Simulect
basiliximab
Species
Monkey
Longest study
4 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Partial / alternative Partial / alternative
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rhesus and cynomolgus monkey (primates only)
“Apart from the studies performed in primates, no toxicity studies in rodents or non-rodent animals except primates could have been carried out because of the species specificity of the antibody.”
Why that species
Binds primate IL-2 receptor alpha chain but not dog; species specificity precluded rodent and non-primate studies
“Simulect bound specifically to the α-chain of the primate IL-2-receptor, but not to the dog IL-2 receptor.”
Surrogate molecule
No surrogate; the clinical antibody was tested in rhesus and cynomolgus monkeys
“Apart from the studies performed in primates, no toxicity studies in rodents or non-rodent animals except primates could have been carried out because of the species specificity of the antibody.”
Species: general tox
Rhesus monkey (4-week IV repeat-dose)
“Repeated dose toxicity study has been performed in monkeys (4 weeks intravenous in the rhesus monkey with an 8 week treatment, doses at 0.5 to 4.5 mg/kg every 4th day).”
Species: DART
Cynomolgus monkey (embryo-fetal development); no fertility studies
“No maternal toxicity, embryotoxicity, or teratogenicity was observed in cynomolgus monkeys 100 days post coitum following dosing with basiliximab during the organogenesis period; blood levels in pregnant monkeys were 13-fold higher than those seen in human patients.”
Species: carcinogenicity
Not conducted
“No long-term or fertility studies in laboratory animals have been performed to evaluate the potential of Simulect to produce carcinogenicity or fertility impairment, respectively.”
Surrogate used in
No surrogate used; clinical antibody tested in primates only due to species specificity
“Apart from the studies performed in primates, no toxicity studies in rodents or non-rodent animals except primates could have been carried out because of the species specificity of the antibody.”
Study lengthopen answer page →
Longest pivotal study
4 weeks
“Pharmacokinetics of SDZ CIH 621 following single or multiple administration were studied in rhesus and cynomolgous monkeys in a 4-weeks intravenous toxicity studies.”
Pivotal GLP studies
4-week IV rhesus monkey study, 0.5 to 4.5 mg/kg every 4th day; plus cynomolgus embryo-fetal study
“Repeated dose toxicity study has been performed in monkeys (4 weeks intravenous in the rhesus monkey with an 8 week treatment, doses at 0.5 to 4.5 mg/kg every 4th day).”
Route in tox
IV
“Repeated dose toxicity study has been performed in monkeys (4 weeks intravenous in the rhesus monkey with an 8 week treatment, doses at 0.5 to 4.5 mg/kg every 4th day).”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames and V79 Chinese hamster cell chromosomal aberration assays
“Negative results have been obtained in the Ames test and in chromosomal aberration tests with V79 Chinese Hamster Cells as expected for a proteinous substances like Simulect.”
Carcinogenicity
Not conducted; no long-term animal studies
“No long-term or fertility studies in laboratory animals have been performed to evaluate the potential of Simulect to produce carcinogenicity or fertility impairment, respectively.”
Reproductive & developmental
No fertility studies; cynomolgus organogenesis study: no maternal toxicity, embryotoxicity or teratogenicity at 13-fold human exposure
“No maternal toxicity, embryotoxicity, or teratogenicity was observed in cynomolgus monkeys 100 days post coitum following dosing with basiliximab during the organogenesis period; blood levels in pregnant monkeys were 13-fold higher than those seen in human patients.”
Safety pharmacology
Incorporated into repeat-dose monkey study; no ECG or other findings
“No drug-related effects on body weight, no clinical or hematological findings, ophalmoscopic or electrocardiographic findings.”
Genotox: Ames
Ames test negative
“Negative results have been obtained in the Ames test and in chromosomal aberration tests with V79 Chinese Hamster Cells as expected for a proteinous substances like Simulect.”
Genotox: in vitro mammalian
Chromosomal aberration test in V79 Chinese hamster cells negative
“Negative results have been obtained in the Ames test and in chromosomal aberration tests with V79 Chinese Hamster Cells as expected for a proteinous substances like Simulect.”
Genotox: in vivo
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.
Carcinogenicity model
Not conducted; acceptable for a monoclonal antibody
“The mutagenic/oncogenic potential has not been investigated which is acceptable for a monoclonal antibody.”
Carcinogenicity timing
Not required for a monoclonal antibody
“The mutagenic/oncogenic potential has not been investigated which is acceptable for a monoclonal antibody.”
hERG / QT
No hERG assay; no electrocardiographic findings in repeat-dose rhesus monkey study
“No drug-related effects on body weight, no clinical or hematological findings, ophalmoscopic or electrocardiographic findings.”
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 Simulect 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: No toxic effects up to the maximum dose of 5 mg/kg in rhesus monkeys; no target organs identified (EMA assessment report, p. 6)
NOAEL / key findings
No toxic effects up to the maximum dose of 5 mg/kg in rhesus monkeys; no target organs identified
“the results of several repeated dose toxicity studies in Rhesus monkeys indicated no toxic effects up to the maximum dose of 5mg/kg.”
Risksopen answer page →
Immune & cytokine safety
Anti-idiotype antibodies in 75% of low-dose monkeys after four weeks, increasing clearance; offspring immunotoxicity not studied
“Increased clearance occurred in the low dose group corresponding to the occurrence of anti-idiotypic antibodies in 75% of the animals of this group after four weeks of administration.”
Biodistribution & persistence
Human tissue binding specific to CD25-expressing cells, mostly in lymphoid organs
“Binding studies of Simulect with standard tissues of human origin indicate specificity for cells expressing CD25 which mostly exist within lymphoid organs.”
Modality-specific risk
Fetal immune development risk from IL-2 receptor blockade and placental IgG transfer
“Because IgG molecules are known to cross the placental barrier, because the IL-2 receptor may play an important role in development of the immune system, and because animal reproduction studies are not always predictive of human response”
Anti-drug antibodies: animals
Anti-idiotypic antibodies in 75% of low-dose monkeys after four weeks, with increased clearance
“Increased clearance occurred in the low dose group corresponding to the occurrence of anti-idiotypic antibodies in 75% of the animals of this group after four weeks of administration.”
Anti-drug antibodies: patients
Anti-chimeric antibodies in 1 of 270 patients; anti-mouse antibodies in 6 of 172 (4 also received OKT3)
“The immunogenicity of Simulect is low, only 1 of 270 tested patients developed anti-chimeric antibodies. Six of 172 patients developed anti-mouse antibodies, whereas 4 of them also received OKT3 in addition to Simulect.”
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 Simulect 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: No toxic effects up to the maximum dose of 5 mg/kg in rhesus monkeys; no target organs identified (EMA assessment report, p. 6)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
4-week IV rhesus monkey study (0.5 to 4.5 mg/kg every 4th day); recovery phase not stated
“Repeated dose toxicity study has been performed in monkeys (4 weeks intravenous in the rhesus monkey with an 8 week treatment, doses at 0.5 to 4.5 mg/kg every 4th day).”
Pivotal GLP studies
4-week IV rhesus monkey study, 0.5 to 4.5 mg/kg every 4th day; plus cynomolgus embryo-fetal study
“Repeated dose toxicity study has been performed in monkeys (4 weeks intravenous in the rhesus monkey with an 8 week treatment, doses at 0.5 to 4.5 mg/kg every 4th day).”
DART package
Species: DART
Cynomolgus monkey (embryo-fetal development); no fertility studies
“No maternal toxicity, embryotoxicity, or teratogenicity was observed in cynomolgus monkeys 100 days post coitum following dosing with basiliximab during the organogenesis period; blood levels in pregnant monkeys were 13-fold higher than those seen in human patients.”
Reproductive & developmental
No fertility studies; cynomolgus organogenesis study: no maternal toxicity, embryotoxicity or teratogenicity at 13-fold human exposure
“No maternal toxicity, embryotoxicity, or teratogenicity was observed in cynomolgus monkeys 100 days post coitum following dosing with basiliximab during the organogenesis period; blood levels in pregnant monkeys were 13-fold higher than those seen in human patients.”
PPND / ePPND: when
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.
Carcinogenicity
Species: carcinogenicity
Not conducted
“No long-term or fertility studies in laboratory animals have been performed to evaluate the potential of Simulect to produce carcinogenicity or fertility impairment, respectively.”
Carcinogenicity model
Not conducted; acceptable for a monoclonal antibody
“The mutagenic/oncogenic potential has not been investigated which is acceptable for a monoclonal antibody.”
Carcinogenicity timing
Not required for a monoclonal antibody
“The mutagenic/oncogenic potential has not been investigated which is acceptable for a monoclonal antibody.”
Safety marginopen answer page →
Safety margin at NOAEL
Cynomolgus embryo-fetal study: no maternal toxicity or teratogenicity at blood levels 13-fold human
“No maternal toxicity, embryotoxicity, or teratogenicity was observed in cynomolgus monkeys 100 days post coitum following dosing with basiliximab during the organogenesis period; blood levels in pregnant monkeys were 13-fold higher than those seen in human patients.”
NOAEL / key findings
No toxic effects up to the maximum dose of 5 mg/kg in rhesus monkeys; no target organs identified
“the results of several repeated dose toxicity studies in Rhesus monkeys indicated no toxic effects up to the maximum dose of 5mg/kg.”
Efficacy evidenceopen answer page →
Efficacy evidence
In vitro IL-2 binding blockade on T-lymphocytes (human/primate cells) and human tissue binding; no in vivo model
“Receptor blocking profiles of Simulect and its murine progenitor RFT5 were comparable; they demonstrate equal potency in their ability to inhibit the binding of radiolabelled IL-2 on the IL-2 receptor expressed on T-lymphocytes.”
Why that model
Binds primate IL-2 receptor α-chain but not dog IL-2 receptor
“Simulect bound specifically to the α-chain of the primate IL-2-receptor, but not to the dog IL-2 receptor.”
Reviewer's view of the efficacy data
IL-2 binding and lymphocyte proliferation completely inhibited at clinically achieved concentrations
“The binding of IL-2 and consequentially lymphocyte proliferation are completely inhibited at concentrations achieved in the clinical setting, thus indicating the successful grafting and expression of the variable regions of the heavy and light chain.”
Flexibilityopen answer page →
Flexibility accepted
DARTVerdict not stated
Monkey embryo-fetal study without immunotoxicology assessment of the offspring
“Immunotoxicology studies have not been performed in the offspring.”
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