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.”
Species: general tox
Rat (up to 6 months) and monkey (up to 9 months); oral
“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)”
Species: DART
Rat (fertility, EFD, pre/postnatal, juvenile) and rabbit (EFD)
“fertility and early embryonic development studies in rats; embryofetal development studies in rats and rabbits; a pre- and postnatal development study in rats; and a juvenile animal toxicity study in rats.”
Species: carcinogenicity
Rat (104-week) and Tg rasH2 mouse (6-month)
“Carcinogenicity studies were conducted in mice (6-month study in Tg rasH2 mice) and rats (104-week study).”
Surrogate used in
No surrogate used; abrocitinib tested in rats and monkeys, species sensitive to JAK inhibition
“According to the applicant, 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.”
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.”
Genotox: Ames
Negative
“Abrocitinib was not mutagenic in the bacterial mutagenicity assay (Ames assay).”
Genotox: in vitro mammalian
In vitro TK6 micronucleus: positive (aneugenic)
“Although abrocitinib was aneugenic in the in vitro TK6 micronucleus assay, abrocitinib was not aneugenic or clastogenic in an in vivo rat bone marrow micronucleus assay.”
Genotox: in vivo
Rat bone marrow micronucleus: negative (not aneugenic or clastogenic)
“Although abrocitinib was aneugenic in the in vitro TK6 micronucleus assay, abrocitinib was not aneugenic or clastogenic in an in vivo rat bone marrow micronucleus assay.”
Carcinogenicity model
104-week rat (benign thymomas in females); 6-month Tg rasH2 mouse (negative)
“Carcinogenicity studies were conducted in mice (6-month study in Tg rasH2 mice) and rats (104-week study).”
Carcinogenicity timing
104-week rat and 6-month Tg rasH2 mouse studies completed before the marketing application
“Carcinogenicity studies were conducted in mice (6-month study in Tg rasH2 mice) and rats (104-week study).”
hERG / QT
hERG IC50 95 µM; no clinically relevant inhibition
“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.”
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
No clinical immunogenicity studies conducted
“No clinical studies in immunogenicity were conducted in the atopic dermatitis program.”
Label warnings
Boxed warning: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, and THROMBOSIS
- Serious Infections
- Mortality
- Malignancy and Lymphoproliferative Disorders
- Major Adverse Cardiovascular Events
- Thrombosis
- Hypoglycemia in Patients with Diabetes
- Laboratory Abnormalities
- Immunizations
Thrombosis & embolismInfectionsCardiovascularSecondary malignancyMetabolic & endocrine
US prescribing information, Boxed Warning and 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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month oral cynomolgus monkey study with 12-week recovery
“Study title/ number: A 9-Month Oral Gavage Toxicity and Toxicokinetic Study of PF-04965842 in Cynomolgus Monkeys with a 12-Week Recovery Phase / 13MA055”
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)”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal, juvenile) and rabbit (EFD)
“fertility and early embryonic development studies in rats; embryofetal development studies in rats and rabbits; a pre- and postnatal development study in rats; and a juvenile animal toxicity study in rats.”
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.”
PPND / ePPND: when
Rat PPND completed before the marketing application
“In an oral pre- and postnatal development study in rats, abrocitinib (doses: 0, 10, 30, and 60 mg/kg/day) caused a high rate of total litter loss and markedly decreased F1 survival at 60 mg/kg/day”
Carcinogenicity
Species: carcinogenicity
Rat (104-week) and Tg rasH2 mouse (6-month)
“Carcinogenicity studies were conducted in mice (6-month study in Tg rasH2 mice) and rats (104-week study).”
Carcinogenicity model
104-week rat (benign thymomas in females); 6-month Tg rasH2 mouse (negative)
“Carcinogenicity studies were conducted in mice (6-month study in Tg rasH2 mice) and rats (104-week study).”
Carcinogenicity timing
104-week rat and 6-month Tg rasH2 mouse studies completed before the marketing application
“Carcinogenicity studies were conducted in mice (6-month study in Tg rasH2 mice) and rats (104-week study).”
Safety marginopen answer page →
Safety margin at NOAEL
Rat EFD: NOAEL 2.3x (skeletal effects) and 10x (embryo-fetal lethality) human AUC at 200 mg
“The margins of exposure at the NOAEL of 30 mg/kg/day for embryo-fetal lethality and at the NOAEL of 10 mg/kg/day for skeletal effects to the clinical exposure at 200 mg in terms of total AUC are presented in SmPC section 5.3 as 10 and 2.3-fold, respectively.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Adjuvant-induced arthritis rat model (paw swelling; ex vivo STAT phosphorylation)
“Abrocitinib treatment resulted in a dose dependent inhibition of paw swelling (disease severity) in the rats after seven days of treatment which was significant for the dose levels between 5-50 mg/kg.”
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
CHMP: pharmacological activity proven in the AIA rat (reduced paw swelling, STAT phosphorylation inhibition)
“Pharmacological activity has been proven in a study on adjuvant induced arthritis (AIA) rat, symptomatically by dose dependent reduction of paw swelling and functionally by inhibition of STAT phosphorylation in ex vivo samples.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesCriticised but acceptedBeyond the letter
Cynomolgus monkey used as non-rodent species without initial cross-reactivity data; CHMP questioned its pharmacological relevance
Why: Monkey previously used for tofacitinib; builds on prior experience and data from other JAK inhibitors · Class precedent
“Indeed, the pharmacological relevance of the monkey was therefore questionable, as no cross-reactivity studies with abrocitinib had been presented.”
“Overall, given the historical context and the possibility to build on previous experience and data from other JAK inhibitors, the use of monkey in the development programme was considered sufficiently justified by CHMP.”
Juvenile toxQuestioned
No NOAEL in the juvenile rat study: bone malformations and fractures at all doses; mechanism unexplained
“Because adverse bone findings were noted at all dose levels, a NOAEL could not be established.”
“Thus, there is a remaining uncertainty regarding the developmental bone effects, which should receive further clinical attention.”
GenotoxicityAcceptedBeyond the letter
Positive (aneugenic) in vitro micronucleus assay accepted on a negative in vivo rat micronucleus assay
Why: Negative in vivo micronucleus; no genotoxic risk at the clinical dose of 200 mg QD · Weight of evidence
“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.”
“Collectively, the genotoxicity studies presented do not indicate a genotoxic risk for abrocitinib at the proposed clinical dose of 200 mg QD.”
Safety marginAccepted with a conditionBeyond the letter
No margin for rat thymoma: benign thymomas in females from the lowest dose, at low exposure margins
Why: Human relevance unclear; thymoma data included in SmPC section 5.3 · Other reason
“However, thymomas were evident in females already from the lowest dose, with low margins of exposure to human exposure.”
“Nevertheless, given the unclear human relevance of the thymoma findings, the applicant included data in section 5.3 of the SmPC.”
Impurity or metaboliteVerdict not stated
Mutagenic impurity PF-07216658 controlled by a benchmark-modelled PDE of 1.36 μg/kg/day (170 ppm)
“Based on benchmark modelling, a PDE which was established at 1.36 μg/kg/day corresponding to a concentration limit of 170 ppm.”
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