Zeposia
ozanimod
Species
MonkeyRat
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Partial / alternative Partial / alternative
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“The main repeated dose toxicity studies have been conducted in Sprague Dawley rats and Cynomolgus monkeys with daily oral administration of ozanimod for up to 26 and 39 weeks, respectively.”
Why that species
Pharmacological activity in the toxicology species
“Ozanimod was pharmacologically active in the nonclinical species (rat, monkey, rabbit, mouse) used to conduct the pivotal toxicology studies.”
Surrogate molecule
No surrogate; the clinical compound was tested
“The main repeated dose toxicity studies have been conducted in Sprague Dawley rats and Cynomolgus monkeys with daily oral administration of ozanimod for up to 26 and 39 weeks, respectively.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey)
“The main repeated dose toxicity studies have been conducted in Sprague Dawley rats and Cynomolgus monkeys with daily oral administration of ozanimod for up to 26 and 39 weeks, respectively.”
Pivotal GLP studies
26-week rat and 39-week cynomolgus monkey daily oral studies
“The main repeated dose toxicity studies have been conducted in Sprague Dawley rats and Cynomolgus monkeys with daily oral administration of ozanimod for up to 26 and 39 weeks, respectively.”
Route in tox
Oral
“All studies employed the oral route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Ozanimod negative (Ames, mouse lymphoma, rat micronucleus); metabolite CC1084037 positive in vitro chromosome aberration, negative in vivo
“Metabolite CC1084037 was negative in an Ames assay, and positive in an in vitro chromosomal aberration assay in human (TK6) cells but negative in an in vivo rat micronucleus/comet assay.”
Carcinogenicity
26-week Tg.rasH2 mouse: hemangioma/hemangiosarcoma; 2-year rat: no tumors
“Oral administration of ozanimod (0, 8, 25, or 80 mg/kg/day) to Tg.rasH2 mice for 26-weeks resulted in an increase in hemangioma and hemangiosarcoma (combined) in males and females at the mid and high doses tested. Oral administration of ozanimod (0, 0.2, 0.7, or 2 mg/kg/day) to rats for 2 years resulted in no increase in tumors.”
Reproductive & developmental
No fertility effects; embryolethality and developmental effects (e.g., incomplete ossification, cleft palate) in rats and/or rabbits
“There were no effects on fertility in male or female animals dosed with ozanimod. Embryolethality and developmental effects (e.g., incomplete skeletal ossification, malpositioned vertebrae, malformed or absent arteries, anasarca, malpositioned testes, and cleft palate) occurred in pregnant rats and/or rabbits exposed to ozanimod and its metabolites during gestation.”
Safety pharmacology
Potent hERG inhibition by ozanimod and metabolite CC112273 (IC50 0.2 and 0.6 µM)
“Cardiovascular: In a GLP in vitro hERG assay, ozanimod and the major human metabolite, CC112273, were determined to be potent hERG inhibitors (IC50 of 0.2 and 0.6 µM, respectively; 100503.SJD, 170531.SFD).”
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 Zeposia 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: Lymphopenia and lymphoid depletion; lung weight increase and alveolar histiocytosis set NOAELs of 0.2 (rat) and 0.1 (monkey) mg/kg/day (EMA assessment report, p. 28)
NOAEL / key findings
Lymphopenia and lymphoid depletion; lung weight increase and alveolar histiocytosis set NOAELs of 0.2 (rat) and 0.1 (monkey) mg/kg/day
“In both rats and monkeys, the severity of these lung toxicities did not deteriorate in long-term toxicity studies, but they were incompletely reversible after the 6 weeks recovery period and served to determine the no observed adverse effect level (NOAEL)s (0.2 and 0.1 mg/kg/day in rats and monkeys, respectively) in these investigations.”
Risksopen answer page →
Immune & cytokine safety
Decreased T and B lymphocytes; suppressed T-dependent IgM and IgG antibody responses
“Immunotoxicity assessment revealed the expected pharmacological action of decreased T- and B-lymphocyte counts and an inhibitory effect on primary and secondary T-dependent IgM and IgG antibody responses.”
Biodistribution & persistence
Radioactivity persisted in hippocampus and uveal tract at final time point; BLQ in all other tissues
“At the final time point, radioactivity was still detected in the hippocampus and uveal tract; radioactivity was BLQ in all other tissues.”
Modality-specific risk
Disproportionate human metabolites (CC112273, CC1084037) insufficiently covered in toxicology studies
“Consequently, clinically relevant exposure levels (AUC0- t/AUC0-24) of CC112273 CC1084037 were not attained at the NOAEL in the toxicology program of ozanimod”