Delgocitinib (ANZUPGO) — Drug Profile | TrialistMD

JAK Inhibitor (Pan-JAK) · Small Molecule · Dermatology

Delgocitinib

ANZUPGO® · 2% cream (20 mg/g)

First-in-class topical pan-JAK inhibitor (JAK1/2/3/TYK2) approved for moderate to severe chronic hand eczema (CHE) in adults with inadequate response to, or for whom topical corticosteroids are not advisable. NDA 219155 · LEO Pharma A/S · Approved July 2025.

NDA Number

219155

Approval Date

July 2025

Mechanism

Pan-JAK inhibitor

Route

Topical

Indication

Moderate–Severe CHE

Sponsor

LEO Pharma A/S

Overview

§1

Drug Class

Pan-JAK Inhibitor

JAK1, JAK2, JAK3, TYK2

Formulation

2% Cream

20 mg/g · Topical

Indication

Moderate–Severe CHE

Adults · TCS-inadequate or inadvisable

Application Type

NDA 505(b)(1)

Standard Review · NDA 219155

Drug Summary

§1.1

INN	Delgocitinib
Brand Name	ANZUPGO®
Applicant	LEO Pharma A/S (distributed by LEO Pharma Inc., Madison, NJ)
Also known as	JTE-052 / LEO 124249
Pharmacologic Class	Janus kinase (JAK) inhibitor — pan-JAK (JAK1, JAK2, JAK3, TYK2)
Molecular Formula	C₁₆H₁₈N₆O · MW 310.35 g/mol
Approved Dosage Form	Cream, 2% (20 mg/g); white to slightly brown
Approved Indication	Topical treatment of moderate to severe chronic hand eczema (CHE) in adults who have had an inadequate response to, or for whom topical corticosteroids are not advisable
Limitations of Use	Use in combination with other JAK inhibitors or potent immunosuppressants is not recommended
NDA Number	219155
Review Type	Standard (Priority Review request denied)
Submission Date	July 23, 2024
PDUFA Goal Date	July 23, 2025
Review Completion Date	July 21, 2025
Review Division	Division of Dermatology and Dentistry (DDD)
Prior Approvals (same compound)	EU: September 19, 2024 (ANZUPGO, CHE); Japan: January 2020 (CORECTIM ointment, AD)

Clinical Development Program

§1.2

Trial	Design	Population	N	Primary Endpoint
DELTA 1 (LP0133-1401; NCT04871711)	Randomized, double-blind, vehicle-controlled, 16 weeks	Adults with moderate–severe CHE	487 (2:1 ratio)	IGA-CHE treatment success at Week 16
DELTA 2 (LP0133-1402; NCT04872101)	Randomized, double-blind, vehicle-controlled, 16 weeks	Adults with moderate–severe CHE	472 (2:1 ratio)	IGA-CHE treatment success at Week 16
DELTA 3 (LP0133-1403; NCT04949841)	Open-label extension, 36 weeks	Subjects completing DELTA 1 or DELTA 2	801	TEAEs (safety primary); IGA-CHE (secondary)
Phase 2b (LP0133-1273)	5-arm, double-blind, vehicle-controlled, 16 weeks	Adults with mild–severe CHE	258	Dose-response (1, 3, 8, 20 mg/g vs vehicle)
PK Trial (LP0133-2285)	Phase 1, maximal use PK	Adults with moderate–severe CHE, 15 subjects	15	Cmax, AUC0-12 at Day 1 and Day 8

Disease Background — Chronic Hand Eczema

§1.3

Unmet Need: At the time of ANZUPGO approval, the only FDA-approved products for CHE were topical corticosteroids (TCS). Long-term TCS use carries risks including skin atrophy; CHE often requires prolonged treatment, creating an unmet need for alternative non-steroidal topical therapy.

CHE Subtypes (enrolled)	Atopic hand eczema 35.9%, hyperkeratotic eczema 21.5%, irritant contact dermatitis 19.6%, allergic contact dermatitis 13.9%, vesicular hand eczema 9.1%, contact urticaria/protein contact dermatitis 0.1%
Overlapping subtypes	28% of subjects had ≥2 overlapping CHE subtypes
Disease severity (enrolled)	IGA-CHE 3 (moderate) or 4 (severe); HESD itch ≥4/10 at baseline
Key assessments	IGA-CHE (0–4 scale); HESD itch and pain scores (0–10 NRS, daily diary); HECSI (area and severity composite); DLQI; HEIS
IGA-CHE Scale	0 = Clear; 1 = Almost clear; 2 = Mild; 3 = Moderate; 4 = Severe

Source: FDA Integrated Review NDA 219155 (Ref ID 5629504); FDA Prescribing Information ANZUPGO (Ref ID 5629364).

Baseline Characteristics

§2

Population: Full Analysis Set (FAS) — all randomized and dosed subjects. Delgocitinib 20 mg/g BID vs. vehicle cream BID for 16 weeks. 2:1 randomization stratified by region and baseline IGA-CHE score.

Demographics

§2.1

Characteristic	DELTA 1 — Delgocitinib (N=325)	DELTA 1 — Vehicle (N=162)	DELTA 2 — Delgocitinib (N=313)	DELTA 2 — Vehicle (N=159)
Age, mean (SD), years	44.3 (14.3)	42.9 (14.1)	45.3 (14.6)	42.6 (14.3)
Age median, years	45.0	42.5	46.0	42.0
Age range	19–87	20–73	18–83	18–86
18 to <65 years, n (%)	297 (91.4%)	154 (95.1%)	285 (91.1%)	150 (94.3%)
≥65 years, n (%)	27 (8.3%)	8 (4.9%)	28 (8.9%)	8 (5.0%)
Female, n (%)	202 (62.2%)	104 (64.2%)	203 (64.9%)	108 (67.9%)
White, n (%)	283 (87.1%)	144 (88.9%)	294 (93.9%)	146 (91.8%)
Asian, n (%)	14 (4.3%)	5 (3.1%)	8 (2.6%)	7 (4.4%)
Black or African American, n (%)	3 (0.9%)	1 (0.6%)	2 (0.6%)	1 (0.6%)
Hispanic or Latino, n (%)	14 (4.3%)	4 (2.5%)	2 (0.6%)	5 (3.1%)
Europe, n (%)	260 (80.0%)	130 (80.2%)	249 (79.6%)	126 (79.2%)
North America, n (%)	65 (20.0%)	32 (19.8%)	64 (20.4%)	33 (20.8%)

Baseline Disease Severity

§2.2

Parameter	DELTA 1 — Delgocitinib (N=325)	DELTA 1 — Vehicle (N=162)	DELTA 2 — Delgocitinib (N=313)	DELTA 2 — Vehicle (N=159)
IGA-CHE Moderate (score=3), n (%)	218 (67.1%)	109 (67.3%)	238 (76.0%)	121 (76.1%)
IGA-CHE Severe (score=4), n (%)	107 (32.9%)	53 (32.7%)	75 (24.0%)	38 (23.9%)
HESD itch score, mean (SD)	7.1 (1.6)	7.2 (1.7)	7.0 (1.5)	7.0 (1.5)
HESD itch score, median	7.2	7.6	7.1	7.1
HESD pain score, mean (SD)	6.8 (2.0)	6.8 (2.0)	6.6 (1.8)	6.5 (2.0)
HESD pain score, median	7.1	7.2	6.7	6.7
HESD total score, mean (SD)	7.2 (1.7)	7.2 (1.7)	7.0 (1.5)	6.9 (1.5)

Disease History & Prior Treatment

§2.3

Atopic dermatitis comorbidity	46% of subjects diagnosed with AD
Atopic diathesis	38.7% (allergic rhinitis, asthma, etc.)
Occupation-related CHE	36.6% of subjects had occupation contributory to CHE development/chronicity
CHE impact on employment	60.8% of subjects
Patch tested	78.6% of subjects; 36% had positive results
Prior systemic therapy	All subjects had received prior systemic therapy including oral corticosteroids
Prior alitretinoin	12%
Prior traditional immunosuppressants	7.4%
Prior dupilumab	0.6%

Source: FDA Integrated Review NDA 219155 (Ref ID 5629504), Table 10, pp. 47–48.

Efficacy

§3

Primary Endpoint: Proportion of subjects achieving IGA-CHE Treatment Success (IGA-CHE TS) at Week 16, defined as IGA-CHE score of 0 (clear) or 1 (almost clear) with ≥2-point improvement from baseline. Statistical framework: Non-Responder Imputation (NRI) — data after rescue treatment, permanent discontinuation, or missing data imputed as non-response. Closed testing procedure controlling FWER. CMH test stratified by region and baseline IGA-CHE score.

Primary Endpoint — IGA-CHE Treatment Success at Week 16

§3.1

DELTA 1 (LP0133-1401) · IGA-CHE TS · Week 16 Delgocitinib N=325 vs. Vehicle N=162 · FAS · NRI imputation

Delgocitinib 20 mg/g BID

19.7%

Vehicle BID

9.9%

Difference: 9.8% (95% CI: 3.6%, 16.1%) p = 0.006

DELTA 2 (LP0133-1402) · IGA-CHE TS · Week 16 Delgocitinib N=313 vs. Vehicle N=159 · FAS · NRI imputation

Delgocitinib 20 mg/g BID

29.1%

Vehicle BID

6.9%

Difference: 22.2% (95% CI: 15.8%, 28.5%) p <0.001

IGA-CHE Treatment Success Over Time

§3.2

Source: FDA Integrated Review NDA 219155 (Ref ID 5629504), Figure 6; FDA PI ANZUPGO (Ref ID 5629364), Figure 1. Data points at Weeks 2, 4, 8, 16 from explicitly reported Table 13 values. Intermediate timepoints not individually tabulated are not plotted.

Key Secondary Endpoints — Pooled DELTA 1 & DELTA 2

§3.3

HESD Itch ≥4-point Improvement from Baseline · Week 16 Among subjects with baseline HESD itch ≥4; NRI imputation

Delgocitinib — DELTA 1 (N=323)

47.1%

Vehicle — DELTA 1 (N=161)

23.0%

Difference: 24.1% (95% CI: 15.5%, 32.6%) p <0.001

Delgocitinib — DELTA 2 (N=309)

47.2%

Vehicle — DELTA 2 (N=156)

19.9%

Difference: 27.4% (95% CI: 19.0%, 35.8%) p <0.001

HESD Pain ≥4-point Improvement from Baseline · Week 16 Among subjects with baseline HESD pain ≥4; NRI imputation

Delgocitinib — DELTA 1 (N=291)

49.1%

Vehicle — DELTA 1 (N=149)

27.5%

Difference: 21.7% (95% CI: 12.4%, 30.9%) p <0.001

Delgocitinib — DELTA 2 (N=294)

48.6%

Vehicle — DELTA 2 (N=141)

22.7%

Difference: 26.0% (95% CI: 17.0%, 35.1%) p <0.001

Additional Secondary Endpoint Results

§3.4

Endpoint	DELTA 1 Delgocitinib	DELTA 1 Vehicle	DELTA 2 Delgocitinib	DELTA 2 Vehicle	p-value
IGA-CHE TS at Week 8	22.8% (74/325)	10.5% (17/162)	32.3% (101/313)	9.4% (15/159)	<0.001 (both)
IGA-CHE TS at Week 4	15.4% (50/325)	4.9% (8/162)	14.7% (46/313)	8.2% (13/159)	<0.001; 0.043
HECSI-75 at Week 16	49.2% (160/325)	23.5% (38/162)	49.5% (155/313)	18.2% (29/159)	<0.001 (both)
HECSI-90 at Week 16	29.5% (96/325)	12.3% (20/162)	31.0% (97/313)	8.8% (14/159)	<0.001 (both)
% change HECSI, LS mean, Wk 16	−56.5%	−21.2%	−58.9%	−13.4%	<0.001 (both)
DLQI change, LS mean, Wk 16	−7.6	−3.9	−7.0	−3.1	<0.001 (both)
DLQI ≥4-point reduction at Wk 16	74.4% (227/305)	50.0% (74/148)	72.2% (216/299)	45.8% (70/153)	<0.001 (both)
HESD itch ≥4-pt improve, Wk 8	42.7% (138/323)	21.7% (35/161)	42.4% (131/309)	13.5% (21/156)	<0.001 (both)
HESD itch ≥4-pt improve, Wk 4	30.7% (99/323)	11.2% (18/161)	30.4% (94/309)	12.2% (19/156)	<0.001 (both)
HESD itch ≥4-pt improve, Wk 2	15.5% (50/323)	6.2% (10/161)	12.9% (40/309)	6.4% (10/156)	0.004; 0.031
HESD total score change LS mean Wk 16	−3.4	−1.7	−3.2	−1.4	<0.001 (both)
HEIS change LS mean Wk 16	−1.5	−0.8	−1.4	−0.6	<0.001 (both)

FDA Assessment — HECSI & HEIS Interpretability: The FDA concluded that HECSI-based endpoint scores have limited interpretability as the HECSI did not adequately clinically characterize the severity and extent of hand eczema. The HEIS PDAL domain was not considered fit-for-purpose. Primary and key secondary endpoints (IGA-CHE TS, HESD itch, HESD pain) were considered the interpretable efficacy evidence.

HESD Itch Response Over Time

§3.5

Source: FDA Integrated Review NDA 219155 (Ref ID 5629504), Table 13 and Figure 7; FDA PI ANZUPGO (Ref ID 5629364), Figure 2. Data points at Weeks 2, 4, 8, 16 from explicitly tabulated values.

Source: FDA Integrated Review NDA 219155 (Ref ID 5629504), Tables 12–13, Figures 6–8; FDA PI ANZUPGO (Ref ID 5629364), Table 2, Figures 1–3.

Safety & ADRs

§4

No Boxed Warning. The review team concluded that a Boxed Warning is not warranted at this time given: (1) application area <5% BSA; (2) maximal use study demonstrated low systemic exposure (sub-nanomolar in ~33% of subjects on Day 1); (3) adverse reactions including thrombosis, malignancy, and MACE were not observed during development; (4) dose-dependent risk for major toxicities. Warnings & Precautions labeling covers potential JAK inhibitor class risks.

Safety Population (16-week)

638

Delgocitinib-treated (DELTA 1+2)

Long-term Exposure

198

Continuous delgocitinib BID × 52 weeks (DELTA 3)

Any TEAE (Delgocitinib)

45.6%

291/638; Vehicle: 47.7% (153/321)

Deaths (Development Program)

All assessed unrelated to study drug

Warnings & Precautions

§4.1

Serious Infections: ANZUPGO may increase risk of infections. Eczema herpeticum observed in 1 subject in controlled trials. Serious and sometimes fatal infections (bacterial, mycobacterial, invasive fungal, viral) reported with oral/topical JAK inhibitors. Viral reactivation including herpes zoster observed. Avoid use with active/serious infection; interrupt if serious infection develops.
Viral Reactivation: Herpes virus reactivation (herpes zoster) reported in clinical trials. In DELTA 3 (36-week extension): 1 case eczema herpeticum, 2 cases herpes zoster. Hepatitis B/C screening and monitoring recommended. Not recommended with active hepatitis B or C.
Non-melanoma Skin Cancers: Basal cell carcinoma cases reported. Periodic skin examinations recommended. Advise sun-protective clothing and broad-spectrum sunscreen.
Immunizations: Complete all age-appropriate vaccinations (including herpes zoster) prior to initiation. Avoid live vaccines immediately prior to, during, and immediately after treatment.
Potential Risks Related to JAK Inhibition: In a large postmarketing safety trial of an oral JAK inhibitor in RA (patients ≥50 years + ≥1 CV risk factor), higher rates of all-cause mortality, MACE, overall thrombosis, DVT, PE, and malignancies were observed vs. TNF blockers. ANZUPGO is not indicated for RA. Topical and oral JAK inhibitors associated with increased lipid parameters (total cholesterol, LDL, triglycerides).

Overview of Adverse Events — Pooled DELTA 1 & DELTA 2 (16 weeks)

§4.2

Event Category	Delgocitinib (N=638)	Vehicle (N=321)	Risk Difference (95% CI)
Any TEAE	291 (45.6%)	153 (47.7%)	−2.1% (−8.7%, 4.6%)
Any SAE	11 (1.7%)	6 (1.9%)	−0.1% (−2.4%, 1.5%)
SAEs requiring hospitalization	11 (1.7%)	6 (1.9%)	−0.1% (−2.4%, 1.5%)
Fatal SAEs	0	0	—
AE leading to permanent discontinuation	3 (0.5%)	11 (3.4%)	−3.0% (−5.6%, −1.3%)*
Severe or worse TEAEs	15 (2.4%)	9 (2.8%)	−0.5% (−3.1%, 1.6%)
Moderate TEAEs	108 (16.9%)	56 (17.4%)	−0.5% (−5.8%, 4.4%)

*95% CI excludes zero. Source: FDA Integrated Review NDA 219155 (Ref ID 5629504), Table 23.

TEAEs Occurring at ≥1% — Pooled DELTA 1 & DELTA 2 (Selected)

§4.3

Preferred Term	Delgocitinib (N=638) n (%)	Vehicle (N=321) n (%)	Risk Difference (95% CI)
COVID-19	71 (11.1%)	34 (10.6%)	0.5% (−3.9%, 4.5%)
Nasopharyngitis	44 (6.9%)	24 (7.5%)	−0.6% (−4.4%, 2.7%)
Headache	28 (4.4%)	13 (4.0%)	0.3% (−2.7%, 2.9%)
Hypertension	7 (1.1%)	0	1.1% (−0.1%, 2.2%)
Upper respiratory tract infection	9 (1.4%)	1 (0.3%)	1.1% (−0.4%, 2.4%)
Back pain	7 (1.1%)	1 (0.3%)	0.8% (−0.7%, 2.0%)
Oral herpes	7 (1.1%)	2 (0.6%)	0.5% (−1.2%, 1.7%)
Influenza	7 (1.1%)	2 (0.6%)	0.5% (−1.2%, 1.7%)
Arthralgia	7 (1.1%)	4 (1.2%)	−0.1% (−2.1%, 1.2%)
Dermatitis contact	7 (1.1%)	6 (1.9%)	−0.8% (−3.0%, 0.7%)
Hand dermatitis	4 (0.6%)	13 (4.0%)	−3.4% (−6.2%, −1.6%)*

*95% CI excludes zero. Note: No ADRs occurred at ≥1% in the delgocitinib group at greater frequency than vehicle that were considered drug-related. Source: FDA Integrated Review NDA 219155 (Ref ID 5629504), Table 27.

Adverse Reactions (ADRs) — From PI §6.1

§4.4

ADRs reported in ≤1% of ANZUPGO-treated subjects in TRIAL 1 and TRIAL 2: Application site pain, paresthesia, pruritus, erythema; bacterial skin infections including finger cellulitis, paronychia, other skin infections; leukopenia; neutropenia. In TRIAL 3 (36-week OLE): 1 case eczema herpeticum, 2 cases herpes zoster.

Serious Adverse Events

§4.5

SOC / Preferred Term	Delgocitinib (N=638)	Vehicle (N=321)
Any SAE	11 (1.7%)	6 (1.9%)
Infections (COVID-19 pneumonia, bacterial keratitis, peritonsillar abscess, tonsillitis)	4 (0.6%)	0
Nervous system disorders	3 (0.5%)	1 (0.3%)
Skin and subcutaneous tissue	1 (0.2%)	2 (0.6%)
Neoplasm (gallbladder adenocarcinoma)	1 (0.2%)	0
Gastrointestinal (inguinal hernia)	1 (0.2%)	0
Vascular (venous thrombosis)	0	1 (0.3%)

Deaths

§4.6

3 Deaths in Development Program — All Assessed Unrelated to Study Drug: (1) 63-year-old male: metastatic esophageal cancer; received vehicle for 16 weeks then 1 application of delgocitinib before discontinuing. (2) 72-year-old male: unknown cause on Day 362; complex comorbidities (renal cell carcinoma, cirrhosis, hepatitis B). (3) 72-year-old male: fatal myocardial infarction ~218 days after last dose of delgocitinib; history of hypertension. All assessed unrelated to study product by trial investigators and review team.

Nonclinical Safety

§4.7

Carcinogenicity Not carcinogenic in 2-year dermal study in mice (up to 5% delgocitinib ointment; ~600× MRHD). In 2-year oral rat study: benign thymoma in females at 30 mg/kg/day (2,274× MRHD); no findings at 10 mg/kg/day (580× MRHD).

Genotoxicity Not mutagenic in Ames assay. Induced polyploidy in human peripheral blood lymphocytes in vitro but no chromosomal structural aberrations. No chromosomal aberrations in rat bone marrow in vivo. No micronuclei in mouse epidermal cells (dermal).

Reproductive Toxicity Female rat fertility NOAEL: 30 mg/kg/day (1,087× MRHD). Embryofetal NOAEL (rat): 3 mg/kg/day (120× MRHD); skeletal variations at ≥10 mg/kg. Rabbit embryofetal NOAEL: 3 mg/kg/day (193× MRHD). Pre/postnatal development NOAEL: 10 mg/kg/day (378× MRHD).

Cardiac Safety (QTc) No clinically significant QTc interval prolongation at 193× the mean maximal concentration provided by recommended topical dose. No hERG inhibitory effect at clinically relevant concentrations.

General Toxicology 9-month dermal toxicity (minipigs): NOAEL = 5% delgocitinib (20 mg/kg/day); 15× MRHD. 9-month oral toxicity (dogs): NOAEL = 0.6 mg/kg/day; 206× MRHD. Skin lesions in dogs at 3 mg/kg/day.

Postmarketing (CORECTIM ointment — Japan) 3,571 case reports from estimated 4 million patients (2020–April 2025). Most frequent AEs: application site erythema 9.6%, irritation 5.8%, acne 5.6%. 86 reports EH, 21 reports herpes zoster. No cases of thrombosis, MACE, or GI perforation.

Special Populations Safety

§4.8

Pregnancy	Insufficient human data. Animal NOAEL: rat embryofetal 3 mg/kg (120× MRHD); rabbit embryofetal 3 mg/kg (193× MRHD). Oral delgocitinib present in rat milk.
Lactation	No human milk data. Delgocitinib present in rat milk after oral dosing. PMR 4877-2 required (lactation milk study).
Pediatric	Safety and efficacy not established. PREA waiver granted for ages 0–<11 years (impractical). PMR 4877-1 required: adolescents 12–17 years.
Geriatric	59/691 subjects (8.5%) aged ≥65 years; 10 (1.4%) aged ≥75 years. No overall differences in safety or efficacy vs. younger adults.
Renal Impairment	Studies not conducted; low systemic exposures and no PK–AE relationship identified.
Hepatic Impairment	Studies not conducted; low systemic exposures and no PK–AE relationship identified.

Source: FDA Integrated Review NDA 219155 (Ref ID 5629504), §§7.1–7.7; FDA PI ANZUPGO (Ref ID 5629364), §§5, 6.1, 8, 13.1.

Pharmacology & PK

§5

Cmax (Steady-State)

0.53 ± 0.28 ng/mL

Mean ± SD at steady-state dosing; BID topical application

AUC0–12 (Steady-State)

4.2 ± 1.88 h·ng/mL

Mean ± SD at steady-state therapeutic dosing regimen

Tmax (Day 8)

6.4 ± 4.36 h

Following BID topical application for 8 days

Cmax (Day 1, PK Trial)

1.53 ± 2.24 ng/mL

Mean ± SD; 0.87 g applied BID (Trial LP0133-2285, N=15)

AUC0–12 (Day 1, PK Trial)

6.1 ± 8.14 h·ng/mL

Mean ± SD; Trial LP0133-2285 (N=15 subjects with CHE)

Half-life (t½)

~21 hours

Estimated following twice-daily dosing for 8 days

Plasma Protein Binding

22–29%

Low protein binding

Accumulation

None

No accumulation with BID topical application (Day 1 vs Day 8 similar)

Renal Excretion

~75%

Unchanged drug excreted in urine after oral administration

Absorption

§5.1

Topical PK: Absolute bioavailability of the 2% cream was not determined. Systemic exposure under maximal use conditions (CHE patients) was lower than oral dose used in the TQT study. In TRIAL 2, single PK sample assessed 2–6 hours post-dose: mean plasma concentration at Week 1: 0.42 ng/mL; Week 4: 0.50 ng/mL; Week 16: 0.35 ng/mL. Approximately 33% of subjects had sub-nanomolar systemic exposure on Day 1 in the maximal use study.

Distribution

§5.2

Volume of distribution not applicable (topical formulation; systemic exposures are very low). Plasma protein binding is 22–29% (low). Delgocitinib is a substrate of P-glycoprotein (P-gp) in vitro; not a substrate of BCRP. Weak substrate of OCT2 and OAT3.

Metabolism

§5.3

Parameter	Detail
Main plasma component	Unchanged delgocitinib (minimal metabolism)
Primary enzymes	CYP3A4/5 (primary); minor contribution from CYP1A1, CYP2C9, CYP2C19, CYP2D6
Metabolic pathways	Oxidation and glucuronide conjugation
Metabolites detected (oral)	4 metabolites by oxidation/glucuronidation; each <2% of unchanged delgocitinib plasma concentrations
Human-specific metabolites	None identified

Elimination

§5.4

Primary route of excretion is renal — approximately 75% of total dose excreted unchanged in urine following oral administration. Terminal half-life approximately 21 hours. Mass balance study not conducted for topical formulation.

Special Population PK

§5.5

Pediatric	Not established for CHE. Separate AD data in children (TRIAL LP0133-1181) — pharmacokinetics evaluated by age group.
Geriatric	No overall differences in safety or effectiveness in subjects ≥65 years (59 subjects, 8.5% of safety population).
Renal Impairment	Studies not conducted due to low systemic exposures and absence of PK–AE relationship.
Hepatic Impairment	Studies not conducted due to low systemic exposures and absence of PK–AE relationship.
Body Weight	No therapeutic individualization studies conducted.

Drug–Drug Interactions

§5.6

No clinical DDI studies conducted with ANZUPGO. Based on low systemic exposure following topical administration, clinically meaningful DDIs are not anticipated.

In Vitro Finding	Clinical Relevance
CYP inhibition/induction	Does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, 3A5; does not induce CYP1A2, 2B6, 3A4
Transporter inhibition	Does not inhibit P-gp, BCRP, OCT2, OATP1B1, or OATP1B3 at clinically relevant concentrations
P-gp substrate	Delgocitinib is a substrate of P-gp; BCRP non-substrate
Immunosuppressants / other JAKi	Combination not studied; not recommended per Limitations of Use (additive immunological effects possible)

Mechanism of Action

§5.7

Delgocitinib inhibits the enzymatic activity of all four Janus kinase family members: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2), with IC₅₀ values of 0.00280, 0.00264, 0.0125, and 0.0578 μM respectively. JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors and their subsequent localization to the nucleus, leading to expression of cytokine-responsive genes. Delgocitinib inhibits phosphorylation of STATs stimulated by IL-2, IL-6, GM-CSF, IL-23, and IFN-α in human PBMCs. It also inhibits IL-13 secretion by mast cells, TNF-α production by monocytes, and human T and B cell proliferation. Additionally, delgocitinib reverses IL-4/IL-13-mediated reduction in skin-barrier gene expression in primary human keratinocytes. The exact mechanism of action in the treatment of CHE is currently not known.

Pharmacodynamics

§5.8

Pharmacodynamics of delgocitinib in the treatment of CHE are unknown per the PI. At 193× the mean maximal plasma concentration achieved with the recommended topical dose, clinically significant QTc interval prolongation was not observed in the TQT study. No dose-proportionality or exposure-response analyses applicable to topical formulation. The 20 mg/g BID dose was selected based on Phase 2b dose-response results comparing 1, 3, 8, and 20 mg/g strengths.

Source: FDA Integrated Review NDA 219155 (Ref ID 5629504), Table 5 (pp. 27–29), §§5, 13.1; FDA PI ANZUPGO (Ref ID 5629364), §§12.1–12.3.

Dosing & Contraindications

§6

Approved Dose

2% (20 mg/g)

Single approved strength

Route

Topical

Hands and wrists only

Frequency

Twice Daily (BID)

Apply thin layer to affected areas

Quantity Limit

30 g / 2 weeks

Max 60 g per month

Standard Dosing

Apply a thin layer of ANZUPGO cream, 2%, twice daily to affected areas on the hands and wrists only
No loading dose; no titration schedule
Maximum quantity: 30 g per 2 weeks (60 g per month)
Duration of therapy: not defined in PI — ongoing as needed per clinical response
Topical use only — not for oral, ophthalmic, or intravaginal use

Dose Modifications

No dose modification for renal impairment (studies not conducted; low systemic exposure)
No dose modification for hepatic impairment (studies not conducted)
No age-based or weight-based adjustments established
Interrupt treatment if a serious infection develops; resume only after infection resolves
Consider interruption if herpes zoster episode develops

Preparation & Administration

Clean and dry affected areas prior to applying
Apply thin layer to affected skin of hands and wrists only
Avoid contact with eyes, mouth, or other mucous membranes; if contact occurs, rinse thoroughly with water
Caregiver should wash hands after applying
Breastfeeding women: avoid direct contact with nipple and surrounding area after applying to hands/wrists
Storage: 20°C–25°C (68°F–77°F); excursions permitted 15°C–30°C; do not freeze

Immunizations & Pre-treatment

Complete all age-appropriate vaccinations (including herpes zoster) per current immunization guidelines prior to treatment initiation
Avoid live vaccines immediately prior to, during, and immediately after ANZUPGO treatment
Consider screening for TB, viral hepatitis B/C reactivation per clinical guidelines
Periodic skin examinations recommended throughout treatment

Contraindications

§6.4

None. ANZUPGO has no contraindications listed in the approved prescribing information (PI §4).

Warnings Relevant to Dosing

§6.5

Quantity Limit: Do not exceed 30 g per 2 weeks or 60 g per month. Application restricted to skin of the hands and wrists only — not for use on other body areas.

Combination with immunosuppressants: Use with other JAK inhibitors or potent immunosuppressants is not recommended (Limitations of Use). Combination use has not been studied.

Drug Interactions Affecting Dosing

§6.6

No clinical DDI studies conducted. Due to the low systemic exposure from topical application and the in vitro DDI profile (no CYP or transporter inhibition/induction at clinically relevant concentrations), dose adjustments for co-administered drugs are not anticipated.

How Supplied

§6.7

30 g laminated tube	NDC 50222-280-30
60 g laminated tube	NDC 50222-280-60
Appearance	White to slightly brown cream containing 2% delgocitinib (20 mg/g)
Inactive ingredients	Benzyl alcohol, butylated hydroxyanisole, cetostearyl alcohol, citric acid monohydrate, edetate disodium, hydrochloric acid, mineral oil, polyoxyl 20 cetostearyl ether, purified water

Source: FDA PI ANZUPGO (Ref ID 5629364), §§2–4, 16; FDA Integrated Review NDA 219155 (Ref ID 5629504).

Regulatory History

§7

NDA Key Facts

§7.1

Application Number	NDA 219155
Application Type	NDA 505(b)(1) — New Molecular Entity (NME)
Applicant	LEO Pharma A/S
Original Developer	Japan Tobacco Inc. (JTE-052); licensed to LEO Pharma globally (ex-Japan) in November 2014
Submission Date	July 23, 2024
Received Date	July 23, 2024
PDUFA Goal Date	July 23, 2025
Review Completion Date	July 21, 2025
Review Division	Division of Dermatology and Dentistry (DDD)
Review Type	Standard (Priority Review request denied — insufficient clinical evidence of substantial improvement over existing therapies)
Breakthrough Therapy Designation	No — Denied (request August 26, 2020; denied for lack of preliminary clinical evidence of substantial improvement)
Fast Track Designation	Yes — Granted June 12, 2020 (request May 5, 2020; earlier request February 17, 2020 denied for inadequate development plan)
Orphan Drug Designation	Not applicable
Advisory Committee	Not convened
Medical Review Ref ID	5629504
PI Ref ID	5629364
INDs Cross-Referenced	IND 135351 (cream formulation, submitted May 25, 2018); IND 128008 (ointment formulation, submitted October 19, 2015)

Regulatory Timeline

§7.2

JANUARY 2020

CORECTIM (delgocitinib ointment 0.5%) approved in Japan

Approval for atopic dermatitis in adults; later extended to pediatric patients (≥2 years, 2021; ≥6 months, 2023)

FEBRUARY 17, 2020

Fast Track Designation Request #1 submitted

Denied — development plan deemed inadequate

MAY 5, 2020

Fast Track Designation Request #2 submitted

Granted June 12, 2020 for investigation of delgocitinib cream in treatment of moderate to severe CHE

AUGUST 26, 2020

Breakthrough Therapy Designation Request submitted

Denied — lack of preliminary clinical evidence of substantial improvement over existing therapies on clinically significant endpoint(s)

SEPTEMBER–DECEMBER 2020

End-of-Phase 2 Meetings with FDA

September 2020 teleconference (Minutes: October 23, 2020) — FDA provided feedback on Phase 3 trial design for DELTA 1, DELTA 2, and DELTA 3. December 2020 informal teleconference re: run-in period (Memo to File: January 14, 2021)

APRIL 2021

Phase 3 DELTA 1 (NCT04871711) & DELTA 2 (NCT04872101) initiated

Phase 3 Protocol Version 4.0 dated August 20, 2021 for both trials. Conducted as non-IND trials outside the United States

SEPTEMBER 2023

Pre-NDA Meeting

Meeting Minutes dated October 27, 2023. FDA and Applicant agreed on content and format of comprehensive data package

SEPTEMBER 19, 2024

ANZUPGO approved in European Union

Marketing authorisation for moderate to severe CHE in adults; also subsequently approved in UK, Switzerland, UAE

JULY 23, 2024

NDA 219155 submitted to FDA

Standard review. Proprietary name ANZUPGO proposed July 23, 2024; conditionally acceptable September 23, 2024

JULY 21–23, 2025

NDA 219155 Approved — ANZUPGO (delgocitinib) cream, 2%

Approved indication: topical treatment of moderate to severe CHE in adults who have had an inadequate response to, or for whom topical corticosteroids are not advisable. Review completed July 21, 2025 (PDUFA: July 23, 2025). Revised PI date: 7/2025.

Key Review Issues

§7.3

Impact of No Run-In Period on Efficacy Assessment The absence of a run-in period raised questions about whether subjects had truly failed TCS therapy as required per inclusion criteria. The FDA concluded that, while a run-in would have provided cleaner documentation, the inclusion criteria for prior TCS inadequate response was sufficient for evaluation of efficacy in the intended population.

HECSI/HEIS Endpoint Interpretability FDA determined that the HECSI did not adequately characterize CHE severity for regulatory purposes, and the HEIS PDAL domain was not fit-for-purpose. Efficacy approval was based on IGA-CHE TS, HESD itch, and HESD pain endpoints — all considered interpretable and clinically meaningful.

Formulation Change Impact on PK and Safety The NDA relied on a cream formulation (2%) rather than ointment (0.5% CORECTIM). A maximal use PK trial (Trial LP0133-1180) and Phase 3 PK substudy (DELTA 2) were conducted with the cream formulation to characterize systemic exposure and support safety assessment of the commercial formulation.

JAK Inhibitor Class Safety Labeling Key deliberation concerned whether delgocitinib’s topical route and low systemic exposure justify class-level Boxed Warning. FDA concluded Boxed Warning not warranted (low BSA, sub-nanomolar exposures in many subjects, absence of MACE/thrombosis/malignancy events in development). Warnings & Precautions section covers potential JAK inhibition risks. PMR 4877-3 required for long-term active-controlled safety trial.

Postmarketing Requirements & Commitments

§7.4

3 PMRs Issued: PMR 4877-1 (PREA — pediatric efficacy/safety/PK study), PMR 4877-2 (lactation milk study), and PMR 4877-3 (long-term randomized active-controlled safety trial).

PMR/PMC	Study Type	Objective	Key Milestones
PMR 4877-1 (PREA)	Pediatric efficacy, safety & PK study	Assess delgocitinib cream in adolescents ages 12–17 years with moderate to severe CHE	Final Report: October 2025. (Ages 0–<11 waived as impossible/impractical)
PMR 4877-2 (§505(o))	Milk-only lactation PK study	Measure delgocitinib concentrations in breast milk using validated assay; assess effects on breastfed infant	Draft Protocol: 01/2026; Final Protocol: 07/2026; Study Completion: 07/2028; Final Report: 01/2029
PMR 4877-3 (§505(o))	Randomized, active-controlled clinical trial	Evaluate long-term safety of delgocitinib in moderate to severe CHE — sufficient size and duration to characterize safety events of interest (bone marrow effects, viral reactivation)	Draft Protocol: 01/2026; Final Protocol: 07/2026; Trial Completion: 07/2029; Final Report: 01/2030

Regulatory Notes

§7.5

Benefit-Risk Conclusion	Benefits of delgocitinib cream outweigh risks for treatment of moderate to severe CHE in adults with inadequate response to, or for whom TCS are not advisable. Delgocitinib demonstrated statistically superior and clinically meaningful efficacy vs. vehicle in both pivotal trials (DELTA 1 and DELTA 2).
Primary Efficacy Standard	21 CFR 314.126(a)(b) — substantial evidence of effectiveness met by two adequate and well-controlled trials (DELTA 1 and DELTA 2)
Boxed Warning Decision	Not required — low BSA application, sub-nanomolar systemic exposures in ~33% of subjects, no MACE/thrombosis/malignancy in development program, dose-dependent risk for major JAK toxicities
Global Development Notes	Phase 3 trials conducted as non-IND trials outside the US (Europe + North America). Ointment IND 128008 (original Japan program) cross-referenced; cream IND 135351 primary US development vehicle.
Source Document Ref IDs	Medical Review: Ref ID 5629504 · Prescribing Information: Ref ID 5629364

Source: FDA Integrated Review NDA 219155 (Ref ID 5629504), §12 Summary of Regulatory History, §24 Postmarketing Requirements; FDA PI ANZUPGO (Ref ID 5629364).