Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Mundipharma GmbH, De-Saint-Exupery-Strasse 10, Frankfurt Am Main, 60549, Germany
Pharmacotherapeutic group: Antimycotics for systemic use, other antimycotics for systemic use
ATC code: J02AX08
Rezafungin selectively inhibits fungal 1,3-β-D-glucan synthase. This results in inhibition of the formation of 1,3-β-D-glucan, an essential component of the fungal cell wall which is not present in mammalian cells. Inhibition of 1,3-β-D-glucan synthesis results in rapid and concentration-dependent fungicidal activity in Candida species (spp.).
Rezafungin MIC90 values (obtained using a modified EUCAST methodology) are generally ≤0.016 mg/L across non-parapsilosis Candida spp. (Candida parapsilosis MIC90 = 2 mg/L).
When tested against a collection of clinical isolates of Candida spp. enriched for echinocandin-resistant and/or azole-resistant strains, rezafungin activity was similar to that of anidulafungin.
Reduced susceptibility to echinocandins, including rezafungin, arises from mutations in glucan synthase catalytic subunit-encoding FKS genes (FKS1 for most Candida spp.; FKS1 and FKS2 for C. glabrata).
MIC (minimum inhibitory concentration) interpretative criteria for susceptibility testing have been established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for rezafungin and are listed here: https://www.ema.europa.eu/documents/other/minimum-inhibitoryconcentration-mic-breakpoints_en.xlsx
A modified EUCAST broth microdilution MIC methodology has been used for testing the susceptibility of Candida spp. to rezafungin as well as to obtain the respective interpretative breakpoints.
The efficacy of rezafungin in the treatment of patients with candidaemia and/or invasive candidiasis (C/IC) was evaluated in a single Phase 3 study.
The Phase 3 study was multicentre, prospective, randomised and double-blind. Patients with septic arthritis in a prosthetic joint, osteomyelitis, endocarditis or myocarditis, meningitis, endophthalmitis, chorioretinitis or any central nervous system infection, chronic disseminated candidiasis and urinary tract candidiasis secondary to obstruction or surgical instrumentation were excluded from the study. Subjects were randomised in a 1:1 ratio to receive rezafungin as a 400 mg loading dose on Day 1, followed by 200 mg on Day 8 and once weekly thereafter, for a total of 2 to 4 weeks or caspofungin as a single 70 mg intravenous loading dose on Day 1 followed by caspofungin 50 mg intravenous once daily for a total treatment of 14 days to 28 days.
For rezafungin and caspofungin treatment groups, 70.0% and 68.7% patients, respectively, had a final diagnosis of candidaemia only. Most of them had a modified APACHE II score <20, representing 84.0% and 81.8% of rezafungin and caspofungin subjects, respectively. For rezafungin and caspofungin treatment groups, 88.0% and 93.9% patients, respectively, had an ANC ≥500/mm³ at baseline.
The primary efficacy outcome was global response (confirmed by the Data Review Committee [DRC]) at Day 14. Global response was determined from clinical response, mycological response, and radiologic response (for qualifying subjects with IC). Non-inferiority was to be concluded if the lower bound of the 95% confidence interval (CI) for the difference in Day 14 cure rates (rezafungin – caspofungin) was > -20%. Secondary efficacy outcomes included all-cause mortality at Day 30 [30-day ACM] and global response at Day 5. The results of these endpoints are shown in Table 2 for the mITT analysis set, defined as all subjects with a documented Candida infection based on Central Laboratory evaluation of a blood culture or a culture from a normally sterile site obtained ≤4 days (96 hours) before randomisation and who received ≥1 dose of investigational medicinal product.
Table 2. Summary of results from the phase 3 ReSTORE study (mITT analysis set):
| Rezafungin (R) (N=93) n (%) | Caspofungin (C) (N=94) n (%) | Difference (R-C) (95% CI)1 | |
|---|---|---|---|
| Global Response (Cure)1 | |||
| Day 5 | 52 (55.9) | 49 (52.1) | 3.8 (-10.5, 17.9) |
| Day 14 | 55 (59.1) | 57 (60.6) | -1.1 (-14.9, 12.7) |
| Day 30 ACM (Deceased)2,3 | 22 (23.7) | 20 (21.3) | 2.4 (-9.7, 14.4) |
1 Two-sided 95% confidence intervals (CIs) for the observed differences in cure rates (rezafungin minus caspofungin) is calculated adjusting for the two randomisation strata (diagnosis [candidaemia only; invasive candidiasis] and APACHE II score/ANC [APACHE II score ≥20 OR ANC <500 cells/mm³; APACHE II score <20 AND ANC ≥500 cells/mm³] at screening) using methodology of Miettinen and Nurminen. Cochran-Mantel-Haenszel weights are used for the stratum weights.
2 Two-sided 95% confidence interval (CI) for the observed difference in death rates, rezafungin minus caspofungin treatment group, is calculated using the unadjusted methodology of Miettinen and Nurminen.
3 Subjects who died on or before Day 30, or with unknown survival status.
The European Medicines Agency has deferred the obligation to submit the results of studies with REZZAYO in one or more subsets of the paediatric population in treatment of invasive candidiasis (see section 4.2 for information on paediatric use).
The pharmacokinetics of rezafungin have been characterised in healthy subjects, special populations and patients. Rezafungin has a long half-life, allowing for once-weekly dosing. Steady state is achieved with the first loading dose (twice the weekly maintenance dose).
Rezafungin is rapidly distributed with a volume of distribution approximately equal to body water (~40 L). Protein binding of rezafungin is high in humans (>97%).
In vitro, rezafungin was stable across species after incubation with liver and intestinal microsomes and with hepatocytes.
In a single-dose clinical trial, radiolabelled (14C) rezafungin (approximately 400 mg/200 µCi of radioactivity) was administered to healthy volunteers. The main circulating moiety was parent rezafungin; plasma AUC of rezafungin accounted for ~77% of total radiocarbon AUC, with individual metabolites accounting for less than 10% each.
Following single doses of rezafungin (intravenous infusion over 1 hr; 50, 100, 200, and 400 mg), mean total body clearance of rezafungin was low (approximately 0.2 L/h) throughout the dose levels with a mean terminal half-life of 127 to 146 hours. The fraction of dose excreted in urine as unchanged rezafungin was <1% at all dose levels, indicating minor contribution of renal clearance in rezafungin excretion.
In a single-dose clinical trial, radiolabelled (14C) rezafungin (approximately 400 mg/200 µCi of radioactivity) was administered to healthy volunteers. Estimated, mean total recovery of radioactivity was 88.3% at Day 60, based on interpolated data (from return visits to the clinical unit on Day 29 and Day 60). Approximately 74% of the recovered radioactive dose was in faeces (primarily as unchanged rezafungin) and 26% in urine (mainly as metabolites), indicating that elimination of rezafungin is primarily faecal excretion, as unchanged rezafungin.
Following single dose intravenous infusion, the pharmacokinetics of rezafungin are linear over a dose range of 50 to 1 400 mg. Time to reach maximum plasma concentration (Tmax) was observed at the end of infusion, as expected, for all doses and AUC increased in a dose proportional manner.
Rezafungin PK was examined in subjects with moderate (Child-Pugh B, n=8) and severe (Child-Pugh C, n=8) hepatic impairment. Mean rezafungin exposure was reduced by approximately 30% in subjects with moderate and severe hepatic impairment compared to matched subjects with normal hepatic function. Rezafungin PK was similar in subjects with moderate and severe hepatic impairment, and rezafungin exposure did not change with increasing degree of hepatic impairment. Hepatic impairment did not have a clinically meaningful effect on rezafungin PK.
A population PK analysis, including data from Phase 1, Phase 2 and Phase 3 studies, showed that creatinine clearance was not a significant covariate of rezafungin PK.
A population PK analysis, including data from Phase 1, Phase 2 and Phase 3 studies, showed that age was not a significant covariate of rezafungin PK.
A population PK analysis including data from Phase 1, Phase 2 and Phase 3 studies, showed that body surface area was a significant covariate of rezafungin PK. Simulation of exposure in clinically obese patients (body mass index (BMI) ≥30) showed that exposure was reduced in these subjects, but the reduction is not considered clinically meaningful.
A population PK analysis including data from Phase 1, Phase 2 and Phase 3 studies showed that gender and ethinicity were not significant covariates of rezafungin PK.
Rezafungin induced an acute histamine-release response in rats, but not in monkeys.
Rezafungin was negative for genotoxicity in the bacterial and mammalian cell in vitro studies, and in a rat micronucleus study.
During reproductive toxicology studies, rezafungin did not affect mating or fertility in male and female rats following intravenous (short bolus) administration once every 3 days at doses up to 45 mg/kg (6 times the clinical exposure, based on AUC determined in a separate rat study). During the male fertility study, decreased sperm motility was noted at ≥30 mg/kg and most males at 45 mg/kg showed mild/moderate hypospermia and had no detectable motile sperm. At rezafungin doses ≥ 30 mg/kg there was an increased incidence of sperm with abnormal morphology as well as mild to moderate degeneration of the seminiferous tubules.
In a 3-month toxicology study in rats, rezafungin was intravenously (short bolus) dosed once every 3 days. Males dosed at 45 mg/kg showed minimal tubular degeneration/atrophy in the testes and cellular debris in the epididymides at the end of 3 months. The incidence of this finding reduced by the end of a 4-week reversibility period.
By contrast, there were no testicular, epidydimal or spermatogenesis effects at 45 mg/kg (about 4.7 times the clinical dose based on AUC comparisons) in rats dosed intravenously (short bolus) once weekly for 6 months or after a 6-month recovery period.
Sperm concentration, production rate, morphology and motility were unaffected in adult monkeys dosed once weekly with rezafungin, up to 30 mg/kg (about 6 times the clinical dose based on AUC comparisons) for 11 or 22 weeks or after a 52-week recovery period.
No reproductive or developmental toxicity was observed with rezafungin following intravenous administration to pregnant rats and rabbits at ≥3.0-fold the predicted human AUC plasma concentration at steady state.
In a pre- and post-natal development study in rats administered up to 45 mg/kg rezafungin intravenously, there were no adverse effects on offspring growth, maturation, or measures of neurobehavioral or reproductive function. Rezafungin was measurable at low concentrations in the plasma of the foetuses of dosed animals (with concentrations in foetal plasma 2.0-3.6% of those found in maternal plasma) and was excreted in maternal milk (with concentrations in milk 22-26 % of those found in maternal plasma).
Reversible intention tremors (defined as a tremor that is more pronounced when movements are initiated) were observed in one 3-month monkey study with administration once every 3 days and had higher incidence at ≥30 mg/kg. The no observed effect level (NOEL) for intention tremors is considered to be 10 mg/kg in this study (about 2.5 times the clinical dose based on AUC comparisons). Intention tremors were not observed in the 6-month monkey study, in which animals were dosed intravenously once a week with up to 30 mg/kg (about 5.8 times the clinical dose based on AUC comparisons) or in any rat studies.
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