Humira
adalimumab
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.”
Species: general tox
Cynomolgus monkey (4- and 39-week studies)
“The studies in cynomolgus monkeys are considered most relevant for human safety assessment. Repeat dose toxicity studies of 4 weeks (32 – 157 mg/kg bw) and 39 weeks (32- 215 mg/kg bw) duration were performed.”
Species: DART
Cynomolgus monkey (developmental toxicity study only); male fertility not studied
“Effects on male fertility have not been studied. In females, no study beyond the developmental toxicity study in cynomolgus monkey has been performed.”
Species: carcinogenicity
Not conducted: no suitable rodent model (low/no affinity for mouse/rat TNFα, rapid MAHA)
“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).”
Surrogate used in
No surrogate antibody; human TNFα transgenic mice (Tg197, Tg5453) used as arthritis models
“Moreover, it prevented development of arthritis in two transgenic mouse models, the Tg197 (expressing a soluble human TNFα transgene) and Tg5453 (expressing a transgene that encodes human pro-TNFα), serving as disease models of polyarthritis.”
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.”
Genotox: Ames
Bacterial gene mutation test: negative
“The genotoxic potential of adalimumab was tested in vitro by gene mutations in bacteria and in vivo in the mouse micronucleus test. No genotoxic effects were seen.”
Genotox: in vitro mammalian
Not conducted: incomplete battery accepted, genotoxicity tests not needed for a monoclonal antibody (ICH S6)
“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).”
Genotox: in vivo
Mouse micronucleus test: negative
“The genotoxic potential of adalimumab was tested in vitro by gene mutations in bacteria and in vivo in the mouse micronucleus test. No genotoxic effects were seen.”
Carcinogenicity model
Not conducted: no conventional or alternative model available
“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).”
Carcinogenicity timing
Not required: lack of studies justified by absence of a relevant model
“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).”
hERG / QT
No hERG assay; no clinically concerning findings in dog cardiovascular safety pharmacology
“The studies in dogs (CV effects) and with human blood are considered more relevant. There were no findings in these studies that raise any clinical concerns.”
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
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: 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.”
Anti-drug antibodies: animals
MAHA (mice) and PAHA (monkeys) after single doses, affecting elimination; 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.”
Anti-drug antibodies: patients
AAA in 5.5% (58/1,053) of patients in pivotal trials vs 0.5% on placebo
“In the pivotal trials, AAA were identified in 58/1,053 (5.5%) patients treated with adalimumab, compared with 2/370 (0.5%) on placebo.”
Label warnings
Boxed warning: Serious infections and malignancy
- Serious Infections
- Malignancies
- Hypersensitivity Reactions
- Hepatitis B Virus Reactivation
- Neurologic Reactions
- Hematological Reactions
- Increased Risk of Infection W hen Used with Anakinra
- Heart Failure
- Autoimmunity
- Immunizations
- Increased Risk of Infection When Used with Abatacept
InfectionsSecondary malignancyHypersensitivity & infusion reactionsHepatotoxicityNeurotoxicityCytopeniasCardiovascularImmune-mediated reactions
US prescribing information, Boxed Warning and 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
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 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
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: 39-week monkey NOAEL 32 mg/kg; thymus and spleen immune effects, mostly reversible over 20-week recovery (EMA assessment report, p. 7)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week study with 20-week recovery
“In the 39 weeks study, most of these changes were reversible within the 20-week recovery period.”
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.”
DART package
Species: DART
Cynomolgus monkey (developmental toxicity study only); male fertility not studied
“Effects on male fertility have not been studied. In females, no study beyond the developmental toxicity study in cynomolgus monkey has been performed.”
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.”
PPND / ePPND: when
No standard postnatal toxicity study: no appropriate model (limited rodent TNF cross-reactivity, neutralizing antibodies in rodents)
“Carcinogenicity studies, and standard assessment of fertility and postnatal toxicity, were not performed with adalimumab due to the lack of appropriate models for an antibody with limited cross-reactivity to rodent TNF and the development of neutralizing antibodies in rodents.”
Carcinogenicity
Species: carcinogenicity
Not conducted: no suitable rodent model (low/no affinity for mouse/rat TNFα, rapid MAHA)
“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).”
Carcinogenicity model
Not conducted: no conventional or alternative model available
“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).”
Carcinogenicity timing
Not required: lack of studies justified by absence of a relevant model
“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).”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey embryo-fetal/perinatal study: no fetal harm at up to 373x MRHD exposure (AUC)
“In an embryo-fetal perinatal development study, pregnant cynomolgus monkeys received adalimumab from gestation days 20 to 97 at doses that produced exposures up to 373 times that achieved with the MRHD without methotrexate (on an AUC basis with maternal IV doses up to 100 mg/kg/week).”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human TNFα transgenic arthritis mice (Tg197, Tg5453); hTNFα-induced lethality (mice) and pyrexia (rabbits)
“In vivo, adalimumab inhibited hTNFα-induced lethality in D-galactosamine sensitised mice and hTNFα-induced pyrexia in rabbits. Moreover, it prevented development of arthritis in two transgenic mouse models, the Tg197 (expressing a soluble human TNFα transgene) and Tg5453 (expressing a transgene that encodes human pro-TNFα), serving as disease models of polyarthritis.”
Why that model
Adalimumab neutralises murine TNFα only weakly and does not bind rat TNFα
“Neutralisation of murine TNFα was considerably weaker (>2.0 x 10-7), and adalimumab did not bind rat TNFα.”
Reviewer's view of the efficacy data
CHMP: primary pharmacodynamic studies gave adequate evidence of efficacy in vitro and in vivo
“Overall, the primary pharmacodynamic studies provided adequate evidence that adalimumab was effective in in vitro and in vivo studies.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies for chronic immune-mediated indications; no conventional or alternative model available
Why: Low or no affinity for rodent TNFα and anti-drug antibodies after single doses; risk from immunosuppression reflected in SPC · No relevant species · Pharmacology or kinetics
“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).”
“However, the consequences of long-term immunosuppression are unknown and an increased risk of a poorer control of nascent tumours cannot be ruled out. The lack of carcinogenicity studies has been reflected in the SPC.”
DARTCriticised but acceptedBeyond the letter
No male fertility study; in females, no study beyond the monkey developmental toxicity study
Why: Rat and mouse not relevant models; monkey reproductive organ histopathology and human tissue cross-reactivity showed no concern · No relevant species · Weight of evidence
“Effects on male fertility have not been studied. In females, no study beyond the developmental toxicity study in cynomolgus monkey has been performed.”
“However, neither the rat nor the mouse is considered as particularly relevant models for human safety assessment. The human tissue cross-reactivity studies and the histopathological evaluation of male and female reproductive organs in the repeat dose toxicity studies in monkeys revealed no cause for concern.”
OtherCriticised but acceptedBeyond the letter
Adalimumab detected in control monkeys in the 4- and 39-week studies; anti-drug antibodies in treated animals could not be determined
Why: High adalimumab levels throughout indicate anti-drug antibodies did not markedly neutralise activity · Pharmacology or kinetics
“In both the 4 and 39 weeks primate studies, low levels of adalimumab were detected in control monkeys.”
“However, high concentrations of adalimumab were detected in samples from treated animals throughout the study, which support that PAHAs had not markedly neutralised the adalimumab activity during the study.”
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