Dupilumab provides important clinical benefits to patients with atopic dermatitis who do not achieve clear or almost clear skin according to the Investigator’s Global Assessment: a pooled analysis of data from two phase III trials J.I. Silverberg1*, E.L. Simpson2*, M. Ardeleanu3, D. Thaçi4, S. Barbarot5, J. Bagel6, Z. Chen3, L. Eckert7, J. Chao3, A. Korotzer3, E. Rizova8, A.B. Rossi8, Y. Lu3, N.M.H. Graham3, T. Hultsch8, G. Pirozzi9, and B. Akinlade3 1Department of Dermatology, Preventive Medicine and Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, U.S.A.; 2Department of Dermatology, Oregon Health & Science University, Portland, OR, U.S.A.; 3Regeneron Pharmaceuticals, Inc., Tarrytown, NY, U.S.A.; 4University of Lübeck, Lübeck, Germany; 5Service de Dermatologie, Centre Hospitalier Universitaire (CHU) de Nantes, Nantes, France; 6Eczema Treatment Center of Central New Jersey, East Windsor, NJ, U.S.A.; 7Sanofi, Chilly-Mazarin, France; 8Sanofi Genzyme, Cambridge, MA, U.S.A.; 9Sanofi, Bridgewater, NJ, U.S.A. *Co-first author: contributed equally to this work. British Journal of Dermatology DOI:10.1111/bjd.17791

Jonathan I. Silverberg MD, PhD, MPH Associate Professor of Dermatology, Preventive Medicine and Medical Social Sciences, Northwestern University Feinberg School of Medicine

Introduction What’s already known? An Investigator’s Global Assessment (IGA) score of 0 or 1 (clear or almost clear skin) is considered the regulatory standard for treatment success in trials of patients with atopic dermatitis (AD) in the U.S.A. It is currently unknown whether patients receiving dupilumab treatment for moderate-to-severe AD derive clinical and quality of life benefit even if they have an end-of-treatment IGA score of > 1.

Objective To evaluate the treatment effect of dupilumab in patients with IGA > 1 at the end of treatment, using other validated outcome measures for AD signs, symptoms, and quality of life

Methods (1): Study design and treatments Post-hoc analysis of data from two randomized, double-blind, placebo-controlled, phase 3 trials (LIBERTY AD SOLO 1 and 2)1 Patients were randomized (1:1:1) to 16 weeks of dupilumab 300 mg weekly, OR every 2 weeks (q2w), OR placebo This analysis was based on patients assigned to dupilumab 300 mg q2w or placebo 1.Simpson EL, et al. N Engl J Med 2016; 375:2335–48.

Methods (2): Key eligibility criteria Aged ≥ 18 years Moderate-to-severe AD (IGA 3 or 4) inadequately controlled with topical treatment or for whom topical treatment was inadvisable Chronic AD for ≥ 3 years

Methods (3): Key endpoints For patients who did not achieve IGA 0 or 1 at Week 16: EASI score Peak Pruritus NRS score Proportion of BSA affected DLQI score POEM score BSA, body-surface area; DLQI, Dermatology Life Quality Index; EASI, Eczema Area and Severity Index; NRS, Numerical Rating Scale; POEM, Patient-Oriented Eczema Measure.

Results (1): Baseline characteristics Compared with patients with IGA ≤ 1 at Week 16, those with IGA > 1 were more likely to have IGA 4 at baseline and had a longer disease duration, a higher proportion of BSA affected by AD, and worse baseline EASI and POEM scores Among patients with IGA > 1, baseline characteristics were generally balanced between treatment groups Characteristic IGA > 1 at Week 16 IGA ≤ 1 at Week 16 Placebo (n = 396) Dupilumab 300 mg q2w (n = 278) Placebo (n = 47) Dupilumab 300 mg q2w (n = 171) Median age (IQR), y 37.5 (26.0, 49.0) 36.0 (27.0, 46.0) 30.0 (24.0, 43.0) 35.0 (25.0, 48.0) Median disease duration (IQR), y 28.0 (19.0, 40.0) 26.0 (18.0, 39.0) 22.0 (10.0, 32.0) 23.0 (15.0, 36.0) Median affected BSA (IQR), % 55.5 (37.5, 75.3) 57.5 (41.0, 77.5) 38.0 (30.0, 57.0) 42.0 (32.0, 58.5) Median EASI score (IQR) 31.2 (22.8, 43.1) 33.8 (23.4, 44.8) 25.2 (18.1, 37.1) 24.4 (19.2, 33.6) IGA 4, n (%) 206 (52.0) 165 (59.4) 11 (23.4) 54 (31.6) Median Peak Pruritus NRS score (IQR) 7.7 (6.4, 8.8) 7.7 (6.5, 8.9) 7.4 (6.0, 8.0) 7.6 (6.0, 8.6) Median DLQI score (IQR) 15.0 (10.0, 21.0) 11.0 (7.0, 17.0) 13.0 (8.0, 19.0) Median POEM score (IQR) 22.0 (17.0, 26.0) 22.0 (18.0, 26.0) 17.0 (12.0, 23.0) 19.0 (15.0, 24.0) IQR, interquartile range.

Results (2): EASI score in patients with IGA > 1 at Week 16 Among patients assigned to dupilumab who had IGA > 1 at Week 16, 50% achieved EASI-50 and 21% achieved EASI-75 (LOCF method) A significantly higher proportion of patients achieved EASI-75 and EASI-50 with dupilumab than placebo Change in EASI score LS mean % change from baseline to Week 16 in EASI score –100 –90 –80 –70 –60 –50 –40 –30 –20 –10 Placebo Dupilumab 300 mg q2w LOCF Observed values n = 396 n = 278 n = 370 n = 262 * Proportion achieving EASI-75 Patients achieving EASI-75 at Week 16 ( %) LOCF Observed values 10 20 30 40 50 60 70 80 90 100 Placebo Dupilumab 300 mg q2w n = 396 n = 278 n = 370 n = 262 * Proportion achieving EASI-50 Patients achieving EASI-50 at Week 16 ( %) LOCF Observed values 10 20 30 40 50 60 70 80 90 100 Placebo Dupilumab 300 mg q2w n = 396 n = 278 n = 370 n = 262 * *P < 0.001 vs placebo. Error bars indicate standard error. EASI-75, 75% improvement from baseline in EASI score; EASI-50, 50% improvement from baseline in EASI score; LOCF, last observation carried forward; LS, least squares; n, number of patients with IGA >1. Two imputation methods were implemented: (i) postbaseline last observation carried forward (LOCF), where IGA anchor categories and efficacy responses were determined with consideration of rescue medication use, and the last assessment values prior to rescue medication use were carried forward; and (ii) observed value, where IGA anchor categories and efficacy responses at week 16 were quantified based on observed values disregarding the use of rescue medication (to reflect a real‐world situation).

Results (3): Peak Pruritus NRS and proportion of BSA affected in patients with IGA > 1 at Week 16 At Week 16, the decrease in Peak Pruritus NRS score from baseline was significantly higher in the dupilumab group than placebo The decrease from baseline in percentage of BSA affected was also significantly greater in the dupilumab group than placebo Change in Peak Pruritus NRS score LS mean % change from baseline to Week 16 in Peak Pruritus NRS –100 –90 –80 –70 –60 –50 –40 –30 –20 –10 Placebo Dupilumab 300 mg q2w LOCF Observed values n = 395 n = 275 n = 360 n = 255 * Change in proportion of BSA affected by AD LS mean % change from baseline to Week 16 in BSA affected by AD –100 –90 –80 –70 –60 –50 –40 –30 –20 –10 Placebo Dupilumab 300 mg q2w LOCF Observed values n = 396 n = 278 n = 370 n = 262 *   *P < 0.001 vs. placebo. Error bars indicate standard error. n, number of patients with IGA >1.

Results (4): DLQI and POEM scores in patients with IGA > 1 at Week 16 Among patients with IGA > 1, improvement in DLQI and POEM scores from baseline to week 16 was significantly greater in the dupilumab group than the placebo group Change in DLQI score LS mean change from baseline to Week 16 in DLQI score –10 –8 –6 –4 –2 Placebo Dupilumab 300 mg q2w LOCF Observed values n = 396 n = 278 n = 370 n = 262 * n = 396 n = 278 n = 368 n = 261 Change in POEM score LS mean change from baseline to Week 16 in POEM total score –12 –10 –8 –6 –4 –2 Placebo Dupilumab 300 mg q2w LOCF Observed values * *P < 0.001 vs. placebo. Error bars indicate standard error. n, number of patients with IGA >1.

Case (1): 48 years old, AD for 8 years Before and after 16 weeks of treatment with dupilumab 300 mg q2w BASELINE WEEK 16 IGA 0 or 1 EASI-50 Peak Pruritus NRS ≥3-point improvement DLQI ≥4-point improvement This table indicates whether the patient’s response met the defined threshold of clinical significance for each outcome. Photos courtesy of Sanofi Genzyme/Regeneron. Checkbox table created by Ana B. Rossi and Marthe Vuillet. This is an individual case and not representative of results from all patients.

Case (1): 48 years old, AD for 8 years Before and after 16 weeks of treatment with dupilumab 300 mg q2w BASELINE WEEK 16 This spider graphic shows percentage of improvement achieved at week 16 in each outcome. Photos courtesy of Sanofi Genzyme/Regeneron. Spider web graphic created by Ana B. Rossi and Marthe Vuillet. This is an individual case and not representative of results from all patients.

Case (1): 48 years old, AD for 8 years Before and after 16 weeks of treatment with dupilumab 300 mg q2w BASELINE WEEK 16 Baseline Week 16 IGA 0–4 EASI 0–72 BSA 0–100 Pruritus 0–10 Sleep 0–10 POEM 0–28 DLQI 0–30 This rainbow colour scale graphic displays change in absolute values from baseline (red) to Week 16 (blue) for each outcome. Photos courtesy of Sanofi Genzyme/Regeneron. Rainbow graphic created by Ana B. Rossi & Marthe Vuillet. This is an individual case and not representative of results from all patients.

Discussion (1) Patients with IGA > 1 at Week 16 had more severe disease at baseline Despite not achieving IGA ≤ 1, these patients derived important clinical and statistically significant benefits from dupilumab treatment compared with placebo, including improvements in: EASI Peak Pruritus NRS Proportion of BSA affected Quality of life (DLQI, POEM)

Discussion (2) An endpoint of IGA ≤ 1 is recommended for drug registrational trials by regulators in the U.S.A. (but not Europe) However, IGA scales have several limitations Lack of standardization and validation Minimal clinically important difference has not been established Most scales do not account for lesion extent or location Most scales do not account for symptom burden Use of the same endpoint (IGA ≤ 1) in mild, moderate, and severe disease favours drugs evaluated for mild disease

Discussion (3) IGA ≤ 1 remains a valid measure of an exceptionally good response However, these findings suggest that IGA scale fails to capture the full spectrum of clinical benefits that patients with moderate-to- severe AD may derive from effective treatments, especially for symptoms and quality of life This underscores the importance of using multiple outcome measures, including validated measures of AD lesion severity and extent (e.g. EASI) and patient-reported outcomes, to adequately assess treatment effects

Conclusions What does this study add? This post-hoc analysis of patients with an end-of-treatment IGA > 1 from two randomized, placebo-controlled trials showed that after 16 weeks of treatment, dupilumab significantly improved other outcome measures compared with placebo, including measures of signs, symptoms, and quality of life These results show that the regulatory IGA ≤ 1 endpoint used in clinical trials considerably underestimates clinically relevant dupilumab treatment effects, underscoring potential limitations of the IGA scale

Call for correspondence Why not join the debate on this article through our correspondence section? Rapid responses should not exceed 350 words, four references and one figure Further details can be found here