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.”
Species: general tox
Rat (26-week) and cynomolgus monkey (39-week)
“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.”
Species: DART
Rat (fertility, EFD, PPND, juvenile) and rabbit (EFD)
“Studies on embryo-foetal development were conducted in rats and rabbits, while all the others were conducted in rats only.”
Species: carcinogenicity
Tg.rasH2 mouse (26-week) and rat (2-year)
“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.”
Surrogate used in
No surrogate used; ozanimod tested directly in pharmacologically active species
“Ozanimod was pharmacologically active in the nonclinical species (rat, monkey, rabbit, mouse) used to conduct the pivotal toxicology studies.”
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).”
Genotox: Ames
Negative (ozanimod and metabolites CC112273, CC1084037)
“Ozanimod was negative in a battery of in vitro (Ames, mouse lymphoma tk) and in vivo (rat micronucleus) assays. Metabolite CC112273 was negative in in vitro (Ames, chromosomal aberration in mammalian cell) assays.”
Genotox: in vitro mammalian
Ozanimod negative in mouse lymphoma tk; metabolite CC1084037 positive in in vitro TK6 chromosomal aberration/micronucleus assay
“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.”
Genotox: in vivo
Rat micronucleus negative (ozanimod); rat micronucleus/comet negative (CC1084037)
“Ozanimod was negative in a battery of in vitro (Ames, mouse lymphoma tk) and in vivo (rat micronucleus) assays.”
Carcinogenicity model
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.”
Carcinogenicity timing
6-month Tg.rasH2 mouse and 2-year rat studies completed before the marketing application
“Adequate coverage for ozanimod and the three major metabolites was achieved in the 6-month carcinogenicity study conducted in mouse. In the 2-year carcinogenicity study conducted in rat, adequate exposure (> 50% exposure at the MRHD) to the parent, RP101124, and CC112273 was achieved”
hERG / QT
Ozanimod and CC112273 potent hERG inhibitors in vitro (IC50 0.2 and 0.6 µM) but no QTc prolongation in monkeys
“potent hERG inhibitors in vitro (ICso of 0.2 and 0.6 µM, respectively), but QTc prolongation was not observed in monkeys dosed with ozanimod.”
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”
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
- Infections
- Progressive Multifocal Leukoencephalopathy
- Bradyarrhythmia and Atrioventricular Conduction Delays
- Liver Injury
- Fetal Risk
- Increased Blood Pressure
- Respiratory Effects
- Macular Edema
- Cutaneous Malignancies
- Posterior Reversible Encephalopathy Syndrome
- Unintended Additive Immunosuppressive Effects from Prior Treatment with Immunosuppressive or Immune-Modulating Drugs
- Severe Increase in Multiple Sclerosis Disability after Stopping ZEPOSIA
- Immune System Effects after Stopping ZEPOSIA
InfectionsNeurotoxicityCardiovascularHepatotoxicityEmbryo-fetal toxicityPulmonary toxicityOcular toxicitySecondary malignancySkin 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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week oral cynomolgus monkey study with 6-week recovery
“A 39-week oral toxicity study of RPC1063 with a 6-week recovery period in Cynomolgus monkeys”
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.”
DART package
Species: DART
Rat (fertility, EFD, PPND, juvenile) and rabbit (EFD)
“Studies on embryo-foetal development were conducted in rats and rabbits, while all the others were conducted in rats only.”
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.”
PPND / ePPND: when
Rat PPND completed before the marketing application; a further PPND study of metabolite CC1084037 was judged unnecessary
“However, the available data demonstrate that ozanimod, administered to pregnant animals, has clear adverse effects on the developing organism, including teratogenicity, which are consistent with the critical role of the S1P1 and S1P5 receptors in embryogenesis (including vascular and neural development) and should discourage use during pregnancy. Therefore, I do not believe the sponsor needs to conduct such a study.”
Carcinogenicity
Species: carcinogenicity
Tg.rasH2 mouse (26-week) and rat (2-year)
“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.”
Carcinogenicity model
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.”
Carcinogenicity timing
6-month Tg.rasH2 mouse and 2-year rat studies completed before the marketing application
“Adequate coverage for ozanimod and the three major metabolites was achieved in the 6-month carcinogenicity study conducted in mouse. In the 2-year carcinogenicity study conducted in rat, adequate exposure (> 50% exposure at the MRHD) to the parent, RP101124, and CC112273 was achieved”
Safety marginopen answer page →
Safety margin at NOAEL
Chronic NOAEL: rat ozanimod 10.4x, total active drug 0.62x; monkey ozanimod 3.73x, total active drug 0.515x human AUC
“Based on measured or estimated exposures (AUC), at the chronic toxicity NOAEL, in rats, systemic exposures to ozanimod, the metabolites RP101124, CC112273 and CC1084037 and total active drug in humans (ozanimod+CC112273+CC1084037) were calculated to be 10.4-, 17.7-, 0.0446-, 0.0036- and 0.62-times, respectively, those expected in humans. In Cynomolgus monkeys, these multiples at the NOAEL were 3.73, 0.445, 0.316, 0.363 and 0.515, respectively.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse EAE model and cuprizone demyelination model; lymphocyte reduction in rats, mice, dogs and monkeys
“Consistent with the impact of ozanimod and its metabolites on circulating lymphocytes, efficacy in the mouse (C57BL/6) experimental autoimmune encephalomyelitis model and cuprizone demyelination model were demonstrated.”
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: efficacy in EAE and cuprizone models provides biological plausibility for treating MS
“Efficacy in these models provides biological plausibility for the use of ozanimod to treat MS in humans.”
Flexibilityopen answer page →
Flexibility accepted
Impurity or metaboliteAccepted with a conditionBeyond the letter
Major active human metabolites CC112273 and CC1084037 under-represented in pivotal toxicity, carcinogenicity and DART studies
Why: Higher CC112273 exposure not achievable by direct dosing; inadequate coverage addressed through SmPC embryo-fetal and carcinogenic risk wording · Pharmacology or kinetics
“Overall, the nonclinical studies are adequate to support approval of ozanimod for the proposed indication, although systemic exposures to the two major (and active) human metabolites (CC112273 and CC1084037) were lower in several pivotal studies than in humans at the maximum recommended human dose (0.92 mg/day).”
“The Applicant was requested to address the clinical implications of the inadequate coverage of CC112273 and CC1084037 levels in the above-mentioned studies by amendments of sections 4.4 and 4.6 of the SmPC concerning the embryo-foetal risks and section 4.4 of the SmPC concerning carcinogenic risks (immunosuppressive effects and cutaneous neoplasms).”
DARTCriticised but acceptedBeyond the letter
Rat pre- and postnatal development study lacked adequate exposure to metabolite CC1084037; primary reviewer sought a postmarketing study
Why: Clear adverse developmental effects including teratogenicity already shown for ozanimod and should discourage use in pregnancy · Weight of evidence · Pharmacology or kinetics
“Dr. Toscano concluded that the PPND study is inadequate because of the lack of sufficient exposure to CC1084037 and recommended the metabolite be assessed in a PPND study as a post-marketing requirement.”
“However, the available data demonstrate that ozanimod, administered to pregnant animals, has clear adverse effects on the developing organism, including teratogenicity, which are consistent with the critical role of the S1P1 and S1P5 receptors in embryogenesis (including vascular and neural development) and should discourage use during pregnancy. Therefore, I do not believe the sponsor needs to conduct such a study.”
Safety marginVerdict not stated
No NOAEL and no safety margin in the rabbit embryo-fetal study: malformations at the lowest dose
“However, in this species, malformations were already noted at the lowest dose level and consequently no NOAEL and no safety margin with respect to clinical exposure could be established.”
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