| Patent / Application | Type | Assignee | Filed | Expiry (~) | |
|---|---|---|---|---|---|
| WO 2007/058338 A1 (US 7,919,617 B2; EP 1,953,148 B1; JP 4,975,757 B2) | Composition of matter (originator) | Otsuka Pharmaceutical Co., Ltd. | 2006-11-16 (priority 2005-11-15, JP 2005-330289) | ~Nov 2026 nominal (US 7,919,617 expiry ~2026-2027 absent PTE); PTE filing window opens at FDA approval (2026-02-12) — up to 5 yr PTE possible → effective LoE 2028–2031 | |
| WO 2010/041680 A1 / JP 5,628,114 B2 | Crystal form / polymorph (originator) | Otsuka Pharmaceutical Co., Ltd. | 2009-10-07 (priority JP 2008-263071) | ~Oct 2029 nominal | |
| WO 2017/170219 / JP 6,832,946 B2 | Topical formulation | Otsuka Pharmaceutical Co., Ltd. | ~2017 | ~2037 nominal | |
| Process patent(s) — Otsuka | Process | Otsuka Pharmaceutical Co., Ltd. | ~2008–2015 | ~2028–2035 | |
| [Acrotech / Medimetriks licensing-related filings] | License / territory | Acrotech Biopharma Inc (US); Medimetriks Pharmaceuticals (prior US rights holder for atopic dermatitis) | — | — |
Compiled: 2026-05-23 · Trigger event: FDA approval, 2026-02-12 Innovator: Acrotech Biopharma Inc (US licensee; originator Otsuka Pharmaceutical Co., Ltd., Japan — OPA-15406 / MM-36) Status: Approved NME
Mechanism: Topical PDE4 (cAMP-specific phosphodiesterase 4) inhibitor with preferential PDE4B binding (ChEMBL CHEMBL2093863); inhibits cAMP hydrolysis in keratinocytes and T-cells → reduces pro-inflammatory cytokine release (TNF-α, IL-4, IL-5, IL-13). PMID 27189825 + 30386231
Synthesis Route of the Originator
Convergent synthesis disclosed in Otsuka WO 2007/058338 (Example 5). Eastern fragment is a 4-(difluoromethoxy)-3-isopropoxybenzamide (INT-2) that condenses with 1,3-dichloroacetone under Robinson-Gabriel conditions to give the 2-aryl-4-(chloromethyl)-1,3-oxazole (INT-3); azide displacement then Staudinger reduction (or hydrogenolysis) installs the 4-(aminomethyl) handle (INT-5). Final amide coupling of INT-5 with 2-ethoxybenzoyl chloride (or 2-ethoxybenzoic acid + HATU/EDC) delivers difamilast. Aryl SM (3,4-disubstituted benzonitrile/benzamide) is built from vanillin-class catechol via selective O-isopropylation then O-difluoromethylation of the residual phenol (ClCF₂H, base) — both transformations are commodity-scale.
Key intermediates
Crystal Forms, Salts, and Solid-State Profile
- API in approved drug product: free base (anhydrous, white-to-off-white crystalline solid; per ADQUEY label)
- Strengths approved: 1% ointment (10 mg difamilast / g; topical, BID dosing)
- Third-party polymorph activity: No US-filed third-party polymorph activity identified as of 2026-05-23 — atypical given imminent NCE clock; monitor SureChEMBL and Espacenet quarterly
- Originator polymorph filing: WO 2010/041680 / JP 5,628,114 (Otsuka) — claims specific anhydrous Form I and a hydrate; Orange Book listing pending FDA approval-stage publication
Key peer-reviewed literature
- Rakib MA et al., Trends Pharmacol Sci 2026 — Topical difamilast for the treatment of mild-to-moderate atopic dermatitis(PMID 41956916)
- Maekawa M et al., Cureus 2026 — Genetically Confirmed Localized Perianal Hailey-Hailey Disease Successfully Treated…(PMID 42158788)
- — et al., Am J Health Syst Pharm 2026 — Difamilast (PMID 41967473)
- Ran GL et al., Adv Skin Wound Care 2026 — Phosphodiesterase 4 Inhibitor Use in Pediatric Patients With Atopic Dermatitis: A… (PMID 41860296)
- Kitakaze K et al., J Dermatol 2026 — Difamilast Ointment, a Topical PDE4 Inhibitor, for Pediatric Cheilitis Granulomatosa:…(PMID 41589051)
- Zhang L et al., Eur J Clin Pharmacol 2026 — Efficacy and safety of treatments for atopic dermatitis: a model based meta-analysis… (PMID 41618061)
- Saeki H et al., Dermatol Ther (Heidelb) 2026 — A Phase 3, Long-Term, Open-Label Study of Difamilast Ointment to Evaluate Efficacy and… (PMID 41171590)
- Tsuji G et al., J Dermatol Sci 2025 — Difamilast induces human beta defensin 3 production via CREB and NRF2 in human keratinocytes (PMID 40783345)
- Nitulescu G et al., Curr Issues Mol Biol 2025 — Targeting Intracellular Pathways in Atopic Dermatitis with Small Molecule Therapeutics (PMID 40864813)
- Yamamoto-Hanada K et al., Clin Exp Allergy 2025 — DIFENSE Study Protocol: Early Intervention With Difamilast Ointment in Infantile… (PMID 40139221)