Xocova
ensitrelvir
Species
MonkeyRat
Longest study
4 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
“Evaluation of the safety of S-217622 (ensitrelvir) fumaric acid, included safety pharmacology in rats and dogs, repeat-dose oral toxicity studies in rats and monkeys (2- and 4-week), genotoxicity studies, reproductive and developmental toxicity studies in rats and rabbits, and other mechanistic studies.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“In a 4-week oral repeat-dose toxicology study in cynomolgus monkeys, ensitrelvir was administered at 0, 3, 10 or 30 mg/kg/day.”
Study lengthopen answer page →
Longest pivotal study
4 (4-week rat and monkey)
“In a 4-week oral repeat-dose toxicology study in cynomolgus monkeys, ensitrelvir was administered at 0, 3, 10 or 30 mg/kg/day.”
Pivotal GLP studies
2- and 4-week oral studies in rats and cynomolgus monkeys
“Evaluation of the safety of S-217622 (ensitrelvir) fumaric acid, included safety pharmacology in rats and dogs, repeat-dose oral toxicity studies in rats and monkeys (2- and 4-week), genotoxicity studies, reproductive and developmental toxicity studies in rats and rabbits, and other mechanistic studies.”
Route in tox
Oral
“In a 4-week oral repeat-dose toxicology study in cynomolgus monkeys, ensitrelvir was administered at 0, 3, 10 or 30 mg/kg/day.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro TK6 micronucleus and in vivo rat micronucleus assays
“Ensitrelvir was not genotoxic in the reverse mutation bacterial (Ames) test, in vitro micronucleus assay using human lymphoblastoid TK6 cells, or the in vivo rat micronucleus assays.”
Carcinogenicity
Not conducted (short treatment duration)
“Carcinogenesis studies were not conducted due to the short duration of drug administration.”
Reproductive & developmental
Rabbit EFD: axial skeletal malformations, embryofetal lethality and abortion with maternal toxicity (NOAEL 30 mg/kg/day, 3x)
“In rabbits, malformations and variations of the axial skeleton, embryofetal lethality, abortion, and post-implantation loss, accompanied by maternal toxicity were observed, with a NOAEL of 30 mg/kg/day and a safety margin of 3X.”
Safety pharmacology
No adverse CV, respiratory or CNS effects; hERG 39% inhibition at 100 µM, low QT risk
“There were no adverse effects in any of the cardiovascular, respiratory, and central nervous system assessments in dogs and rats. In the hERG assay, the maximum tested concentration of 100 µmol/L inhibited the hERG current by 39%, which was not considered significant and suggested a low risk for QT prolongation.”
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 Xocova 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: 4-week monkey NOAEL 10 mg/kg/day; reduced food intake, weight loss, clinical pathology and multi-organ histopathology at 30 mg/kg (FDA pharmacology/toxicology review, p. 12)
NOAEL / key findings
4-week monkey NOAEL 10 mg/kg/day; reduced food intake, weight loss, clinical pathology and multi-organ histopathology at 30 mg/kg
“The NOAEL was 10 mg/kg/day based on adverse findings at 30 mg/kg, including decreased food consumption and body weight loss in females, changes in clinical pathology parameters, along with extensive histopathological changes in several organs.”
Risksopen answer page →
Immune & cytokine safety
20-40% decreases in T- and B-cell populations in 4-week monkey study
“Immunophenotyping revealed 20-40% decreases in various T-cell and B-cell populations (males and females).”
Biodistribution & persistence
Highly protein-bound; highest tissue levels in liver; minimal CNS penetration (rat)
“Ensitrelvir was highly protein-bound (97.4% to >98.9%) across all species, predominantly to albumin, with highest tissue concentrations in the liver and minimal CNS penetration (rat distribution study), with excretion occurring primarily through feces and urine.”
Modality-specific risk
Embryofetal, pre/postnatal and juvenile toxicity in rats and rabbits
“Additionally, significant safety concerns were identified in the embryo-fetal development, pre- and post-natal development and juvenile toxicology studies in rabbits and rats.”