Tremfya
guselkumab
Species
Monkey
Longest study
24 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 applicant submitted one single dose and one pivotal 5-week (IV/SC)/24-week (SC) repeat dose toxicity studies in cynomolgus monkey”
Why that species
Comparable IL-23 binding in human, NHP and guinea pig; only partial or no binding to dog, mouse, rat
“Guselkumab demonstrated comparable species binding to IL-23 from humans, non-human primates (including cynomolgus monkeys), and guinea pigs, but only partial or no binding to dog, mouse, or rat IL-23.”
Surrogate molecule
No surrogate; guselkumab itself was used, including in guinea pig fertility studies
“The influence of guselkumab administration on fertility was assessed in female and male Guinea Pigs that were dosed 50 or 100 mg/kg guselkumab subcutaneously twice a week.”
Study lengthopen answer page →
Longest pivotal study
24 weeks
“Five-week SC and IV and 24-week SC toxicology studies were conducted in young adult to adult cynomolgus monkeys administered guselkumab SC at doses of 10 or 50 mg/kg, once per week for 5 or 24 weeks”
Pivotal GLP studies
Cynomolgus monkey study: weekly IV/SC for 5 weeks (phase 1) or SC for 24 weeks (phase 2), up to 50 mg/kg
“Once weekly administration of guselkumab via the IV and SC route for 5 weeks (phase 1) or SC 24 weeks (phase 2) up to 50 mg/kg”
Route in tox
Subcutaneous and intravenous
“administered guselkumab SC at doses of 10 or 50 mg/kg, once per week for 5 or 24 weeks or IV at a dose of 50 mg/kg for 5 weeks”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6R1)
“Genetic toxicology studies are not applicable to mAbs and were not conducted with guselkumab based on ICH S6R1 guidance”
Carcinogenicity
Not conducted; evidence does not support a link between IL-23 inhibition and increased cancer risk
“does not support a causal mechanistic/target-related link between IL-23 inhibition and increased cancer risk”
Reproductive & developmental
Monkey ePPND: no adverse developmental effects up to 30 times the MRHD; neonatal deaths at 6- to 30-times the MRHD
“no adverse developmental effects were observed in infants born to pregnant monkeys after subcutaneous administration of guselkumab during organogenesis through parturition at doses up to 30 times the maximum recommended human dose (MRHD). Neonatal deaths were observed at 6- to 30-times the MRHD”
Safety pharmacology
Dedicated cardiovascular study in telemetered cynomolgus monkeys
“A dedicated cardiovascular (CV) safety pharmacology study was undertaken in telemetered cynomolgus 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 Tremfya 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: NOAEL 50 mg/kg/week for 5-week IV and 24-week SC dosing in monkeys (FDA multi-discipline review, p. 58)
NOAEL / key findings
NOAEL 50 mg/kg/week for 5-week IV and 24-week SC dosing in monkeys
“The no observed adverse effect level (NOAEL) was 50 mg/kg/week for 5-week IV administration and for 24-week SC administration in cynomolgus monkeys”
Risksopen answer page →
Immune & cytokine safety
No effect on hematology, immunophenotyping, TDAR, immune tissue histopathology or T/B-cell distribution in monkeys or offspring
“Guselkumab treatment had no effect on hematology, immunophenotyping, TDAR to KLH, histopathology of immune tissues, or T- and B-cell distribution in monkeys or their offspring.”
Biodistribution & persistence
Transplacental transfer to infants; milk below quantifiable concentration
“Guselkumab exposure in infants was likely a result of transplacental distribution, as milk samples were below the lowest quantifiable concentration for guselkumab.”
Modality-specific risk
Infection risk: IL-23 contributes to immunity against bacterial and fungal pathogens
“IL-23 may contribute to immunity for a variety of bacterial and fungal pathogens, as assessed in animal models of these infections which has been reported in literature.”