ABSTRACT
Atopic dermatitis (AD) is a chronic, recurrent, highly pruritic immune-mediated inflammatory disease, with an unmet need for additional effective therapies. Results from phase IIb and phase III clinical trials demonstrated that upadacitinib (UPA) was efficacious with a favourable benefit-risk profile vs. placebo (PBO) in the treatment of moderate-to-severe AD. Here, we analyse the efficacy and safety of UPA in adolescent and adult subgroups using data from three phase III studies. Data from three randomized, double-blind, placebo-controlled, multicentre phase III studies [Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422) and AD Up (NCT03568318)] were used to assess the efficacy and safety of UPA in adolescents and adults. Across the three studies, adolescents (aged 12 to < 18years) and adults (aged 18-75years) with moderate-to-severe AD were randomized 1: 1: 1 to UPA 15mg (UPA15), UPA 30mg (UPA30) or PBO orally once daily, either alone (Measure Up 1 and Measure Up 2) or with concomitant topical corticosteroids (AD Up). This analysis includes prespecified efficacy endpoints in adolescents and adults at week 16: achievement of 75% improvement in Eczema Area and Severity Index (EASI-75), validated Investigator's Global Assessment-Atopic Dermatitis score of clear or almost clear (vIGA-AD 0/1), Worst Pruritus Numerical Rating Scale (WP-NRS) improvement of ≥ 4, Dermatology Life Quality Index (DLQI) or Children's DLQI score of 0 or 1 (DLQI 0/1 or CDLQI 0/1), and Hospital Anxiety and Depression Scale (HADS)-Anxiety (HADS-A) < 8 and HADS-Depression (HADS-D) < 8. The primary approach for evaluating categorical endpoints was NRI-C (nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19). Safety was assessed as treatment-emergent adverse events (AEs) in all patients who received ≥ 1 dose of study drug and analysed as an integrated dataset for all three studies. In total, 124, 104 and 116 adolescents plus 723, 732 and 785 adults were randomized and treated in Measure Up 1, Measure Up 2 and AD Up, respectively. EASI-75 response rates at week 16 across adolescent and adult subgroups for both doses of UPA were consistent with the overall study population results;treatment with UPA30 yielded numerically better results than with UPA15. Most patients in both subgroups achieved EASI-75 with UPA15 (> 55%), and numerically greater proportions of patients achieved EASI-75 for UPA30 (> 72%), with response rates for both UPA doses demonstrating significantly better efficacy than PBO (≥ 30%). vIGA-AD 0/1 was achieved by > 38% and > 50% of patients receiving UPA15 and UPA30, respectively, in both subgroups, with response rates for both UPA doses demonstrating significantly better efficacy than PBO (< 12%). A WP-NRS improvement of ≥ 4 was achieved by > 33% of adolescents and > 42% of adults receiving UPA15 vs. > 50% of adolescents and > 60% of adults receiving UPA30, with response rates for both UPA doses demonstrating significantly better efficacy than PBO (< 16%). CDLQI 0/1 was achieved by > 13% (UPA15) and ≥ 19% (UPA30) of adolescents aged 12 to <16years, while DLQI 0/1 was achieved by ≥ 0% (UPA15) and ≥ 27% (UPA30) of adolescents aged 16 to <18years;most adolescent rates for DLQI 0/1 and CDLQI 0/1 were not significantly greater than PBO. In the adult subgroup, DLQI 0/1 was achieved by > 24% and > 37% receiving UPA15 and UPA30, respectively, both significantly greater than PBO. Achievement of HADS-A<8 and HADS-D<8 was comparable for adolescents and adults, with response rates for both UPA doses being significantly higher than PBO: ≥ 40% for UPA15 and > 41% for UPA30 in both subgroups. Rates of serious AEs and AEs leading to discontinuation were generally similar across treatment groups for both adolescents and adults. Rates of acne-the most common AE-were higher with UPA than PBO, and similar for adolescents and adults. Serious infections were reported infrequently (< 1%) with UPA in both adolescents and adults. Opportunistic infections were reported in < 1% of adults, with n ne in adolescents. Rates of herpes zoster virus infection were higher with UPA than PBO in both adolescents and adults. No adjudicated gastrointestinal perforation, major adverse cardiovascular events or venous thromboembolic events were reported in the UPA groups. No malignancies were reported in adolescents. Adolescent and adult responses to UPA15 and UPA30 treatment were consistent across clinical, quality-of-life and patient-reported outcome assessments, with similar and acceptable safety in both populations.