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.”
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.”
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.”