Patient-level meta-analysis of efficacy and safety from STRIVE and ReSTORE: randomized, double-blinded, multicentre Phase 2 and Phase 3 trials of rezafungin in the treatment of candidaemia and/or invasive candidiasis

Abstract Background Rezafungin is a next-generation echinocandin in development for treatment of candidaemia and invasive candidiasis (IC) and for prevention of invasive fungal disease caused by Candida, Aspergillus and Pneumocystis spp. in blood and marrow transplantation. Rezafungin once-weekly (QWk) was compared to caspofungin once-daily (QD) in two double-blind, randomized, controlled trials in patients with candidaemia and/or IC: STRIVE (Phase 2; NCT02734862) and the recently completed ReSTORE (Phase 3; NCT03667690). STRIVE demonstrated the efficacy and safety profile of rezafungin. ReSTORE showed rezafungin noninferiority to caspofungin for 30 day all-cause mortality (ACM) and global response at Day 14 with comparable safety. Patient-level meta-analyses of efficacy and safety from both trials are presented. Methods Details of STRIVE and ReSTORE were previously described. In this analysis of data from both trials, patients who received rezafungin QWk (400 mg in Week 1, then 200 mg) were compared with those who received caspofungin QD (70 mg on Day 1 followed by 50 mg) for ≥14 days (up to 4 weeks). Efficacy endpoints included 30 day ACM (primary US FDA), mycological response at Day 5 (secondary), and time to first negative blood culture (TTNBC) (exploratory). Safety was evaluated by adverse events (AEs). Results Groups were well matched (Table 1). Figure 1 shows 30 day ACM (overall and by final diagnosis). Mycological response at Day 5 was 73.4% (102/139) and 64.5% (100/155) in rezafungin and caspofungin groups, respectively (difference=9.5, 95% CI=−0.9, 19.9). In patients with positive blood culture before randomization, median TTNBC was 22.3 h in rezafungin-treated versus 26.3 h in caspofungin-treated patients (stratified log rank p=0.0034, not adjusted for multiplicity). The summary of AEs (Table 2) demonstrates similar outcomes for rezafungin and caspofungin groups. Conclusions In the Phase 2/3 patient-level meta-analysis, rezafungin QWk demonstrated efficacy with a similar 30 day ACM rate and safety comparable to that of caspofungin QD. Data for mycological eradication at Day 5 and TTNBC support results from the primary efficacy endpoint and provide initial evidence for the theory that high, front-loaded drug exposure leads to faster fungal clearance. Further analysis of this integrated dataset may provide additional insights on rezafungin efficacy and safety.