When a team designs an atopic dermatitis program, choosing the endpoints is one of the first regulatory decisions it makes. The primary endpoint, the co-primaries, the ranking of key secondary endpoints and the timepoint all shape sample size, trial length and the claims that can go on the label. FDA approvals of systemic biologics, oral JAK inhibitors and new topical agents since 2017 now give a substantial body of precedent for planning an end-of-phase 2 meeting or arguing for an endpoint strategy.
The analysis below reviews the primary and key secondary endpoints behind FDA atopic dermatitis approvals since 2017, drawing on approved labeling and review documents. It covers how the investigator global assessment responder endpoint, EASI-75 and itch numeric rating scale response were defined and ranked, which timepoints were used, and how systemic and topical products differed in the endpoints they relied on.
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Atopic dermatitis endpoints behind FDA approvals since 2017: IGA 0/1, EASI-75 and itch NRS in systemic vs topical products
Key takeaways
- The IGA responder endpoint is the constant. Every systemic and topical atopic dermatitis (AD) label reviewed uses an investigator global assessment of clear (0) or almost clear (1). In almost every program this also requires at least a 2-grade improvement from baseline, and it is the primary or co-primary endpoint. The instrument varies (IGA, ISGA, vIGA-AD), but the responder definition is essentially the same 433238242256274339442328.
- Systemic products usually add EASI-75 as a co-primary endpoint. Tralokinumab (Adbry), abrocitinib (Cibinqo), upadacitinib (Rinvoq) and nemolizumab (Nemluvio) used IGA 0/1 plus EASI-75 as co-primaries 287238242300. Dupilumab (Dupixent) and lebrikizumab (Ebglyss) used IGA 0/1 with at least a 2-point improvement as the sole primary, and reported EASI-75 as an additional endpoint 206203.
- Topical products rely on a single IGA-success primary endpoint over a shorter window. Their labels generally do not report EASI-75. Timepoints are Day 29 (crisaborole), Week 4 (roflumilast cream, difamilast) or Week 8 (ruxolitinib cream, tapinarof) 256339328274442. Systemic trials measured at Week 16, or Week 12 for most abrocitinib trials 233238.
- Itch NRS response is the standard key secondary endpoint. It is almost always defined as a ≥4-point improvement on a 0 to 10 scale and analyzed only in patients with a baseline score of at least 4. Systemic programs report it in all age groups studied. Topical programs report it only in patients aged 12 and older, and some topical labels (crisaborole, difamilast) report no itch endpoint at all 233282242274339443255362.
Products covered
This overview covers FDA-labeled AD products with an approval or efficacy supplement on or after January 1, 2017. Eucrisa's original approval (December 14, 2016) predates that window; it qualifies through its 2020 and 2023 efficacy supplements (Drugs@FDA, NDA 207695).
| Route / class | Product (application) | Labeled AD population in pivotal program |
|---|---|---|
| Systemic, anti-IL-4Rα mAb | Dupixent (BLA 761055) 1 | Moderate-to-severe AD; adults, adolescents, children down to 6 months 206218208 |
| Systemic, anti-IL-13 mAb | Adbry (BLA 761180; original approval 2021-12-27) 35 | Moderate-to-severe AD; adults and adolescents 287288 |
| Systemic, anti-IL-13 mAb | Ebglyss (BLA 761306) 11 | Moderate-to-severe AD; ≥12 years, ≥40 kg 203 |
| Systemic, anti-IL-31RA mAb | Nemluvio (BLA 761391/761390) 1641 | Moderate-to-severe AD; ≥12 years, with TCS/TCI 300 |
| Systemic, oral JAK inhibitor | Cibinqo (NDA 213871; original approval 2022-01-14) 36 | Moderate-to-severe AD; ≥12 years 238 |
| Systemic, oral JAK inhibitor | Rinvoq (NDA 211675) 42 | Moderate-to-severe AD; ≥12 years 252 |
| Topical PDE4 inhibitor | Eucrisa 2% ointment (NDA 207695; original approval 2016-12-14) 7264 | Mild-to-moderate AD; pivotal population 2 to 79 years 256 |
| Topical JAK inhibitor | Opzelura 1.5% cream (NDA 215309) 70 | Mild-to-moderate AD; ≥12 years (TRuE-AD1/2) and 2 to 11 years (TRuE-AD3) 274272 |
| Topical PDE4 inhibitor | Zoryve cream (NDA 215985) 66 | Mild-to-moderate AD; ≥6 years (0.15%) and 2 to 5 years (0.05%) 339333 |
| Topical AhR agonist | Vtama cream (NDA 215272; AD supplement 2024-12-12) 57 | Moderate-to-severe AD; ≥2 years 391 |
| Topical PDE4 inhibitor | Adquey 1% ointment (NDA 219474; original approval 2026-02-12) 68 | Mild-to-moderate AD; ≥2 years 329 |
Systemic products: endpoint architecture and results
Common design features
Systemic pivotal trials enrolled moderate-to-severe patients with near-identical entry criteria: IGA ≥3, EASI ≥16 and ≥10% BSA involvement 206287203300. Abrocitinib, upadacitinib and nemolizumab also required a baseline itch score of at least 4 at entry 238252380. Most programs ran paired monotherapy trials plus a trial with concomitant topical corticosteroids (TCS). Rescue therapy or missing data were imputed as nonresponse 233290242.
Primary endpoints and Week 16 (or Week 12) results, drug vs placebo
| Product | Primary endpoint(s) | Monotherapy results | With TCS results |
|---|---|---|---|
| Dupixent 300 mg Q2W | IGA 0/1 + ≥2-point improvement, Wk 16 (EASI-75 as other endpoint) 206 | SOLO 1: 38% vs 10%; SOLO 2: 36% vs 9% 433 | CHRONOS: 39% vs 12% 433 |
| Adbry 300 mg Q2W | Co-primary IGA 0/1 and EASI-75, Wk 16 287 | ECZTRA 1: IGA 16% vs 7%, EASI-75 25% vs 13%; ECZTRA 2: IGA 21% vs 9%, EASI-75 33% vs 10% 290 | ECZTRA 3: IGA 38% vs 27%, EASI-75 56% vs 37% 290 |
| Ebglyss 250 mg Q2W | IGA 0/1 + ≥2-point improvement, Wk 16 (EASI-75, EASI-90, itch as other outcomes) 203 | ADvocate 1: 43% vs 13%; ADvocate 2: 33% vs 11% 196 | ADhere: the label says only that results were consistent with the monotherapy trials; no figures given 199 |
| Nemluvio 30 mg Q4W | Co-primary IGA success (0/1 + ≥2-point) and EASI-75, Wk 16 300 | Not studied as monotherapy 300 | ARCADIA 1: IGA 36% vs 25%, EASI-75 44% vs 29%; ARCADIA 2: IGA 38% vs 26%, EASI-75 42% vs 30% 301 |
| Cibinqo 200 mg / 100 mg QD | Co-primary IGA 0/1 + ≥2-grade and EASI-75, Wk 12 238 | AD-1: IGA 44%/24% vs 8%, EASI-75 62%/40% vs 12%; AD-2: IGA 38%/28% vs 9%, EASI-75 61%/44% vs 10% 323 | AD-3 (adults): IGA 47%/36% vs 14%, EASI-75 68%/58% vs 27% 323; AD-4 (adolescents): IGA 46%/39% vs 24%, EASI-75 71%/64% vs 41% 319 |
| Rinvoq 30 mg / 15 mg QD | Co-primary vIGA-AD 0/1 + ≥2-grade and EASI-75, Wk 16 242 | AD-1: vIGA 62%/48% vs 8%, EASI-75 80%/70% vs 16%; AD-2: vIGA 52%/39% vs 5%, EASI-75 73%/60% vs 13% 241 | AD-3: vIGA 59%/40% vs 11%, EASI-75 77%/65% vs 26% 251 |
Two design points matter for comparing programs. First, the Adbry label defines IGA response as IGA 0/1 and does not state a separate ≥2-grade improvement requirement 287. Second, placebo response rises when patients use background TCS. In ECZTRA 3 the placebo + TCS IGA rate was 27%, and across both ARCADIA trials (all patients on TCS/TCI) it was 25 to 26% 290301. The corresponding placebo rates in monotherapy trials were in the single digits or low teens 433323241.
Key secondary endpoints in systemic programs
Itch NRS ≥4-point response (Week 16 unless stated), drug vs placebo:
- Dupixent (weekly averaged Peak Pruritus NRS, baseline ≥4 subgroup): SOLO 1 41% vs 12%; SOLO 2 36% vs 10%; CHRONOS 59% vs 20% 233207.
- Adbry (weekly average Worst Daily Pruritus NRS, a secondary endpoint): ECZTRA 1 20% vs 10%; ECZTRA 2 25% vs 9%; ECZTRA 3 46% vs 35% 282285.
- Ebglyss (Pruritus NRS, 0 to 10): ADvocate 1 46% vs 13%; ADvocate 2 40% vs 12% 195202.
- Nemluvio (PP-NRS, explicitly the key secondary endpoint): ARCADIA 1 33% vs 15%; ARCADIA 2 36% vs 15% 302300.
- Rinvoq (Worst Pruritus NRS, assessed at Weeks 1, 4 and 16): at Week 16, 30 mg / 15 mg vs placebo was 60%/52% vs 12% (AD-1), 60%/42% vs 9% (AD-2) and 64%/52% vs 15% (AD-3 with TCS). The label shows the Week 1 and Week 4 results graphically only 241251242.
- Cibinqo (PP-NRS4, early timepoint): at Week 2, 200 mg / 100 mg vs placebo was 28%/11% vs 2% (AD-1), 24%/11% vs 2% (AD-2), 30%/14% vs 8% (AD-3) and 25%/13% vs 8% (AD-4). The label describes a Week 12 benefit without giving percentages 395399.
Deeper skin clearance and other patient-reported outcomes:
- EASI-90: Dupixent 36% vs 8% (SOLO 1), 30% vs 7% (SOLO 2) and 40% vs 11% (CHRONOS) 233. Ebglyss 38% vs 9% and 31% vs 10% 195.
- Rinvoq reports both EASI-90 and EASI-100 as secondary endpoints. In AD-1, EASI-90 was 66%/53% vs 8% and EASI-100 was 27%/17% vs 2% 241242.
- Rinvoq also reports a skin-pain NRS ≥4-point response in the monotherapy trials: 63%/54% vs 15% in AD-1 242.
- Ebglyss reports maintenance of EASI-75 at Week 52 among Week 16 responders 201. Dupixent reports maintenance of IGA 0/1 at Week 36 in SOLO CONTINUE (53% on continued dupilumab vs 10% on placebo) 221.
Pediatric systemic extensions
Pediatric programs kept the adult endpoint set. Dupixent in adolescents (AD-1526) showed IGA 0/1 + ≥2-point improvement of 24% vs 2%, EASI-75 of 42% vs 8% and Peak Pruritus NRS ≥4-point response of 37% vs 5% 218. In children aged 6 months to 5 years on concomitant TCS (AD-1539), the Dupixent primary endpoint was IGA 0/1 without a stated ≥2-point improvement requirement (28% vs 4%). This trial used a Worst Scratch/Itch NRS rather than a patient-rated pruritus NRS (48% vs 9%) 208. Adbry's adolescent trial (ECZTRA 6) used co-primary IGA 0/1 and EASI-75 (21% vs 4% and 29% vs 6%) and an Adolescent Worst Pruritus NRS secondary endpoint (23% vs 3%) 293288.
Topical products: endpoint architecture and results
Common design features
Topical pivotal trials were vehicle-controlled, usually randomized 2:1, and run as monotherapy 256391328. Most enrolled mild-to-moderate disease (IGA 2 to 3) and set BSA caps: 3 to 20% for ruxolitinib cream, 5 to 40% for difamilast and 5 to 95% treatable BSA for crisaborole 274328256. Tapinarof is the exception. Its ADORING program enrolled moderate-to-severe patients (87% moderate) with a mean baseline EASI of 12.9 391. Pediatric patients were a large share of topical programs. For example, 86% of crisaborole subjects and 80% of tapinarof subjects were aged 2 to 17 256391.
Primary endpoints and results, drug vs vehicle
| Product | Primary endpoint and timepoint | Results |
|---|---|---|
| Eucrisa 2% ointment BID | ISGA success (0/1 + ≥2-grade), Day 29 256 | Trial 1: 32.8% vs 25.4%; Trial 2: 31.4% vs 18.0% 256 |
| Opzelura 1.5% cream BID | IGA treatment success (0/1 + ≥2-grade), Week 8 274 | TRuE-AD1: 53.8% vs 15.1%; TRuE-AD2: 51.3% vs 7.6%; TRuE-AD3 (2 to 11 years): 56.5% vs 10.8% 274272 |
| Zoryve cream (0.15%; 0.05% in 2 to 5 years) | vIGA-AD success (0/1 + ≥2-grade), Week 4 339 | INTEGUMENT-1: 32.0% vs 15.2%; INTEGUMENT-2: 28.9% vs 12.0%; INTEGUMENT-PED: 25.4% vs 10.7% 339333 |
| Vtama cream QD | vIGA-AD treatment success (0/1 + ≥2-grade), Week 8 391 | ADORING 1: 45% vs 14%; ADORING 2: 46% vs 18% 442 |
| Adquey 1% ointment BID | IGA success (0/1 + ≥2-grade), Week 4 328 | Trial 1: 21% vs 3%; Trial 2: 38% vs 13%; Trial 3 (2 to 14 years): 47% vs 18% 362 |
None of the topical labels reviewed report EASI-75 as a primary or secondary result 256274339442328. For Opzelura, Zoryve, Adquey and Eucrisa, the labels contain no EASI-75 data at all 401339362255.
Key secondary endpoints in topical programs
- Opzelura: Itch NRS (7-day average of worst itch in the prior 24 hours) ≥4-point reduction at Week 8, in patients aged ≥12 with baseline ≥4. Results were 52.2% vs 15.4% (TRuE-AD1) and 50.7% vs 16.3% (TRuE-AD2). The label reports no itch data for the 2 to 11 year trial 274402.
- Zoryve: Secondary endpoints were vIGA-AD success at Weeks 1 and 2, and Worst Itch NRS success (≥4-point reduction, patients ≥12 with baseline ≥4) at Weeks 1, 2 and 4. Week 4 itch results were 33.6% vs 20.7% (INTEGUMENT-1) and 30.2% vs 12.4% (INTEGUMENT-2). The Week 1 vIGA-AD difference in INTEGUMENT-2 was not statistically significant 339337. The 2 to 5 year trial had only early vIGA-AD secondary endpoints 333.
- Vtama: PP-NRS ≥4-point reduction at Week 8 in patients ≥12 with baseline ≥4 was 56% vs 34% (ADORING 1) and 53% vs 24% (ADORING 2). These vehicle itch responses are notably high 443.
- Eucrisa and Adquey: The labels report no itch NRS, EASI or other secondary efficacy results 255362. Eucrisa shows ISGA success over time (Days 8 to 29) graphically only 262.
How systemic and topical endpoint strategies differ
| Dimension | Systemic products | Topical products |
|---|---|---|
| Disease severity | Moderate-to-severe; IGA ≥3, EASI ≥16, BSA ≥10% 206287203 | Mostly mild-to-moderate (IGA 2 to 3) with BSA caps; tapinarof moderate-to-severe 274328391 |
| Primary endpoint | IGA 0/1 (+≥2-grade), usually co-primary with EASI-75 287238242300 | IGA/ISGA/vIGA-AD success alone 256274339442328 |
| Primary timepoint | Week 16; Week 12 for most abrocitinib trials 233238 | Day 29 or Week 4 (PDE4 products); Week 8 (ruxolitinib, tapinarof) 256339328274442 |
| Comparator | Placebo, as monotherapy and with background TCS 433290251 | Vehicle, monotherapy only 256391328 |
| EASI-75 | Primary or key secondary in every program; EASI-90/EASI-100 often reported 233195241 | Not reported in labels 401339362 |
| Itch NRS ≥4-point | Key secondary in all programs; early timepoints for JAK inhibitors (Week 1/2) 242395 | Secondary only in patients ≥12 with baseline ≥4; absent from two labels 274339443255362 |
| Itch at entry | Required (baseline ≥4) for abrocitinib, upadacitinib and nemolizumab 238252380 | Not an entry criterion; baseline ≥4 defines the analysis subgroup only 274339443 |
| Pediatric evidence | Separate adolescent or pediatric trials using the adult endpoint set 218288208 | Pediatric patients enrolled within pivotal trials or in dedicated pediatric trials 256391272333 |
Regulatory context and open questions
FDA's AD-specific guidance, Atopic Dermatitis: Timing of Pediatric Studies During Development of Systemic Drugs (final, October 2018), addresses when to include pediatric age groups, including children under 2 years, and says FDA will address technical aspects of pediatric AD development in a future guidance. It does not define IGA success, EASI thresholds or itch NRS responder criteria 420421. The label precedents above are therefore the main public reference for endpoint selection.
Three questions remain open for sponsors:
- Which itch instrument to use. The labels use Peak Pruritus, Worst Pruritus, Worst Daily Pruritus and Worst Itch NRS, plus observer-reported scratch/itch scales for young children. This variation limits comparison across programs 207285242339208.
- How to handle high vehicle itch responses in topical trials. One example is the 34% vehicle rate in ADORING 1 443.
- What evidence is needed to support EASI-based labeling claims for topical products. No topical label reviewed reports EASI-75 401339362.