Efficacy and safety of lebrikizumab in adult and adolescent patients with moderate-to-severe atopic dermatitis inadequately controlled with or ineligible for ciclosporin A: a placebo-controlled, randomized phase IIIb clinical study (ADvantage)

Abstract Background Ciclosporin A (CsA) is approved for severe atopic dermatitis (AD), but its efficacy may not be optimal, and its toxicity limits longer-term use. The recently approved lebrikizumab has demonstrated robust efficacy and favourable safety in adults and adolescents with moderate-to-severe AD. Objectives To evaluate the efficacy and safety of lebrikizumab combined with topical corticosteroids (TCS) in adults and adolescents with moderate-to-severe AD who had a history of inadequate response to CsA or for whom CsA was not medically advisable. Methods This was a placebo-controlled, randomized phase IIIb clinical study (ADvantage; NCT05149313). Patients were randomized 2 : 1 to receive either lebrikizumab 250 mg plus TCS (with a loading dose of lebrikizumab 500 mg at baseline and week 2) or placebo plus TCS, delivered subcutaneously, every 2 weeks (Q2W), for the 16-week induction period. Following this, all patients received lebrikizumab 250 mg Q2W during a 36-week open-label maintenance period (with TCS use at investigator discretion). The primary endpoint was the proportion of patients who achieved ≥ 75% improvement from baseline in Eczema Area and Severity Index (EASI 75) at week 16. Results In total, 331 patients were randomized, 220 to receive lebrikizumab plus TCS and 111 to receive placebo plus TCS. At week 16, a significantly higher proportion of the lebrikizumab group vs. the placebo group achieved EASI 75 (68.4% vs. 40.8%; P 0.001). At week 16, a greater proportion of the treatment group achieved ≥ 90% improvement from baseline in EASI (EASI 90) (42.9% vs. 20.8%; P 0.001), Investigator’s Global Assessment of clear/almost clear skin (IGA 0/1) with ≥ 2-point improvement from baseline (42.0% vs. 24.5%; P 0.01), and ≥ 4-point improvement in pruritus numeric rating scale (NRS) (49.9% vs. 29.7%; P 0.05). At week 52, the proportion of patients treated with lebrikizumab with/without TCS who achieved EASI 75 and EASI 90 further increased to 88.9% and 71.7%, respectively; 64.4% achieved IGA 0/1 response and 71.3% achieved a ≥ 4-point improvement in pruritus NRS. The incidence of treatment-emergent adverse events (TEAEs) was 62.3% in the lebrikizumab plus TCS group vs. 53.2% in the placebo plus TCS group at week 16, and 76.9% in the lebrikizumab group at week 52. Serious adverse events and TEAEs leading to discontinuation at week 16 were low and similar in lebrikizumab vs. placebo groups (1.4% vs. 0.9% and 0.5% vs. 0.9%, respectively), and remained low at week 52 (5.9% and 2.5%, respectively). Conclusions Lebrikizumab 250 mg Q2W combined with TCS significantly improved signs and symptoms of AD at week 16 in adults and adolescents with moderate-to-severe AD and history of inadequate response to CsA or for whom CsA was not medically advisable, and those benefits were maintained and/or further improved by week 52. Safety was consistent with the known lebrikizumab safety profile.