Rezafungin 200mg powder for solution for infusion vials

Abstract Background Rezafungin (RZF) is a novel echinocandin exhibiting distinctive pharmacokinetics/pharmacodynamics. STRIVE was a phase 2, double-blind, randomized trial designed to compare the safety and efficacy of RZF once weekly (QWk) to caspofungin (CAS) once daily for treatment of candidemia and/or invasive candidiasis (IC). Methods Adults with systemic signs and mycological confirmation of candidemia and/or IC were randomized to RZF 400 mg QWk (400 mg), RZF 400 mg on week 1 then 200 mg QWk (400/200 mg), or CAS 70 mg as a loading dose followed by 50 mg daily for ≤4 weeks. Efficacy assessments included overall cure (resolution of signs of candidemia/IC + mycological eradication) at day 14 (primary endpoint), investigator-assessed clinical response at day 14, and 30-day all-cause mortality (ACM) (secondary endpoints), and time to negative blood culture. Safety was evaluated by adverse events and ACM through follow-up. Results Of 207 patients enrolled, 183 were in the microbiological intent-to-treat population (~21% IC). Overall cure rates were 60.5% (46/76) for RZF 400 mg, 76.1% (35/46) for RZF 400/200 mg, and 67.2% (41/61) for CAS; investigator-assessed clinical cure rates were 69.7% (53/76), 80.4% (37/46), and 70.5% (43/61), respectively. In total, 30-day ACM was 15.8% for RZF 400 mg, 4.4% for RZF 400/200 mg, and 13.1% for CAS. Candidemia was cleared in 19.5 and 22.8 hours in RZF and CAS patients, respectively. No concerning safety trends were observed; ACM through follow-up was 15.2% (21/138) for RZF and 18.8% (13/69) for CAS. Conclusions RZF was safe and efficacious in the treatment of candidemia and/or IC. Clinical Trials Registration NCT02734862

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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.

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The epidemiology of invasive fungal infections is changing, with new populations at risk and the emergence of resistance caused by the selective pressure from increased usage of antifungal agents in prophylaxis, empiric therapy, and agriculture. Limited antifungal therapeutic options are further challenged by drug–drug interactions, toxicity, and constraints in administration routes. Despite the need for more antifungal drug options, no new classes of antifungal drugs have become available over the last 2 decades, and only one single new agent from a known antifungal class has been approved in the last decade. Nevertheless, there is hope on the horizon, with a number of new antifungal classes in late-stage clinical development. In this review, we describe the mechanisms of drug resistance employed by fungi and extensively discuss the most promising drugs in development, including fosmanogepix (a novel Gwt1 enzyme inhibitor), ibrexafungerp (a first-in-class triterpenoid), olorofim (a novel dihyroorotate dehydrogenase enzyme inhibitor), opelconazole (a novel triazole optimized for inhalation), and rezafungin (an echinocandin designed to be dosed once weekly). We focus on the mechanism of action and pharmacokinetics, as well as the spectrum of activity and stages of clinical development. We also highlight the potential future role of these drugs and unmet needs.

Abstract licence: CC BY-NC 4.0

Invasive candidiasis/candidemia (IC/C) is associated with a substantial health economic burden driven primarily by prolonged hospital stay. The once-weekly IV echinocandin, rezafungin acetate, has demonstrated non-inferiority to caspofungin in the treatment of IC/C. This paper reports a post hoc pooled exploratory analysis of length of stay (LoS) for hospital and intensive care unit (ICU) stays in two previously published clinical trials (ReSTORE [NCT03667690] and STRIVE [NCT02734862], that compared rezafungin with daily IV caspofungin (stable patients in the caspofungin group who met relevant criteria could step down to fluconazole after 3 days or more). LoS outcomes were analysed descriptively in the pooled modified intention to treat (mITT) population (all patients who had a documented Candida infection in line with trial requirements and received at least one dose of study drug). In addition, to adjust for an imbalance between treatment groups in the proportion receiving mechanical ventilation at baseline, a generalised linear model with mechanical ventilation as a binary covariate was applied. Responses to an exploratory question in the phase 3 trial on possible earlier discharge with weekly rezafungin are also reported. 294 patients were included (rezafungin 139, caspofungin 155), of whom 126 (43%) had ICU admission. Patients treated with rezafungin had a numerically shorter LoS than with caspofungin in all analyses. Mean total LoS was 25.2 days, vs 28.3 days with caspofungin, and mean ICU LoS was 16.1 vs 21.6 days for rezafungin and caspofungin, respectively. After adjustment for mechanical ventilation status the difference in ICU LoS was 4.1 days, a relative difference of 24% (95% CI -11%, 72%). Physicians would have considered earlier discharge for 16% of patients (30/187) with weekly rezafungin, an average of 5–6 days earlier. Rezafungin may enable shorter hospital and ICU LoS in IC/C compared with daily IV caspofungin, with accompanying savings in resource use. Further research is needed to confirm this in the real-world setting. Trial registration. NCT03667690 (ReSTORE; September 12, 2018); NCT02734862 (STRIVE; April 12, 2016).

Abstract licence: CC BY-NC-ND 4.0

Abstract Background Rezafungin is approved for use in adults with candidemia and/or invasive candidiasis (IC) based on data from the ReSTORE trial (NCT03667690), which demonstrated noninferior efficacy to caspofungin. For regulatory purposes, an additional cohort of patients from China was recruited to ReSTORE. Here, we compared rezafungin and caspofungin in patients with candidemia and/or IC through analysis of the ReSTORE global data plus the China extension study. Methods Adults with candidemia/IC were randomized (1:1) to receive weekly rezafungin (400/200 mg) or daily caspofungin (70/50 mg) for ≤28 days. Noninferiority was concluded for primary efficacy endpoints if the upper bound of the 95% confidence interval (CI) was below 20% for Day 30 all-cause mortality and if the weighted lower bound was above −20% for Day 14 global cure. Additional efficacy outcomes and safety were evaluated. Results Overall, 246 patients were randomized (122 rezafungin and 124 caspofungin). Noninferiority was demonstrated for both primary endpoints. Day 30 all-cause mortality was 25.2% and 24.8% (treatment difference 0.4%; 95% CI −10.8, 11.6) and Day 14 global cure was 56.5% and 57.3% (weighted treatment difference −1.0%; 95% CI −13.5, 11.6) with rezafungin versus caspofungin, respectively. Day 5 mycological eradication was numerically higher (68.7% vs 63.2%) and time to negative blood culture was numerically shorter (median 26.5 vs 38.8 h). Safety was comparable between groups; 53.3% (64/120; rezafungin) and 53.7% (66/123; caspofungin) of patients experienced serious adverse events. Conclusions This analysis confirmed the overall efficacy and safety of rezafungin demonstrated in ReSTORE, with early efficacy related to front-loaded exposure.

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The global double‐blind, randomised, Phase 3 ReSTORE trial (NCT03667690) demonstrated noninferiority of rezafungin versus caspofungin for all‐cause mortality at Day 30 and global cure at Day 14 in patients with candidemia and/or invasive candidiasis.

Abstract licence: CC BY 4.0