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.”
Species: general tox
Cynomolgus monkey (most relevant species); mouse studies used analogous anti-mouse TNFα antibody cV1q
“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. For the studies in mice, an analogous anti-mouse TNFα monoclonal antibody designated cV1q, developed during the non-clinical testing of another TNFα inhibitor, infliximab (Remicade), was used.”
Species: DART
Cynomolgus monkey (golimumab; EFD, PPND) and CD-1 mouse (surrogate cV1q)
“Reproductive toxicity was evaluated both in cynomolgus monkeys and in CD-1 mice, using the analogous mouse anti-TNFα antibody cV1q.”
Species: carcinogenicity
Not conducted (no pharmacologic activity in rodents)
“No carcinogenicity study was performed with golimumab as standard rodent studies are not meaningful due to lack of pharmacologic activity in this species.”
Surrogate used in
Yes: mouse surrogate cV1q for supportive reproductive/developmental and chronic toxicity studies
“Supportive toxicology studies were conducted in mice using the analogous anti-mouse TNFα monoclonal antibody, cV1q, to evaluate the effects of antiTNFα 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”
Genotox: Ames
Not conducted
“Genotoxicity studies as outlined in ICH S2B (1997) have not been conducted for golimumab.”
Genotox: in vitro mammalian
Not conducted
“Genotoxicity studies as outlined in ICH S2B (1997) have not been conducted for golimumab.”
Genotox: in vivo
Not conducted
“Genotoxicity studies as outlined in ICH S2B (1997) have not been conducted for golimumab.”
Carcinogenicity model
Not conducted; rodent studies not meaningful due to lack of pharmacologic activity
“No carcinogenicity study was performed with golimumab as standard rodent studies are not meaningful due to lack of pharmacologic activity in this species.”
Carcinogenicity timing
Not required; lack of studies addressed in SPC and risk management plan
“The lack of long-term carcinogenicity studies is reflected in the SPC and addressed in the risk management plan.”
hERG / QT
Monkey CV safety pharmacology inconclusive (restraint-induced tachycardia); no hERG assay
“Tachycardia, here probably resulting from restraining of the animals, is well known to blunt any potential effect on rhythm disturbance or effect on cardiac repolarisation. For these reasons it seems impossible to reasonably conclude about any potential impact of golimumab on the cardiovascular system.”
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
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: 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.”
Anti-drug antibodies: animals
ADA-positive monkeys showed accelerated clearance and shortened half-life
“In monkeys that tested positive for anti-golimumab antibodies, accelerated CL and shortened t1/2 were observed.”
Anti-drug antibodies: patients
Antibodies to golimumab in 4.3% of subjects across Phase 3 studies
“The overall incidence of antibodies was 4.3% across all subjects treated in Phase 3 studies with similar rates in each rheumatologic indication.”
Label warnings
Boxed warning: SERIOUS INFECTIONS and MALIGNANCY
- Serious Infections
- Malignancies
- Congestive Heart Failure
- Demyelinating Disorders
- Autoimmunity
- Use with Abatacept
- Use with Anakinra
- Switching Between Biological Disease Modifying Antirheumatic Drugs (DMARDs)
- Hematologic Cytopenias
- Vaccinations/Therapeutic Infectious Agents
- Hypersensitivity Reactions
InfectionsSecondary malignancyCardiovascularNeurotoxicityImmune-mediated reactionsCytopeniasHypersensitivity & infusion 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 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
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: Monkey NOAEL 50 mg/kg despite lymphocyte increases; margin ~600 (Cmax) and 50 (AUC) (EMA assessment report, p. 14)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week (6-month) cynomolgus monkey studies, SC and IV, each with 3-month recovery
“T-2002-001 Cynomolgus monkey / 8/sex/group 0; 25; 50 twice a week/ SC 3 or 6 months (3 months) Golimumab derived from C524A cell line systemic toxicity: 50 mg/kg T-2000-007 Cynomolgus monkey / 5/sex/group 0; 10; 50 once a week/ IV 1 month (37 days) Golimumab derived from C466D cell line 50 mg/kg T-2004-006 Cynomolgus monkey / 8/sex/group 0; 10; 50 once a week/ IV 6 months (3 months)”
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.”
DART package
Species: DART
Cynomolgus monkey (golimumab; EFD, PPND) and CD-1 mouse (surrogate cV1q)
“Reproductive toxicity was evaluated both in cynomolgus monkeys and in CD-1 mice, using the analogous mouse anti-TNFα antibody cV1q.”
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.”
PPND / ePPND: when
PPND in cynomolgus monkey (study T-2004-007, gestation day 50 to lactation day 33): completed before the marketing application
“In the prenatal and postnatal development study T-2004-007, where cynomolgus infants were exposed to golimumab in utero (from Day 50 of gestation) and during lactation (until Day 33 after delivery), golimumab was transferred across the placenta from mothers to foetuses and the offspring had high serum golimumab concentrations after birth.”
Carcinogenicity
Species: carcinogenicity
Not conducted (no pharmacologic activity in rodents)
“No carcinogenicity study was performed with golimumab as standard rodent studies are not meaningful due to lack of pharmacologic activity in this species.”
Carcinogenicity model
Not conducted; rodent studies not meaningful due to lack of pharmacologic activity
“No carcinogenicity study was performed with golimumab as standard rodent studies are not meaningful due to lack of pharmacologic activity in this species.”
Carcinogenicity timing
Not required; lack of studies addressed in SPC and risk management plan
“The lack of long-term carcinogenicity studies is reflected in the SPC and addressed in the risk management plan.”
Safety marginopen answer page →
Safety margin at NOAEL
Chronic SC monkey NOAEL 50 mg/kg: ~50x human AUC (~600x Cmax)
“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.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse arthritis model: single golimumab dose (1-30 mg/kg) delayed onset of clinical symptoms
“Investigations were also performed in vivo in a mouse model of arthritis. A single dose of golimumab (1, 3, 10 or 30 mg/kg) significantly delayed onset of clinical symptoms compared to a vehicle control group.”
Why that model
Golimumab does not neutralize rat or mouse TNFα
“No neutralization of rat or mouse TNFα by golimumab was observed.”
Reviewer's view of the efficacy data
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.
Flexibilityopen answer page →
Flexibility accepted
Safety marginAcceptedBeyond the letter
Nominal monkey margins of 50 and above uncertain: golimumab has 34-fold lower affinity and 72-fold lower potency for cynomolgus TNFα
Why: Clinical safety profile of anti-TNFα agents is fairly well established · Class precedent · Human data
“The margins to human exposure, when comparing Cmax and AUC values are in general large, from 50 and above, however it has to be taken into account that golimumab was shown to have 34-fold less affinity and to be 72-fold less potent in neutralizing cynomolgus TNFα”
“However, since the clinical safety profile of an anti-TNFα agent is fairly well established, the uncertainty of the exposure margins relative to the human exposure is not considered a concern.”
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity study; rodent studies not meaningful; lymphoma or other malignancy risk cannot be excluded
Why: No pharmacologic activity in rodents; gap reflected in SPC and risk management plan · No relevant species
“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.”
“The lack of long-term carcinogenicity studies is reflected in the SPC and addressed in the risk management plan.”
OtherVerdict not stated
Mouse studies used the analogous anti-mouse TNFα antibody cV1q, developed for infliximab, instead of golimumab
Why: Golimumab shows little or no neutralization of mouse TNFα
“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. For the studies in mice, an analogous anti-mouse TNFα monoclonal antibody designated cV1q, developed during the non-clinical testing of another TNFα inhibitor, infliximab (Remicade), was used.”
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