Mayzent
siponimod
Species
MonkeyRat
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
“Pivotal oral (gavage) toxicity studies were conducted in Wistar rat (up to 26 weeks) and cynomolgus monkey (up to 52 weeks).”
Why that species
Pharmacologically relevant species
“These species are pharmacologically relevant for the assessment of the safety of siponimod.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Pivotal oral (gavage) toxicity studies were conducted in Wistar rat (up to 26 weeks) and cynomolgus monkey (up to 52 weeks).”
Species: general tox
Wistar rat (up to 26 weeks) and cynomolgus monkey (up to 52 weeks)
“Pivotal oral (gavage) toxicity studies were conducted in Wistar rat (up to 26 weeks) and cynomolgus monkey (up to 52 weeks).”
Species: DART
Wistar rat (male and female fertility, EFD, pre/postnatal) and New Zealand White rabbit (EFD)
“A battery of oral (gavage) reproductive and development toxicology studies was conducted; separate male and female fertility and early embryonic development studies in Wistar rat, embryofetal development studies in Wistar rat and New Zealand White rabbit, and a pre- and postnatal development study in Wistar rat.”
Species: carcinogenicity
Mouse and rat (oral, up to 104 weeks)
“Oral carcinogenicity studies of siponimod were conducted in mice and rats. In mice administered siponimod (0, 2, 8, or 25 mg/kg/day) for up to 104 weeks”
Surrogate used in
No surrogate used
“Pivotal oral (gavage) toxicity studies were conducted in Wistar rat (up to 26 weeks) and cynomolgus monkey (up to 52 weeks).”
Study lengthopen answer page →
Longest pivotal study
52 (52-week monkey)
“Pivotal oral (gavage) toxicity studies were conducted in Wistar rat (up to 26 weeks) and cynomolgus monkey (up to 52 weeks).”
Pivotal GLP studies
26-week rat and 52-week cynomolgus monkey oral gavage studies
“Pivotal oral (gavage) toxicity studies were conducted in Wistar rat (up to 26 weeks) and cynomolgus monkey (up to 52 weeks).”
Route in tox
Oral gavage
“Pivotal oral (gavage) toxicity studies were conducted in Wistar rat (up to 26 weeks) and cynomolgus monkey (up to 52 weeks).”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, mammalian cell assays and mouse and rat micronucleus assays
“In genetic toxicology studies, siponimod was negative in the in vitro reverse mutation assay in bacterial cell (Ames) and mammalian cell assays and in in vivo clastogenicity assays (micronucleus) in mouse and rat.”
Carcinogenicity
Mouse: malignant lymphoma (females) and hemangiosarcoma (both sexes) at all doses; rat: thyroid follicular tumors in high-dose males
“The carcinogenicity study in mouse was adequate and positive for malignant lymphoma in F at all doses and for hemangiosarcoma and combined hemangioma and hemangiosarcoma in M and F at all doses. The carcinogenicity study in rat was adequate and positive for thyroid follicular cell adenoma and combined follicular cell adenoma and carcinoma in HDM.”
Reproductive & developmental
Teratogenic in rats; embryofetal lethality in rats and rabbits; no fetal NOAEL in rats, 0.1 mg/kg/day in rabbits
“In the reproductive and development studies, oral siponimod was teratogenic in rats and lethal to fetuses in both rats and rabbits, without a clear NOAEL for fetal toxicity in rats (<1 mg/kg/day) and a NOAEL of 0.1 mg/kg/day in rabbit.”
Safety pharmacology
Decreased heart rate and second-degree AV block in guinea pigs and monkeys; decreased blood pressure in guinea pigs
“In cardiovascular safety pharmacology studies, oral siponimod acutely decreased heart rate and caused second-degree AV block in guinea pigs and monkeys, and decreased blood pressure in guinea pigs, with NOAELs of <0.03 mg/kg in guinea pigs and 60 mg/kg in monkeys.”
Genotox: Ames
Negative
“Siponimod was negative in a battery of in vitro (Ames, chromosomal aberration in mammalian cells) and in vivo (micronucleus in mouse and rat) assays.”
Genotox: in vitro mammalian
Chromosomal aberration in mammalian cells: negative
“Siponimod was negative in a battery of in vitro (Ames, chromosomal aberration in mammalian cells) and in vivo (micronucleus in mouse and rat) assays.”
Genotox: in vivo
Mouse and rat micronucleus: negative
“Siponimod was negative in a battery of in vitro (Ames, chromosomal aberration in mammalian cells) and in vivo (micronucleus in mouse and rat) assays.”
Carcinogenicity model
Oral mouse and rat studies, up to 104 weeks; mouse: malignant lymphoma and hemangiosarcoma at all doses
“Oral carcinogenicity studies of siponimod were conducted in mice and rats. In mice administered siponimod (0, 2, 8, or 25 mg/kg/day) for up to 104 weeks, there was an increase in malignant lymphoma in females at all doses and in hemangiosarcoma and combined hemangioma and hemangiosarcoma at all doses in males and females.”
Carcinogenicity timing
2-year mouse and rat completed before the marketing application
“Two-year carcinogenicity studies were conducted in mice and rats.”
hERG / QT
Minimal hERG inhibition (91% of control current at 25 μM)
“The hERG tail current, expressed in HEK293 cells, was minimally inhibited by siponimod (91% of control at 25 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 Mayzent 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: Lung toxicity NOAELs: <5 mg/kg mouse, 50 (M) and 10 (F) mg/kg rat, 100 mg/kg monkey (FDA pharmacology/toxicology review, p. 14)
NOAEL / key findings
Lung toxicity NOAELs: <5 mg/kg mouse, 50 (M) and 10 (F) mg/kg rat, 100 mg/kg monkey
“The NOAEL for lung toxicities were <5 mg/kg in mice, 50 and 10 mg/kg in M and F rats, and 100 mg/kg in monkeys.”
Risksopen answer page →
Immune & cytokine safety
Lymphoid depletion with reduced WBC and lymphocytes in all species, attributed to pharmacology
“Lymphoid tissues (depletion) were target organs in all species and was accompanied by decreased circulating levels of WBC and lymphocytes; this effect of siponimod was attributed to the pharmacological action of the drug.”
Biodistribution & persistence
CNS penetration in rats: brain and spinal cord exposure 0.8- to 4.4-fold blood
“In rats, siponimod was detected in brain and CSF after oral administration. Siponimod exposures in brain and spinal cord were between 0.8- and 4.4-fold that in blood.”
Modality-specific risk
Cardiovascular effects (monitorable), reproductive/developmental toxicity and carcinogenicity; lung toxicity margins adequate
“Safety margins to toxicities observed with administration of siponimod are adequate (lung), can be monitored (cardiovascular), or are described in the labeling (reproductive and development, and carcinogenicity).”
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
- Macular Edema
- Bradyarrhythmia and Atrioventricular Conduction Delays
- Respiratory Effects
- Liver Injury
- Cutaneous Malignancies
- Hypersensitivity Reactions
- Increased Blood Pressure
- Fetal Risk
- Posterior Reversible Encephalopathy Syndrome
- Unintended Additive Immunosuppressive Effects From Prior Treatment With Immunosuppressive or Immune-Modulating Therapies
- Severe Increase in Disability After Stopping MAYZENT
- Immune System Effects After Stopping MAYZENT
InfectionsNeurotoxicityOcular toxicityCardiovascularPulmonary toxicityHepatotoxicitySecondary malignancySkin reactionsHypersensitivity & infusion reactionsEmbryo-fetal toxicity
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 Mayzent 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: Lung toxicity NOAELs: <5 mg/kg mouse, 50 (M) and 10 (F) mg/kg rat, 100 mg/kg monkey (FDA pharmacology/toxicology review, p. 14)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
52-week cynomolgus monkey (oral gavage) with 8-week recovery
“Study №: 0770339. A 52-week toxicity study of BAF312 administered orally via nasal gavage to Cynomolgus monkeys, with an 8-week recovery period.”
Pivotal GLP studies
26-week rat and 52-week cynomolgus monkey oral gavage studies
“Pivotal oral (gavage) toxicity studies were conducted in Wistar rat (up to 26 weeks) and cynomolgus monkey (up to 52 weeks).”
DART package
Species: DART
Wistar rat (male and female fertility, EFD, pre/postnatal) and New Zealand White rabbit (EFD)
“A battery of oral (gavage) reproductive and development toxicology studies was conducted; separate male and female fertility and early embryonic development studies in Wistar rat, embryofetal development studies in Wistar rat and New Zealand White rabbit, and a pre- and postnatal development study in Wistar rat.”
Reproductive & developmental
Teratogenic in rats; embryofetal lethality in rats and rabbits; no fetal NOAEL in rats, 0.1 mg/kg/day in rabbits
“In the reproductive and development studies, oral siponimod was teratogenic in rats and lethal to fetuses in both rats and rabbits, without a clear NOAEL for fetal toxicity in rats (<1 mg/kg/day) and a NOAEL of 0.1 mg/kg/day in rabbit.”
PPND / ePPND: when
PPND in rat completed before the marketing application
“In the pre- and postnatal development study in rat, siponimod was administered at doses of 0, 0.05, 0.15, and 0.5 mg/kg from GD 6 to lactation day 20.”
Carcinogenicity
Species: carcinogenicity
Mouse and rat (oral, up to 104 weeks)
“Oral carcinogenicity studies of siponimod were conducted in mice and rats. In mice administered siponimod (0, 2, 8, or 25 mg/kg/day) for up to 104 weeks”
Carcinogenicity model
Oral mouse and rat studies, up to 104 weeks; mouse: malignant lymphoma and hemangiosarcoma at all doses
“Oral carcinogenicity studies of siponimod were conducted in mice and rats. In mice administered siponimod (0, 2, 8, or 25 mg/kg/day) for up to 104 weeks, there was an increase in malignant lymphoma in females at all doses and in hemangiosarcoma and combined hemangioma and hemangiosarcoma at all doses in males and females.”
Carcinogenicity timing
2-year mouse and rat completed before the marketing application
“Two-year carcinogenicity studies were conducted in mice and rats.”
Safety marginopen answer page →
Safety margin at NOAEL
52-week monkey NOAEL (low dose) AUC >50-fold human exposure at recommended daily dose
“The low dose (LD) was identified as an NOAEL. Plasma siponimod exposures (AUC) at that dose were 95400 and 124000 ng*hr/mL in males and females, respectively, which provide substantial safety margins (>50-fold) compared to that at the recommended human daily dose.”
NOAEL / key findings
Lung toxicity NOAELs: <5 mg/kg mouse, 50 (M) and 10 (F) mg/kg rat, 100 mg/kg monkey
“The NOAEL for lung toxicities were <5 mg/kg in mice, 50 and 10 mg/kg in M and F rats, and 100 mg/kg in monkeys.”
Efficacy evidenceopen answer page →
Efficacy evidence
Rodent EAE (experimental autoimmune encephalomyelitis) models; oral and ICV siponimod reduced clinical signs
“In animal models of experimental autoimmune encephalomyelitis (EAE), oral and ICV administration of siponimod resulted in reduce adverse clinical signs.”
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
EMA: efficacy shown in rat and mouse EAE models, correlating with lymphocyte reduction; with fingolimod precedent, proof of concept sufficient
“Efficacy has been demonstrated in both rat and mouse models of experimental autoimmune encephalomyelitis which mostly correlated with the expected pharmacodynamic effect of reducing peripheral lymphocyte counts. Taken with the known clinical efficacy of the first-in-class S1P modulator, fingolimod, sufficient proof of concept has been shown.”
Flexibilityopen answer page →
Flexibility accepted
Impurity or metaboliteCriticised but acceptedBeyond the letter
Human metabolites M3 and M17 not measured in pivotal repeat-dose studies; exposure inferred from non-GLP metabolite-to-parent ratios with unvalidated assays
Why: Not in line with ICH S3A, but justification agreed; M3 and M17 considered adequately qualified in pivotal studies · Other reason
“Concentrations of metabolites M3 and M17 were not directly assessed in pivotal repeat-dose toxicity studies. Instead, levels in these studies were inferred based on the ratio of metabolite to parent observed in non-GLP PK and exploratory studies in relevant species, and no method validation has been submitted for the methods of analysis used to determine metabolite concentrations in these studies.”
“Although the approach was not in line with ICH S3A guidance, the CHMP agreed with the provided justification for this approach and that the safety of metabolites M3 and M17 were adequately qualified in pivotal non-clinical repeat-dose toxicity studies.”
Safety marginAccepted with a conditionBeyond the letter
No exposure margin at the embryo-fetal NOAEL (0.2-fold clinical exposure at 2 mg daily)
Why: Embryonic malformations and no margins; use in pregnancy and without effective contraception contraindicated, as for fingolimod · Class precedent
“Hence, no safety margin could be determined at the NOAEL for embryo-foetal development with respect to clinical exposure at the 2 mg daily dose (0.2 fold the exposure level), whereas the NOAEL for maternal toxicity of 1 mg/kg/day corresponds to a margin of exposure of 1.7 fold.”
“In view of the observed embryonic malformations and the lack of any safety margins, the use of siponimod during pregnancy and by women of childbearing potential not using effective contraception has been contraindicated in line with fingolimod.”
Safety marginAccepted with a conditionBeyond the letter
No safety margin for cardiovascular effects (bradycardia, AV block) at the guinea pig NOAEL
Why: Cardiovascular toxicities can be monitored clinically · Other reason
“On a body surface area basis, NOAELs were <0.24 and 720 mg/m2 for guinea pig and monkey, respectively. The human dose is 0.3 mg/m2, resulting in no safety margin.”
“Safety margins to toxicities observed with administration of siponimod are adequate (lung), can be monitored (cardiovascular), or are described in the labeling (reproductive and development, and carcinogenicity).”
Juvenile toxAccepted with a conditionBeyond the letter
No juvenile animal toxicity study before approval; required postmarketing to support pediatric development
Why: Supports later pediatric clinical development under PREA · Other reason
“A post-marketing requirement for a juvenile animal toxicology study is recommended to support clinical development of siponimod in the pediatric population under PREA.”
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