Xcopri
cenobamate
Species
MonkeyRatMouse
Longest study
52 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 (mouse up to 13 weeks)
“The toxicology package included repeat-dose toxicity (up to 13 weeks in mice, 26 weeks in rats, and 52 weeks in monkeys, in vitro and in vivo genotoxicity,”
Why that species
Monkey metabolic profile similar to human
“Monkey had a similar metabolic profile as the human profile.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the chronic (26-week) oral rat study, mortality was seen at the HD of 48 mg/kg/day and CNS clinical signs (decreased activity, uncoordinated gait) at doses ≥ 24 mg/kg/day.”
Species: general tox
Mouse (up to 13 weeks), rat (26 weeks) and cynomolgus monkey (52 weeks)
“The toxicology package included repeat-dose toxicity (up to 13 weeks in mice, 26 weeks in rats, and 52 weeks in monkeys,”
Species: DART
Rat and rabbit
“A potential for adverse effects on development was identified in rat and rabbit studies.”
Species: carcinogenicity
Tg rasH2 mouse (26-week) and rat (104-week)
“carcinogenicity (26-week in transgenic rasH2 mice, 104-week in rats)”
Surrogate used in
No surrogate used; cenobamate tested directly in mice, rats and monkeys
“The toxicology package included repeat-dose toxicity (up to 13 weeks in mice, 26 weeks in rats, and 52 weeks in monkeys,”
Study lengthopen answer page →
Longest pivotal study
52 (52-week monkey)
“The 52-week chronic toxicity study in the monkey initially included oral doses up to 27 mg/kg/day,”
Pivotal GLP studies
26-week rat and 52-week cynomolgus monkey oral studies; 13-week mouse
“The toxicology package included repeat-dose toxicity (up to 13 weeks in mice, 26 weeks in rats, and 52 weeks in monkeys, in vitro and in vivo genotoxicity,”
Route in tox
Oral (gavage)
“CBM was administered once daily by oral gavage to cynomolgus monkeys (3/sex/group)”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, mouse lymphoma and rat bone marrow micronucleus assays
“CBM was negative for genotoxicity in in vitro (Ames, mouse lymphoma) and in vivo (rat bone marrow micronucleus) assays.”
Carcinogenicity
26-week rasH2 mouse and 2-year rat: no drug-related neoplasms
“A 26-week study in transgenic RasH2 mice and a 2-year study in Sprague-Dawley rats were conducted. The executive carcinogenicity assessment committee concluded that the studies were adequate and that there were no drug-related neoplasms in either study.”
Reproductive & developmental
Rat EFD: embryofetal death, lower fetal weight and incomplete ossification at maternally toxic high dose
“Oral administration of CBM to pregnant rats throughout organogenesis at doses of up to 60 mg/kg/day resulted in increased embryofetal mortality, reduced fetal body weights, and incomplete fetal skeletal ossification at the highest dose tested, which was associated with maternal toxicity.”
Safety pharmacology
Concentration-dependent hERG inhibition, IC50 1869 μM (11x clinical steady-state Cmax at 400 mg MRHD)
“CBM produced concentration-dependent inhibition of hERG-mediated potassium currents; the IC50 was estimated as 1869 μM, which is 11X higher than the clinical steady state Cmax after daily dosing at the MRHD of 400 mg (45.5 μg/mL; 169 μM).”
Genotox: Ames
Negative
“CBM was negative for genotoxicity in in vitro (Ames, mouse lymphoma) and in vivo (rat bone marrow micronucleus) assays.”
Genotox: in vitro mammalian
Mouse lymphoma assay: negative
“CBM was negative for genotoxicity in in vitro (Ames, mouse lymphoma) and in vivo (rat bone marrow micronucleus) assays.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“CBM was negative for genotoxicity in in vitro (Ames, mouse lymphoma) and in vivo (rat bone marrow micronucleus) assays.”
Carcinogenicity model
26-week Tg rasH2 mouse (up to 35 mg/kg/day) and rat up to 90 weeks (up to 20 mg/kg): no tumor increase
“Administration of CBM to Tg.rasH2 mice at oral doses up to 35 mg/kg/day for 26 weeks did not result in an increase in tumors. Administration to rats for up to 90 weeks did not result in an increase in tumors at oral doses up to 20 mg/kg”
Carcinogenicity timing
26-week rasH2 mouse and 2-year rat studies completed before the marketing application; judged adequate
“A 26-week study in transgenic RasH2 mice and a 2-year study in Sprague-Dawley rats were conducted. The executive carcinogenicity assessment committee concluded that the studies were adequate and that there were no drug-related neoplasms in either study.”
hERG / QT
hERG IC50 1869 μM, 11x clinical steady-state Cmax at MRHD 400 mg
“CBM produced concentration-dependent inhibition of hERG-mediated potassium currents; the IC50 was estimated as 1869 μM, which is 11X higher than the clinical steady state Cmax after daily dosing at the MRHD of 400 mg (45.5 μg/mL; 169 μM).”
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 Xcopri 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: 26-week rat NOAEL 12 mg/kg/day; male-rat-specific kidney changes and adaptive liver hypertrophy (FDA pharmacology/toxicology review, p. 7)
NOAEL / key findings
26-week rat NOAEL 12 mg/kg/day; male-rat-specific kidney changes and adaptive liver hypertrophy
“Microscopic changes in the kidney (males) and liver (males and females) were attributed to drug, but renal changes were male rat specific, and the liver finding (centrilobular hepatocellular hypertrophy) is considered adaptive. The NOAEL (12 mg/kg/day) was associated with Week 26 Cmax and AUC0-t values of 9.3 ug/mL and 113.9 ug.h/mL in males and 17.6 ug/mL and 213.7 ug.h/mL in females, respectively.”
Risksopen answer page →
Immune & cytokine safety
Bone marrow lymphoid hyperplasia in 52-week monkey study, persisting after recovery at high dose
“Lymphoid hyperplasia of bone marrow was seen at the end of the treatment period in the MD and HD groups and was still present after the recovery period at the HD.”
Biodistribution & persistence
Rat: wide distribution incl. brain (tissue/blood ratios ~1); highest in kidney (4.7) and liver (2.7)
“Tissue distribution of [14C]-CBM in male S-D rats following a single oral dose showed the highest tissue-to-blood ratios in kidney (4.7) and liver (2.7), with most ratios (including brain) around 1.”
Modality-specific risk
Dose-limiting acute neurotoxicity with minimal safety margins
“In all toxicology species, acute neurotoxicity was dose-limiting and resulted in minimal to no safety margins to clinical exposures (see Table 2 under section 5 below).”
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
- Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity
- QT Shortening
- Suicidal Behavior and Ideation
- Liver Injury
- Neurological Adverse Reactions
- Withdrawal of Antiepileptic Drugs
Hypersensitivity & infusion reactionsCardiovascularPsychiatricHepatotoxicityNeurotoxicity
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 Xcopri 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: 26-week rat NOAEL 12 mg/kg/day; male-rat-specific kidney changes and adaptive liver hypertrophy (FDA pharmacology/toxicology review, p. 7)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
52-week oral cynomolgus monkey study with 3-month recovery
“Study title: YKP3089: a 52-week oral toxicity study, with 13-week and 26-week interim portions, including 4-week recovery (following 13 weeks of administration) or a 3-month recovery (following 52 weeks of administration), in cynomolgus monkeys”
Pivotal GLP studies
26-week rat and 52-week cynomolgus monkey oral studies; 13-week mouse
“The toxicology package included repeat-dose toxicity (up to 13 weeks in mice, 26 weeks in rats, and 52 weeks in monkeys, in vitro and in vivo genotoxicity,”
DART package
Species: DART
Rat and rabbit
“A potential for adverse effects on development was identified in rat and rabbit studies.”
Reproductive & developmental
Rat EFD: embryofetal death, lower fetal weight and incomplete ossification at maternally toxic high dose
“Oral administration of CBM to pregnant rats throughout organogenesis at doses of up to 60 mg/kg/day resulted in increased embryofetal mortality, reduced fetal body weights, and incomplete fetal skeletal ossification at the highest dose tested, which was associated with maternal toxicity.”
PPND / ePPND: when
PPND in rat (oral) completed and submitted with the marketing application
“In the pre- and postnatal development study in rat, cenobamate was administered orally to female rat throughout gestation and lactation at doses of 0, 11, 22, and 44 mg/kg.”
Carcinogenicity
Species: carcinogenicity
Tg rasH2 mouse (26-week) and rat (104-week)
“carcinogenicity (26-week in transgenic rasH2 mice, 104-week in rats)”
Carcinogenicity model
26-week Tg rasH2 mouse (up to 35 mg/kg/day) and rat up to 90 weeks (up to 20 mg/kg): no tumor increase
“Administration of CBM to Tg.rasH2 mice at oral doses up to 35 mg/kg/day for 26 weeks did not result in an increase in tumors. Administration to rats for up to 90 weeks did not result in an increase in tumors at oral doses up to 20 mg/kg”
Carcinogenicity timing
26-week rasH2 mouse and 2-year rat studies completed before the marketing application; judged adequate
“A 26-week study in transgenic RasH2 mice and a 2-year study in Sprague-Dawley rats were conducted. The executive carcinogenicity assessment committee concluded that the studies were adequate and that there were no drug-related neoplasms in either study.”
Safety marginopen answer page →
Safety margin at NOAEL
Acute neurotoxicity dose-limiting in all species, with minimal to no safety margins to clinical exposure
“In all toxicology species, acute neurotoxicity was dose-limiting and resulted in minimal to no safety margins to clinical exposures (see Table 2 under section 5 below).”
NOAEL / key findings
26-week rat NOAEL 12 mg/kg/day; male-rat-specific kidney changes and adaptive liver hypertrophy
“Microscopic changes in the kidney (males) and liver (males and females) were attributed to drug, but renal changes were male rat specific, and the liver finding (centrilobular hepatocellular hypertrophy) is considered adaptive. The NOAEL (12 mg/kg/day) was associated with Week 26 Cmax and AUC0-t values of 9.3 ug/mL and 113.9 ug.h/mL in males and 17.6 ug/mL and 213.7 ug.h/mL in females, respectively.”
Efficacy evidenceopen answer page →
Efficacy evidence
Rodent seizure models (battery); antiepileptic effects in mice and rats at 0.3-30 mg/kg
“Cenobamate, administered IP and/or PO, produced antiepileptic effects in mice and rats at doses between 0.3 and 30 mg/kg.”
Why that model
Standard animal epilepsy models considered predictive of efficacy against generalized and partial seizures
“CBM was shown to be active in various standard animal models of epilepsy thought to be predictive of efficacy against generalized and partial seizures.”
Reviewer's view of the efficacy data
EMA: adequate nonclinical pharmacodynamic package
“The applicant provided an adequate non-clinical package with studies covering primary and secondary pharmacodynamics, and safety pharmacology.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted with a conditionBeyond the letter
Rat embryo-fetal study inadequate: high embryofetal death left too few fetuses to evaluate teratogenic potential; repeat study required postmarketing
“There was a small increase in visceral malformations at the HD; however, teratogenic potential could not be fully evaluated because of the high rate of embryofetal deaths, which resulted in an inadequate number of fetuses examined.”
“A repeat embryofetal development study in rat should be conducted as a postmarketing requirement.”
Safety marginVerdict not stated
Minimal to no safety margins to clinical exposure; acute neurotoxicity dose-limiting in all species
“In all toxicology species, acute neurotoxicity was dose-limiting and resulted in minimal to no safety margins to clinical exposures (see Table 2 under section 5 below).”
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