Adbry
tralokinumab
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
“Therefore, cynomolgus monkey was selected as a single pharmacologically relevant species for use in nonclinical studies with tralokinumab.”
Why that species
95% IL-13 sequence homology with cynomolgus monkey versus 55-62% in rodents; no mouse cross-reactivity
“The IL-13 amino acid sequence homology between human and cynomolgus monkey is 95%, whereas that between human and rodent is 55% for mouse and 62% for rat. Tralokinumab did not cross-react with mouse IL-13.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkey
“Therefore, cynomolgus monkey was selected as a single pharmacologically relevant species for use in nonclinical studies with tralokinumab.”
Species: general tox
Cynomolgus monkey only (single pharmacologically relevant species)
“The toxicity studies have been performed in line with the requirements of ICH S6 (R1) using cynomolgus monkeys as the single species in which there is relevant pharmacological activity.”
Species: DART
Cynomolgus monkey (male and female fertility, pilot EFD, PPND and ePPND)
“reproductive and developmental toxicity studies in cynomolgus monkeys, including two fertility, one pilot embryofetal development, one prenatal and postnatal development study, and an enhanced prenatal and postnatal development (ePPND) study”
Species: carcinogenicity
Not conducted; rodent studies not possible (no activity against rodent IL-13)
“No carcinogenicity studies have been performed and considering the lack of activity against IL-13 of rodent origin, traditional rodent studies are not possible.”
Surrogate used in
No surrogate used; clinical antibody tested in cynomolgus monkey
“Therefore, cynomolgus monkey was selected as a single pharmacologically relevant species for use in nonclinical studies with tralokinumab.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“The no observed adverse effect level (NOAEL) for tralokinumab in cynomolgus monkeys was 90 mg/kg/week in the 13-week SC toxicology study and 100 mg/kg/week in the 26-week IV toxicology study.”
Pivotal GLP studies
Cynomolgus monkey 4-, 13- and 26-week weekly IV studies; 4- and 13-week weekly SC studies
“The repeat dose toxicity studies included 4-, 13- and 26-weeks studies with weekly IV dosing at levels up to 100 mg/kg and weekly SC injections of up to 350 mg/injection for 4- and 13-weeks.”
Route in tox
IV and SC
“Three IV and two SC repeat-dose toxicity studies were submitted.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“Genotoxicity No studies have been performed in accordance with ICH S6(R1).”
Carcinogenicity
Not conducted; weight-of-evidence assessment found no concern for increased carcinogenic risk
“In line with ICH S6 (R1), a weight of evidence approach has been provided which suggests that there are no identified concerns for increased carcinogenic risk with the use of tralokinumab.”
Reproductive & developmental
Monkey fertility, EFD, PPND and ePPND studies; ePPND: no embryofetal toxicity, malformations or infant developmental effects to 6 months
“No treatment-related adverse effects on embryofetal toxicity or malformations, or on morphological, functional, or immunological development were observed in the infants from birth to 6 months of age.”
Safety pharmacology
Incorporated into repeat-dose monkey studies; no cardiovascular, respiratory or behavioral effects up to 100 mg/kg/week
“Repeated administration of tralokinumab up to 100 mg/kg/week had no adverse effects on the evaluated parameters for cardiovascular, respiratory, and behavioral effects.”
Genotox: Ames
Not conducted (ICH S6)
“Genotoxicity and carcinogenicity studies were not conducted since they are not considered applicable and/or warranted.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Genotoxicity and carcinogenicity studies were not conducted since they are not considered applicable and/or warranted.”
Genotox: in vivo
Not conducted (ICH S6)
“Genotoxicity and carcinogenicity studies were not conducted since they are not considered applicable and/or warranted.”
Carcinogenicity model
Not conducted; no activity against rodent IL-13; weight-of-evidence assessment instead
“No carcinogenicity studies have been performed and considering the lack of activity against IL-13 of rodent origin, traditional rodent studies are not possible.”
Carcinogenicity timing
Not required: considered not applicable and/or warranted
“Genotoxicity and carcinogenicity studies were not conducted since they are not considered applicable and/or warranted.”
hERG / QT
No hERG; monkey repeat-dose ECG: no effects on heart rate, blood pressure, PR, QRS or QT
“No tralokinumab related effects were seen on heart rate, blood pressure or P-R, QRS and Q-T waves.”
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 Adbry 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 90 mg/kg/week (13-week SC) and 100 mg/kg/week (26-week IV); no adverse effects or target organs (FDA integrated review, p. 131)
NOAEL / key findings
NOAEL 90 mg/kg/week (13-week SC) and 100 mg/kg/week (26-week IV); no adverse effects or target organs
“The no observed adverse effect level (NOAEL) for tralokinumab in cynomolgus monkeys was 90 mg/kg/week in the 13-week SC toxicology study and 100 mg/kg/week in the 26-week IV toxicology study.”
Risksopen answer page →
Immune & cytokine safety
No significant modulation of CD4/CD8 T cells, NK cells or mature B cells in 26-week monkey study
“In addition, the 26-week study included an immunophenotyping assessment which indicated that tralokinumab did not significantly modulate any of the immune cell populations investigated which including CD4 and CD8 T cells, NK cells and mature B cells.”
Biodistribution & persistence
Placental transfer in monkeys, neonate serum levels comparable to or above maternal
“There was clear evidence of placental transfer in both studies with neonate serum levels measured comparable or even in excess of maternal levels.”
Modality-specific risk
Low circulating IL-13 in naive monkeys may mask pharmacological effects, limiting predictivity
“Whilst there were no apparent tralokinumab related effects in these studies, this could be explained by very low circulating IL-13 levels in naïve monkeys.”
Anti-drug antibodies: animals
ADA in few monkeys (including controls); not considered to affect exposure
“Anti-drug antibodies (ADAs) to tralokinumab were measured and in general were found in few animals, which also included control animals, and were not thought to have affected exposure levels.”
Anti-drug antibodies: patients
4.6% ADA across all trial periods; 0.9% persistent; 1.0% neutralizing
“Across all trial periods, the ADA incidence for subjects who received ADBRY was 4.6%; 0.9% had persistent ADA and 1.0% had neutralizing antibodies.”
Label warnings
- Hypersensitivity
- Conjunctivitis and Keratitis
- Parasitic (Helminth) Infections
- Risk of Infection with Live Vaccines
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 Adbry 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 90 mg/kg/week (13-week SC) and 100 mg/kg/week (26-week IV); no adverse effects or target organs (FDA integrated review, p. 131)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey IV study with 13-week treatment-free period
“CAT-354: 26-Week Intravenous Toxicity Study in Cynomolgus Monkeys With a 13-Week Treatment-Free Period (Study #CRL509615)”
Pivotal GLP studies
Cynomolgus monkey 4-, 13- and 26-week weekly IV studies; 4- and 13-week weekly SC studies
“The repeat dose toxicity studies included 4-, 13- and 26-weeks studies with weekly IV dosing at levels up to 100 mg/kg and weekly SC injections of up to 350 mg/injection for 4- and 13-weeks.”
DART package
Species: DART
Cynomolgus monkey (male and female fertility, pilot EFD, PPND and ePPND)
“reproductive and developmental toxicity studies in cynomolgus monkeys, including two fertility, one pilot embryofetal development, one prenatal and postnatal development study, and an enhanced prenatal and postnatal development (ePPND) study”
Reproductive & developmental
Monkey fertility, EFD, PPND and ePPND studies; ePPND: no embryofetal toxicity, malformations or infant developmental effects to 6 months
“No treatment-related adverse effects on embryofetal toxicity or malformations, or on morphological, functional, or immunological development were observed in the infants from birth to 6 months of age.”
PPND / ePPND: when
PPND and ePPND in cynomolgus monkey (IV): final reports submitted with the marketing application
“The Applicant submitted final study reports for two subcutaneous fertility studies, an intravenous pilot embryo-fetal developmental study, an intravenous prenatal and postnatal development study and an intravenous ePPND study in cynomolgus monkeys.”
Carcinogenicity
Species: carcinogenicity
Not conducted; rodent studies not possible (no activity against rodent IL-13)
“No carcinogenicity studies have been performed and considering the lack of activity against IL-13 of rodent origin, traditional rodent studies are not possible.”
Carcinogenicity model
Not conducted; no activity against rodent IL-13; weight-of-evidence assessment instead
“No carcinogenicity studies have been performed and considering the lack of activity against IL-13 of rodent origin, traditional rodent studies are not possible.”
Carcinogenicity timing
Not required: considered not applicable and/or warranted
“Genotoxicity and carcinogenicity studies were not conducted since they are not considered applicable and/or warranted.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 26-week IV NOAEL 100 mg/kg/week = 18x human AUC at MRHD (10x on mg/kg basis)
“The NOAEL of 100 mg/kg/week in the 26-week IV toxicology study is 10 times the MRHD based on a mg/kg of 10 mg/kg/week. The mean AUC0-168h values associated with the NOAEL are 694,805 and 677,731 µg hr/mL for males and females, respectively, which are 18 times the MRHD based on AUC comparison for males and females.”
NOAEL / key findings
NOAEL 90 mg/kg/week (13-week SC) and 100 mg/kg/week (26-week IV); no adverse effects or target organs
“The no observed adverse effect level (NOAEL) for tralokinumab in cynomolgus monkeys was 90 mg/kg/week in the 13-week SC toxicology study and 100 mg/kg/week in the 26-week IV toxicology study.”
Efficacy evidenceopen answer page →
Efficacy evidence
In vivo type-2 inflammation models (IL-13-induced mouse, monkey allergen challenge); no AD model; AD support from in vitro human skin cells
“The in vivo proof of principle experiments have been performed using models of type 2 immune responses mediated through signalling via IL-13. While some of the in vitro data suggest applicability of tralokinumab in treatment of AD, no relevant model of AD (e.g. ex vivo or in vitro human skin models) was presented in a proof of concept study.”
Why that model
Tralokinumab does not bind mouse IL-13, so mouse models required injected human IL-13 (weaker at mouse receptor)
“Several of the models were performed in mice whereas previously discussed the endogenous mouse IL-13 is not bound by tralokinumab. For these studies, injection of human recombinant IL-13 was used since it can bind the mouse IL-13 receptor and mediate signalling in this manner, however, the activity of human IL-13 at the mouse receptor is less than that of mouse IL-13 at the same receptor.”
Reviewer's view of the efficacy data
EMA: in vivo data limited and asthma-oriented, but give some limited evidence of modulating type-2 disease
“The in vivo experiments are limited and were likely designed with an indication for the treatment of asthma, which was originally one of the clinical indications pursued for tralokinumab. Nevertheless, they do provide some limited evidence that the use of tralokinumab can modulate several aspects of a disease associated with a type II immune response.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No 2-year carcinogenicity study for a chronic dermatology indication; literature weight-of-evidence assessment instead
Why: Executive Carcinogenicity Assessment Committee judged a 2-year study not needed, provided trial subjects are monitored for tumours · Weight of evidence
“The Applicant was advised that “A 2-year carcinogenicity study with tralokinumab is not needed. However, subjects enrolled in clinical trials with tralokinumab should be monitored for potential development of tumors” on 08/12/2011 under the IND.”
OtherAcceptedBeyond the letter
Subcutaneous (clinical route) toxicity limited to 13-week bridging study; 26-week chronic study used IV dosing
Why: Similar toxicity profiles after repeat-dose SC and IV administration · Pharmacology or kinetics
“It was determined that this 13-week subcutaneous toxicity study conducted with tralokinumab in cynomolgus monkeys provided an adequate bridge to the 13-week and 26-week intravenous toxicity studies conducted with tralokinumab in cynomolgus monkeys due to the similar toxicity profiles noted after repeat-dose SC versus IV administration.”
OtherCriticised but acceptedBeyond the letter
Earlier 4-week SC bridging study had no control group and used males only
Why: Supplemented by a 13-week SC bridging study conducted at the Agency's recommendation
“The 4-week SC study did have an increased incidence and severity of liver and kidney fat staining, however, there were significant deficiencies in this bridging study since no control groups were utilised and the study was only performed using male animals.”
“The Applicant subsequently conducted a 13-week bridging subcutaneous toxicity in cynomolgus monkey as per the recommendation of the Agency.”
Juvenile toxAcceptedBeyond the letter
No dedicated juvenile toxicity study; ePPND study in monkeys used to assess toxicity in juvenile animals
Why: ePPND study judged adequate and supports treatment of paediatric subjects · Other reason
“An adequate ePPND study in cynomolgus monkeys was conducted with tralokinumab to evaluate the potential toxicity in juvenile animals.”
“The results from this ePPND study support treatment of pediatric subjects with tralokinumab.”
Similar precedents
EbglyssAntibodies · lebrikizumab · IL-13Monkey only · 39 wkBenlystaAntibodies · belimumab · BLyS (BAFF)Monkey only · 26 wkBimzelxAntibodies · bimekizumab · IL-17A/IL-17FMonkey only · 26 wkCimziaAntibodies · certolizumab pegol · TNF-αMonkey only · 52 wkCosentyxAntibodies · secukinumab · IL-17AMonkey only · 26 wkHumiraAntibodies · adalimumab · TNF-αMonkey only · 39 wk