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.”
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,”
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.”