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.”
Species: general tox
Rat (up to 26 weeks) and cynomolgus monkey (up to 39 weeks)
“Repeated dose toxicity studies were conducted in rats up to 26 weeks and in monkeys up to 39 weeks.”
Species: DART
Rat and rabbit (embryo-fetal development)
“In embryo-fetal development toxicity studies in rats and rabbits, embryo-lethality was noted at the highest doses (128- and 174-fold the human AUC 24 at the human therapeutic dose for rats and rabbits, respectively).”
Species: carcinogenicity
Wistar rat (104-week) and transgenic rasH2 mouse (26-week)
“Carcinogenicity of fezolinetant was investigated in the 104-week carcinogenicity study with Wistar rats administered the test substance at the dose levels of 10, 30 and 100 mg/kg/day by oral gavage, and in the 26-week study with transgenic RasH2 mice.”
Surrogate used in
No surrogate used; fezolinetant has similar human and monkey NK3 affinity (8-fold lower in rat)
“Fezolinetant has a similar affinity for human and monkey NK3 receptors and 8-fold less for rat NK3 receptors.”
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.”
Genotox: Ames
Negative
“The GLP-compliant in vitro Ames test and chromosome aberration test in human peripheral blood lymphocytes, conducted according to OECD guidelines 471 and 473, respectively, were clearly negative.”
Genotox: in vitro mammalian
Human lymphocyte chromosome aberration: negative
“The GLP-compliant in vitro Ames test and chromosome aberration test in human peripheral blood lymphocytes, conducted according to OECD guidelines 471 and 473, respectively, were clearly negative.”
Genotox: in vivo
In vivo reticulocyte micronucleus: no increase at any dose (negative)
“There were no statistically significant increases in the percentage of micronucleated reticulocytes at any dose level in male or female animals sampled on either Day 4 or Day 30.”
Carcinogenicity model
104-week Wistar rat; 26-week transgenic rasH2 mouse
“Carcinogenicity of fezolinetant was investigated in the 104-week carcinogenicity study with Wistar rats administered the test substance at the dose levels of 10, 30 and 100 mg/kg/day by oral gavage, and in the 26-week study with transgenic RasH2 mice.”
Carcinogenicity timing
Rat and transgenic mouse studies completed; final reports judged negative by ECAC before approval
“Carcinogenicity studies were done in rats and transgenic mice. The final study reports were presented at the 10/25/22 Executive Carcinogenicity Assessment (ECAC) meeting and both studies were considered negative.”
hERG / QT
hERG IC50 ~350-fold above free 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”
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
Boxed warning: Risks of hepatotoxicity
- Hepatotoxicity
Hepatotoxicity
US prescribing information, Boxed Warning and 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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week female monkey (GLP) with 4-week recovery
“8331280*** (GLP) FEMALE Monkey, oral gavage @ 0, 10, 25, and 40 mg/kg/day fezolinetant for 39 weeks with 4- week recovery”
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.”
DART package
Species: DART
Rat and rabbit (embryo-fetal development)
“In embryo-fetal development toxicity studies in rats and rabbits, embryo-lethality was noted at the highest doses (128- and 174-fold the human AUC 24 at the human therapeutic dose for rats and rabbits, 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.”
PPND / ePPND: when
PPND study report submitted under the IND before the NDA and reviewed in the NDA
“The Sponsor submitted carcinogenicity study reports and pre-and post-natal developmental study report under IND 130277 eCTD 0115. The carcinogenicity studies and the pre-postnatal developmental study are being reviewed under the current NDA submission.”
Carcinogenicity
Species: carcinogenicity
Wistar rat (104-week) and transgenic rasH2 mouse (26-week)
“Carcinogenicity of fezolinetant was investigated in the 104-week carcinogenicity study with Wistar rats administered the test substance at the dose levels of 10, 30 and 100 mg/kg/day by oral gavage, and in the 26-week study with transgenic RasH2 mice.”
Carcinogenicity model
104-week Wistar rat; 26-week transgenic rasH2 mouse
“Carcinogenicity of fezolinetant was investigated in the 104-week carcinogenicity study with Wistar rats administered the test substance at the dose levels of 10, 30 and 100 mg/kg/day by oral gavage, and in the 26-week study with transgenic RasH2 mice.”
Carcinogenicity timing
Rat and transgenic mouse studies completed; final reports judged negative by ECAC before approval
“Carcinogenicity studies were done in rats and transgenic mice. The final study reports were presented at the 10/25/22 Executive Carcinogenicity Assessment (ECAC) meeting and both studies were considered negative.”
Safety marginopen answer page →
Safety margin at NOAEL
26-week rat and 39-week monkey NOAELs ~148x and 43x human AUC at MRHD
“In the pivotal 26-week rat and 39-week monkey studies, the mid-dose levels of 200 (rat) and 25 (monkey) mg/kg/day fezolinetant were the NOAELs, with margins of 148X and 43X MRHD based on AUC, respectively.”
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).”
Efficacy evidenceopen answer page →
Efficacy evidence
Ovariectomized rat (postmenopause model): attenuated hot flash-like symptoms
“In vivo pharmacology studies demonstrated fezolinetant attenuated hot flash-like symptoms in ovariectomized (OVX) rats (a nonclinical model of postmenopause).”
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
EMA: proof-of-concept shown in rat OVX model with supporting NK3/MnPO mechanism
“The applicant showed proof-of-concept for fezolinetant induced reductions in vasomotor symptoms in a rat OVX model, and provided evidence for a molecular mechanism implicating fezolinetant as a hNK3 receptor antagonist that leads to reduced activity in the median preoptic nucleus, associated with temperature regulation.”
Flexibilityopen answer page →
Flexibility accepted
OtherAcceptedBeyond the letter
Sub-chronic and chronic toxicity studies conducted in female animals only
Why: Product intended for hot flushes in menopausal women · Other reason
“As the product is intended to be administered for the treatment of hot flushes in menopausal women, sub-chronic and chronic studies were performed in female animals only, which is acceptable.”
DARTAcceptedBeyond the letter
Rat fertility and early embryonic development study dosed females only (no male fertility assessment)
Why: Indication is hot flushes associated with menopause · Other reason
“Considering the proposed indication for the treatment of hot flushes associated with menopause, the dosing of only female animals is considered acceptable.”
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