Stelara
ustekinumab
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.”
Species: general tox
Cynomolgus monkey
“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.”
Species: DART
Cynomolgus monkey and mouse
“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.”
Species: carcinogenicity
Not conducted (ICH S6)
“In accordance with the guideline entitled ‘Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals’ (ICH S6), carcinogenicity studies were not performed.”
Surrogate used in
Yes: rat-mouse chimaeric anti-mouse IL-12/23p40 antibody CNTO 3913 for mouse female fertility
“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.”
Genotox: Ames
Genotox: in vitro mammalian
Genotox: in vivo
Carcinogenicity model
Not conducted; ustekinumab does not bind or neutralise mouse or rat IL-12/IL-23, precluding rodent studies
“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.”
Carcinogenicity timing
Not required under ICH S6
“In accordance with the guideline entitled ‘Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals’ (ICH S6), carcinogenicity studies were not performed.”
hERG / QT
No hERG assay; no ECG interval changes or cardiovascular issues in monkey toxicity studies
“Taken together, the data generated in toxicity studies did not suggest a relationship between CNTO 1275 (STELARA, ustekinumab) administration and changes in ECG intervals or identify cardiovascular safety issues.”
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
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
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.”
Anti-drug antibodies: animals
Anti-ustekinumab antibodies in monkeys associated with accelerated clearance and shortened half-life
“Development of anti- ustekinumab antibodies was found to be associated with accelerated clearance and shortened half-life of ustekinumab in monkeys.”
Anti-drug antibodies: patients
~6 to 12.4% in psoriasis and psoriatic arthritis trials, generally low-titer
“Approximately 6 to 12.4% of subjects treated with STELARA in clinical trials in subjects with plaque psoriasis and psoriatic arthritis developed antibodies to ustekinumab, which were generally low-titer.”
Label warnings
- Infections
- Theoretical Risk for Vulnerability to Particular Infections
- Pre-treatment Evaluation for Tuberculosis
- Malignancies
- Serious Hypersensitivity Reactions
- Posterior Reversible Encephalopathy Syndrome (PRES)
- Immunizations
- Noninfectious Pneumonia
InfectionsSecondary malignancyHypersensitivity & infusion reactionsNeurotoxicity
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
IV toxicology studies in primates supported the first human dose (NOAEL 500-fold above the first dose tier)
“supported by IV toxicology studies in primates that demonstrated no observed adverse effect level at doses 500-fold higher than the first dose tier studied in humans and 10-fold higher than the highest dose studied.”
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
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week SC cynomolgus monkey study with 12-week recovery
“26-week Subcutaneous Dose Toxicity and Toxicokinetic Study with CNTO 1275 (STELARA, ustekinumab) in Cynomolgus Monkeys with a 12-week Recovery Period (Study T-2001-004)”
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).”
DART package
Species: DART
Cynomolgus monkey and mouse
“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.”
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.”
PPND / ePPND: when
PPND in cynomolgus monkey (SC): completed before the marketing application
“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.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S6)
“In accordance with the guideline entitled ‘Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals’ (ICH S6), carcinogenicity studies were not performed.”
Carcinogenicity model
Not conducted; ustekinumab does not bind or neutralise mouse or rat IL-12/IL-23, precluding rodent studies
“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.”
Carcinogenicity timing
Not required under ICH S6
“In accordance with the guideline entitled ‘Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals’ (ICH S6), carcinogenicity studies were not performed.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 45 mg/kg twice-weekly SC: steady-state Cmax ~116-fold human Cmax at 90 mg SC
“The mean steady-state Cmax value following a 45 mg/kg twice-weekly SC dose in monkeys was approximately 116-fold higher than the median Cmax value following 4 weekly 90 mg SC doses in subjects with psoriasis.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Marmoset experimental autoimmune encephalomyelitis (EAE) model with the clinical antibody
“CNTO 1275 (STELARA, ustekinumab) was pharmacologically active in non-human primates in a marmoset experimental autoimmune encephalomyelitis model (EAE) and was effective in suppressing EAE incidence and severity in marmosets.”
Why that model
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.”
Reviewer's view of the efficacy data
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.
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity or rodent tumour immune surveillance studies; ustekinumab does not bind mouse or rat IL-12/IL-23
Why: No rodent cross-reactivity; malignancy to be monitored under the Risk Management Plan · No relevant species
“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.”
“Monitoring of malignancy will be a part of the comprehensive Risk Management Plan for CNTO 1275.”
DARTAcceptedBeyond the letter
Female fertility tested only in mice with a surrogate anti-mouse IL-12/23p40 antibody
Why: Monkey has less robust reproductive characteristics; outcome limited to hazard identification · Other reason
“The choice of this model was justified on the basis of the less robust reproductive characteristics of the monkey; it is accepted that the outcome is limited to the identification of potential female fertility hazards through blocking IL12/23 and not as a definitive estimate of risk for ustekinumab.”
OtherAcceptedBeyond the letter
Only two dose levels studied and mostly one species for toxicology
Why: Considered acceptable for this type of product · Low-risk modality
“Only two dose levels of ustekinumab were studied and mostly only one species for the toxicology, but this was considered acceptable for this type of product.”
OtherAcceptedBeyond the letter
Anti-drug antibody response in monkey toxicity studies could not be determined
Why: Pharmacokinetic indices showed adequate exposure · Pharmacology or kinetics
“A general finding in the toxicity studies was that it was not possible to discern whether there had been an anti-antibody response to ustekinumab, although some animals were noted to have greater clearance than others.”
“This was not considered to have invalidated the studies and the pharmacokinetic indices were considered to show that adequate exposure was demonstrated.”
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