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.”
Species: general tox
Rat and cynomolgus monkey (oral, 2- and 4-week)
“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)”
Species: DART
Rat (fertility, EFD, pre/postnatal, juvenile) and rabbit (EFD)
“Additionally, significant safety concerns were identified in the embryo-fetal development, pre- and post-natal development and juvenile toxicology studies in rabbits and rats.”
Species: carcinogenicity
Not conducted (short treatment duration)
“Carcinogenesis studies were not conducted due to the short duration of drug administration.”
Surrogate used in
No surrogate used
“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.”
Genotox: Ames
Negative
“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.”
Genotox: in vitro mammalian
In vitro micronucleus (human TK6 cells): negative
“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.”
Genotox: in vivo
Rat micronucleus: negative
“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 model
Not conducted (five-day human dosing)
“conducted due to the short duration (five days) of drug administration in humans.”
Carcinogenicity timing
Not required: short treatment duration
“Carcinogenesis studies were not conducted due to the short duration of drug administration.”
hERG / QT
39% hERG inhibition at 100 µM (highest tested); low QT risk
“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.”
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
- Embryofetal Toxicity
- Risk of Serious Adverse Reactions Due to Drug Interactions
- Hypersensitivity Reactions Including Anaphylaxis
Embryo-fetal toxicityHypersensitivity & infusion reactions
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
4-week oral cynomolgus monkey study with 4-week recovery; a 4-week rat study with recovery ties
“Duration of study: 4 weeks plus 4-week recovery (control and high dose only)”
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.”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal, juvenile) and rabbit (EFD)
“Additionally, significant safety concerns were identified in the embryo-fetal development, pre- and post-natal development and juvenile toxicology studies in rabbits and rats.”
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.”
PPND / ePPND: when
PPND in rat (oral) completed before the marketing application
“In a pre-and post-natal development study, ensitrelvir was administered to pregnant rats at oral doses of 20, 60 or 1000 mg/kg/day from GD 6 to post-natal day (PND) 20.”
Carcinogenicity
Species: carcinogenicity
Not conducted (short treatment duration)
“Carcinogenesis studies were not conducted due to the short duration of drug administration.”
Carcinogenicity model
Not conducted (five-day human dosing)
“conducted due to the short duration (five days) of drug administration in humans.”
Carcinogenicity timing
Not required: short treatment duration
“Carcinogenesis studies were not conducted due to the short duration of drug administration.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL 10 mg/kg/day: 3x (shorter study) and 4x (4-week study) human exposure
“The no observable adverse effect level (NOAEL) was established at 10 mg/kg/day in both monkey studies and the safety margin was 3X and 4X, respectively.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
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.
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
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.
Flexibilityopen answer page →
Flexibility accepted
Impurity or metaboliteCriticised but accepted
Eight drug-substance impurities with carcinogenic concern classified as ICH M7 Class 5 on lack of mutagenicity
Why: Sponsor cited ICH M7 and its Q&A; FDA read the guideline differently but agreed with the assessment · Within the guideline
“The Sponsor stated that for the 8 impurities in question, “in accordance with the ICH M7 guideline and its Q&A, substances that have sufficient data demonstrating lack of mutagenicity are classified as Class 5, even if the substances have potential for non-mutagenic carcinogenicity.””
“We agreed with the Sponsor’s assessment and no further follow up is planned.”
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