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.”
Species: general tox
Rat (6-month) and cynomolgus monkey (9-month)
“Pivotal repeat-dose GLP studies were conducted in CByB6F1 mice (≤28 days), Sprague-Dawley rats (≤6 months) and cynomolgus monkeys (≤9 months).”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“fertility and pre- and postnatal development (PPND) (rat) and embryo-fetal development (EFD) (rat and rabbit) studies”
Species: carcinogenicity
Rat (2-year) and Tg rasH2 mouse (6-month)
“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.”
Surrogate used in
No surrogate used; deucravacitinib tested directly
“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.”
Genotox: Ames
Negative (parent and two major metabolites)
“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.”
Genotox: in vitro mammalian
In vitro chromosome aberration (parent) and in vitro micronucleus (metabolites): 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.”
Genotox: in vivo
Rat erythrocyte micronucleus: 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 model
2-year oral rat; 6-month oral Tg rasH2 mouse; no tumor increase
“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.”
Carcinogenicity timing
6-month rasH2 mouse and 2-year rat studies completed and reviewed in the NDA
“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.”
hERG / QT
43.9% hERG inhibition at 10 µM (717x RHD free Cmax); low potential for cardiac ion channel effects
“BMS-986165 inhibited hERG currents by 43.9% at 10 μM (717× RHD free Cmax).”
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.”
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
- Hypersensitivity Reactions
- Infections
- Tuberculosis
- Malignancy including Lymphomas
- Rhabdomyolysis and Elevated CPK
- Laboratory Abnormalities
- Immunizations
- Potential Risks Related to JAK Inhibition
Hypersensitivity & infusion reactionsInfectionsSecondary malignancyMusculoskeletal
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month cynomolgus monkey (oral) with 2-month recovery
“The 9-month toxicity study in monkeys showed that liver-related findings were limited to mostly minimal to mild increases in total bilirubin throughout the study in females at doses ≥ 3 mg/kg/day and males at 10/5 mg/kg/day and that the bilirubin changes were reversible after the 2-month recovery period.”
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).”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“fertility and pre- and postnatal development (PPND) (rat) and embryo-fetal development (EFD) (rat and rabbit) studies”
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 ) .”
PPND / ePPND: when
PPND in rat completed and reviewed in the NDA
“In a rat oral pre- and postnatal development study, deucravacitinib (0, 5, 15, and 50 mg/kg/day) had no adverse effects on maternal reproductive function or effects on survival, sexual maturation, neurobehavioral, and reproductive function of the offspring, when administered from GD 6 to lactation day (LD) 20.”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and Tg rasH2 mouse (6-month)
“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.”
Carcinogenicity model
2-year oral rat; 6-month oral Tg rasH2 mouse; no tumor increase
“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.”
Carcinogenicity timing
6-month rasH2 mouse and 2-year rat studies completed and reviewed in the NDA
“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.”
Safety marginopen answer page →
Safety margin at NOAEL
NOAEL 5 mg/kg/day ~9x RHD AUC
“The changes in the above clinical chemistry parameters at the no-observed-adverse-effect level (NOAEL) of 5 mg/kg/day (9× RHD AUC) are not considered to be clinically meaningful”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse IL-23-induced acanthosis (psoriasis), anti-CD40 and T-cell transfer colitis, NZB/W lupus nephritis
“BMS-986165 was evaluated for efficacy against the IL-23-induced acanthosis model of psoriasis in mice, murine anti-CD40 induced colitis, T-cell transfer colitis, and lupus nephritis in lupus-prone NZB/W mice.”
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: nonclinical pharmacology adequately characterised
“The non-clinical pharmacological properties of deucravacitinib have been adequately characterised.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginCriticised but acceptedBeyond the letter
Low margin in GLP monkey cardiovascular telemetry study: NOEL at 3x clinical Cmax
Why: Hemodynamic changes in psoriasis patients were not clinically meaningful · Human data
“The safety margin on the GLP cardiovascular telemetry study in monkeys was low (NOEL = 0.65 mg/kg (Cmax 0.13 µg/mL; 3X RHD Cmax). Clinically, hemodynamic changes occurred in BMS-986165-treated subjects with psoriasis, however the changes were not clinically meaningful.”
Safety pharmacologyVerdict not stated
No stand-alone CNS or respiratory safety pharmacology studies; endpoints incorporated into rat and monkey repeat-dose studies
“No independent safety pharmacology study was conducted to assess the potential CNS effects and potential respiratory effects of BMS-986165. However, in repeat-dose toxicity studies, in rat and monkey the safety pharmacology assessment of central nervous and respiratory system were included.”
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