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).”
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.”
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).”