Ebglyss
lebrikizumab
Species
Monkey
Longest study
39 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
“Thus, cynomolgus monkeys were selected as a single pharmacologically relevant species for use in nonclinical studies with lebrikizumab.”
Why that species
Binds human and cynomolgus monkey IL-13 with pM affinity; no binding to mouse or rat IL-13
“Lebrikizumab binds with pM affinity to IL-13 of human and cynomolgus monkey, but not IL-13 of mouse or rat.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkey
“No surrogates were developed and used in lebrikizumab nonclinical studies.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“Safety pharmacology parameters were included in the 6- and 39-week intravenous and/or 13-week subcutaneous repeat-dose toxicology studies in cynomolgus monkeys.”
Pivotal GLP studies
GLP cynomolgus monkey repeat-dose studies of 6 weeks, 13 weeks and 9 months
“GLP-compliant repeat-dose studies of 6 weeks, 13 weeks and 9 months in duration were conducted in cynomolgus monkeys to evaluate the toxicity and TK of lebrikizumab.”
Route in tox
IV and SC
“Monkeys of different ages and maturity (1 to 4.5 years) were used, and IV and SC routes of administration were evaluated.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“Genetic toxicology studies are not applicable to monoclonal antibodies and were not conducted with lebrikizumab based on ICH S6 guidance.”
Carcinogenicity
Not conducted; weight-of-evidence (literature, no proliferative lesions or immunosuppression in 9-month monkey study) indicates low potential
“There was no evidence of tissue proliferation (i.e., hyperplasia, pre-neoplastic lesions) or immunosuppression in the 9-month intravenous toxicology study in cynomolgus monkeys that received lebrikizumab doses up to 25 mg/kg/week. The overall data suggest that lebrikizumab has low carcinogenic potential.”
Reproductive & developmental
Monkey EFD and PPND: no adverse effects; NOAEL 150/50 mg/kg/week (loading/maintenance); crossed placenta
“No embryofetal toxicity or malformations, or test article related effects on morphological, functional, or immunological development were observed in the infants from birth through 6 months of age. The NOAEL for maternal and developmental toxicity was 150/50 mg/kg/week (loading/maintenance doses).”
Safety pharmacology
Incorporated into repeat-dose monkey studies; no cardiovascular, respiratory or behavioral effects up to 25 mg/kg/week
“Repeated administration of lebrikizumab up to 25 mg/kg/week IV or SC had no adverse effects on the evaluated parameters for cardiovascular, respiratory or behavioral effects.”
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 Ebglyss 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: NOAEL = highest dose: 22.7 mg/kg/week (6-week IV), 25 mg/kg/week (9-month IV and 13-week SC) (FDA multi-discipline review, p. 50)
NOAEL / key findings
NOAEL = highest dose: 22.7 mg/kg/week (6-week IV), 25 mg/kg/week (9-month IV and 13-week SC)
“The NOAEL for lebrikizumab in cynomolgus monkeys was the highest dose tested in all three studies, i.e., 22.7 mg/kg/week in the 6-week intravenous toxicology study and 25 mg/kg/week in the 9-month intravenous toxicology study and 13-week subcutaneous toxicology study.”
Risksopen answer page →
Immune & cytokine safety
Low-level ADA in several monkeys without appreciable impact on exposure
“Several animals had low levels of anti-drug antibodies (ADA) with no appreciable impact on exposure.”
Biodistribution & persistence
No specific TCR staining in any human or cynomolgus monkey tissue
“No specific lebrikizumab staining was observed in any human or cynomolgus monkey tissues.”
Modality-specific risk
Conjunctivitis and keratitis seen clinically with IL-13 inhibition; not reproduced in healthy monkeys
“Conjunctivitis and keratitis were reported more frequently in patients treated with lebrikizumab (8.5 % and 0.6% respectively) compared to placebo in controlled clinical studies. Ophthalmological examinations did not suggest any ocular effects in long-term repeat-dose toxicity studies in healthy cynomolgus monkeys.”