Outcomes by baseline pathogen and susceptibility in the ReSTORE Phase 3 trial of rezafungin once weekly compared with caspofungin once daily in patients with candidaemia and/or invasive candidiasis

Abstract Background Rezafungin is a next-generation, once-weekly echinocandin in development for treatment of candidaemia and invasive candidiasis (IC), and for prevention of invasive fungal diseases caused by Candida, Aspergillus, and Pneumocystis in allogeneic blood and marrow transplant recipients (Figure 1). ReSTORE (NCT03667690) is a global, double-blind, double-dummy, 1:1 randomized, controlled, Phase 3 non-inferiority trial that evaluated the efficacy and safety of rezafungin once weekly (QWk) versus caspofungin once daily (QD) in patients with candidaemia and/or IC. This analysis of the completed ReSTORE trial was conducted to evaluate outcomes by baseline pathogen and susceptibility. Methods In ReSTORE, adults (≥18 y) with systemic signs and mycological confirmation of candidaemia and/or IC received either rezafungin QWk (400 mg Week 1, then 200 mg QWk) or caspofungin QD for ≥14 days (up to 4 weeks) with optional oral fluconazole step-down in the caspofungin arm. The primary endpoints were global cure at day (D)14 (per Data Review Committee confirmation of investigator-assessed clinical cure [and radiological cure for IC) + mycological eradication]) and all-cause mortality (ACM) at D30 (Figure 2). Secondary endpoints included mycological eradication at D14. For this analysis, D14 global cure and mycological eradication by treatment group were analysed by Candida species and in vitro susceptibility at baseline (CLSI broth microdilution MIC values; M27 Ed4) (Figure 3). Results A total of 204 Candida isolates were recovered in 187 patients across both treatment groups. Of the 204 isolates, Candida albicans was the most common species, followed by Candida glabrata, Candida tropicalis, and Candida parapsilosis; 61% of all baseline isolates were non-albicans Candida (Figure 3). The rates of D14 global cure and mycological eradication by pathogen are shown in Tables 1 and 2. Overall, outcomes by Candida species and MIC did not appear to be affected by MIC values for either rezafungin or caspofungin (Table 3). Conclusions Rezafungin was efficacious across multiple Candida species in the Phase 3 ReSTORE trial that demonstrated non-inferiority of rezafungin to caspofungin. There was no clear correlation between increased MIC values and clinical outcomes.