Rezzayo
rezafungin
Species
MonkeyRat
Longest study
26 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“Pivotal repeated dose toxicity studies include studies in rats and cynomolgus monkeys with treatment durations, in both animal species, of 4, 13 and 26 weeks.”
Why that species
Monkey: similar in vitro metabolic stability and protein binding to human; predictive of echinocandin toxicity in humans
“Cynomolgus monkeys were chosen as the nonrodent toxicology species due to similar in vitro metabolic stability and protein binding characteristics to humans and because monkeys have been shown to be predictive for echinocandin-induced toxicity in humans.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the 26-week study, rezafungin was administered once weekly at 0, 10, 25, or 45 mg/kg.”
Species: general tox
Rat and cynomolgus monkey (4, 13 and 26 weeks)
“Pivotal repeated dose toxicity studies include studies in rats and cynomolgus monkeys with treatment durations, in both animal species, of 4, 13 and 26 weeks.”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Reproductive toxicity studies comprised studies on fertility and early embryonic development (Sprague Dawley rats), embryo-fetal development (Sprague Dawley rats, New Zealand White rabbits) and pre and postnatal development (Sprague Dawley rats).”
Species: carcinogenicity
Not conducted (short-term indication)
“No carcinogenicity studies have been conducted. Considering the proposed therapeutic indication and the proposed duration of treatment, this was considered a satisfactory approach.”
Surrogate used in
No surrogate used; monkey chosen as predictive of echinocandin toxicity in humans
“Cynomolgus monkeys were chosen as the nonrodent toxicology species due to similar in vitro metabolic stability and protein binding characteristics to humans and because monkeys have been shown to be predictive for echinocandin-induced toxicity in humans.”
Study lengthopen answer page →
Longest pivotal study
26 (26-week rat and monkey)
“Pivotal repeated dose toxicity studies include studies in rats and cynomolgus monkeys with treatment durations, in both animal species, of 4, 13 and 26 weeks.”
Pivotal GLP studies
4-, 13- and 26-week rat and cynomolgus monkey intravenous studies
“Pivotal repeated dose toxicity studies include studies in rats and cynomolgus monkeys with treatment durations, in both animal species, of 4, 13 and 26 weeks.”
Route in tox
Intravenous (slow bolus in rats, infusion in monkeys)
“In the pivotal rat studies, this was by slow intravenous bolus; in the pivotal monkey studies, by 20- to 60- min intravenous infusions.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro mammalian clastogenicity and in vivo rat bone marrow micronucleus assays
“Rezafungin was negative in a standard battery of assays, including an in vitro bacterial reverse mutation assay, an in vitro mammalian clastogenicity assay, and an in vivo rat bone marrow micronucleus assay.”
Carcinogenicity
Not conducted (short-term treatment indication)
“No carcinogenicity studies have been conducted. Considering the proposed therapeutic indication and the proposed duration of treatment, this was considered a satisfactory approach.”
Reproductive & developmental
Rat fertility unaffected up to 45 mg/kg; decreased sperm motility and hypospermia in males at ≥30 mg/kg
“Rezafungin did not affect mating or fertility in male and female rats following IV 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). 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.”
Safety pharmacology
Telemetered monkey: no effects on body temperature, blood pressure, ECG or respiration up to 10 mg/kg
“Administration of a 20 minute IV infusion of rezafungin to telemetered male cynomolgus monkeys (NC-059), did not cause changes in body temperature, blood pressure, ECG and respiratory parameters at doses up to 10 mg/kg,”
Genotox: Ames
Negative
“Rezafungin was negative in a standard battery of assays, including an in vitro bacterial reverse mutation assay, an in vitro mammalian clastogenicity assay, and an in vivo rat bone marrow micronucleus assay.”
Genotox: in vitro mammalian
In vitro mammalian clastogenicity assay: negative
“Rezafungin was negative in a standard battery of assays, including an in vitro bacterial reverse mutation assay, an in vitro mammalian clastogenicity assay, and an in vivo rat bone marrow micronucleus assay.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Rezafungin was negative in a standard battery of assays, including an in vitro bacterial reverse mutation assay, an in vitro mammalian clastogenicity assay, and an in vivo rat bone marrow micronucleus assay.”
Carcinogenicity model
Not conducted (proposed indication and treatment duration)
“No carcinogenicity studies have been conducted. Considering the proposed therapeutic indication and the proposed duration of treatment, this was considered a satisfactory approach.”
Carcinogenicity timing
Not conducted; considered unnecessary given indication and short treatment duration
“No carcinogenicity studies have been conducted. Considering the proposed therapeutic indication and the proposed duration of treatment, this was considered a satisfactory approach.”
hERG / QT
No hERG inhibition up to 1.1 µM (max testable), above estimated free clinical Cmax
“In the pivotal study, rezafungin did not affect hERG current up to a concentration of 1.1 μM, the maximum concentration able to be evaluated, which exceeds the estimated free drug Cmax in the clinic.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Rezzayo don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Rat 26-week: nerve fiber/axonal degeneration at 25 and 45 mg/kg, persisting through 26-week recovery (FDA integrated review, p. 74)
NOAEL / key findings
Rat 26-week: nerve fiber/axonal degeneration at 25 and 45 mg/kg, persisting through 26-week recovery
“In a 26-week study of weekly rezafungin in rats, nerve fiber/axonal degeneration increased in incidence and severity at 25 and 45 mg/kg and persisted at the end of the 26-week recovery period.”
Risksopen answer page →
Immune & cytokine safety
Acute transient histamine-release response in rats; mild histamine-like response in monkeys
“Rezafungin induced an acute transient histamine-release response in rats. In monkeys, both the vehicle and rezafungin induced a mild transient histamine-like response in some studies.”
Biodistribution & persistence
Widespread distribution in rat; tissue exposure ~4-fold plasma in kidney, lung, liver, spleen, lower in heart and brain
“Tissue distribution was evaluated in rats after IV administration of rezafungin, demonstrating widespread exposure in various organs, with tissue/plasma AUC ratios that were comparable (approximately 4-fold higher in tissue than plasma) for major (kidney, lung, liver, spleen) organs with the exception of the heart and brain.”
Modality-specific risk
Neurotoxicity signal in nonhuman primates and rats
“A neurotoxicity safety signal was identified in subchronic rezafungin dosing studies in nonhuman primates and rats.”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Label warnings
- Hypersensitivity Reactions, including Anaphylaxis
- Infusion-Related Reactions
- Photosensitivity
- Hepatic Adverse Reactions
Hypersensitivity & infusion reactionsSkin reactionsHepatotoxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Rezzayo don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Rat 26-week: nerve fiber/axonal degeneration at 25 and 45 mg/kg, persisting through 26-week recovery (FDA integrated review, p. 74)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week rat and cynomolgus monkey (IV, weekly), with 6-month (rat) and 12-month (monkey) recovery
“All pivotal studies included recovery periods; these were of 6 or 12 months duration in the 26-week studies in rats and cynomolgus monkeys, respectively.”
Pivotal GLP studies
4-, 13- and 26-week rat and cynomolgus monkey intravenous studies
“Pivotal repeated dose toxicity studies include studies in rats and cynomolgus monkeys with treatment durations, in both animal species, of 4, 13 and 26 weeks.”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Reproductive toxicity studies comprised studies on fertility and early embryonic development (Sprague Dawley rats), embryo-fetal development (Sprague Dawley rats, New Zealand White rabbits) and pre and postnatal development (Sprague Dawley rats).”
Reproductive & developmental
Rat fertility unaffected up to 45 mg/kg; decreased sperm motility and hypospermia in males at ≥30 mg/kg
“Rezafungin did not affect mating or fertility in male and female rats following IV 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). 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.”
PPND / ePPND: when
Rat PPND completed before the marketing application; no effects on pre- and postnatal development
“The study revealed no effects on pre-and postnatal development up to the reproduction of the F1 generation, and, therefore, the NOAEL for pre- and postnatal development was set at 45 mg/kg/day.”
Carcinogenicity
Species: carcinogenicity
Not conducted (short-term indication)
“No carcinogenicity studies have been conducted. Considering the proposed therapeutic indication and the proposed duration of treatment, this was considered a satisfactory approach.”
Carcinogenicity model
Not conducted (proposed indication and treatment duration)
“No carcinogenicity studies have been conducted. Considering the proposed therapeutic indication and the proposed duration of treatment, this was considered a satisfactory approach.”
Carcinogenicity timing
Not conducted; considered unnecessary given indication and short treatment duration
“No carcinogenicity studies have been conducted. Considering the proposed therapeutic indication and the proposed duration of treatment, this was considered a satisfactory approach.”
Safety marginopen answer page →
Safety margin at NOAEL
26-week NOAELs: rat (45 mg/kg) ~4-fold and monkey (30 mg/kg) ~6-fold human AUC
“According to the provided calculations of exposure multiples, in the longest-term repeated dose toxicity studies (26-week), systemic exposure at the determined NOAEL in monkeys (30 mg/kg) was nearly 6-fold that expected in patients, based on AUC0-168hr; at the NOAEL in rats (45 mg/kg) was nearly 4-fold that expected in patients.”
NOAEL / key findings
Rat 26-week: nerve fiber/axonal degeneration at 25 and 45 mg/kg, persisting through 26-week recovery
“In a 26-week study of weekly rezafungin in rats, nerve fiber/axonal degeneration increased in incidence and severity at 25 and 45 mg/kg and persisted at the end of the 26-week recovery period.”
Efficacy evidenceopen answer page →
Efficacy evidence
Neutropenic murine candidiasis model (C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. dubliniensis)
“The Applicant conducted several studies examining the nonclinical PK-PD of REZ in a neutropenic candidiasis murine model with C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, or C. dubliniensis.”
Why that model
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reviewer's view of the efficacy data
FDA: useful for dose selection, but translational utility uncertain given lack of established animal models for candidiasis/IC
“While these nonclinical findings might be valuable in rationalizing dosage selection for clinical study evaluation, the translational utility of these findings to candidemia/IC patient care remains to be determined; especially considering the lack of established animal models for candidiasis and IC (see Section 14.2.3 for more details).”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies
Why: Proposed indication and short duration of treatment · Other reason
“No carcinogenicity studies have been conducted. Considering the proposed therapeutic indication and the proposed duration of treatment, this was considered a satisfactory approach.”
Juvenile toxAcceptedBeyond the letter
No juvenile animal studies
Why: Application covers adult patients only · Other reason
“No studies in juvenile animals have been conducted. The lack of such studies is accepted, as the present Marketing Application Authorization refers to the use of Rezzayo in adult patients only.”
Safety marginAccepted with a conditionBeyond the letter
Male reproductive organ effects in rats with a low (2-fold AUC) safety margin
Why: Effects on male rat reproductive organs and spermatogenesis described in the SmPC
“Based on human exposure data and animal toxicokinetics data extrapolated from the 4-week repeated dose toxicity study, there is a low safety margin (2-fold, based on AUC) for the effects observed in male reproductive organs.”
“As mentioned before, information on the effects observed on male rat reproductive organs and spermatogenesis has been adequately included in the SmPC.”
Safety marginAccepted with a conditionBeyond the letter
Intention tremors in monkeys with relatively low safety margins (2.53 to 6.15-fold AUC)
Why: Intention tremor information included in SmPC section 5.3
“Considering that the available information suggests that rezafungin may induce dose-dependent intention tremors with relatively low safety margins (2.53 to 6.15- fold, based on systemic exposure [AUC0-168] from the 13-week [NOAEL of 10 mg/kg/dose, since intention tremors were observed at ≥30 mg/kg/dose] and 6 months study [NOAEL of 30 mg/kg/dose, the maximum tested dose])”
“The information included on intention tremors in section 5.3 of the SmPC is adequate.”
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