Humira
adalimumab
Sources:EMA assessment report ↗
Species
Monkey
Longest study
39 wk
Genotox
Partial / alternative Partial / alternative
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only (pivotal repeat-dose)
“The studies in cynomolgus monkeys are considered most relevant for human safety assessment.”
Why that species
Potent neutralization of cynomolgus monkey TNFα; weak murine TNFα neutralization, no rat TNFα binding, rapid anti-drug antibodies in mice
“In vitro, adalimumab is a potent inhibitor of TNFα from human, various primates including cynomolgus monkey, and dog (IC50s 10-10 –10-11 M). Neutralisation of murine TNFα was considerably weaker (>2.0 x 10-7), and adalimumab did not bind rat TNFα.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys
“The studies in cynomolgus monkeys are considered most relevant for human safety assessment.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“Repeat dose toxicity studies of 4 weeks (32 – 157 mg/kg bw) and 39 weeks (32- 215 mg/kg bw) duration were performed.”
Pivotal GLP studies
Cynomolgus monkey 4-week (32-157 mg/kg) and 39-week (32-215 mg/kg) repeat-dose studies
“Repeat dose toxicity studies of 4 weeks (32 – 157 mg/kg bw) and 39 weeks (32- 215 mg/kg bw) duration were performed.”
Route in tox
IV (clinical route SC)
“Adalimimab was generally administered via the i.v. route, while the intended clinical route is s.c. administration.”
Skipped studiesopen answer page →
Genotoxicity
Limited tests (bacterial mutation, mouse micronucleus) negative; not needed for a monoclonal antibody (ICH S6)
“No genotoxic effects were seen. This is not a complete genotoxicity test battery (see CPMP/ICH/174/95, S2B). However, for a monoclonal antibody, genotoxicity tests are considered to be of limited value and are therefore not needed (CPMP/ICH/302/95, S6).”
Carcinogenicity
Not conducted: no relevant rodent model; no direct carcinogenic signal, but impaired tumour control from immunosuppression cannot be ruled out
“No carcinogenicity study was performed with adalimumab. The lack of such studies is justified because there is no conventional or alternative model available, (i.e adalimumab has low/no affinity for mouse/rat TNFα, and MAHA developed after single doses).”
Reproductive & developmental
Monkey embryo-fetal/perinatal study: no effects on dams, gestation, parturition, fetuses or infants
“There were no treatment related effects on the maternal animals, gestation, parturition, on fetuses or on the infants.”
Safety pharmacology
Stand-alone CNS, cardiovascular (dog), GI, renal studies; no findings of clinical concern
“A number of general pharmacology/safety pharmacology studies were performed focussing on the CNS, cardiovascular system, GI tract, renal function, female uterus, local anaesthesia, and in vitro studies with human blood.”
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 Humira 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: 39-week monkey NOAEL 32 mg/kg; thymus and spleen immune effects, mostly reversible over 20-week recovery (EMA assessment report, p. 7)
NOAEL / key findings
39-week monkey NOAEL 32 mg/kg; thymus and spleen immune effects, mostly reversible over 20-week recovery
“In the 39 weeks study, most of these changes were reversible within the 20-week recovery period. In this study, the NOAEL was 32 mg/kg, with an AUC of 304 800 µg*h/ml.”
Risksopen answer page →
Immune & cytokine safety
Anti-drug antibodies (MAHA, PAHA) after single doses in mice and monkeys; PAHA neutralising
“However, both MAHA and PAHA developed after single doses, and affected the elimination. Moreover, analyses of biological activity of serum samples showed that PAHA were neutralising.”
Biodistribution & persistence
Placental transfer in monkeys: fetal exposure 5-10% of maternal serum levels
“Available data showed that fetuses were exposed to adalimimab, corresponding to 5-10% of the maternal serum levels.”
Modality-specific risk
Reduced host defence against infections from TNFα inhibition; possible poorer tumour control
“The clinical experience with authorised anti-TNF therapies clearly confirms a reduced defence against infections as the main adverse effect of such treatment.”