Anzupgo
delgocitinib
Species
RatMouseDogPig
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog (oral); minipig and mouse (dermal)
“repeat-dose toxicity studies in mice (dermal; 3 months), rats (oral; up to 6 months), dogs (oral; up to 9 months), and minipigs (dermal; up to 9 months)”
Why that species
Comparable inhibitory effect in human, mouse and rat T cells
“Comparison of human, mouse and rat T cells demonstrated a comparable inhibitory effect across all species, supporting the in vivo species selection.”
Surrogate molecule
No surrogate; the clinical compound was tested
“No treatment-related changes were observed in a 9-month dermal toxicity study in minipigs treated with delgocitinib ointment.”
Species: general tox
Mouse (dermal), rat (oral), dog (oral) and minipig (dermal)
“repeat-dose toxicity studies in mice (dermal; 3 months), rats (oral; up to 6 months), dogs (oral; up to 9 months), and minipigs (dermal; up to 9 months)”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Reproductive and developmental toxicology studies included fertility and early embryonic development studies in male and female rats, embryo-fetal development studies in rats and rabbits, and a pre- and postnatal development study in rats.”
Species: carcinogenicity
Mouse (104-week dermal) and rat (2-year oral)
“In the dermal carcinogenicity study in mice, delgocitinib ointment (1%, 3% and 5%) was administered once daily for 104 weeks. No drug-related neoplastic findings were noted at topical doses up to 5% delgocitinib ointment. In the 2-year oral carcinogenicity study in rats, increased incidence of benign thymoma was noted in females at 30 mg/kg/day”
Surrogate used in
No surrogate used; delgocitinib tested directly
“No treatment-related changes were observed in a 9-month dermal toxicity study in minipigs treated with delgocitinib ointment.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month oral dog and dermal minipig)
“repeat-dose toxicity studies in mice (dermal; 3 months), rats (oral; up to 6 months), dogs (oral; up to 9 months), and minipigs (dermal; up to 9 months)”
Pivotal GLP studies
6-month oral rat, 9-month oral dog and 9-month dermal minipig studies; 3-month dermal mouse
“repeat-dose toxicity studies in mice (dermal; 3 months), rats (oral; up to 6 months), dogs (oral; up to 9 months), and minipigs (dermal; up to 9 months)”
Route in tox
Oral (rats, dogs) and dermal (minipigs, mice)
“repeat-dose toxicity studies in mice (dermal; 3 months), rats (oral; up to 6 months), dogs (oral; up to 9 months), and minipigs (dermal; up to 9 months)”
Skipped studiesopen answer page →
Genotoxicity
Ames negative; polyploidy in human lymphocytes in vitro; negative in vivo rat bone marrow chromosome aberration assay
“Delgocitinib was not mutagenic in the Ames assay. Delgocitinib had the potential to induce polyploidy in human peripheral blood lymphocytes, but not chromosomal structural aberrations in vitro. Delgocitinib did not induce chromosomal aberrations (structural or numerical aberrations) in rat bone marrow cells in vivo.”
Carcinogenicity
Dermal mouse: no drug-related tumors; 2-year oral rat: benign thymoma in females at 30 mg/kg/day
“No drug-related neoplastic findings were noted at topical doses up to 5% delgocitinib ointment. In the 2-year oral carcinogenicity study in rats, increased incidence of benign thymoma was noted in females at 30 mg/kg/day”
Reproductive & developmental
Adverse effects only at higher doses in all reproductive studies; NOAELs established with acceptable margins
“Adverse effects were seen at higher doses in each of the reproductive and developmental toxicology studies, but a NOAEL was established in each study with acceptable margins of exposures.”
Safety pharmacology
No cardiovascular, respiratory or neurological effects; no remarkable hERG inhibition at clinically relevant concentrations
“Delgocitinib had no effects on cardiovascular, respiratory, or neurological parameters at clinically relevant doses. Delgocitinib had no remarkable inhibitory effect on the human ether-à-go-go-related gene (hERG) current at clinically relevant concentrations.”
Genotox: Ames
Negative
“Delgocitinib was not mutagenic in the Ames assay. Delgocitinib had the potential to induce polyploidy in human peripheral blood lymphocytes, but not chromosomal structural aberrations in vitro.”
Genotox: in vitro mammalian
Human lymphocyte chromosomal aberration: polyploidy induced, no structural aberrations
“Delgocitinib was not mutagenic in the Ames assay. Delgocitinib had the potential to induce polyploidy in human peripheral blood lymphocytes, but not chromosomal structural aberrations in vitro.”
Genotox: in vivo
Rat bone marrow chromosomal aberration and hairless mouse skin micronucleus: negative
“Delgocitinib did not induce chromosomal aberrations (structural or numerical aberrations) in rat bone marrow cells in vivo. Delgocitinib ointment (5%) did not induce micronuclei in the epidermal cells of hairless mice.”
Carcinogenicity model
104-week dermal mouse (negative); 2-year oral rat (benign thymoma in females at 30 mg/kg/day)
“In the dermal carcinogenicity study in mice, delgocitinib ointment (1%, 3% and 5%) was administered once daily for 104 weeks. No drug-related neoplastic findings were noted at topical doses up to 5% delgocitinib ointment. In the 2-year oral carcinogenicity study in rats, increased incidence of benign thymoma was noted in females at 30 mg/kg/day”
Carcinogenicity timing
104-week dermal mouse and 2-year oral rat studies completed
“In the dermal carcinogenicity study in mice, delgocitinib ointment (1%, 3% and 5%) was administered once daily for 104 weeks. No drug-related neoplastic findings were noted at topical doses up to 5% delgocitinib ointment. In the 2-year oral carcinogenicity study in rats, increased incidence of benign thymoma was noted in females at 30 mg/kg/day”
hERG / QT
No remarkable hERG inhibition at clinically relevant concentrations; no cardiovascular effects
“Delgocitinib had no effects on cardiovascular, respiratory, or neurological parameters at clinically relevant doses. Delgocitinib had no remarkable inhibitory effect on the human ether-à-go-go-related gene (hERG) current at clinically relevant concentrations.”
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 Anzupgo 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 small molecules 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: 9-month dermal minipig NOAEL 5% (20 mg/kg/day, max feasible); 9-month oral dog NOAEL 0.6 mg/kg/day, skin lesions at 3.0 mg/kg/day (FDA integrated review, p. 77)
NOAEL / key findings
9-month dermal minipig NOAEL 5% (20 mg/kg/day, max feasible); 9-month oral dog NOAEL 0.6 mg/kg/day, skin lesions at 3.0 mg/kg/day
“The no-observed-adverse-effect level (NOAEL) was 5% (20 mg/kg/day) delgocitinib ointment, the maximum feasible dose. Skin lesions were observed in a 9-month oral toxicity study in dogs at 3.0 mg/kg/day and the dose was lowered to 1.5 mg/kg/day from Week 24. The NOAEL was 0.6 mg/kg/day.”
Risksopen answer page →
Immune & cytokine safety
Immunotoxic in a 4-week oral rat study, an expected immunosuppressive effect
“Delgocitinib was immunotoxic in a 4-week oral dose study in rats; however, this is an expected effect because of the pharmacological/immunosuppressive nature of delgocitinib.”
Biodistribution & persistence
Binding to melanin-containing tissues (skin, eyes) in dogs
“Distribution study in dogs with 14C-delgocitinib indicated binding of radioactivity to melanin-containing tissues including skin and eyeballs.”
Modality-specific risk
JAK-mediated immunosuppression, only partly assessable in animals; relevance of oral studies to topical use
“The relevance of oral studies for the topical formulation was initially questioned. The potential adverse effects of pharmacological JAK-inhibitory action on immune response in laboratory animals (housed in clean environment) could be assessed to a limited degree.”
Anti-drug antibodies: animals
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.
Anti-drug antibodies: patients
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.
Label warnings
- Serious Infections
- Non-melanoma Skin Cancers
- Immunizations
- Potential Risks Related to JAK Inhibition
InfectionsSecondary malignancySkin reactions
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 Anzupgo 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 small molecules 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: 9-month dermal minipig NOAEL 5% (20 mg/kg/day, max feasible); 9-month oral dog NOAEL 0.6 mg/kg/day, skin lesions at 3.0 mg/kg/day (FDA integrated review, p. 77)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month oral dog study with 3-month (13-week) recovery
“In nine-month oral dose toxicity study with a three-month recovery period the highest dose level of 3.0 mg/kg was reduced to 1.5 mg/kg from week 24 of the dosing period due to serious skin lesions and dosing was withdrawn from week 26 (week 1 of the recovery period) to investigate the reversibility of any toxicity during a 13-week recovery period.”
Pivotal GLP studies
6-month oral rat, 9-month oral dog and 9-month dermal minipig studies; 3-month dermal mouse
“repeat-dose toxicity studies in mice (dermal; 3 months), rats (oral; up to 6 months), dogs (oral; up to 9 months), and minipigs (dermal; up to 9 months)”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Reproductive and developmental toxicology studies included fertility and early embryonic development studies in male and female rats, embryo-fetal development studies in rats and rabbits, and a pre- and postnatal development study in rats.”
Reproductive & developmental
Adverse effects only at higher doses in all reproductive studies; NOAELs established with acceptable margins
“Adverse effects were seen at higher doses in each of the reproductive and developmental toxicology studies, but a NOAEL was established in each study with acceptable margins of exposures.”
PPND / ePPND: when
PPND in rat completed before the marketing application
“A pre- and postnatal development study was conducted in rats.”
Carcinogenicity
Species: carcinogenicity
Mouse (104-week dermal) and rat (2-year oral)
“In the dermal carcinogenicity study in mice, delgocitinib ointment (1%, 3% and 5%) was administered once daily for 104 weeks. No drug-related neoplastic findings were noted at topical doses up to 5% delgocitinib ointment. In the 2-year oral carcinogenicity study in rats, increased incidence of benign thymoma was noted in females at 30 mg/kg/day”
Carcinogenicity model
104-week dermal mouse (negative); 2-year oral rat (benign thymoma in females at 30 mg/kg/day)
“In the dermal carcinogenicity study in mice, delgocitinib ointment (1%, 3% and 5%) was administered once daily for 104 weeks. No drug-related neoplastic findings were noted at topical doses up to 5% delgocitinib ointment. In the 2-year oral carcinogenicity study in rats, increased incidence of benign thymoma was noted in females at 30 mg/kg/day”
Carcinogenicity timing
104-week dermal mouse and 2-year oral rat studies completed
“In the dermal carcinogenicity study in mice, delgocitinib ointment (1%, 3% and 5%) was administered once daily for 104 weeks. No drug-related neoplastic findings were noted at topical doses up to 5% delgocitinib ointment. In the 2-year oral carcinogenicity study in rats, increased incidence of benign thymoma was noted in females at 30 mg/kg/day”
Safety marginopen answer page →
Safety margin at NOAEL
Dermal minipig: no toxicity up to 20 mg/kg/day, 20x (male) and 11x (female) human exposure
“In dermal studies, in which no toxicity was observed up to 20 mg/kg/day of delgocitinib in minipigs [20 (M) and 11 (F)-fold higher exposure than human exposure], NOAEL was not identified.”
NOAEL / key findings
9-month dermal minipig NOAEL 5% (20 mg/kg/day, max feasible); 9-month oral dog NOAEL 0.6 mg/kg/day, skin lesions at 3.0 mg/kg/day
“The no-observed-adverse-effect level (NOAEL) was 5% (20 mg/kg/day) delgocitinib ointment, the maximum feasible dose. Skin lesions were observed in a 9-month oral toxicity study in dogs at 3.0 mg/kg/day and the dose was lowered to 1.5 mg/kg/day from Week 24. The NOAEL was 0.6 mg/kg/day.”
Efficacy evidenceopen answer page →
Efficacy evidence
Rat DNCB-induced dermatitis model (topical): dose-dependent suppression of ear swelling
“The topical administration of delgocitinib ointment for three weeks in the ears of rat skin inflammation model (DNCB-induced dermatitis) showed dose-dependent suppression of ear swelling (male rats).”
Why that model
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.
Reviewer's view of the efficacy data
EMA: proof of concept for topical use in CHE demonstrated; animal models fit for purpose
“The mode of action (JAK inhibition) of delgocitinib is a well-known strategy in the treatment of inflammatory diseases and the studies demonstrated the proof of concept of the use of topical delgocitinib in CHE. The selected animal models were fit for purpose in the PD assessment of topical delgocitinib.”
Flexibilityopen answer page →
Flexibility accepted
Safety pharmacologyAcceptedBeyond the letter
No toxicokinetics in safety pharmacology studies; margins derived from repeat-dose study exposures
Why: Identical dosing in rat and dog studies; resulting margins exceed 1000-fold clinical exposure · Pharmacology or kinetics
“As the TK analysis was not included in the safety pharmacology studies, the safety margins have been calculated based on the exposure measured in the repeat-dose toxicity studies.”
“An uncertainty is associated with this approach, however, as the dosing was identical in these rat and dog studies and the resulting safety margins for expected human clinical exposure are > 1000, this approach is acceptable to the CHMP.”
Efficacy modelAcceptedBeyond the letter
In vivo topical pharmacology studies used ointment, not the commercial cream formulation
Why: Formulation difference not considered to affect the in vivo pharmacodynamic assessment
“The formulation of topical delgocitinib used in the in vivo PD studies (ointment) differs from the suggested commercial formulation (cream). However, this is not considered to impact the assessment of in vivo PD of delgocitinib and the studies were considered acceptable.”
Safety marginQuestioned
Nonclinical exposure threshold (3 months at about 40 ng/mL) used to argue over 80-fold margin against systemic JAK-class risks
Why: Applicant: human exposure about 0.5 ng/mL; FDA: extrapolation may not predict human sensitivity to JAK inhibition
“Nonclinical studies showed that continuous exposure for at least 3 months at systemic levels around 40 ng/mL is needed before JAK inhibition-related adverse effects are observed. Human exposure of approximately 0.5 ng/mL provides a safety margin in excess of 80-fold.”
“Furthermore, the Applicant’s extrapolation from nonclinical data showing that 3 months of exposure at 40 ng/mL is needed for adverse effects may not accurately predict human sensitivity to JAK inhibition.”
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