INTRODUCTION
Commensal
Candida species (spp.) are present on the skin and mucosa of 50%–70% of healthy individuals, but invasive candidiasis (IC), encompassing candidemia and infection of deep tissues, can occur as an opportunistic infection in immunocompromised or immunosuppressed individuals (
1,
2). In healthcare settings, IC and candidemia are among the most frequently seen fungal diseases and bloodstream infections, respectively, and are associated with substantial morbidity and mortality (
1–3). Five spp. account for most cases
—C. albicans,
Nakaseomyces glabratus (the previous classification as
C. glabrata is retained in this report),
Pichia kudriavzevii (termed
C. krusei herein),
C. tropicalis, and
C. parapsilosis—although
C. auris has also demonstrated high potential for nosocomial transmission since its emergence (
1,
2).
IC is treated with systemic antifungals comprising azoles, amphotericin B, and echinocandins, with guidelines recommending echinocandin therapy for first-line use (
4,
5). Echinocandins target 1,3-β-D-glucan synthase, resulting in destabilization of the fungal cell wall; however, mutations within
FKS gene “hotspot” (HS) regions give rise to resistance (
6). There has also been a rise in IC cases caused by non-
albicans Candida spp., such as
C. glabrata and
C. auris, which have a higher intrinsic resistance potential (
7). Increased rates of fluconazole resistance have also been reported, with intrinsic resistance seen in
C. krusei (
8,
9). As such, there is an urgent need for novel, effective antifungal agents.
Rezafungin received US Food and Drug Administration (FDA) approval in March 2023 for the treatment of candidemia and IC in patients aged ≥18 years with limited or no alternative treatment options (
10) and was approved in the European Union for the treatment of IC in adults in December 2023 (
11). This next-generation echinocandin is also in development for the prevention of invasive fungal diseases caused by
Candida,
Aspergillus, and
Pneumocystis spp. in patients undergoing allogeneic blood and marrow transplantation (
12). Compared with other echinocandins, rezafungin has an increased molecular stability, which results in a longer half-life that translates to higher, front-loaded exposure and allows weekly, rather than daily, administration (
6,
13). The front-loaded exposure enhances antifungal activity early in treatment, potentially reducing the opportunity for
FKS resistance-conferring mutations to arise (
6,
13). Rezafungin has shown activity against a broad range of isolates, including azole-resistant
Candida spp., and requires lower pharmacokinetic/pharmacodynamic (PK/PD) target exposures than other echinocandins (
14,
15), which could enable treatment of some isolates with elevated MICs (
13,
14). A study using 2021 provisional Clinical and Laboratory Standards Institute (CLSI) clinical susceptible-only breakpoints showed that a global 2019–2020 panel of
Candida spp. had high susceptibility to rezafungin based on MICs (
16). The inclusion of a CLSI MIC susceptibility breakpoint for rezafungin against
C. auris (≤0.5 µg/mL) in the most recent CLSI Performance Standards for Antifungal Susceptibility Testing of Yeasts document (the provisional CLSI breakpoints were approved as of 20 January 2024, unpublished data) also highlights the promise of rezafungin, given this is the first
C. auris susceptibility breakpoint defined for an antifungal agent (
17).
The Phase 3 ReSTORE trial in patients with candidemia and/or IC, on which FDA approval was based, compared weekly treatment with rezafungin vs daily treatment with caspofungin, an established echinocandin (
12). Rezafungin was non-inferior to caspofungin for the efficacy endpoints of all-cause mortality at day 30 (primary endpoint for FDA) and global cure at day 14 (primary endpoint for European Medicines Agency), with a similar safety profile. Here, we report an analysis of efficacy outcomes from the ReSTORE study in subgroups defined by baseline pathogen and susceptibility. Isolates demonstrating reduced echinocandin susceptibility were characterized for the presence of
FKS mutations, and findings were evaluated in light of CLSI breakpoints and those breakpoints recently granted by the FDA (
18).
DISCUSSION
In this analysis of the Phase 3 ReSTORE study, rezafungin demonstrated efficacy based on rates of global cure and mycological eradication at day 14 and the day 30 all-cause mortality rate, regardless of baseline Candida spp. Efficacy outcomes did not appear to be impacted by MIC values across Candida spp. for either rezafungin or caspofungin. Although the distribution of Candida isolates in ReSTORE was largely WT and susceptible to rezafungin based on CLSI interpretation, rezafungin treatment was also successful in the limited number of patients from ReSTORE who had non-susceptible baseline Candida isolates and FKS mutant isolates.
The MIC data from this study were consistent with the worldwide reported antimicrobial activity (2019–2020) of rezafungin and caspofungin against
Candida spp. (
16). The rates of all-cause mortality at day 30 by pathogen spp. at baseline and treatment-specific MIC value were comparable between the two treatment groups. There were some numerical differences in global cure and mycological eradication between the treatments for certain species; however, the small sample sizes prohibited drawing broad conclusions on comparative efficacy by
Candida pathogen. In other studies, correlations between MIC values and patient outcomes have not consistently been seen. For example, higher caspofungin MICs correlated with poor treatment outcomes among patients with
C. glabrata, IC, and prior echinocandin exposure in a retrospective study (
19), whereas an analysis of caspofungin clinical trial data found no such correlation (
20). In addition, a correlation between high MIC and poor treatment outcomes was found in an analysis of 32 clinical isolates from candidemia patients treated with fluconazole (
21) but was not observed in a larger population-based cohort (
22). These findings suggest a multifactorial relationship between MIC values and treatment outcomes and the need for additional factors to be considered (
23). Catheter placement is one such clinical risk factor affecting treatment outcomes that should be taken into account (
24,
25).
A relationship between echinocandin exposure (area under the curve), MIC, and efficacy has been found for micafungin (
26), underlining the importance of considering PK/PD parameters when evaluating breakpoints in the context of candidemia and IC. PK/PD simulations of the older echinocandins found that caspofungin and micafungin were likely to achieve therapeutic drug exposures in the majority of simulated patients relative to
C. glabrata MIC
90 values, whereas anidulafungin was not likely to achieve therapeutic drug exposures (
27). Similar PK/PD simulations with a once-weekly 400 mg rezafungin regimen found a 100% probability of PK/PD target attainment across weeks 1–6 for the
C. glabrata MIC
90 of 0.12 µg/mL (
28).
A clinical “susceptible” breakpoint for
C. glabrata of ≤0.5 µg/mL was approved by the CLSI Subcommittee on Antifungal Susceptibility Tests on 20 January 2024; this breakpoint is higher than those established for anidulafungin (≤0.12 µg/mL), caspofungin (≤0.12 µg/mL), and micafungin (≤0.06 µg/mL) (
17). As a drug that provides high plasma drug concentrations early in therapy, rezafungin may be better positioned to treat infections caused by isolates with higher MICs, as the epidemiology of
C. glabrata moves toward reduced susceptibility to treatment with echinocandins. In the rezafungin clinical program, there were three patients (one in the ReSTORE study and two in the expanded access program) who had infections caused by
FKS mutant
C. glabrata isolates exhibiting reduced
in vitro susceptibility to the approved echinocandins and rezafungin; however, all had positive treatment outcomes with rezafungin (
29,
30). Of note, the ReSTORE trial
FKS mutant
C. glabrata isolate that was a mycological eradication success possessed the same Fks alteration (Fks2 HS1 F659V) as an isolate used in a neutropenic mouse model where rezafungin was also efficacious (
11).
Despite a limited sample size, the prevalence of fluconazole-resistant isolates in the ReSTORE trial is reflective of increasing rates observed clinically over time for
C. glabrata,
C. tropicalis (particularly in the Asia-Pacific region), and
C. parapsilosis (
8,
9). Notably, all fluconazole-resistant isolates in the trial were susceptible to rezafungin and comparator echinocandins (data not shown), further supporting the role of echinocandins as first-line therapy for candidemia and IC.
As with the primary analysis of the ReSTORE trial (
12), potential limitations of this analysis are that the study excluded those with specific forms of IC typically requiring long courses of antifungal treatment or occurring at sites where echinocandin penetration is poor, such as the urinary tract and the central nervous system. The study also excluded pediatric patients. These exclusion criteria limit the generalizability of the results of this analysis to these specific patient subgroups. The relatively small sample size in some of the baseline
Candida pathogen groups is a further limitation specific to this analysis, as is the small number of samples with elevated and non-WT MICs, and the lack of echinocandin-resistant pathogens and
C. auris isolates.
Conclusions
Overall, these data further support the efficacy of rezafungin in candidemia and IC. We found that rezafungin demonstrated efficacy for a global cure, mycological eradication, and day 30 all-cause mortality regardless of baseline Candida spp. Efficacy outcomes across Candida spp. did not appear to be impacted by MIC values for either rezafungin or caspofungin; assessment of other clinical factors may be warranted.
ACKNOWLEDGMENTS
We thank all participants and investigators involved in ReSTORE. Medical writing support (including development of a draft outline and subsequent drafts in consultation with the authors, assembling tables and figures, collating author comments, copyediting, fact checking, and referencing) was provided by Caroline Greenwood, BSc (Hons), of Aspire Scientific (Bollington, UK) and funded by Melinta Therapeutics (Parsippany, NJ, USA).
The analysis described in this manuscript was funded by Melinta Therapeutics. The ReSTORE study was co-funded by Cidara Therapeutics and Mundipharma. Rezafungin is being developed by Cidara Therapeutics (San Diego, CA, USA) in partnership with Mundipharma (Cambridge, UK). Melinta Therapeutics (Parsippany, NJ, USA) holds the license to commercialize rezafungin in the USA.
A.D. reports consulting fees from Cidara. C.A. reports being an employee of Melinta. C.G.C. and M.C. report being an employee of JMI Laboratories. In 2022, JMI Laboratories was contracted to provide services for AbbVie, Inc., AimMax Therapeutics, Amicrobe, Inc., Appili Therapeutics, Armata Pharmaceuticals, Astellas Pharma, Inc., Basilea Pharmaceutica AG, Becton, Dickinson and Company, bioMérieux, Biosergen AB, Bugworks, Cerba Research NV, Cidara Therapeutics, Cipla USA Inc., ContraFect Corporation, CorMedix Inc., Crestone, Inc., Curza Global, LLC, Diamond V, Discuva Ltd., Entasis Therapeutics, Enveda Biosciences, Evopoint Biosciences, Fedora Pharmaceuticals, Fox Chase Chemical Diversity Center, Genentech, Gilead Sciences, Inc., GSK plc, Institute for Clinical Pharmacodynamics, Iterum Therapeutics plc, Janssen Biopharma, Johnson & Johnson, Kaleido Biosciences, LifeMine Therapeutics, Medpace, Inc, Lysovant Sciences, Inc, Meiji Seika Pharma, Melinta Therapeutics, Menarini Group, Merck & Co., MicuRx Pharmaceutical Inc., Mundipharma International Ltd., Mutabilis, Nabriva Therapeutics, National Cancer Institute, National Institutes of Health, Ohio State University, Omnix Medical Ltd., Paratek Pharmaceuticals, Pfizer, PolyPid Ltd., PPD, Prokaryotics, Inc., Pulmocide Ltd, Qpex Biopharma, Revagenix, Roche Holding AG, Roivant Sciences, Scynexis, Inc., SeLux Diagnostics, Shionogi & Co., Ltd., Sinovent Pharmaceuticals, Inc., Spero Therapeutics, Sumitovant Biopharma, Inc., TenNor Therapeutics, ThermoFisher Scientific, US Food and Drug Administration, VenatoRx Pharmaceuticals, Washington University, Watershed Medical, LLC, Wockhardt, and Zoetis, Inc. G.R.T. reports grants and consulting fees from Amplyx, Astellas, Cidara, F2G, and Manye; grants from Merck; and data safety monitoring board membership for Pfizer, outside of the submitted work. J.A.A. reports being an employee of Melinta. J.B.L. reports being an employee and shareholder of Cidara. K.B. reports being an employee and shareholder of Cidara. P.G.P. reports grants from and data review committee membership for Cidara and Melinta; grants from Astellas, Scynexis, and Merck; and advisory board membership for F2G and Matinas, outside of the submitted work. T.S. reports being an employee and stockholder of Cidara. All other authors (C.P. and D.A.) declare no competing interests.