FDA Approved · February 2026
PDE-4 Inhibitor · Dermatology · Atopic Dermatitis
Difamilast
ADQUEY™ · Acrotech Biopharma Inc.
A selective topical phosphodiesterase-4 (PDE-4) inhibitor — the first new molecular entity in its class approved for topical use in mild to moderate atopic dermatitis in adults and pediatric patients ≥2 years of age. Originally developed in Japan by Otsuka Pharmaceutical, ADQUEY was approved in the United States in February 2026 under NDA 219474 based on two pivotal Phase 3 trials conducted in Japan.
Drug Overview
Indication
Mild to Moderate AD
Adults & pediatric patients ≥2 years
Mechanism
PDE-4 Inhibitor
Topical, new molecular entity
Approved Dose
1% BID
Topical ointment, thin layer
Japan Approval
Sep 2021
Marketed as Moizerto® Ointment
Mechanism of Action
Difamilast is an inhibitor of phosphodiesterase-4 (PDE-4), a major cyclic adenosine monophosphate (cyclic AMP)-metabolizing enzyme. Inhibition of PDE-4 leads to intracellular accumulation of cyclic AMP, which in turn decreases production of various cytokines and chemokines involved in the inflammatory cascade underlying atopic dermatitis. The specific mechanism(s) by which difamilast exerts its therapeutic action in AD is not fully defined.
In atopic dermatitis, disrupted skin barrier function leads to allergen sensitization and dysregulated Th2-predominant immune responses. PDE-4 inhibition attenuates these responses by reducing cAMP degradation in immune cells, downregulating pro-inflammatory mediator production. Difamilast demonstrated efficacy in a mouse model of chronic contact dermatitis.
Competitive Landscape
| Drug | Target | Formulation | Approval | Population |
|---|---|---|---|---|
| Crisaborole (EUCRISA) | PDE-4 Inhibitor | 2% ointment | Dec 2016 | ≥2 years, mild-moderate AD |
| Roflumilast (ZORYVE) | PDE-4 Inhibitor | 0.05%/0.15% cream; 0.3% foam | Jul 2022 / 2023 | ≥2 years (cream), ≥6 years (foam) |
| Tacrolimus (PROTOPIC) | Calcineurin Inhibitor | 0.03%/0.1% ointment | Dec 2000 | ≥2 years; moderate-severe AD |
| Pimecrolimus (ELIDEL) | Calcineurin Inhibitor | 1% cream | Dec 2001 | ≥2 years, mild-moderate AD |
| Difamilast (ADQUEY) ▶ | PDE-4 Inhibitor | 1% ointment | Feb 2026 | ≥2 years, mild-moderate AD |
Key Drug Information
| Parameter | Detail |
|---|---|
| Proprietary Name | ADQUEY™ |
| INN / Generic Name | Difamilast |
| Code Names | OPA-15406 · OPC-271 · MM36 · Moizerto® (Japan) |
| Manufacturer | Acrotech Biopharma Inc., East Windsor, NJ 08520 USA (Made in Canada) |
| Pharmacologic Class | Phosphodiesterase 4 (PDE-4) Inhibitor |
| Dosage Forms | Ointment 1% (white to off-white) · 27 g tube · 85 g tube |
| NDC | 72893-017-08 (27 g) · 72893-017-09 (85 g) |
| Storage | 20°C–25°C; excursions to 15°C–30°C; store away from direct sunlight and moisture |
| Inactive Ingredients | Mineral oil, paraffin, propylene carbonate, white petrolatum, white wax |
| Molecular Formula | C₂₃H₂₄F₂N₂O₅ · MW 446.44 g/mol |
| PI Revision Date | February 2026 |
Clinical Efficacy
Primary Endpoint
IGA Success
at Week 4
at Week 4
IGA 0 or 1, ≥2-grade improvement
Trial Design
RCT, DB, Vehicle-Ctrl
4-week treatment duration
Pivotal Trials (Ph3)
2
271-102-00007 & 271-102-00008 (Japan)
Total Subjects (Pivotal)
612
Phase 3 trials (all trials)
Phase 3 Primary Endpoint Results — IGA Success at Week 4
Trial 271-102-00007 (Trial 2) · Japan · Phase 3 Pivotal
Adults & adolescents ≥15 years · N=364 · 4-week treatment · IGA 2–3, BSA 5–40% (excl. scalp)
ADQUEY 1% BID (N=182)
38.5%
Vehicle (N=182)
12.6%
Trial 271-102-00008 (Trial 3) · Japan · Phase 3 Pivotal
Pediatric subjects 2–14 years · N=251 · 4-week treatment · IGA 2–3, BSA 5–40% (excl. scalp)
ADQUEY 1% BID (N=85)
47.1%
Difamilast 0.3% (N=83)
44.6%
Vehicle (N=83)
18.1%
Trial 271-12-205 (Trial 1) · USA / Australia / Poland · Phase 2 Multinational (Supportive)
Adults & adolescents ≥10 years · N=121 · 8-week treatment · IGA 2–3, BSA 5–40% (excl. face/neck)
ADQUEY 1% BID (N=43)
20.9%
Difamilast 0.3% (N=41)
14.6%
Vehicle (N=37)
2.7%
Trial MEDI-MM36-301 · United States · Phase 3 (Early Terminated)
Adults & pediatric patients ≥2 years · N=153 of 336 planned · Terminated early for “business reasons”
ADQUEY 1% BID (N=94)
11.7%
Vehicle (N=59)
11.9%
Early termination limits meaningful interpretation. FDA review concluded this does not preclude substantial evidence of effectiveness based on other completed trials.
IGA Success Rate Over Time — Phase 3 Pivotal Trials
Trial 271-102-00007 (Adults/Adolescents ≥15 yrs) — IGA Success % by Week
N=182 per arm · Primary endpoint: Week 4 · Digitized from FDA Medical Review Figure 13 (Ref ID: 5743278)
Source: FDA Multi-Disciplinary Review, NDA 219474 (Ref ID 5743278). Values digitized from Figure 13. Wk0=0 by definition (all subjects at baseline).
Trial 271-102-00008 (Pediatric 2–14 yrs) — IGA Success % by Week
N=85/83/83 · Three arms including Difamilast 0.3% · Digitized from FDA Medical Review Figure 14 (Ref ID: 5743278)
Source: FDA Multi-Disciplinary Review, NDA 219474 (Ref ID 5743278). Values digitized from Figure 14.
IGA Success at Week 4 — All Trials Summary
ADQUEY 1% vs Vehicle across all completed trials
Source: FDA Prescribing Information NDA 219474 (Ref ID 5745225) Table 2; Medical Review Table 46 and Table 34.
Phase 2 Dose-Response (Supporting Efficacy)
A consistent dose-response relationship was observed across all Phase 2 trials: the difamilast ointment 1% group had a higher response rate than 0.3%, and both active treatment groups outperformed vehicle. This dose-response relationship was observed in Trial 271-12-205 (multinational), Trial 271-15-001 (Japan, adults ≥15 yrs), and Trial 271-102-00002 (Japan, ≥2 yrs).
| Trial | Difamilast 1% (IGA Success) | Difamilast 0.3% | Vehicle | p-value (1% vs vehicle) |
|---|---|---|---|---|
| 271-12-205 (Multinational, ≥10 yr, 8 wk) | 9/43 (20.9%) | 6/41 (14.6%) | 1/37 (2.7%) | 0.017 |
| 271-15-001 (Japan, ≥15 yr, 8 wk) | 15/67 (22.4%) | 10/67 (14.9%) | 6/66 (9.1%) | 0.033 |
| 271-102-00002 (Japan, ≥2 yr, 4 wk) | 10/25 (40.0%) | 9/24 (37.5%) | 2/24 (8.3%) | 0.011 |
Long-Term Open-Label Extension
In open-label trials of both Japanese and US subjects, 857 adult and pediatric subjects continued twice-daily treatment with ADQUEY for up to 52 weeks. Application site adverse reactions that led to drug discontinuation included pain, pruritus, vesicles, blistering, erythema, burning, and contact dermatitis. The safety profile was consistent with the controlled trials.
Safety & Adverse Drug Reactions
Safety Population (Controlled)
532
Subjects in Trials 2 & 3 (4 weeks)
Long-Term Exposure
857
Subjects in OL extension (up to 52 wk)
Boxed Warning
None
No contraindications identified
Most Common ADR (≥1%)
Nasopharyngitis
6% ADQUEY vs 4% vehicle
Adverse Reactions ≥1% (4-Week Controlled Trials 2 & 3)
| Adverse Reaction | ADQUEY 1% (N=267) | Vehicle (N=265) |
|---|---|---|
| Nasopharyngitis | 16 (6%) | 10 (4%) |
Less Common Adverse Reactions (<1%)
In Trials 2 and 3, less common adverse reactions observed with ADQUEY included: application site folliculitis, contact dermatitis, application site rash, and molluscum contagiosum.
Postmarketing Adverse Reactions
General disorders and administration site conditions: Application site swelling has been identified during post-approval use. Because these reactions are reported voluntarily from a population of uncertain size, their frequency cannot be reliably estimated.
Long-Term Safety (Open-Label, up to 52 Weeks)
The following application site adverse reactions occurred that led to drug discontinuation during the open-label extension studies:
Application Site
Pain
Led to discontinuation in some subjects
Application Site
Pruritus
Led to discontinuation in some subjects
Application Site
Vesicles / Blistering
Led to discontinuation in some subjects
Application Site
Erythema
Led to discontinuation in some subjects
Application Site
Burning
Led to discontinuation in some subjects
Application Site
Contact Dermatitis
Led to discontinuation in some subjects
Nonclinical Safety Summary
Carcinogenicity (Rat)
No neoplastic findings
2-year dermal study at 4× MRHD (AUC)
Carcinogenicity (Mouse)
No neoplastic findings
2-year dermal study at 4× MRHD (AUC)
Genotoxicity
Not Genotoxic
Negative: Ames, mouse lymphoma, rat bone marrow micronucleus
Reproductive Toxicity (Rat)
Adverse effects at 263× MRHD
Post-implant loss, decreased fetal weight, visceral abnormalities (VSD) at 100 mg/kg/day SC. NOAEL: 30× MRHD.
Reproductive Toxicity (Rabbit)
Skeletal variations at 14× MRHD
Increased supernumerary lumbar vertebra. NOAEL: 3× MRHD.
Cardiac Safety (QTc)
No significant effect
Not expected to cause clinically significant QTc prolongation at recommended doses
Use in Special Populations
| Population | Summary |
|---|---|
| Pregnancy | Insufficient human data. Animal data showed embryo-fetal toxicity at subcutaneous doses 263× MRHD (rat) and skeletal variations at 14× MRHD (rabbit). Background risk of major birth defects in US: 2–4%. |
| Lactation | No data on presence in human milk. Difamilast/metabolites excreted in lactating rat milk (milk:blood AUC ratio 5.4). Advise breastfeeding women not to apply directly to nipple/areola. |
| Pediatric (≥2 years) | Safety and effectiveness established. 236 subjects aged 2 to <17 years in controlled trials (119 ADQUEY, 117 vehicle). Not established in children <2 years. |
| Geriatric (≥65 years) | Only 2 subjects ≥65 years in trials. Insufficient data to determine if they respond differently from younger adults. |
| Renal Impairment | No substantial PK differences observed with mild or moderate renal impairment. Effect of severe renal impairment (eGFR <30 mL/min) unknown. |
| Hepatic Impairment | No substantial PK differences with mild or moderate hepatic impairment. Effect of severe (Child-Pugh C) hepatic impairment unknown. |
Pharmacology & Pharmacokinetics
Pharmacokinetics
Protein Binding
99%
Not concentration-dependent (in vitro)
Metabolism
CYP3A4 & CYP1A2
O-deethylation, hydroxylation, hydrolysis
Urinary Excretion
<0.1%
Difamilast and Metabolite 1 undetectable in urine
Pediatric vs Adult PK
1.3–1.9×
Higher trough conc. in pediatric patients (corrected by dose)
Absorption — Adult (Mild-Moderate AD)
In 31 adult subjects (BSA: mean 6±3%; range 3–19%), applying ~0.9 g ADQUEY 1% BID for 4 weeks: Day 29 Cmax = 0.76 ± 1.16 ng/mL; AUC₀₋₁₂ = 6.10 ± 8.85 ng·h/mL. Low systemic exposure consistent with the topical nature of the drug.
Absorption — Pediatric (Moderate-Severe AD, Higher BSA)
In 31 pediatric subjects (BSA: mean 44±13%; range 25–80%), applying ~4.3 g BID for 2 weeks: Day 15 Cmax = 16.9 ± 21.9 ng/mL; AUC₀₋₈ = 86.2 ± 79.6 ng·h/mL. Plasma concentrations quantifiable in all subjects. Steady state by Day 15 with no evidence of accumulation.
Metabolism & Major Metabolites
| Metabolite | Pathway | Enzyme |
|---|---|---|
| Metabolite 1 | O-deethylation | CYP3A4 |
| Metabolite 2 | Hydroxylation | CYP1A2 |
| Metabolite 3 | Hydrolysis | Enzymatic |
Drug Interaction Studies
No clinical drug interaction trials have been conducted with topical difamilast. The following is based on in vitro data only.
| System | Finding | Clinical Implication |
|---|---|---|
| CYP1A2, CYP2B6, CYP2C8/9/19, CYP2D6, CYP2E1, CYP3A4 Inhibition | Not expected to inhibit at clinically relevant concentrations | No dose adjustments anticipated for co-administered CYP substrates |
| CYP1A2, CYP2B6, CYP2C9, CYP3A4 Induction | Low induction expected | No clinically significant induction anticipated |
| Transporter — BCRP | Difamilast is a BCRP substrate | Potential for interaction with strong BCRP inhibitors |
| Transporter — P-gp, OATP1B1/B3 | Not a substrate | No interaction expected |
| Transporter inhibition (P-gp, BCRP, OAT1/3, OCT1/2, OATP1B1/B3, MATE1/2-K) | Not expected to inhibit at clinical concentrations | No dose adjustments anticipated |
Special Populations
Based on cross-study analyses, no substantial differences in PK were observed based on age (2–70 years), sex, race, or mild/moderate renal or hepatic impairment. The effect of severe renal impairment or severe hepatic impairment on difamilast PK remains unknown.
Dosing & Administration
Approved Dose
1% BID
Topical ointment, thin layer
Route
Topical only
Not ophthalmic, oral, or intravaginal
Contraindications
None
No identified contraindications
Administration Instructions
| Parameter | Recommendation |
|---|---|
| Application | Apply a thin layer to affected areas twice daily; rub in completely until no longer visible on skin |
| After application | Wash hands after applying; instruct caregiver to wash hands if applying on behalf of patient |
| Infected skin | Avoid areas of skin that are infected (red, warm, swollen, or painful) |
| Eyes / mouth / vagina | Not for use in or near eyes, mouth, or vagina |
| Breastfeeding | Do not apply directly to nipple or areola; avoid inadvertent infant skin contact with treated areas |
| Renal impairment (mild-moderate) | No dose adjustment required |
| Hepatic impairment (mild-moderate) | No dose adjustment required |
| Severe renal or hepatic impairment | Effect unknown; use with caution |
| Pediatric (<2 years) | Not established — safety and efficacy not studied |
| Geriatric (≥65 years) | Insufficient data — only 2 subjects ≥65 years in trials |
Contraindications
None. ADQUEY has no identified contraindications per the approved prescribing information.
Regulatory History
NDA 219474 — Key Facts
| Parameter | Detail |
|---|---|
| Application Number | NDA 219474 |
| Application Type | 505(b)(1) · Standard review |
| Sponsor / Applicant | Acrotech Biopharma Inc. (East Windsor, NJ) |
| Original Developer | Otsuka Pharmaceutical Co., Ltd. (Japan) |
| Submission Date | February 13, 2025 |
| PDUFA Goal Date | February 13, 2026 |
| Review Completion Date | February 10, 2026 |
| Review Division | Division of Dermatology and Dentistry / Office of Inflammation and Immunology (DDD/OII) |
| Japan Approval | September 27, 2021 (Moizerto® Ointment) · Marketed June 1, 2022 |
| Medical Review Ref ID | 5743278 |
| PI Ref ID | 5745225 |
Regulatory Timeline
October 25, 2011
IND 112973 Filed
Otsuka Pharmaceutical initiates US development. First-in-human Phase 1 trial (271-11-202) authorized: tolerability, safety, and PK in 32 healthy adults (single and multiple doses).
November 2013 – September 2014
Pediatric Guidance & BSA Limits
FDA guidance on pediatric development (Nov 2013). FDA required BSA treatment limit of ≤40% with discontinuation if exceeded (Sep 2014).
October 11, 2016
IND Transferred to Medimetriks Pharmaceuticals
Sponsorship transferred; US development continues under Medimetriks.
March 23, 2016
Final CAC Report — Carcinogenicity Studies
Recommendations for 2-year dermal carcinogenicity studies in mice and rats with specific dose requirements.
October 31, 2018
End-of-Phase 2 Meeting
Comprehensive Phase 3 program discussion. FDA agreed on proposed dose (1%), time point for efficacy evaluation, safety database size, and primary endpoint (IGA success). FDA required prospective assessment of depression/suicidal ideation using PHQ-9 and C-SSRS.
March 25 – December 28, 2019
Japanese Phase 3 Trials Completed
Trial 271-102-00007 (≥15 yrs, Mar–Dec 2019) and Trial 271-102-00008 (2–14 yrs, May–Dec 2019) both completed in Japan. Both met primary endpoint (IGA success at Week 4) with p<0.001.
September 11, 2020
Type C Meeting — Modified Development Program
FDA advised that a single US Phase 3 trial (MEDI-MM36-301) could serve as supportive evidence alongside completed Japanese Phase 3 data. FDA expressed concerns about safety database adequacy.
September 27, 2021
Approved in Japan (Moizerto® Ointment)
Difamilast Ointment 1% approved by Japanese regulatory authority. Marketed in Japan from June 1, 2022.
July 23, 2021
US Phase 3 Trial MEDI-MM36-301 Initiated
Medimetriks Pharmaceuticals submits US Phase 3 trial (MEDI-MM36-301). Trial later terminated early for “business reasons” after enrolling 153/336 planned subjects.
December 30, 2021
IND Transferred to Acrotech Biopharma LLC
Sponsorship transferred to Acrotech Biopharma. No pre-NDA meeting held; Acrotech proceeds directly to NDA submission.
February 13, 2025
NDA 219474 Submitted
Acrotech Biopharma Inc. files 505(b)(1) NDA for ADQUEY® (difamilast) ointment, 1%. Proposed indication: mild to moderate atopic dermatitis in adults and pediatric patients ≥2 years.
February 2026
FDA Approval — ADQUEY™ (difamilast) 1%
Approved as proposed. Indication: topical treatment of adults and pediatric patients 2 years and older with mild to moderate atopic dermatitis. No boxed warning; no contraindications.
FDA Review Assessment
The review team concluded that Acrotech Biopharma has provided substantial evidence of effectiveness through two pivotal Japanese Phase 3 trials demonstrating statistically significant and clinically meaningful improvements in AD severity. The efficacy findings are supported by consistent dose-response relationships across Phase 2 trials and additional supportive evidence from multinational Phase 2 cohorts. The early termination of the US Phase 3 trial MEDI-MM36-301 does not preclude a demonstration of substantial evidence of effectiveness.
Limitations of Use
The safety and effectiveness of ADQUEY have not been established in pediatric patients younger than 2 years of age.
Avoid applying ADQUEY to areas of skin that are infected. Breastfeeding women should not apply ADQUEY directly to the nipple or areola to minimize potential infant exposure.
