Simponi
golimumab
Sources:EMA assessment report ↗
Species
MonkeyMouse
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 (mouse surrogate for supportive studies)
“An overview of the repeat-dose toxicity studies with golimumab in cynomolgus monkeys as well as the supportive study with the murine analogous molecule cV1q is given in Table 1.”
Why that species
Golimumab shows little or no neutralization of dog, rabbit, mouse or rat TNFα; cynomolgus monkey most relevant
“The cynomolgus monkey was chosen as the most relevant non-clinical species, since golimumab showed little or no neutralization of dog, rabbit, mouse or rat TNFα.”
Surrogate molecule
Yes: analogous anti-mouse TNFα antibody cV1q, used for mouse chronic toxicity and reproductive/developmental studies
“Supportive toxicology studies were conducted in mice using the analogous anti-mouse TNFα monoclonal antibody, cV1q, to evaluate the effects of anti-TNFα treatment on reproductive development and chronic toxicity.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“In the 6-month subcutaneous study, using doses up to 50 mg/kg, no adverse effects due to golimumab treatment were seen on standard parameters.”
Pivotal GLP studies
Cynomolgus monkey IV and SC repeat-dose studies, once or twice weekly, up to 50 mg/kg, for up to 6 months
“following single or repeated dosing of cynomolgus monkeys via intravenous or subcutaneous administration at doses up to 50 mg/kg once or twice weekly for up to 6 months.”
Route in tox
Subcutaneous and intravenous
“Golimumab was evaluated in subcutaneous and intravenous repeated-dose toxicity studies using doses up to 50 mg/kg either weekly or twice weekly.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted
“Genotoxicity studies as outlined in ICH S2B (1997) have not been conducted for golimumab.”
Carcinogenicity
Not conducted (no pharmacologic activity in rodents); lymphoma/malignancy risk with TNF antagonists cannot be excluded
“No carcinogenicity study was performed with golimumab as standard rodent studies are not meaningful due to lack of pharmacologic activity in this species. However, with the current knowledge, a possible risk for the development of lymphomas or other malignancies in patients treated with a TNF-antagonist cannot be excluded.”
Reproductive & developmental
Monkey PPND: no adverse effects, including on infant immune development through 6 months postpartum
“In cynomolgus monkeys, no adverse effects were seen related to golimumab treatment, including effects on the immunological development in the F1 infants followed for 6 months post delivery.”
Safety pharmacology
Incorporated into monkey repeat-dose studies; no adverse CV, respiratory or CNS effects
“In accordance with relevant guidance documents, safety pharmacology endpoints were incorporated into the toxicology testing. No adverse effects of golimumab were observed in safety pharmacology evaluations for cardiovascular, respiratory and CNS safety”
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 Simponi 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: Monkey NOAEL 50 mg/kg despite lymphocyte increases; margin ~600 (Cmax) and 50 (AUC) (EMA assessment report, p. 14)
NOAEL / key findings
Monkey NOAEL 50 mg/kg despite lymphocyte increases; margin ~600 (Cmax) and 50 (AUC)
“Despite the increase in total lymphocytes, it is agreed by the assessor that a NOAEL can be set to 50 mg/kg, which gives a margin to maximum human exposure of approximately 600 (mean for male/female animals), based on Cmax values and 50 based on AUC values.”
Risksopen answer page →
Immune & cytokine safety
Monkey anti-drug antibodies more frequent at lower doses (3-10 mg/kg) than at 25-50 mg/kg
“The incidence of antibodies to golimumab was greater at lower dose levels (3 and 10 mg/kg), than at higher dose levels (25 and 50 mg/kg).”
Biodistribution & persistence
Crosses placenta with substantial fetal exposure in monkeys; present in monkey breast milk
“When golimumab was administered to pregnant monkeys, it was shown to cross the placenta and substantial golimumab exposure was observed in the foetal circulation. Golimumab was also found in monkey breast milk.”
Modality-specific risk
TNF blockade: possible lymphoma/malignancy risk and infection risk in infants exposed in utero
“However, with the current knowledge, a possible risk for the development of lymphomas or other malignancies in patients treated with a TNF-antagonist cannot be excluded.”