Bylvay
odevixibat
Species
RatDog
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 dog
“The nonclinical safety profile of odevixibat has been extensively explored in (1) single and repeated dose toxicity studies in rats (up to 6 months) and dogs (up to 9 months)”
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
“The NOAEL (no observed adverse effect level) in the 26-week oral toxicity study in rats and the 39-week oral toxicity study in dogs was the high dose (300 mg/kg/day and 150 mg/kg/day, respectively).”
Species: general tox
Rat (26-week) and dog (39-week)
“The NOAEL (no observed adverse effect level) in the 26-week oral toxicity study in rats and the 39-week oral toxicity study in dogs was the high dose (300 mg/kg/day and 150 mg/kg/day, respectively).”
Species: DART
Rat (fertility, EFD, PPND, juvenile) and rabbit (EFD)
“Reproductive and developmental toxicology studies included a fertility study in male and female rats, embryo-fetal development studies in rats and rabbits, and a pre- and postnatal development study in rats. A juvenile animal toxicity study was performed in rats.”
Species: carcinogenicity
Rat and mouse (2-year)
“In the 2-year carcinogenicity studies, odevixibat was not tumorigenic in rats or mice at oral doses up to 100 mg/kg/day.”
Surrogate used in
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.
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“The NOAEL (no observed adverse effect level) in the 26-week oral toxicity study in rats and the 39-week oral toxicity study in dogs was the high dose (300 mg/kg/day and 150 mg/kg/day, respectively).”
Pivotal GLP studies
26-week rat and 39-week dog oral studies
“The NOAEL (no observed adverse effect level) in the 26-week oral toxicity study in rats and the 39-week oral toxicity study in dogs was the high dose (300 mg/kg/day and 150 mg/kg/day, respectively).”
Route in tox
Oral (gavage)
“39-Week Oral (Gavage) Toxicity Study in the Dog Followed by a 4-Week Recovery Period (8348308)”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro mouse lymphoma and in vivo rat micronucleus assays
“Odevixibat tested negative in the bacterial reverse mutation (Ames) assay, the in vitro mouse lymphoma cell forward mutation assay, and the in vivo rat micronucleus test.”
Carcinogenicity
2-year rat and mouse studies: not tumorigenic up to 100 mg/kg/day
“In the 2-year carcinogenicity studies, odevixibat was not tumorigenic in rats or mice at oral doses up to 100 mg/kg/day.”
Reproductive & developmental
Rat fertility and EFD: no adverse findings; rabbit EFD: cardiovascular fetal malformations at all doses
“No adverse findings were observed in the fertility study in male and female Wistar rats, the embryo-fetal development study in rats, or the juvenile toxicity study in rats. In an embryo-fetal development study in pregnant rabbits, fetuses from all maternal groups treated orally with odevixibat showed an increase in cardiovascular malformations”
Safety pharmacology
No concerns in cardiovascular, respiratory, CNS, gastrointestinal or renal safety pharmacology studies
“There were no nonclinical safety issues of significant concern as assessed by the secondary pharmacology screens or the cardiovascular, respiratory, central nervous system, gastrointestinal, or renal safety pharmacology studies conducted during the development program.”
Genotox: Ames
Negative
“Odevixibat tested negative in the bacterial reverse mutation (Ames) assay, the in vitro mouse lymphoma cell forward mutation assay, and the in vivo rat micronucleus test.”
Genotox: in vitro mammalian
Mouse lymphoma forward mutation assay: negative
“Odevixibat tested negative in the bacterial reverse mutation (Ames) assay, the in vitro mouse lymphoma cell forward mutation assay, and the in vivo rat micronucleus test.”
Genotox: in vivo
Rat micronucleus: negative
“Odevixibat tested negative in the bacterial reverse mutation (Ames) assay, the in vitro mouse lymphoma cell forward mutation assay, and the in vivo rat micronucleus test.”
Carcinogenicity model
2-year rat and 2-year mouse oral; not tumorigenic up to 100 mg/kg/day
“In the 2-year carcinogenicity studies, odevixibat was not tumorigenic in rats or mice at oral doses up to 100 mg/kg/day.”
Carcinogenicity timing
2-year rat and mouse studies completed before the marketing application
“In the 2-year carcinogenicity studies, odevixibat was not tumorigenic in rats or mice at oral doses up to 100 mg/kg/day.”
hERG / QT
No hERG effect at 1 µM, 7700-fold the IBAT IC50
“Odevixibat did not affect the hERG potassium channel at the tested concentration (1 μM), which is 7700-fold higher than the IC50 (0.13 nM) in the human IBAT transfected cell assay (0062SZ).”
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 Bylvay 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: NOAELs were the high doses: 300 mg/kg/day in the 26-week rat and 150 mg/kg/day in the 39-week dog study (FDA integrated review, p. 78)
NOAEL / key findings
NOAELs were the high doses: 300 mg/kg/day in the 26-week rat and 150 mg/kg/day in the 39-week dog study
“The NOAEL (no observed adverse effect level) in the 26-week oral toxicity study in rats and the 39-week oral toxicity study in dogs was the high dose (300 mg/kg/day and 150 mg/kg/day, respectively).”
Risksopen answer page →
Immune & cytokine safety
No effects on thymus, spleen, lymph nodes or bone marrow; dedicated immunotoxicity studies not performed
“The risk of immunotoxicity has been evaluated based on results from the standard toxicity studies. No obvious signs in related organs have been detected in response to odevixibat treatment (e.g. changes in thymus, spleen, lymph nodes, bone marrow).”
Biodistribution & persistence
Poorly absorbed; radioactivity mainly in GI tract contents, none detected in CNS
“Most of the radioactivity was found in the content of the gastrointestinal tract, whereas none was detected in the central nervous system (CNS).”
Modality-specific risk
Embryofetal toxicity: cardiovascular malformations in rabbit fetuses without a NOAEL
“The malformations occurred in the heart and great vessels in rabbit fetuses and were observed at maternal plasma exposures (AUC) that were approximately 2.1 times the human exposure at the maximum recommended dose of 120 mcg/kg.”
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
- Hepatoxicity
- Diarrhea
- Fat-Soluble Vitamin Deficiency
HepatotoxicityGastrointestinalMetabolic & endocrine
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 Bylvay 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: NOAELs were the high doses: 300 mg/kg/day in the 26-week rat and 150 mg/kg/day in the 39-week dog study (FDA integrated review, p. 78)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week oral gavage dog study with 4-week recovery
“Table 56. Study Information, 39-Week Oral (Gavage) Administration Toxicity Study in the Dog Followed by a 4-Week Recovery Period (8348308)”
Pivotal GLP studies
26-week rat and 39-week dog oral studies
“The NOAEL (no observed adverse effect level) in the 26-week oral toxicity study in rats and the 39-week oral toxicity study in dogs was the high dose (300 mg/kg/day and 150 mg/kg/day, respectively).”
DART package
Species: DART
Rat (fertility, EFD, PPND, juvenile) and rabbit (EFD)
“Reproductive and developmental toxicology studies included a fertility study in male and female rats, embryo-fetal development studies in rats and rabbits, and a pre- and postnatal development study in rats. A juvenile animal toxicity study was performed in rats.”
Reproductive & developmental
Rat fertility and EFD: no adverse findings; rabbit EFD: cardiovascular fetal malformations at all doses
“No adverse findings were observed in the fertility study in male and female Wistar rats, the embryo-fetal development study in rats, or the juvenile toxicity study in rats. In an embryo-fetal development study in pregnant rabbits, fetuses from all maternal groups treated orally with odevixibat showed an increase in cardiovascular malformations”
PPND / ePPND: when
Rat PPND completed before the marketing application
“Reproductive and developmental toxicology studies included a fertility study in male and female rats, embryo-fetal development studies in rats and rabbits, and a pre- and postnatal development study in rats.”
Carcinogenicity
Species: carcinogenicity
Rat and mouse (2-year)
“In the 2-year carcinogenicity studies, odevixibat was not tumorigenic in rats or mice at oral doses up to 100 mg/kg/day.”
Carcinogenicity model
2-year rat and 2-year mouse oral; not tumorigenic up to 100 mg/kg/day
“In the 2-year carcinogenicity studies, odevixibat was not tumorigenic in rats or mice at oral doses up to 100 mg/kg/day.”
Carcinogenicity timing
2-year rat and mouse studies completed before the marketing application
“In the 2-year carcinogenicity studies, odevixibat was not tumorigenic in rats or mice at oral doses up to 100 mg/kg/day.”
Safety marginopen answer page →
Safety margin at NOAEL
Dog 39-week NOAEL 150 mg/kg: 31x (males) and 41x (females) human exposure
“NOAEL: 150 mg/kg Safety margin1 31 (males), 41 (females)”
NOAEL / key findings
NOAELs were the high doses: 300 mg/kg/day in the 26-week rat and 150 mg/kg/day in the 39-week dog study
“The NOAEL (no observed adverse effect level) in the 26-week oral toxicity study in rats and the 39-week oral toxicity study in dogs was the high dose (300 mg/kg/day and 150 mg/kg/day, respectively).”
Efficacy evidenceopen answer page →
Efficacy evidence
Mdr2-/- mouse cholestasis model: reduced liver weight and serum markers of liver damage and cholestasis
“A4250 (odevixibat) reduced liver/body weight ratios and serum markers of liver damage and cholestasis in Mdr2-/- mice, a mouse model of cholestasis.”
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
FDA: nonclinical studies supportive of the mechanistic rationale (confirmatory evidence)
“The nonclinical studies are supportive of the mechanistic rationale.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginAccepted with a conditionBeyond the letter
Rabbit fetal cardiovascular malformations at all doses; low exposure multiple (about 2.1 times human AUC), no developmental NOAEL
Why: Findings described in pregnancy labeling and form the basis for a pregnancy registry postmarketing requirement
“The cardiovascular malformations in rabbit fetuses justify a concern for a clinically significant risk to embryo-fetal development. These finding were observed in one of the two animal species tested. The exposure multiple at which the fetal cardiovascular malformations occurred is low (approximately 2.1 times the human AUC at 120 mcg/kg).”
“The following nonclinical information was used in support of the labeling (Package Insert) and formed the basis for a pregnancy registry PMR.”
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