Efficacy and safety of rezafungin and caspofungin in candidaemia and invasive candidiasis: pooled data from two prospective randomised controlled trials.
The Lancet. Infectious diseases
BACKGROUND:Rezafungin, a new US Food and Drug Administration-approved, long-acting echinocandin to treat candidaemia and invasive candidiasis, was efficacious with a similar safety profile to caspofungin in clinical trials. We conducted pooled analyses of the phase 2 STRIVE and phase 3 ReSTORE rezafungin trials. METHODS:ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial conducted at 66 tertiary care centres in 15 countries. STRIVE was a multicentre, double-blind, double-dummy, randomised phase 2 trial conducted at 44 centres in 10 countries. Adults (≥18 years) with candidaemia or invasive candidiasis were treated with once-a-week intravenous rezafungin (400 mg and 200 mg) or once-a-day intravenous caspofungin (70 mg and 50 mg). Efficacy was evaluated in a pooled modified intent-to-treat (mITT) population. Primary efficacy endpoint was day 30 all-cause mortality (tested for non-inferiority with a pre-specified margin of 20%). Secondary efficacy endpoint was mycological response. Safety was also evaluated. The STRIVE and ReSTORE trials are registered with ClinicalTrials.gov, NCT02734862 and NCT03667690, and both studies are complete. FINDINGS:ReSTORE was conducted from Oct 12, 2018, to Oct 11, 2021, and STRIVE from July 26, 2016, to April 18, 2019. The mITT population, pooling the data from the two trials, comprised 139 patients for rezafungin and 155 patients for caspofungin. Day 30 all-cause mortality rates were comparable between groups (19% [26 of 139] for the rezafungin group and 19% [30 of 155] for the caspofungin group) and the upper bound of the 95% CI for the weighted treatment difference was below 10% (-1·5% [95% CI -10·7 to 7·7]). Mycological eradication occurred by day 5 in 102 (73%) of 139 rezafungin patients and 100 (65%) of 155 caspofungin patients (weighted treatment difference 10·0% [95% CI -0·3 to 20·4]). Safety profiles were similar across groups. INTERPRETATION:Rezafungin was non-inferior to caspofungin for all-cause mortality, with a potential early treatment benefit, possibly reflecting rezafungin's front-loaded dosing regimen. These findings are of clinical importance in fighting active and aggressive infections and reducing the morbidity and mortality caused by candidaemia and invasive candidiasis. FUNDING:Melinta Therapeutics and Cidara Therapeutics.
10.1016/S1473-3099(23)00551-0
Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial.
Lancet (London, England)
BACKGROUND:Rezafungin is a next-generation, once-a-week echinocandin in development for the treatment of candidaemia and invasive candidiasis and for the prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp after blood and marrow transplantation. We aimed to compare the efficacy and safety of intravenous rezafungin versus intravenous caspofungin in patients with candidaemia and invasive candidiasis. METHODS:ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial done at 66 tertiary care centres in 15 countries. Adults (≥18 years) with systemic signs and mycological confirmation of candidaemia or invasive candidiasis were eligible for inclusion and randomly assigned (1:1) to receive intravenous rezafungin once a week (400 mg in week 1, followed by 200 mg weekly, for a total of two to four doses) or intravenous caspofungin (70 mg loading dose on day 1, followed by 50 mg daily) for no more than 4 weeks. The primary endpoints were global cure (consisting of clinical cure, radiological cure, and mycological eradication) at day 14 for the European Medical Agency (EMA) and 30-day all-cause mortality for the US Food and Drug Administration (FDA), both with a target non-inferiority margin of 20%, assessed in the modified intention-to-treat population (all patients who received one or more doses of study drug and had documented Candida infection based on a culture from blood or another normally sterile site obtained within 96 h before randomisation). Safety was evaluated by the incidence and type of adverse events and deaths in the safety population, defined as all patients who received any amount of study drug. The trial is registered with ClinicalTrials.gov, NCT03667690, and is complete. FINDINGS:Between Oct 12, 2018, and Aug 29, 2021, 222 patients were screened for inclusion, and 199 patients (118 [59%] men; 81 [41%] women; mean age 61 years [SD 15·2]) were randomly assigned (100 [50%] patients to the rezafungin group and 99 [50%] patients to the caspofungin group). 55 (59%) of 93 patients in the rezafungin group and 57 (61%) of 94 patients in the caspofungin group had a global cure at day 14 (weighted treatment difference -1·1% [95% CI -14·9 to 12·7]; EMA primary endpoint). 22 (24%) of 93 patients in the rezafungin group and 20 (21%) of 94 patients in the caspofungin group died or had an unknown survival status at day 30 (treatment difference 2·4% [95% CI -9·7 to 14·4]; FDA primary endpoint). In the safety analysis, 89 (91%) of 98 patients in the rezafungin group and 83 (85%) of 98 patients in the caspofungin group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events that occurred in at least 5% of patients in either group were pyrexia, hypokalaemia, pneumonia, septic shock, and anaemia. 55 (56%) patients in the rezafungin group and 52 (53%) patients in the caspofungin group had serious adverse events. INTERPRETATION:Our data show that rezafungin was non-inferior to caspofungin for the primary endpoints of day-14 global cure (EMA) and 30-day all-cause mortality (FDA). Efficacy in the initial days of treatment warrants evaluation. There were no concerning trends in treatment-emergent or serious adverse events. These phase 3 results show the efficacy and safety of rezafungin and support its ongoing development. FUNDING:Cidara Therapeutics and Mundipharma.
10.1016/S0140-6736(22)02324-8
Rezafungin-Mechanisms of Action, Susceptibility and Resistance: Similarities and Differences with the Other Echinocandins.
Journal of fungi (Basel, Switzerland)
Rezafungin (formerly CD101) is a new β-glucan synthase inhibitor that is chemically related with anidulafungin. It is considered the first molecule of the new generation of long-acting echinocandins. It has several advantages over the already approved by the Food and Drug Administration (FDA) echinocandins as it has better tissue penetration, better pharmacokinetic/phamacodynamic (PK/PD) pharmacometrics, and a good safety profile. It is much more stable in solution than the older echinocandins, making it more flexible in terms of dosing, storage, and manufacturing. These properties would allow rezafungin to be administered once-weekly (intravenous) and to be potentially administered topically and subcutaneously. In addition, higher dose regimens were tested with no evidence of toxic effect. This will eventually prevent (or reduce) the selection of resistant strains. Rezafungin also has several similarities with older echinocandins as they share the same in vitro behavior (very similar Minimum Inhibitory Concentration required to inhibit the growth of 50% of the isolates (MIC) and half enzyme maximal inhibitory concentration 50% (IC)) and spectrum, the same target, and the same mechanisms of resistance. The selection of mutants occurred at similar frequency for rezafungin than for anidulafungin and caspofungin. In this review, rezafungin mechanism of action, target, mechanism of resistance, and in vitro data are described in a comparative manner with the already approved echinocandins.
10.3390/jof6040262
An evaluation of Rezafungin: the latest treatment option for adults with candidemia and invasive candidiasis.
Expert opinion on pharmacotherapy
INTRODUCTION:Invasive fungal infections, especially candidemia and invasive candidiasis, continue to cause substantial morbidity and mortality. In addition, the emergence of drug-resistant species, notably and , along with limitations in available treatments, highlights the urgent need for novel, effective antifungal agents. AREAS COVERED:This review discusses the results of in vitro studies evaluating the spectrum and highlights the pharmacokinetic/pharmacodynamic properties. It also includes discussions on two key clinical studies that assess safety, tolerability, and efficacy. EXPERT OPINION:Rezafungin has demonstrated comparable efficacy to other echinocandins in two clinical studies and exhibits in vitro activity against a broad range of species and spp. It has a favorable safety profile with minimal side effects, and no drug interactions or effects on QT intervals. In contrast to other echinocandins, it demonstrates dose-dependent killing, a prolonged half-life, and low clearance make it suitable for once-weekly dosing, which is supported by clinical trials confirming its efficacy. Rezafungin offers a promising option for the outpatient management of difficult to treat fungal infections. It has become a valuable addition to the antifungal arsenal, with the potential to reduce hospital length of stay and hospitalization costs and combat drug-resistant species.
10.1080/14656566.2024.2331775
Outcomes by spp. in the ReSTORE Phase 3 trial of rezafungin versus caspofungin for candidemia and/or invasive candidiasis.
Antimicrobial agents and chemotherapy
Rezafungin is a long-acting, intravenously administered echinocandin for the treatment of candidemia and invasive candidiasis (IC). Non-inferiority of rezafungin vs caspofungin for the treatment of adults with candidemia and/or IC was demonstrated in the Phase 3 ReSTORE study based on the primary endpoints of day 14 global cure and 30-day all-cause mortality. Here, an analysis of ReSTORE data evaluating efficacy outcomes by baseline species is described. Susceptibility testing was performed for species using the Clinical and Laboratory Standards Institute reference broth microdilution method. There were 93 patients in the modified intent-to-treat population who received rezafungin; 94 received caspofungin. Baseline species distribution was similar in the two treatment groups; (occurring in 41.9% and 42.6% of patients in the rezafungin and caspofungin groups, respectively), (25.8% and 26.6%), and (21.5% and 18.1%) were the most common pathogens. Rates of global cure and mycological eradication at day 14 and day 30 all-cause mortality by species were comparable in the rezafungin and caspofungin treatment groups and did not appear to be impacted by minimal inhibitory concentration (MIC) values for either rezafungin or caspofungin. Two patients had baseline isolates with non-susceptible MIC values (both in the rezafungin group: one non-susceptible to rezafungin and one to caspofungin, classified as intermediate); both were candidemia-only patients in whom rezafungin treatment was successful based on the day 30 all-cause mortality endpoint. This analysis of ReSTORE demonstrated the efficacy of rezafungin for candidemia and IC in patients infected with a variety of species.
10.1128/aac.01584-23
Rezafungin: First Approval.
Drugs
Rezafungin (Rezzayo™), an intravenous once-weekly echinocandin that inhibits 1,3-β-D-glucan synthase, is being developed by Cidara Therapeutics. In March 2023, rezafungin received approval in the USA for the treatment of candidaemia and invasive candidiasis in patients aged ≥ 18 years who have limited or no alternative treatment options. Rezafungin is also being developed for the prevention of invasive fungal diseases in blood and marrow transplant recipients. This article summarizes the milestones in the development of rezafungin leading to the first approval for the treatment of candidaemia and invasive candidiasis.
10.1007/s40265-023-01891-8
Treatment Outcomes Among Patients With a Positive Candida Culture Close to Randomization Receiving Rezafungin or Caspofungin in the ReSTORE Study.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
BACKGROUND:Rezafungin, a novel, once-weekly echinocandin for the treatment of candidemia and/or invasive candidiasis (IC) was noninferior to caspofungin for day 30 all-cause mortality (ACM) and day 14 global cure in the phase 3 ReSTORE trial (NCT03667690). We conducted preplanned subgroup analyses for patients with a positive culture close to randomization in ReSTORE. METHODS:ReSTORE was a multicenter, double-blind, double-dummy, randomized trial in patients aged ≥18 years with candidemia and/or IC treated with once-weekly intravenous rezafungin (400 mg/200 mg) or once-daily intravenous caspofungin (70 mg/50 mg). This analysis comprised patients with a positive blood culture drawn between 12 hours before and 72 hours after randomization or a positive culture from another normally sterile site sampled between 48 hours before and 72 hours after randomization. Efficacy endpoints included day 30 ACM, day 14 global cure rate, and day 5 and 14 mycological response. Adverse events were evaluated. RESULTS:This analysis included 38 patients randomized to rezafungin and 46 to caspofungin. In the rezafungin and caspofungin groups, respectively, day 30 ACM was 26.3% and 21.7% (between-group difference [95% confidence interval], 4.6% [-13.7%, 23.5%]), day 14 global response was 55.3% and 50.0% (between-group difference, 5.3% [-16.1%, 26.0%]), and day 5 mycological eradication was 71.1% and 50.0% (between-group difference, 21.1% [-0.2%, 40.2%]). Safety was comparable between treatments. CONCLUSIONS:These findings support the efficacy and safety of rezafungin compared with caspofungin for the treatment of candidemia and/or IC in patients with a positive culture close to randomization, with potential early treatment benefits for rezafungin.
10.1093/cid/ciae363
In vitro activity of rezafungin against common and rare Candida species and Saccharomyces cerevisiae.
Tóth Zoltán,Forgács Lajos,Locke Jeffrey B,Kardos Gábor,Nagy Fruzsina,Kovács Renátó,Szekely Adrien,Borman Andrew M,Majoros László
The Journal of antimicrobial chemotherapy
BACKGROUND:Rezafungin is a novel echinocandin with excellent activity against common Candida species; however, limited data are available regarding rare Candida species. METHODS:We determined the in vitro susceptibility of 689 clinical isolates of 5 common and 19 rare Candida species, as well as Saccharomyces cerevisiae. The activity of rezafungin was compared with that of anidulafungin, caspofungin, micafungin, amphotericin B and fluconazole, using CLSI broth microdilution methodology (Fourth Edition: M27). RESULTS:Rezafungin MIC90 values were 0.06 mg/L for Candida albicans (n=125), Candida tropicalis (n=51), Candida dubliniensis (n=22), Candida inconspicua (n=41), Candida sojae (n=10), Candida lipolytica (n=10) and Candida pulcherrima (n=10), 0.12 mg/L for Candida glabrata (n=81), Candida krusei (n=53), Candida kefyr (n=52) and Candida fabianii (n=15), 0.25 mg/L for Candida lusitaniae (n=46) and Candida auris (n=19), 0.5 mg/L for Candida metapsilosis (n=15) and S. cerevisiae (n=21), 1 mg/L for Candida orthopsilosis (n=15) and Candida guilliermondii (n=27) and 2 mg/L for Candida parapsilosis sensu stricto (n=59). Caspofungin MIC90 values were 0.25-2 mg/L for all species, while micafungin and anidulafungin MIC90 values were similar to those of rezafungin. Fluconazole resistance was found in C. albicans (5.6%) and C. glabrata (4.9%); rezafungin was effective against these isolates as well. Amphotericin B MIC values did not exceed 2 mg/L. CONCLUSIONS:Rezafungin showed excellent in vitro activity against both WT and azole-resistant Candida species, as well as against S. cerevisiae. Rezafungin had similar activity to other echinocandins (excluding caspofungin) against common Candida species and, notably, against clinically relevant uncommon Candida species.
10.1093/jac/dkz390