734 - Efficacy and safety of upadacitinib vs dupliumab in adults and adolescents with moderate-to-severe atopic dermatitis: results of an open-label, efficacy assessor-blinded head-to-head phase 3b/4 study (Level Up)

Abstract Introduction/Background Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intense itch and eczematous skin lesions. Some patients with AD continue to experience flares and substantial clinical burden despite the use of systemic therapy. Upadacitinib is a selective oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 versus JAK2, JAK3, and tyrosine kinase 2. Dupilumab is a monoclonal antibody inhibiting interleukin-4 and interleukin-13 signaling. Both upadacitinib and dupilumab are approved in multiple countries for the treatment of moderate-to-severe AD in adolescents and adults. Objectives This monotherapy study assessed the efficacy and safety of upadacitinib, initiated at 15 mg once daily (QD) and dose-escalated to 30 mg QD based on clinical response, compared with dupilumab per its label. Results presented here are based on the Week 16 primary analysis. Methods Level Up is a phase 3b/4 global, randomized, open-label, efficacy assessor blinded, head-to-head, multi-center study evaluating upadacitinib vs dupilumab in adolescents and adults with moderate-to-severe AD who had inadequate response to systemic therapy or when use of those therapies was inadvisable. Patients were randomized to upadacitinib 15 mg or dupilumab per its label for 16 weeks of treatment (Period 1), with an extension period to 32 weeks (Period 2) for patients not achieving at least 75% reduction in Eczema Area and Severity Index from baseline (EASI 75) at Week 16. Patients on upadacitinib 15 mg were dose-escalated to 30 mg starting from Week 4 if they had a <EASI 50 response, or a <4-point improvement from baseline for their weekly rolling average of Worst Pruritus Numerical Rating Scale (WP-NRS) score. Patients taking upadacitinib 15 mg who did not achieve EASI 75 starting at Week 8 also had their dose increased to 30 mg. Starting at Week 4, rescue with topical therapy was optional and per investigator’s discretion if protocol criteria were met. The primary endpoint of the study was the simultaneous achievement of 90% or greater reduction in EASI from baseline (EASI 90) and a WP-NRS of 0 or 1 (WP-NRS 0/1) at Week 16. Results A total of 920 patients (803 adults, 117 adolescents) were randomized to upadacitinib (458) or dupilumab (462). At Week 16, upadacitinib showed superior efficacy versus dupilumab in the primary endpoint, where a significantly higher proportion of patients simultaneously achieved EASI 90 and WP-NRS 0/1 at Week 16 (19.9% vs 8.9% for upadacitinib and dupilumab respectively, p<0.0001). Upadacitinib also showed superiority versus dupilumab for all ranked secondary endpoints including skin and itch response endpoints at varying response levels and timepoints. No new safety signals were identified during Period 1. Proportions of patients with any treatment-emergent adverse event were higher for upadacitinib (65.3%) than dupilumab (52.7%). Severe adverse events (AEs) and AEs leading to discontinuation of study treatment were similar between upadacitinib and dupilumab, with no difference in the proportion of serious AEs (0.9%). The most common AE reported was nasopharyngitis for both upadacitinib and dupilumab. One serious infection (0.2%) was reported for dupilumab, and none for upadacitinib. Five opportunistic infections (excluding tuberculosis and herpes zoster) occurred for upadacitinib (all eczema herpeticum) with none for dupilumab. No malignancies, adjudicated major adverse cardiac events, adjudicated venous thromboembolic events (VTEs) or deaths were reported in either treatment group. Conclusions Treatment of moderate-to-severe AD with upadacitinib demonstrated superiority versus dupilumab for the primary endpoint of simultaneous achievement of near complete skin clearance (EASI 90) and no to little itch (WP-NRS 0/1) at Week 16 and for all ranked secondary endpoints. There were no new safety risks compared to the known safety profile of upadacitinib.