Stelara
ustekinumab
Sources:EMA assessment report ↗
Species
Monkey
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“The safety studies include repeated-dose toxicity with periods of recovery in cynomolgus monkeys, and developmental and reproductive toxicity studies in cynomolgus monkeys and mice; a number of non-pivotal studies was also conducted.”
Why that species
Comparable binding and neutralising activity against human and cynomolgus IL-12 and IL-23
“It was shown to have comparable binding and neutralising activity against human and cynomolgus macaque IL-12 and IL-23.”
Surrogate molecule
Yes: CNTO 3913, a rat-mouse chimeric anti-mouse IL-12/23p40 antibody, used for a mouse female fertility study
“Female fertility was investigated in a supportive study in mice using a rat-mouse chimaeric anti-mouse IL-12/23p40 monoclonal Antibody, CNTO 3913.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“CNTO 1275 (STELARA, ustekinumab) was dosed SC twice weekly to 3 dose groups of cynomolgus monkeys of 8/sex/group at doses of 22.5 or 45 mg/kg for 13 or 26 weeks.”
Pivotal GLP studies
Cynomolgus monkey studies: IV up to 45 mg/kg weekly for 1 month; SC up to 45 mg/kg twice weekly for 6 months
“Repeat-dose toxicity studies showed that CNTO 1275 (STELARA, ustekinumab) is generally well tolerated following IV doses up to 45 mg/kg/week for up to 1 month (Studies T-099-003 and T-099-004), and following twice-weekly SC doses up to 45 mg/kg for 6 months (Study T-2001-004).”
Route in tox
Subcutaneous and intravenous
“Repeat-dose toxicity studies showed that CNTO 1275 (STELARA, ustekinumab) is generally well tolerated following IV doses up to 45 mg/kg/week for up to 1 month (Studies T-099-003 and T-099-004), and following twice-weekly SC doses up to 45 mg/kg for 6 months (Study T-2001-004).”
Skipped studiesopen answer page →
Genotoxicity
Carcinogenicity
Not conducted; rodent studies precluded because ustekinumab does not bind or neutralise mouse or rat IL-12 or IL-23
“Direct evaluation of carcinogenic potential of CNTO 1275 (STELARA, ustekinumab) in carcinogenicity studies or rodent tumour immune surveillance models is precluded by the limited species reactivity of CNTO 1275 (STELARA, ustekinumab) which does not bind to or neutralise IL-12 or IL-23 from mice or rats.”
Reproductive & developmental
Monkey EFD (IV or SC) and pre-/postnatal development (SC) studies: no effects on gestation, parturition, lactation or offspring
“In studies of embryo-fetal development in cynomolgus monkeys dosed intravenously or subcutaneously and pre-and post-natal development dosed subcutaneously, there were no effects on gestation, parturition, lactation or morphology or development of the offspring.”
Safety pharmacology
Cardiovascular and respiratory evaluations after single and repeated dosing in monkeys: no findings up to 45 mg/kg
“Cardiovascular/respiratory evaluations following single and repeated dosing with CNTO 1275 (STELARA, ustekinumab) at doses up to 45 mg/kg in monkeys showed no CNTO 1275-related findings.”
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 Stelara 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 monoclonal antibodies 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: Well tolerated at 45 mg/kg twice weekly SC for 6 months in monkeys; no target organs, no delayed toxicity (EMA assessment report, p. 18)
NOAEL / key findings
Well tolerated at 45 mg/kg twice weekly SC for 6 months in monkeys; no target organs, no delayed toxicity
“ustekinumab was generally well tolerated under a regimen of twice weekly subcutaneous dosing at 45 mg/kg for 6 months in cynomolgus monkeys and adequate margins of exposure over the human clinical exposure were demonstrated. No target organs were identified and there was no delayed toxicity after dosing had stopped.”
Risksopen answer page →
Immune & cytokine safety
No adverse effects on functional immune responses, circulating lymphocyte subsets or lymphoid T- and B-cell distribution
“Immunotoxicity evaluations revealed no adverse effects of ustekinumab on functional immune responses, circulating lymphocyte subpopulations or distribution of T- and B-lymphocytes in lymphoid tissue.”
Biodistribution & persistence
Monkey volume of distribution 86-98 mL/kg after 4.5 mg/kg IV; mainly confined to the intravascular space
“The volume of distribution of ustekinumab in monkeys was 86 to 98 mL/kg following a single IV dose of 4.5 mg/kg, suggesting that the distribution of ustekinumab was mainly confined to the intravascular space”
Modality-specific risk
Immunosuppression and infection risk: bacterial enteritis in one monkey in the 6-month study
“The possibility of immune suppression could not be ruled out in the case of one animal in the 6-month study that developed bacterial enteritis.”