Sotyktu
deucravacitinib
Species
MonkeyRat
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 cynomolgus monkey
“Deucravacitinib was evaluated in two pivotal repeat-dose general toxicity studies, one in rats and the other in monkeys.”
Why that species
Similar metabolite profiles across species; every human metabolite detected in rats, no unique human metabolites
“All metabolites present in humans were present in at least 1 of the nonclinical safety species, with every human metabolite being detected in rats, and there were no unique human metabolites.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the 6-month rat toxicity study, deucravacitinib was orally administered at the doses of 0, 5, 15, and 50 mg/kg, once daily.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month monkey)
“In the 9-month monkey toxicity study, deucravacitinib was orally administered at the doses of 0, 1, 3, and 10→5 mg/kg, once daily.”
Pivotal GLP studies
GLP oral studies: mice up to 28 days, rats up to 6 months, cynomolgus monkeys up to 9 months
“Pivotal repeat-dose GLP studies were conducted in CByB6F1 mice (≤28 days), Sprague-Dawley rats (≤6 months) and cynomolgus monkeys (≤9 months).”
Route in tox
Oral
“In the 6-month rat toxicity study, deucravacitinib was orally administered at the doses of 0, 5, 15, and 50 mg/kg, once daily.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration and in vivo rat micronucleus assays; major metabolites also negative
“Deucravacitinib and its two major metabolites, BMT-158170 and BMT-153261, tested negative in a battery of genotoxicity studies, i.e., Ames tests (deucravacitinib and metabolites), an in vitro mammalian chromosome aberration test (deucravacitinib), in vitro micronucleus tests (metabolites), and an in vivo mammalian (rat) erythrocyte micronucleus test.”
Carcinogenicity
2-year rat and 6-month rasH2 mouse: no increase in tumors
“Deucravacitinib did not cause increases of tumor incidences in a 6-month oral carcinogenicity study in transgenic rasH2 mice and a 2-year oral carcinogenicity study in rats.”
Reproductive & developmental
Rat and rabbit EFD: no embryo-fetal effects at ≥72 times the MRHD
“In animal reproduction studies, no effects on embryo-fetal development were observed with oral administration of deucravacitinib to rats and rabbits during organogenesis at doses that were at least 72 times the maximum recommended human dose (MRHD) of 6 mg once daily (see Data ) .”
Safety pharmacology
hERG not inhibited at clinical concentrations; no neurological or respiratory effects in rats and monkeys
“Deucravacitinib is not expected to inhibit hERG potassium channel current at clinically relevant concentrations. During the neurobehavioral and respiratory safety assessments, oral administration of deucravacitinib in rats at doses up to 75 mg/kg/day and in monkeys at doses up to 5 mg/kg/day did not cause neurological or respiratory effects.”
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 Sotyktu 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: Rat 6-month NOAEL 5 mg/kg/day, based on sustained body weight reduction at 15 and 50 mg/kg/day (FDA multi-discipline review, p. 55)
NOAEL / key findings
Rat 6-month NOAEL 5 mg/kg/day, based on sustained body weight reduction at 15 and 50 mg/kg/day
“The NOAEL for the 6-month oral toxicity study in rats was 5 mg/kg/day due to the sustained body weight reduction at 15 and 50 mg/kg/day.”
Risksopen answer page →
Immune & cytokine safety
Immunosuppression: lower lymphocyte counts, lymphoid depletion and reduced TDAR to KLH in rats; reduced TDAR in monkeys
“In rats, dose-dependent minimally to moderately decreased lymphocyte counts (including total T, helper T, cytotoxic T, B, and NK cells) generally correlated with decreased spleen and thymus size and weights, decreased lymphoid cellularity in lymph nodes, thymus and splenic white pulp, and decreased TDAR to KLH-specific IgM and IgG responses.”
Biodistribution & persistence
Substantial but reversible melanin binding (eye uveal tract), not in pigmented skin
“In pigmented rats, there was substantial, but reversible binding of [14C]BMS-986165-derived radioactivity to certain melanin-containing tissues, such as the eye uveal tract, but not in pigmented skin.”
Modality-specific risk
Immunosuppression (expected pharmacology), reversible after dosing stopped
“In summary, at clinically relevant doses, deucravacitinib-related toxicological effects were mostly related to immunosuppression, which was reversable after dosing termination.”