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.”
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.”
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 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: 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”