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).”
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.”
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.”