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.”
Species: general tox
Cynomolgus monkey (pivotal 5-week IV/SC and 24-week SC); guinea pig 3-week tolerability only
“The applicant submitted one single dose and one pivotal 5-week (IV/SC)/24-week (SC) repeat dose toxicity studies in cynomolgus monkey and one 3-week SC toxicity and tolerability study in guinea pigs with guselkumab.”
Species: DART
Guinea pig (fertility and early embryonic development) and cynomolgus monkey (ePPND with 6-month postnatal evaluation)
“The following pharmacology/toxicology studies were reviewed under IND 105004 except “SC Fertility and Early Embryonic Development Study in Male Guinea Pigs (Study # T-2014-021)” and “Enhanced Pre- and Post-natal Development Study in the Cynomolgus Monkey with a 6-Month Postnatal Evaluation (Study # 20029626)”.”
Species: carcinogenicity
Not conducted: 2-year rodent study not feasible (binding restricted to monkeys/guinea pigs)
“Guselkumab cannot be tested in a traditional 2-year rodent study to evaluate its carcinogenic potential due to its species specific binding in monkeys and/or guinea pigs.”
Surrogate used in
No surrogate used
“Thus, cynomolgus monkeys and guinea pigs were selected as the pharmacologically relevant species for use in nonclinical studies with guselkumab.”
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.”
Genotox: Ames
Not conducted (ICH S6R1)
“Genetic toxicology studies are not applicable to mAbs and were not conducted with guselkumab based on ICH S6R1 guidance, Guidance for Industry – Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals.”
Genotox: in vitro mammalian
Not conducted (ICH S6R1)
“Genetic toxicology studies are not applicable to mAbs and were not conducted with guselkumab based on ICH S6R1 guidance, Guidance for Industry – Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals.”
Genotox: in vivo
Not conducted (ICH S6R1)
“Genetic toxicology studies are not applicable to mAbs and were not conducted with guselkumab based on ICH S6R1 guidance, Guidance for Industry – Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals.”
Carcinogenicity model
Not conducted: 2-year rodent study not feasible (binding specific to monkeys/guinea pigs)
“Guselkumab cannot be tested in a traditional 2-year rodent study to evaluate its carcinogenic potential due to its species specific binding in monkeys and/or guinea pigs.”
Carcinogenicity timing
Not required; no nonclinical carcinogenicity studies recommended
“No nonclinical studies to address the carcinogenic potential of guselkumab are recommended.”
hERG / QT
No hERG assay; telemetered monkey CV study: no adverse ECG or blood pressure effects
“There were no adverse effects on ECGs and no treatment related effects on blood pressure in this study.”
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
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: 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.”
Anti-drug antibodies: animals
Immunogenic in guinea pigs and monkeys; ADA in only 2 of 90 monkeys (2.2%)
“Guselkumab was immunogenic in both guinea pigs and monkeys, as expected for a human mAb. ADA were detected in only 2 (2.2%) of 90 monkeys treated with guselkumab, one after a single 50 mg/kg IV dose of guselkumab and one pregnant female and her infant in the ePPND study receiving 10 mg/kg/week SC guselkumab.”
Anti-drug antibodies: patients
Psoriasis: ~6% ADA up to Week 52; ~7% of these neutralizing
“Up to Week 52, approximately 6% of adult subjects treated with TREMFYA developed antidrug antibodies. Of the subjects who developed antidrug antibodies, approximately 7% had antibodies that were classified as neutralizing antibodies.”
Label warnings
- Hypersensitivity Reactions
- Infections
- Tuberculosis
- Hepatotoxicity
- Immunizations
Hypersensitivity & infusion reactionsInfectionsHepatotoxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Country not stated; first-in-human single-dose study in healthy subjects and psoriasis patients (PSO1001)
“CNTO1959PSO1001 (PSO1001) single dose, first-in-human trial in healthy subjects (Part 1) and subjects with moderate to severe plaque psoriasis (Part 2)”
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 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
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: NOAEL 50 mg/kg/week for 5-week IV and 24-week SC dosing in monkeys (FDA multi-discipline review, p. 58)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
24-week SC cynomolgus monkey study (T-2008-007, GLP) with 3-month recovery
“CNTO1959: A 5-Week Subcutaneous and Intravenous and 24-Week Subcutaneous Toxicity Study in Cynomolgus Monkeys with a 3-Month Recovery Period (Study # T-2008-007, GLP)”
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”
DART package
Species: DART
Guinea pig (fertility and early embryonic development) and cynomolgus monkey (ePPND with 6-month postnatal evaluation)
“The following pharmacology/toxicology studies were reviewed under IND 105004 except “SC Fertility and Early Embryonic Development Study in Male Guinea Pigs (Study # T-2014-021)” and “Enhanced Pre- and Post-natal Development Study in the Cynomolgus Monkey with a 6-Month Postnatal Evaluation (Study # 20029626)”.”
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”
PPND / ePPND: when
ePPND in cynomolgus monkey (in place of a standalone EFD study): completed before the marketing application
“A standalone EFD study was not conducted for guselkumab. Instead, an ePPND study was conducted in monkeys with guselkumab.”
Carcinogenicity
Species: carcinogenicity
Not conducted: 2-year rodent study not feasible (binding restricted to monkeys/guinea pigs)
“Guselkumab cannot be tested in a traditional 2-year rodent study to evaluate its carcinogenic potential due to its species specific binding in monkeys and/or guinea pigs.”
Carcinogenicity model
Not conducted: 2-year rodent study not feasible (binding specific to monkeys/guinea pigs)
“Guselkumab cannot be tested in a traditional 2-year rodent study to evaluate its carcinogenic potential due to its species specific binding in monkeys and/or guinea pigs.”
Carcinogenicity timing
Not required; no nonclinical carcinogenicity studies recommended
“No nonclinical studies to address the carcinogenic potential of guselkumab are recommended.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL AUC ~49.9x human AUC after a single 100 mg SC dose
“The exposure margin for the mean AUCDay 161-168 value (5411.67 µg.day/mL) in monkeys was approximately 49.9-fold higher than the mean AUCinf value in psoriasis patients following a single 100 mg/kg SC dose of guselkumab (108.48 µg.day/mL).”
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”
Efficacy evidenceopen answer page →
Efficacy evidence
rhIL-23 challenge in mice: guselkumab attenuated induced serum IL-1α and G-CSF increases
“Guselkumab administration was shown to attenuate rhIL-23 induced increases in serum levels of cytokines IL- 1α and G-CSF without any significant change in TNFα, IP-10 or GM-CSF levels.”
Why that model
No nonclinical model recapitulates human plaque psoriasis
“It is accepted that no nonclinical model of plaque psoriasis that recapitulates all facets of human psoriasis is available.”
Reviewer's view of the efficacy data
EMA: the hIL-23 mouse model is of limited value for showing guselkumab's inhibitory capability
“Overall, this animal model of testing the effectiveness of hIL-23 and consequently the inhibitory capability of guselkumab is of limited value.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies for chronic psoriasis use; literature and monkey-data weight-of-evidence assessment instead
Why: Species-specific binding precludes a rodent study; malignancy risk considered low and listed as an important potential risk in the RMP · No relevant species · Weight of evidence
“Guselkumab cannot be tested in a traditional 2-year rodent study to evaluate its carcinogenic potential due to its species specific binding in monkeys and/or guinea pigs.”
“It was concluded that the risk of malignancy associated with long-term inhibition of IL-23 following administration of guselkumab to humans is considered to be low, but it cannot be completely ruled out as a potential hazard associated with modulation of IL-23 activity. Malignancies has been included has an important potential risk in the RMP.”
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