Adquey (difamilast): what was done before first-in-human, and what came after?

US: single and multiple ascending dose study in healthy adults (Source: FDA multi-discipline review, p. 68.)

Precedia/Small molecules/Adquey/Tox package

Adquey: what was done before first-in-human, and what came after?

difamilast · PDE4 (topical)

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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)”

✓ VerifiedFDA multi-discipline review, p. 68Source ↗

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.”

✓ VerifiedFDA 2005: Estimating the Maximum Safe Starting Dose in Initial Clinical…, p. 7Source ↗

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)

Full method, every step sourced →

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”

✓ VerifiedFDA multi-discipline review, p. 39Source ↗

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”

✓ VerifiedFDA multi-discipline review, p. 39Source ↗

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.”

✓ VerifiedFDA multi-discipline review, p. 39Source ↗

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.”

✓ VerifiedFDA multi-discipline review, p. 40Source ↗

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.”

✓ VerifiedFDA multi-discipline review, p. 39Source ↗

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).”

✓ VerifiedFDA multi-discipline review, p. 40Source ↗

Carcinogenicity model

2-year dermal rat and 2-year dermal mouse; no drug-related neoplasms

✓ VerifiedFDA multi-discipline review, p. 40Source ↗

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.”

✓ VerifiedFDA multi-discipline review, p. 54Source ↗

Summary across all 211 small molecules →

Adquey: what was done before first-in-human, and what came after?

Before first-in-human

Longest repeat-dose systemic studies

DART package

Carcinogenicity

Same question, other small molecules