Veozah
fezolinetant
Species
MonkeyRat
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey (females)
“Repeat dose toxicity studies were conducted in intact female rats and cynomolgus monkeys.”
Why that species
Monkey reproductive system similar to human (LH-sensitive); similar NK3 receptor affinity in human and cynomolgus monkey
“Cynomolgus monkey was selected as the relevant nonrodent species as nonhuman primates are anatomically and functionally similar to humans in the reproductive system, which is known to be affected by LH change. In addition, according to the in vitro radioligand assay, fezolinetant has a similar affinity for the human and cynomolgus monkey NK3 receptor orthologs.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the 26-week rat study (Study No 8331724), fezolinetant was administered orally by daily gavage to sexually mature female rats at a dose of 0 (vehicle), 30, 100, or 200 mg/kg.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey)
“Repeated dose toxicity studies were conducted in rats up to 26 weeks and in monkeys up to 39 weeks.”
Pivotal GLP studies
4-, 13- and 26-week rat and 5-, 13- and 39-week monkey GLP studies
“Pivotal GLP-compliant repeated dose studies were conducted in rats and monkeys and comprised the studies of 4, 13 and 26 weeks duration in rats and 5, 13 and 39 weeks duration in monkeys.”
Route in tox
Oral gavage
“In the 39-week monkey study (Study No 8331280), fezolinetant was administered orally by daily gavage to sexually mature female monkeys at a dose of 0, 10, 25, or 40 mg/kg.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, chromosomal aberration and in vivo micronucleus tests
“Fezolinetant showed no genotoxic potential by the bacterial reverse mutation test, chromosomal aberration test, or in vivo micronucleus test.”
Carcinogenicity
2-year female rat and 26-week rasH2 mouse: no drug-related carcinogenicity (186x and 47x human AUC)
“In a 2-year female rat carcinogenicity study and a 26-week carcinogenicity study in rasH2 transgenic mice, there was no evidence of drug-related carcinogenicity at 186-fold and 47-fold the human AUC 24 at the human therapeutic dose of 45 mg, respectively.”
Reproductive & developmental
Rat and rabbit EFD: embryo-lethality at high doses, no teratogenicity; rat PPND: delayed parturition and embryo-lethality at high doses
“In embryo-fetal toxicity animal studies with fezolinetant, embryo-lethality occurred at high doses above the human therapeutic dose in rats and rabbits, but no teratogenicity was observed. In the pre- and post-natal development animal study, delayed parturition and embryo-lethality occurred at high doses above the human therapeutic dose in rats.”
Safety pharmacology
hERG IC50 ~350-fold above free human Cmax at MRHD; no repolarization or proarrhythmic risk expected
“This translates into a 350-fold difference between human free Cmax at MRHD and IC50 value in hERG assay, indicating that no effects on the cardiovascular system with regard to ventricular repolarization and proarrhythmic risk are to be expected in humans.”
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 Veozah 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: 39-week monkey, high doses: weight loss, lymphocyte hyperplasia (lymph nodes, spleen, lung), kidney perivascular inflammation (FDA pharmacology/toxicology review, p. 19)
NOAEL / key findings
39-week monkey, high doses: weight loss, lymphocyte hyperplasia (lymph nodes, spleen, lung), kidney perivascular inflammation
“In the 39-week monkey study (Study No 8331280), fezolinetant was administered orally by daily gavage to sexually mature female monkeys at a dose of 0, 10, 25, or 40 mg/kg. High doses of fezolinetant resulted in weight loss and microscopic findings (hyperplasia of lymphocytes in lymph nodes, spleen, and lung, as well as perivascular inflammation in the kidney).”
Risksopen answer page →
Immune & cytokine safety
No antigenicity or immunotoxicity studies conducted (not considered necessary)
“No antigenicity and immunotoxicity studies have been conducted with fezolinetant since these studies were not considered necessary.”
Biodistribution & persistence
Highest tissue levels in kidney cortex, clitoris, uveal tract/retina, adrenal gland and liver
“The highest levels of fezolinetant in tissues were associated with the kidney cortex, clitoris, uveal tract/retina, adrenal gland (cortex and medulla) and liver.”
Modality-specific risk
Malignancy and tumor-promoter potential (assessed; no mechanism identified)
“Based on the currently available nonclinical information provided by the Applicant and in the published literature, no biological mechanism was identified that indicated an increased risk of malignancy or tumor promotor activity with fezolinetant or through”