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:”
Species: general tox
Cynomolgus monkey (4-week and 6-month IV GLP studies)
“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.”
Species: DART
Cynomolgus monkey (combined maternal, fetal and neonatal study)
“In a reproductive toxicity study in cynomolgus monkeys combining maternal, fetal and neonatal toxicity evaluations, belimumab was administered intravenously to a total of 45 pregnant female monkeys at a dose of either 5 mg/kg (25 animals) or 150 mg/kg (20 animals); twenty-one control animals received vehicle formulation only.”
Species: carcinogenicity
Not conducted
“Long-term animal studies have not been performed to evaluate the carcinogenic potential of belimumab.”
Surrogate used in
No surrogate used; all toxicology with belimumab in cynomolgus monkey
“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.”
Genotox: Ames
Not conducted (ICH S6)
“No genotoxicity studies were conducted. Belimumab is a monoclonal antibody and is not expected to interact directly with DNA or other chromosomal material.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“No genotoxicity studies were conducted. Belimumab is a monoclonal antibody and is not expected to interact directly with DNA or other chromosomal material.”
Genotox: in vivo
Not conducted (ICH S6)
“No genotoxicity studies were conducted. Belimumab is a monoclonal antibody and is not expected to interact directly with DNA or other chromosomal material.”
Carcinogenicity model
Not conducted
“No carcinogenicity studies have been conducted with belimumab.”
Carcinogenicity timing
Waived: 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.”
hERG / QT
Not conducted: no dedicated safety pharmacology; assessments included in three GLP monkey studies
“No specific safety pharmacology studies were conducted due to the high specificity of belimumab for its target. In accordance with the Guideline CHMP/ICH/539/00, the Applicant included safety pharmacology assessments in three GLP studies in cynomolgus monkeys.”
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
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: 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.”
Anti-drug antibodies: animals
ADA in 12 of 124 monkeys across studies; 6 had reduced belimumab serum concentrations
“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.”
Anti-drug antibodies: patients
0.7% (4/563) at 10 mg/kg and 4.8% (27/559) at 1 mg/kg IV in SLE trials
“In Trials 2 and 3 (intravenous dosing in adults with active SLE), anti‑belimumab antibodies were assessed during the respective 52‑week and 76‑week, placebo‑controlled periods and detected in 4 of 563 (0.7%) subjects receiving BENLYSTA 10 mg/kg and in 27 of 559 (4.8%) subjects receiving BENLYSTA 1 mg/kg.”
Label warnings
- Serious Infections
- Hypersensitivity Reactions, including Anaphylaxis
- Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
- Depression and Suicidality
- Malignancy
- Immunization
- Concomitant Use with Other Biologic Therapies
InfectionsHypersensitivity & infusion reactionsSkin reactionsPsychiatricSecondary malignancy
US prescribing information, 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 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
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: Few noteworthy findings beyond pharmacological B-cell effects; low potential for toxicity (EMA assessment report, p. 19)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
6-month (26-week) GLP cynomolgus monkey (IV) study with a recovery period
“In the 6 months study anti-belimumab antibodies were detected in one low dose and one high dose monkey at Weeks 13 and 26, respectively, with reversal by week 52 during the recovery period”
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.”
DART package
Species: DART
Cynomolgus monkey (combined maternal, fetal and neonatal study)
“In a reproductive toxicity study in cynomolgus monkeys combining maternal, fetal and neonatal toxicity evaluations, belimumab was administered intravenously to a total of 45 pregnant female monkeys at a dose of either 5 mg/kg (25 animals) or 150 mg/kg (20 animals); twenty-one control animals received vehicle formulation only.”
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”
PPND / ePPND: when
Combined embryo-fetal/pre- and postnatal study in cynomolgus monkey: included in the BLA submission
“Your embryo-fetal development/postnatal development study does not appear to have functional characterization of the impact of your product on the developing immune system.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Long-term animal studies have not been performed to evaluate the carcinogenic potential of belimumab.”
Carcinogenicity model
Not conducted
“No carcinogenicity studies have been conducted with belimumab.”
Carcinogenicity timing
Waived: 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.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 4-week high dose: 12x human AUC, 5x Cmax
“The highest dose used in the 4 week study provided an exposure margin of 5 with regard to Cmax and 12 with regard to AUC.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
B-cell reduction and inhibited splenocyte proliferation in normal mice and monkeys; no disease model
“The in vivo studies in mice as well as in monkeys demonstrated that belimumab inhibits splenocyte proliferation and decreased the number of B-cells in spleen, lymph node and circulating B cells.”
Why that model
10-fold lower affinity for mouse BLyS and strong ADA with anaphylactoid deaths on repeat dosing in mice
“Although belimumab binds mouse BLyS, it does so with a 10-fold lower affinity for murine BLyS compared with belimumab binding to human or cynomolgus monkey BLyS. Moreover, multiple injections of belimumab in mice led to a strong anti-drug antibody response that altered the PK and in some cases led to death by an anaphylactoid–like response.”
Reviewer's view of the efficacy data
CHMP: expected reduction of peripheral and lymphoid B cells in monkeys without associated toxicological findings
“Intravenous and subcutaneous administration to monkeys resulted in the expected reduction in the number of peripheral and lymphoid tissue B cell counts with no associated toxicological findings.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity study for a chronic autoimmune indication; malignancy risk deferred to a clinical post-marketing safety study
Why: Rodent studies limited by anti-drug antibodies; malignancy risk can only be evaluated clinically · Pharmacology or kinetics · Human data
“A traditional rodent carcinogenicity study would be limited due to rapid formation of anti-drug-antibodies to both belimumab and a homologous hamster anti-mouse BLyS antibody.”
“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.”
DARTVerdict not stated
No fertility and early embryonic development study; reproductive organs assessed in the 6-month monkey study
Why: No adverse effects on reproductive organs in the 6-month monkey study
“No specific studies on the effects of belimumab on fertility and early embryonic development were conducted. The reproductive organ/tissues were assessed in the 6 months repeat dose toxicology study and there were no indications that belimumab had an adverse effect on reproductive organs.”
DARTQuestioned
Monkey embryo-fetal/postnatal study lacked functional assessment of the developing immune system
“Your embryo-fetal development/postnatal development study does not appear to have functional characterization of the impact of your product on the developing immune system. Exposure to this product during development can alter the offspring's immune system.”
Safety pharmacologyAccepted
No stand-alone safety pharmacology studies; assessments included in three GLP monkey toxicity studies
Why: High target specificity; no abnormalities in the monkey studies · Within the guideline · Pharmacology or kinetics
“No specific safety pharmacology studies were conducted due to the high specificity of belimumab for its target. In accordance with the Guideline CHMP/ICH/539/00, the Applicant included safety pharmacology assessments in three GLP studies in cynomolgus monkeys.”
“Therefore, the Applicant’s justification for not performing a specific safety pharmacology study was considered acceptable.”
Similar precedents
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