooled safety experience from 34 studies of caspofungin in adult and pediatric patients or volunteers (n=1,951).

During the planning of the ReSTORE trial, the FDA recommended safety measures to mitigate the risk of neurotoxicity, including the exclusion of patients “with a history of neuropathy, history of tremors, or [those] receiving neurotoxic medication; addition of safety assessments for neuropathy, ataxia, and tremor; and review of safety information by the data safety monitoring board.”

Currently, four classes of antifungals (echinocandins, azoles, amphotericin B formulations of polyenes, and flucytosine) have shown clinical effectiveness for the treatment of candidemia/IC. The Infectious Diseases Society of America recommends echinocandins as first-line therapy, except when infections affect the central nervous system, the eyes, or the urinary tract. The other antifungals are considered alternatives in the case of drug intolerance, drug-resistant pathogens, or as adjunctive therapy for refractory cases.