Adquey
difamilast
Sources:FDA multi-discipline review ↗
Species
RatDogPig
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, dog and minipig
“Pivotal repeat-dose toxicity studies were conducted in rats (dermal), dogs (subcutaneous), and minipigs (dermal).”
Why that species
Dog the most appropriate species for coverage of the major human metabolites
“The dog is the most appropriate animal species for the major metabolites.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In nonclinical studies, OPA-15406 and OPC-271 were used as codenames for difamilast.”
Species: general tox
Rat (dermal), dog (subcutaneous) and minipig (dermal)
“Pivotal repeat-dose toxicity studies were conducted in rats (dermal), dogs (subcutaneous), and minipigs (dermal).”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“a fertility and early embryonic development study in rats, two embryofetal development studies in rats and rabbits, a prenatal and postnatal development study in rats, and two juvenile animal toxicity studies in rats.”
Species: carcinogenicity
Rat and mouse (2-year dermal)
“In 2-year dermal carcinogenicity studies in rats and mice, no test article-related neoplastic findings were observed in rats or mice that received difamilast at dermal doses up to 3% (3.7 to 10 times the MRHD based on AUC comparison).”
Surrogate used in
No surrogate used; difamilast (OPA-15406/OPC-271) tested directly
“In nonclinical studies, OPA-15406 and OPC-271 were used as codenames for difamilast.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog and minipig)
“repeat-dose subcutaneous (SC) toxicity studies with treatment durations up to 39 weeks in dogs, dermal toxicity studies with treatment durations up to 26 weeks in rats and 39 weeks in minipigs”
Pivotal GLP studies
26-week dermal rat, 39-week subcutaneous dog and 39-week dermal minipig studies
“repeat-dose subcutaneous (SC) toxicity studies with treatment durations up to 39 weeks in dogs, dermal toxicity studies with treatment durations up to 26 weeks in rats and 39 weeks in minipigs”
Route in tox
Dermal (rat, minipig) and subcutaneous (dog)
“Pivotal repeat-dose toxicity studies were conducted in rats (dermal), dogs (subcutaneous), and minipigs (dermal).”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, mouse lymphoma and rat micronucleus assays
“Difamilast was negative in a standard battery of genotoxicity tests, including the Ames test, the mouse lymphoma assay, and an in vivo micronucleus study in rats.”
Carcinogenicity
2-year dermal rat and mouse: no drug-related tumors (3.7-10x MRHD AUC)
“In 2-year dermal carcinogenicity studies in rats and mice, no test article-related neoplastic findings were observed in rats or mice that received difamilast at dermal doses up to 3% (3.7 to 10 times the MRHD based on AUC comparison).”
Reproductive & developmental
Rat EFD at 100 mg/kg/day: fewer live fetuses, lower fetal weight, retarded ossification, ventricular septum defects
“In embryofetal development studies, fewer live fetuses, decreased fetal weight, retarded ossification, and increased membranous ventricular septum defect were noted in rats at the high dose of 100 mg/kg/day.”
Safety pharmacology
No CNS (rat) or cardiovascular/respiratory (dog) effects at single SC doses; hERG IC50 2.54 µM
“There were no significant effects on the central nervous system (CNS) in rats at single SC doses up to 200 mg/kg or cardiovascular or respiratory parameters in conscious dogs at single SC doses up to 30 mg/kg. In an in vitro human Ether-à-go-go Related Gene (hERG) assay, the half-maximal inhibitor concentration (IC50) value for the inhibition on hERG K+ current was 2.54 μM.”
Genotox: Ames
Negative
“Difamilast was negative in a standard battery of genotoxicity tests, including the Ames test, the mouse lymphoma assay, and an in vivo micronucleus study in rats.”
Genotox: in vitro mammalian
Mouse lymphoma assay: negative
“Difamilast was negative in a standard battery of genotoxicity tests, including the Ames test, the mouse lymphoma assay, and an in vivo micronucleus study in rats.”
Genotox: in vivo
Rat micronucleus: negative
“Difamilast was negative in a standard battery of genotoxicity tests, including the Ames test, the mouse lymphoma assay, and an in vivo micronucleus study in rats.”
Carcinogenicity model
2-year dermal rat and 2-year dermal mouse; no drug-related neoplasms
“In 2-year dermal carcinogenicity studies in rats and mice, no test article-related neoplastic findings were observed in rats or mice that received difamilast at dermal doses up to 3% (3.7 to 10 times the MRHD based on AUC comparison).”
Carcinogenicity timing
2-year dermal rat and 2-year dermal mouse completed; reviewed by ECAC before approval
“These two 2-year dermal carcinogenicity studies have been reviewed by the ECAC. The Committee concluded that the studies were adequate and there was no evidence of drug-related neoplasms in either study.”
hERG / QT
hERG margin 7,931-fold; no QTc prolongation in dog at 98x clinical Cmax
“The difamilast nonclinical package demonstrated a large hERG safety margin (7,931-fold) and no QTc prolongation in the in vivo dog study at exposures 98x the clinical Cmax.”
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 Adquey 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: No significant systemic or dermal toxicity; only decreased body weight gain in 26-week dermal rat study (FDA multi-discipline review, p. 49)
NOAEL / key findings
No significant systemic or dermal toxicity; only decreased body weight gain in 26-week dermal rat study
“There were no significant systemic or dermal toxicities noted in these studies, except a decrease in body weight gain observed in a 26-week dermal toxicity study in rats.”
Risksopen answer page →
Immune & cytokine safety
No skin sensitisation potential in guinea pigs
“OPA-15406 ointments did not show skin sensitization potential in guinea pigs under the study conditions.”
Biodistribution & persistence
Crosses the placenta in rats (fetal tissue levels above maternal blood)
“Tissue concentrations of radioactivity in the fetus and in fetal blood, liver, kidney, and lung were higher than maternal blood, indicating 14C-OPA-15406-dependent radioactivity crosses the placental barrier.”
Modality-specific risk
Major human metabolites (MIST): three major metabolites covered by pivotal toxicology studies
“There are three major human metabolites: MAP-15484, MAP-15485 and MAP-15497. Overall, these three major metabolites were well covered with the pivotal nonclinical toxicology studies.”
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.
Tox packageopen answer page →
Before first-in-human
First-in-human: where
US: single and multiple ascending dose study in healthy adults
“271-11-202 Phase 1, FIH, DB, PC, SAD/MAD study Healthy U.S. adults (48)”
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 Adquey 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: No significant systemic or dermal toxicity; only decreased body weight gain in 26-week dermal rat study (FDA multi-discipline review, p. 49)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week subcutaneous dog and 39-week dermal minipig studies; recovery phase not stated
“repeat-dose subcutaneous (SC) toxicity studies with treatment durations up to 39 weeks in dogs, dermal toxicity studies with treatment durations up to 26 weeks in rats and 39 weeks in minipigs”
Pivotal GLP studies
26-week dermal rat, 39-week subcutaneous dog and 39-week dermal minipig studies
“repeat-dose subcutaneous (SC) toxicity studies with treatment durations up to 39 weeks in dogs, dermal toxicity studies with treatment durations up to 26 weeks in rats and 39 weeks in minipigs”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“a fertility and early embryonic development study in rats, two embryofetal development studies in rats and rabbits, a prenatal and postnatal development study in rats, and two juvenile animal toxicity studies in rats.”
Reproductive & developmental
Rat EFD at 100 mg/kg/day: fewer live fetuses, lower fetal weight, retarded ossification, ventricular septum defects
“In embryofetal development studies, fewer live fetuses, decreased fetal weight, retarded ossification, and increased membranous ventricular septum defect were noted in rats at the high dose of 100 mg/kg/day.”
PPND / ePPND: when
PPND in rat completed and reviewed in the NDA
“two embryofetal development studies in rats and rabbits, a prenatal and postnatal development study in rats, and two juvenile animal toxicity studies in rats.”
Carcinogenicity
Species: carcinogenicity
Rat and mouse (2-year dermal)
“In 2-year dermal carcinogenicity studies in rats and mice, no test article-related neoplastic findings were observed in rats or mice that received difamilast at dermal doses up to 3% (3.7 to 10 times the MRHD based on AUC comparison).”
Carcinogenicity model
2-year dermal rat and 2-year dermal mouse; no drug-related neoplasms
“In 2-year dermal carcinogenicity studies in rats and mice, no test article-related neoplastic findings were observed in rats or mice that received difamilast at dermal doses up to 3% (3.7 to 10 times the MRHD based on AUC comparison).”
Carcinogenicity timing
2-year dermal rat and 2-year dermal mouse completed; reviewed by ECAC before approval
“These two 2-year dermal carcinogenicity studies have been reviewed by the ECAC. The Committee concluded that the studies were adequate and there was no evidence of drug-related neoplasms in either study.”
Safety marginopen answer page →
Safety margin at NOAEL
Dog 39-week SC NOAEL 36x (male) and 23x (female) MRHD by AUC
“The no-observed-adverse-effect level (NOAEL) was the high dose of 3 mg/kg/day for both males and females (36 times the maximum recommended human dose (MRHD) for males and 23 times the MRHD for females, respectively, based on area under the plasma concentration-time curve [AUC] comparison).”
NOAEL / key findings
No significant systemic or dermal toxicity; only decreased body weight gain in 26-week dermal rat study
“There were no significant systemic or dermal toxicities noted in these studies, except a decrease in body weight gain observed in a 26-week dermal toxicity study in rats.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse model of chronic contact dermatitis; in vitro PDE-4 inhibition and cytokine suppression in inflammatory cells
“Difamilast inhibits the activity of PDE-4 in in vitro studies, e.g., increasing intracellular cAMP levels in inflammatory cells and inhibiting/suppressing the productions of various cytokines and chemokines. Difamilast showed efficacy in a mouse model of chronic contact dermatitis.”
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
FDA: approvable from a pharmacology/toxicology perspective; no nonclinical PMC/PMR
“This NDA is approvable from a Pharmacology/Toxicology perspective. There is no recommended nonclinical postmarketing commitment (PMC)/postmarketing requirement (PMR) for this NDA.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
39-week dermal minipig NOAEL at the maximum feasible dose gave only 0.38x (males) and 0.30x (females) MRHD by AUC
“In a 39-week dermal minipig toxicity study, the NOAEL was the maximum feasible dose (MFD), 3% ointment applied to 10% of BSA, for both males (8.1 mg/kg/day) and females (8.3 mg/kg/day) based on no systemic or local toxicity at the MFD (0.38 times the MRHD for males and 0.30 times the MRHD for females, respectively, based on AUC comparison).”
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