Cibinqo
abrocitinib
Species
MonkeyRat
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 cynomolgus monkey
“Oral repeat dose toxicity studies in rats (up to 6 months in duration); oral repeat dose toxicity studies in monkeys (up to 9 months in duration)”
Why that species
Used previously for other JAK inhibitors and sensitive to the pharmacology of JAK inhibition
“rats and monkeys were used for the general toxicology programme, as these species have previously been used in development programmes for other similar JAK inhibitors and they are sensitive to the pharmacological action of JAK inhibition.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In a pivotal 6-month oral repeat dose toxicity study in rats, abrocitinib (doses: 0, 30, 45, and 70 mg/kg/day) decreased lymphocytes at all dose levels consistent with its intended pharmacological effect.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month monkey)
“In a pivotal 39-week oral repeat dose toxicity study in monkeys, abrocitinib (doses: 0, 15, 35, and 75 mg/kg/day) decreased lymphocytes at all dose levels consistent with its intended pharmacological effect, but had no adverse effects.”
Pivotal GLP studies
6-month rat and 9-month cynomolgus monkey oral studies
“Oral repeat dose toxicity studies in rats (up to 6 months in duration); oral repeat dose toxicity studies in monkeys (up to 9 months in duration)”
Route in tox
Oral (gavage)
“A 9-Month Oral Gavage Toxicity and Toxicokinetic Study of PF-04965842 in Cynomolgus Monkeys with a 12-Week Recovery Phase”
Skipped studiesopen answer page →
Genotoxicity
Ames negative; aneugenic in in vitro micronucleus assay; negative in vivo rat micronucleus
“Abrocitinib was not mutagenic in an in vitro reverse bacterial mutation assay. Abrocitinib was positive in an in vitro micronucleus assay and determined to be an aneugen in a follow-up study; however, it was not genotoxic in an in vivo micronucleus assay in rats.”
Carcinogenicity
Rat: benign thymoma in females at ≥10 mg/kg/day; no tumors in males
“At doses ≥10 mg/kg/day, abrocitinib significantly increased the incidence of benign thymoma in the thymus of female rats. No abrocitinib-related tumor findings were noted in males.”
Reproductive & developmental
Rat EFD: skeletal variations at ≥30 mg/kg/day and embryofetal lethality at the high dose
“Abrocitinib increased the incidence of skeletal variations at doses ≥30 mg/kg/day, including the incidence of short 13th ribs, thickened ribs (HD only), and cervical arches with reduced ventral processes (HD only). Abrocitinib increased embryofetal lethality at the HD.”
Safety pharmacology
No clinically relevant hERG (IC50 95 µM) or Nav1.5 inhibition in vitro
“In vitro, abrocitinib did not produce clinically relevant inhibition of the hERG potassium current or the Nav1.5 sodium current. Up to 300 µM abrocitinib produced 78% inhibition of the hERG current (IC50: 95 µM) and 31% inhibition of the Nav1.5 current.”
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 Cibinqo 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: Rat NOAEL 30 mg/kg/day; reversible, dose-related urinary crystals at ≥45 mg/kg/day (FDA multi-discipline review, p. 39)
NOAEL / key findings
Rat NOAEL 30 mg/kg/day; reversible, dose-related urinary crystals at ≥45 mg/kg/day
“Abrocitinib produced reversible, dose-related urinary crystals at doses ≥45 mg/kg/day. The NOAEL was 30 mg/kg/day, which corresponds to Day 182 AUC24 and Cmax of 58500 ng·hr/mL and 9110 ng/mL, respectively.”
Risksopen answer page →
Immune & cytokine safety
Monkey KLH assay: dose-related reduction in IgG and IgM from 15 mg/kg/day, with partial recovery
“A KLH study was performed in monkeys from the 9-month study. Abrocitinib exposure gave reduced IgG and IgM values (with dose relation) from 15mg/kg/day with partial recovery.”
Biodistribution & persistence
Low CNS penetration (brain:plasma AUC ratio <0.1)
“The brain:plasma AUClast ratio was <0.1, indicating that the passage over blood-brain barrier was low.”
Modality-specific risk
Immunosuppression and thymoma in female rats at low exposure margins
“Immunosuppression is a clear risk-factor for tumour development, especially spontaneous tumours (like thymomas). However, thymomas were evident in females already from the lowest dose, with low margins of exposure to human exposure.”