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)

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.

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