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.”
Species: general tox
Cynomolgus monkey only: 6-week, 13-week and 9-month GLP repeat-dose studies
“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.”
Species: DART
Cynomolgus monkey (fertility, EFD and PPND)
“Toxicology program consisted of single and repeat-dose toxicity studies, fertility and embryofetal (EFD) development and pre- and postnatal development (PPND) studies in cynomolgus monkeys”
Species: carcinogenicity
Not conducted (weight-of-evidence assessment)
“Carcinogenicity risk assessment was done by weight of evidence approach and no studies were conducted.”
Surrogate used in
No surrogate used
“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.”
Genotox: Ames
Not conducted (ICH S6)
“Genetic toxicology studies are not applicable to monoclonal antibodies and were not conducted with lebrikizumab based on ICH S6 guidance.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Genetic toxicology studies are not applicable to monoclonal antibodies and were not conducted with lebrikizumab based on ICH S6 guidance.”
Genotox: in vivo
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 model
Not conducted; weight of evidence indicates low carcinogenic potential
“The overall data suggest that lebrikizumab has low carcinogenic potential. Further studies to assess carcinogenic risk are considered unwarranted.”
Carcinogenicity timing
Not required: further carcinogenicity studies considered unwarranted (weight of evidence)
“The overall data suggest that lebrikizumab has low carcinogenic potential. Further studies to assess carcinogenic risk are considered unwarranted.”
hERG / QT
No hERG inhibition up to 6.0 mg/mL in vitro; IC50 not determinable
“No inhibitory effects on the hERG ion channel current were observed compared to vehicle control at doses up to 6.0 mg/mL in this in vitro hERG assay. An IC50 value could not be determined.”
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
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: 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.”
Anti-drug antibodies: animals
Variable treatment-emergent ADA in monkeys, reducing lebrikizumab concentrations in some animals
“Lebrikizumab produced variable incidences of treatment-emergent ADA across studies; presence of ADA was associated with reduced serum concentrations of lebrikizumab in some animals.”
Anti-drug antibodies: patients
ADA in 4/145 (2.8%) of EBGLYSS-treated subjects over 12 months; most neutralizing, low titer
“Antibodies to lebrikizumab-lbkz developed in 4/145 (2.8%) of subjects treated with EBGLYSS 250 mg every 2 weeks followed by 250 mg every four weeks during the 12-month treatment period in EBGLYSS studies. Most of these antibodies were neutralizing and of low titers.”
Label warnings
- Hypersensitivity
- Conjunctivitis and Keratitis
- Parasitic (Helminth) Infections
- Vaccinations
Hypersensitivity & infusion reactionsOcular toxicityInfections
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 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
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: 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month IV cynomolgus monkey studies; the female toxicity and cycling study had an 8-month recovery
“A 9-month toxicity and cycling evaluation study of MILR1444A (IV) administered by intravenous injection to sexually mature female Cynomolgus monkeys, with an 8-month recovery period/ 07-1706”
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.”
DART package
Species: DART
Cynomolgus monkey (fertility, EFD and PPND)
“Toxicology program consisted of single and repeat-dose toxicity studies, fertility and embryofetal (EFD) development and pre- and postnatal development (PPND) studies in cynomolgus monkeys”
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).”
PPND / ePPND: when
PPND in cynomolgus monkey (dosing GD 42 to parturition) completed before the marketing application
“In a PPND study, pregnant cynomolgus monkeys received subcutaneous doses of lebrikizumab during organogenesis to parturition (gestation day {GD} 168) at 45 or 150 mg/kg initial loading dose followed by 15 or 50 mg/kg/week from GD 42 to GD 168”
Carcinogenicity
Species: carcinogenicity
Not conducted (weight-of-evidence assessment)
“Carcinogenicity risk assessment was done by weight of evidence approach and no studies were conducted.”
Carcinogenicity model
Not conducted; weight of evidence indicates low carcinogenic potential
“The overall data suggest that lebrikizumab has low carcinogenic potential. Further studies to assess carcinogenic risk are considered unwarranted.”
Carcinogenicity timing
Not required: further carcinogenicity studies considered unwarranted (weight of evidence)
“The overall data suggest that lebrikizumab has low carcinogenic potential. Further studies to assess carcinogenic risk are considered unwarranted.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey IV 25 mg/kg/week for 37 weeks (no fertility effects): Cavg,ss ~15x human exposure at MRHD
“No effects on fertility parameters such as reproductive organs, reproductive hormones or menstrual cycle length were observed in sexually mature female cynomolgus monkeys that were administered intravenous doses of lebrikizumab-lbkz up to 25 mg/kg/week for 37 weeks, which was associated with plasma exposure (C avg,ss ) approximately 15 times the human exposure at the MRHD.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human IL-13-induced airway inflammation in C57BL/6 mice (lebrikizumab reduced inflammatory reactions)
“In an in vivo C57BL/6 mouse airway inflammation model, lebrikizumab reduced human IL-13-induced inflammatory reactions;”
Why that model
No binding to rodent IL-13 limits rodent studies; airway model shares IL-13/STAT6 signalling with AD
“Nevertheless, this issue is not pursued further as the AD and airway inflammation model share some similarities regarding the IL-13 / STAT6 signalling routes, and lack of binding to rodent target limits further the studies in rodents.”
Reviewer's view of the efficacy data
EMA: pharmacology program condensed but adequate to show IL-13 binding specificity and principal mode of action
“The nonclinical pharmacology program of lebrikizumab is condensed but is considered adequate demonstrating the binding specificity to target IL-13 and principal mode of action.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies for a chronic atopic dermatitis indication; weight-of-evidence risk assessment instead
Why: Overall data suggest low carcinogenic potential · Weight of evidence
“The Applicant used weight-of-evidence - based approach to assess the carcinogenicity risk of lebrikizumab.”
“The overall data suggest that lebrikizumab has low carcinogenic potential. Further studies to assess carcinogenic risk are considered unwarranted.”
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