By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved the first antifungal agent to treat candidemia and invasive candidiasis in over a decade.1 Rezafungin is a semisynthetic, second-generation lipopeptide (echinocandin) and an analog to anidulafungin. Its primary difference is an extended elimination half-life that allows once-weekly dosing. The FDA granted rezafungin orphan status, designated the drug as a qualified infectious disease product, and gave the solution a priority review. It will be distributed as Rezzayo.
INDICATIONS
Rezafungin can be prescribed to treat candidemia and invasive candidiasis in patients age 18 years or older with limited or no alternative options.2
DOSAGE
Administer 400 mg intravenously, followed by a dose of 200 mg once weekly.2 Rezafungin is available in a 200-mg single-dose vial for reconstitution.
POTENTIAL ADVANTAGES
Rezafungin’s extended elimination half-life (approximately 150 hours) permits once-weekly dosing compared to once-daily dosing for anidulafungin and caspofungin. It also is more chemically stable and soluble.3
POTENTIAL DISADVANTAGES
Infusion-related reactions, ranging from flushing to chest tightness, have been reported.2 Abnormalities in liver tests and photosensitivity also have been reported. Hypokalemia, hypomagnesemia, and pyrexia were numerically higher with rezafungin vs. capofungin.2 Other adverse reactions, such as diarrhea, vomiting, nausea, abdominal pain, and constipation, were roughly similar to the frequency reported for capofungin.2
COMMENTS
Rezafungin is a second-generation beta-glucan synthetase inhibitor similar to other agents in the same class (e.g., caspofungin and anidulafungin). These drugs interrupt fungal cell wall formation and are similar in terms of the in vitro antifungal activity observed against Candida species.3 The primary trial supporting the approval of rezafungin was a Phase III noninferiority study based on all-cause mortality compared to caspofungin.2,4 Researchers randomized adult subjects with systemic signs and mycologic confirmation of candidemia (70%) or invasive candidiasis (IC; 30%) to rezafungin or caspofungin (70-mg loading dose, followed by 50 mg daily for no more than four weeks). Randomization was stratified based on diagnosis (candidemia only or IC) and by APACHE II score. At baseline, Candida albicans and Candida glabrata were the most common isolated pathogens (approximately 70%).4 After three or more days of IV therapy, subjects on caspofungin could be switched to oral step-down therapy with fluconazole if the subjects met the criteria for cure and subjects were preparing to be discharged. Efficacy was all-cause mortality rate at day 30. The modified intention-to-treat population (positive culture for Candida species and received at least one dose of the study drug) was 93 for rezafungin and 94 for caspofungin. The median duration of IV treatment for each group was 14 days.4 Longer duration (15-28 days) was seen with 28% of the caspofungin group compared to 17% of the rezafungin group. All-cause mortality was 23.7% for rezafungin and 21.3% for caspofungin, a treatment difference of 2.4% (95% CI, -9.7 to 14.4%). This was lower than the prespecified upper bound of 20% corresponding to noninferiority. Other efficacy assessments, such as global cure (i.e., mycological eradication, clinical cure, and radiologic cure), clinical cure (i.e., investigator’s assessment of clinical response), and mycological eradication (i.e., negative blood culture and no change in antifungal therapy), were comparable between agents.2,4
CLINICAL IMPLICATIONS
According to the Infectious Diseases Society of America guidelines, the preferred empiric therapy for suspected candidiasis in nonneutropenic patients in the ICU is an echinocandin (caspofungin, with a loading dose of 70 mg, then 50 mg daily; micafungin, 100 mg daily; or anidulafungin, loading dose of 200 mg, then 100 mg daily).5 All these regimens require daily dosing. Rezafungin permits the convenience of once-weekly dosing with comparable clinical efficacy and significantly fewer catheter-related interventions and associated risk. Rezzayo is expected to be available this summer.
REFERENCES
1. FDA approves Rezzayo, a novel echinocandin. Infectious Disease Special Edition. March 23, 2023.
2. Melinta Therapeutics. Rezzayo prescribing information. March 2023.
3. Garcia-Effron G. Rezafungin-mechanisms of action, susceptibility and resistance: Similarities and differences with the other echinocandins. J Fungi 2020;6:262.
4. Thompson GR 3rd, Soriano A, Cornely OA, et al. Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): A multicentre, double-blind, double-dummy, randomised phase 3 trial. Lancet 2023;401:49-59.
5. Pappas PG, Kauffman CA, Andes DR, et al. Clinical practice guideline for the management of candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 2016;62:e1-e50.
Rezafungin can be prescribed to treat candidemia and invasive candidiasis in patients age 18 years or older with limited or no alternative options.
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