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.”
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.”
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.”