Benlysta
belimumab
Species
Monkey
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
“The non-clinical toxicology program supporting belimumab development has been performed exclusively in the cynomolgus monkey (Macaca fascicularis) based on the following reasons:”
Why that species
Monkey and human BLyS share 96.4% (full-length) and 98% (soluble) identity
“The cynomolgus monkey was considered as the most relevant species in nonclinical studies since the monkey and human BLyS share 96.4% amino acid identity across the full length protein and 98% amino acid identity in the cleaved soluble portion of BLyS”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys
“The non-clinical toxicology program supporting belimumab development has been performed exclusively in the cynomolgus monkey (Macaca fascicularis) based on the following reasons:”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“The toxicology of repeat IV administration of belimumab was assessed in two GLP toxicology studies in cynomolgus monkeys of 4 weeks and 6 months duration, respectively.”
Pivotal GLP studies
GLP IV cynomolgus monkey studies of 4 weeks and 6 months
“The toxicology of repeat IV administration of belimumab was assessed in two GLP toxicology studies in cynomolgus monkeys of 4 weeks and 6 months duration, respectively.”
Route in tox
IV (plus SC local tolerance and immunogenicity studies)
“A local tolerance study of subcutaneously administered belimumab in cynomolgus monkey was conducted to support clinical studies evaluating the SC route of administration of belimumab.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted; not required for a monoclonal antibody
“No genotoxicity studies were conducted. Belimumab is a monoclonal antibody and is not expected to interact directly with DNA or other chromosomal material.”
Carcinogenicity
Not conducted; malignancy risk to be evaluated clinically in a post-marketing safety study
“CHMP concurred with the Applicant’s argumentation that the potential risk for malignancy with belimumab can only be evaluated in a clinical setting; the proposal for a clinical post-marketing safety study was supported.”
Reproductive & developmental
Monkey combined EFD/PPND: no maternal toxicity, embryofetal/infant survival effects or malformations at 9-fold MRHD exposure
“There was no evidence of maternal toxicity, effects on embryofetal and infant survival, or structural abnormalities at exposure approximately 9 times the MRHD of 10 mg/kg intravenously or 20 times the MRHD of 200 mg subcutaneously”
Safety pharmacology
Incorporated into three GLP monkey studies; no abnormalities attributable to belimumab
“In accordance with the Guideline CHMP/ICH/539/00, the Applicant included safety pharmacology assessments in three GLP studies in cynomolgus monkeys. In each of these studies, belimumab was generally safe and well tolerated and no abnormalities were attributable to belimumab.”
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 Benlysta 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: Few noteworthy findings beyond pharmacological B-cell effects; low potential for toxicity (EMA assessment report, p. 19)
NOAEL / key findings
Few noteworthy findings beyond pharmacological B-cell effects; low potential for toxicity
“Aside from effects associated with the pharmacological activity of belimumab, there were few noteworthy findings in the toxicology studies indicating a low potential for toxicity.”
Risksopen answer page →
Immune & cytokine safety
ADA in 12 of 124 monkeys (6 with reduced exposure)
“In summary, across all studies, detectable, treatment emergent anti-belimumab antibodies have been identified in 12 out of 124 monkeys. Of these, 6 monkeys had reduced belimumab serum concentrations.”
Biodistribution & persistence
No specific binding in human tissue cross-reactivity study
“No specific staining of the human tissues by the belimumab antibody was identified at any concentration.”
Modality-specific risk
Infection and malignancy risk from B-cell suppression; not increased in long-term monkey studies
“Long-term toxicology studies in cynomolgus monkeys do not indicate an increased risk of infection or malignancy with belimumab.”