Impact of Oral Abrocitinib Monotherapy on Patient-Reported Symptoms and Quality of Life in Adolescents and Adults with Moderate-to-Severe Atopic Dermatitis: A Pooled Analysis of Patient-Reported Outcomes

All three studies included in this pooled analysis were similarly designed, international, multicenter, randomized, double-blind, placebo-controlled, parallel-group trials (Table 1 of the Electronic Supplementary Material [ESM]). The phase IIb study (NCT02780167) was conducted between April 2016 and April 2017 in Australia, Canada, Germany, Hungary, and the USA [19]. JADE MONO-1 (NCT03349060) was a phase III trial conducted between December 2017 and March 2019 in Australia, Canada, Europe, and the USA [20]. JADE MONO-2 (NCT03575871) was a phase III trial conducted between June 2018 and August 2019 in Australia, Canada, China, Europe, Japan, South Korea, and the USA [21].

All studies had similar eligibility criteria (described previously [19‐21]). Briefly, eligible patients were either 18–75 years of age (phase IIb) or ≥ 12 years of age (phase III) with moderate-to-severe AD (IGA ≥ 3, EASI [26] score ≥12 [phase IIb] or ≥ 16 [phase III], affected percentage of body surface area ≥ 10, PP-NRS [27] (used with permission of Regeneron Pharmaceuticals, Inc. and Sanofi) score ≥ 4 [PP-NRS4; phase III only], and inadequate response to treatment with topical corticosteroids or topical calcineurin inhibitors given for ≥ 4 weeks, a history of topical AD treatments considered medically inadvisable, or a history of systemic therapies for AD. Exclusion criteria were medical history of conditions associated with thrombocytopenia, coagulopathy, or platelet dysfunction; prior systemic JAK inhibitor use; systemic corticosteroid use within 4 weeks of study initiation; and treatment with dupilumab within 6 weeks of study initiation. The phase III studies also excluded patients with suicidal ideation associated with actual intent and method or plan in the past year (Columbia Suicide Severity Rating Scale [C-SSRS] [28] items 4 and 5), history of suicidal behaviors in the past 5 years (any CSSRS suicidal behavior item in the past 5 years), lifetime history of serious or recurrent suicidal behavior (Suicidal Behaviors Questionnaire-Revised [29] total score ≥ 8), clinically significant depression (Patient Health Questionnaire-8 [30] total score ≥ 15), or any other major psychiatric disorder that might require exclusion in the opinion of the investigator. Use of topical medicated therapies for AD (topical corticosteroids, topical calcineurin inhibitors, tars, antibiotic creams, topical antihistamines) and rescue medication (e.g., oral corticosteroids) was not permitted, but patients were allowed to use oral antihistamines and/or topical nonmedicated emollients during the studies.

In the phase IIb study, patients were randomly assigned 1:1:1:1:1 to receive once-daily oral abrocitinib 200 mg, abrocitinib 100 mg, abrocitinib 30 mg, abrocitinib 10 mg, or matching placebo for 12 weeks. In the phase III studies, patients were randomly assigned 2:2:1 (stratified by baseline disease severity [IGA 3 or 4] and age group [12 to < 18 years or ≥ 18 years]) to receive once-daily oral abrocitinib 200 mg, abrocitinib 100 mg, or matching placebo for 12 weeks. This analysis includes patients randomly assigned to receive abrocitinib 200 mg, abrocitinib 100 mg, or placebo.

Patient-reported outcome assessments in all three studies included proportions of patients achieving a ≥ 4-point improvement in itch score (PP-NRS and Pruritus-NRS) [27, 31]. Other PRO assessments included in all studies were: Patient Global Assessment (PtGA) [32, 33] clear or almost clear with a ≥ 2-point improvement; Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD [33]) total score; change from baseline in POEM [35‐37] total score; distributions of patients across DLQI [38] and Children’s Dermatology Life Quality Index (CDLQI [39]) band descriptors; and change from baseline in Hospital Anxiety and Depression Scale (HADS) [40, 41] depression and/or anxiety subscale scores and, among patients with respective baseline subscale scores ≥ 8, proportions of patients achieving subscale scores < 8.

Several additional PRO endpoints were assessed in JADE MONO-1/MONO-2, including change from baseline in the Short Form-36 Health Survey, Version 2, Acute (SF-36v2) [42] mental and physical component summary scores and domain scores (for patients aged ≥ 18 years only), EuroQol 5-Dimension 5-Level Scale (EQ-5D-5L) [43] or EuroQol 5-Dimension Youth Scale (EQ-5D-Y) [44] index score, and Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-F) [45] score or Pediatric FACIT-F (Peds-FACIT-F) [46] score as well as the proportion of patients achieving FACIT-F/Peds-FACIT-F < 30 at week 12 (among patients with FACIT-F/Peds-FACIT-F ≥ 30 at baseline).

JADE MONO-2 assessed two additional PRO endpoints: change from baseline in Work Productivity and Activity Impairment Questionnaire–Atopic Dermatitis, Version 2.0 (WPAI-AD) [47] score (for patients aged ≥ 18 years only) and the proportion of patients and time to achieve a ≥ 4-point improvement in Night Time Itch Scale (NTIS) score for severity of worst itching due to AD during the previous night’s sleep. More detailed descriptions of each PRO assessment are summarized in Table 1.

Binary endpoints were analyzed using the Cochran–Mantel–Haenszel test adjusted by randomization strata. Missing responses for patients who permanently discontinued the study were defined as non-responders at all subsequent visits. Continuous endpoints were analyzed based on the observed data using mixed-model repeated measures with fixed factors of treatment, week, treatment-by-week interaction, study, baseline disease severity, age category, and baseline value and unstructured covariance matrix or compound symmetry covariance matrix.

Overall, 942 patients were included in this pooled analysis. Baseline disease characteristics were similar across treatment groups and across three included studies (Table 2 and Supplementary Table 2 of the ESM). The total population reported moderate-to-severe signs and symptoms of AD per mean POEM total score (Table 3). Furthermore, 62.7% of patients had moderate AD and 37.3% had severe AD per IGA; this distribution was 43.7% and 48.7%, respectively, per PtGA (Table 3). Finally, the patients reported considerable symptoms of anxiety or depression per HADS subscores and a very large effect of AD on their quality of life (QoL) based on mean DLQI and CDLQI total scores (Table 3).

Mean (standard deviation [SD]) Pruritus-NRS (phase IIb)/PP-NRS scores (phase III; 200 mg, 100 mg, and placebo) were 7.0 (1.9), 7.1 (1.9), and 7.0 (1.9) at baseline and 2.9 (2.6), 3.9 (2.7), 5.4 (2.6) at week 12, respectively. Pooled proportions of patients achieving a ≥ 4-point improvement in itch severity based on Pruritus-NRS/PP-NRS score were greater starting at the first post-baseline assessment (week 2) for abrocitinib 200 mg and 100 mg compared with placebo. At week 2, 44.2% (200 mg), 24.9% (100 mg), and 5.8% (placebo) of patients achieved a ≥ 4-point improvement (i.e., response criteria in phase III studies). Proportions achieving a ≥ 4-point improvement in Pruritus-NRS/PP-NRS at weeks 4, 8, and 12 were, respectively, 57.5%, 59.2%, and 57.3% for 200 mg, 35.7%, 39.7%, and 42.9% for 100 mg, and 12.3%, 14.3%, and 16.5% for placebo. Similarly, a significant proportion of patients achieved an itch-free or virtually itch-free status (i.e., PP-NRS 0/1) at week 12 with abrocitinib 200 mg or 100 mg (36.6% and 23.4%, respectively) compared with placebo (5.3%). The median (95% confidence interval [CI]) time to achieve a ≥4-point improvement in Pruritus-NRS/PP-NRS was significantly shorter for abrocitinib 200 mg (15 days [13‐29]) and abrocitinib 100 mg (57 days [30–64]) vs placebo (112 days [92–not estimable]).

Mean (SD) NTIS scores (200 mg, 100 mg, and placebo) were 6.8 (1.9), 6.8 (2.0), and 6.2 (2.1) at baseline and 2.2 (2.3), 3.2 (2.8), and 4.8 (3.0) at week 12, respectively. A higher proportion of patients receiving abrocitinib (100 or 200 mg) experienced a ≥ 4-point improvement in the severity of night-time itch (Fig. 1a). The differences in the proportion of patients who achieved NTIS response at week 12 vs placebo for abrocitinib 200 mg and 100 mg were 44.6% (95% CI 33.0–56.1; p < 0.0001) and 29.8% (95% CI 18.3–41.4; p < 0.0001), respectively. The median (95% CI) time to achieve a ≥ 4-point improvement in the NTIS score was significantly shorter for abrocitinib 200 mg (29 days [14‐33]) and abrocitinib 100 mg (57 days [30–81]) vs placebo (116 days [89–116]; p < 0.0001 for both). Mean (SD) PSAAD scores (200 mg, 100 mg, and placebo) were 5.3 (2.1), 5.3 (2.2), and 5.3 (2.0) at baseline and 2.0 (2.1), 2.8 (2.1), and 4.3 (2.4) at week 12, respectively. Overall, > 50% of patients treated with abrocitinib reported experiencing a clinically important response in pruritus and symptoms as measured by PSAAD (≥ 1-point improvement) starting at week 2 and continuing through week 12; the proportions of responders were greater for both doses of abrocitinib than placebo at all time points (Fig. 1b). As measured with PtGA, the proportions of patients with moderate AD (200 mg, 100 mg, and placebo) were 46.6%, 38.5%, and 48.1% at baseline and 22.7%, 32.8%, and 31.6% at week 12, respectively. The proportions of patients with severe AD (200 mg, 100 mg, and placebo) were 46.3%, 53.1%, and 45.2% at baseline and 7.1%, 12.4%, and 23.9% at week 12, respectively. In the overall monotherapy pool, both doses of abrocitinib improved overall disease severity as rated by patients (PtGA) starting at the first post-baseline assessment (week 2) and continuing through the end of treatment (Fig. 1c). Mean (SD) POEM scores (200 mg, 100 mg, and placebo) were 19.8 (5.8), 20.2 (6.2), and 19.9 (5.8) at baseline and 8.9 (7.5), 12.0 (7.8), and 16.4 (7.1) at week 12, respectively. Compared with placebo-treated patients, abrocitinib-treated patients reported marked reductions in the frequency of symptoms via POEM throughout the study (Fig. 1d).

Mean HADS depression subscale scores (200 mg, 100 mg, and placebo) were 4.2 (3.8), 4.3 (4.0), and 4.5 (3.6) at baseline and 2.4 (3.0), 2.7 (3.2), and 4.0 (3.9) at week 12, respectively. Mean HADS anxiety subscale scores (200 mg, 100 mg, and placebo) were 5.8 (4.0), 6.0 (4.3), and 6.6 (4.0) at baseline and 3.8 (3.7), 4.1 (3.7), and 4.9 (4.0) at week 12, respectively.

Decreases from baseline in HADS depression and anxiety subscale scores were greater for abrocitinib-treated patients at all time points (Fig. 2). Among adults with baseline HADS depression score ≥ 8, 32 of 53 patients (60.4%), 28 of 60 patients (46.7%), and 9 of 33 patients (27.3%) in the 200-mg, 100-mg, and placebo groups, respectively, achieved HADS depression scores < 8 at week 12. Among adults with baseline HADS anxiety scores ≥ 8, 53 of 98 patients (54.1%), 48 of 100 patients (48.0%), and 17 of 67 patients (25.4%) in the 200-mg, 100-mg, and placebo groups, respectively, achieved HADS anxiety score < 8 at week 12.

Mean FACIT-F scores (200 mg, 100 mg, and placebo) were 38.3 (10.6), 37.4 (11.8), and 37.9 (10.2) at baseline and 41.9 (8.9), 40.6 (10.4), and 37.4 (12.1) at week 12, respectively. For adult patients, the least-squares mean change (95% CI) from baseline to week 12 in FACIT-F scores was 3.9 (2.9–4.9) in the abrocitinib 200-mg group and 2.9 (1.9–3.9) in the abrocitinib 100-mg group compared with 0.6 (–2.2 to 0.9) in the placebo group. In adolescent patients, mean Peds-FACIT-F scores (200 mg, 100 mg, and placebo) were 37.1 (7.7), 36.2 (9.0), and 35.8 (7.8) at baseline and 39.8 (6.4), 37.9 (9.0), and 37.7 (7.9) at week 12. Least-squares mean change (95% CI) from baseline to week 12 in Peds-FACIT-F was 3.0 (1.3–4.7) in the abrocitinib 200-mg group and 1.4 (– 0.3 to 3.1) in the abrocitinib 100-mg group vs 1.5 (– 1.1 to 4.0) in the placebo group. Among patients with FACIT-F/Peds-FACIT-F ≥ 30 at baseline (i.e., severe fatigue; n = 224 for abrocitinib 200 mg, n = 209 for abrocitinib 100 mg, n = 93 for placebo), 10 (4.5%), 14 (6.7%), and 13 (14.0%), respectively, achieved FACIT-F/Peds-FACIT-F < 30 at week 12.

Mean EQ-5D-5L index scores (200 mg, 100 mg, and placebo) were 0.80 (0.14), 0.79 (0.15), and 0.78 (0.15) at baseline and 0.9 (0.1), 0.9 (0.1), and 0.8 (0.2) at week 12, respectively. For adult patients, both abrocitinib doses improved EQ-5D-5L index scores compared with placebo (Fig. 3a). Mean EQ-5D-Y index scores (200 mg, 100 mg, and placebo) were 0.65 (0.32), 0.66 (0.36), and 0.63 (0.39) at baseline and 0.9 (0.2), 0.8 (0.3), and 0.8 (0.3) at week 12, respectively. For adolescents, abrocitinib 200 mg improved EQ-5D-Y index scores compared with placebo (Fig. 3b).

Mean SF-36v2 mental component summary scores (200 mg, 100 mg, and placebo) were 47.9 (10.7), 48.3 (10.8), and 48.6 (9.2) at baseline and 51.5 (9.4), 50.3 (10.3), and 48.8 (9.7) at week 12, respectively. Mean SF-36v2 physical component summary scores (200 mg, 100 mg, and placebo) were 46.0 (8.0), 45.2 (9.0), and 46.0 (8.1) at baseline and 51.0 (7.5), 49.6 (7.6), and 46.8 (8.4) at week 12, respectively. Improvements from baseline to week 12 in SF-36v2 mental and physical component summary scores as well as all eight domain scores were greater for abrocitinib 200 mg and 100 mg than for placebo (Fig. 3c). Mean DLQI total scores (200 mg, 100 mg, and placebo) were 14.4 (6.6), 15.1 (7.1), and 14.3 (7.2) at baseline and 4.9 (5.6), 6.9 (6.2), and 10.3 (7.9) at week 12, respectively. By week 12, abrocitinib-treated patients reported a greater shift in DLQI/CDLQI band descriptors toward no or a small impact on disease-specific QoL than placebo-treated patients (Fig. 4). Adult patients treated with abrocitinib 200 mg or 100 mg experienced improvement in all individual items of DLQI (effect on symptom severity, embarrassment or self-consciousness, daily activities, clothing, social/leisure activities, performance of sports, prevention of work/study, impairment of work/study, personal relationships, sex life, and burden of treatment) compared with patients treated with placebo from weeks 2 to 12 (Fig. 1 of the ESM). In adolescent patients, mean CDLQI total scores (200 mg, 100 mg, and placebo) were 13.1 (5.5), 12.4 (6.4), and 12.5 (6.3) at baseline and 4.3 (3.8), 6.4 (5.2), and 9.6 (5.2) at week 12, respectively. Adolescent patients treated with abrocitinib 200 mg or 100 mg experienced improvement in the individual items on CDLQI that address effects on symptom severity, embarrassment or self-consciousness, sleep, and burden of treatment compared with patients treated with placebo from weeks 2 to 12 (Fig. 2 of the ESM). Mean percentages of activity impairment measured by WPAI-AD (200 mg, 100 mg, and placebo) were 43.0 (25.6), 41.0 (27.5), and 41.9 (27.2) at baseline and 20.5 (25.3), 22.7 (25.2), and 38.0 (28.6) at week 12, respectively. Employed abrocitinib-treated patients reported greater reductions from baseline to week 12 in the percentage of impairment while working and the percentage of overall work impairment compared with placebo-treated patients (Table 4). Likewise, abrocitinib-treated patients reported greater reductions in activity impairment from baseline to week 12 than placebo-treated patients (Table 4).