两项针对中重度特应性皮炎的 lebrikizumab 的 3 期临床试验。

Two Phase 3 Trials of Lebrikizumab for Moderate-to-Severe Atopic Dermatitis.

机构信息

From the Department of Dermatology, George Washington University School of Medicine and Health Sciences, Washington, DC (J.I.S.); the Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York (E.G.-Y.); the Institute and Comprehensive Center for Inflammation Medicine, University of Lübeck, Lübeck, Germany (D.T.); the Department of Clinical Medicine, Trinity College Dublin, Dublin (A.D.I.); Dermatology Clinical Research, Henry Ford Health System, Detroit (L.S.G.); Oregon Medical Research Center (A.B.), and the Department of Dermatology, Oregon Health and Science University (E.L.S.) - both in Portland; the Department of Dermatology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei (C.-Y.C.); Eli Lilly, Indianapolis (Z.L., R.G.L., S.G.P.); and the Department of Dermatology and Pediatric Dermatology, National Reference Center for Rare Skin Disorders, Hospital Saint-André, Bordeaux University, Centre National de la Recherche Scientifique, ImmunoConcept, Unité Mixte de Recherche 5164, Bordeaux, France (J.S.).

出版信息

N Engl J Med. 2023 Mar 23;388(12):1080-1091. doi: 10.1056/NEJMoa2206714. Epub 2023 Mar 15.

DOI:10.1056/NEJMoa2206714

PMID:36920778

Abstract

BACKGROUND

Lebrikizumab, a high-affinity IgG4 monoclonal antibody targeting interleukin-13, prevents the formation of the interleukin-4Rα-interleukin-13Rα1 heterodimer receptor signaling complex.

METHODS

We conducted two identically designed, 52-week, randomized, double-blind, placebo-controlled, phase 3 trials; both trials included a 16-week induction period and a 36-week maintenance period. Eligible patients with moderate-to-severe atopic dermatitis (adults [≥18 years of age] and adolescents [12 to <18 years of age, weighing ≥40 kg]) were randomly assigned in a 2:1 ratio to receive either lebrikizumab at a dose of 250 mg (loading dose of 500 mg at baseline and week 2) or placebo, administered subcutaneously every 2 weeks. Outcomes for the induction period were assessed up to 16 weeks and are included in this report. The primary outcome was an Investigator's Global Assessment (IGA) score of 0 or 1 (indicating clear or almost clear skin; range, 0 to 4 [severe disease]) with a reduction (indicating improvement) of at least 2 points from baseline at week 16. Secondary outcomes included a 75% improvement in the Eczema Area and Severity Index score (EASI-75 response) and assessments of itch and of itch interference with sleep. Safety was also assessed.

RESULTS

In trial 1, the primary outcome was met in 43.1% of 283 patients in the lebrikizumab group and in 12.7% of 141 patients in the placebo group (P<0.001); an EASI-75 response occurred in 58.8% and 16.2%, respectively (P<0.001). In trial 2, the primary outcome was met in 33.2% of 281 patients in the lebrikizumab group and in 10.8% of 146 patients in the placebo group (P<0.001); an EASI-75 response occurred in 52.1% and 18.1%, respectively (P<0.001). Measures of itch and itch interference with sleep indicated improvement with lebrikizumab therapy. The incidence of conjunctivitis was higher among patients who received lebrikizumab than among those who received placebo. Most adverse events during the induction period were mild or moderate in severity and did not lead to trial discontinuation.

CONCLUSIONS

In the induction period of two phase 3 trials, 16 weeks of treatment with lebrikizumab was effective in adolescents and adults with moderate-to-severe atopic dermatitis. (Funded by Dermira; ADvocate1 and ADvocate2 ClinicalTrials.gov numbers, NCT04146363 and NCT04178967, respectively.).

摘要

背景

Lebrikizumab 是一种针对白细胞介素-13 的高亲和力 IgG4 单克隆抗体，可防止白细胞介素-4Rα-白细胞介素-13Rα1 异二聚体受体信号复合物的形成。

方法

我们进行了两项设计相同的 52 周随机、双盲、安慰剂对照的 3 期临床试验；两项试验均包括 16 周的诱导期和 36 周的维持期。符合条件的中度至重度特应性皮炎患者（成人[≥18 岁]和青少年[12 至<18 岁，体重≥40kg]）以 2:1 的比例随机分配接受 lebrikizumab 250mg 或安慰剂治疗，每 2 周皮下给药一次。诱导期的结果评估长达 16 周，本报告包括这些结果。主要终点是研究者全球评估（IGA）评分 0 或 1（表示皮肤清晰或几乎清晰；范围 0 至 4[严重疾病]），与基线相比至少下降 2 分在第 16 周。次要终点包括湿疹面积和严重程度指数评分（EASI-75 应答）改善 75%和瘙痒评估以及瘙痒对睡眠的干扰。还评估了安全性。

结果

在试验 1 中， lebrikizumab 组的 283 名患者中有 43.1%和安慰剂组的 141 名患者中有 12.7%达到主要终点（P<0.001）；EASI-75 应答分别为 58.8%和 16.2%（P<0.001）。在试验 2 中， lebrikizumab 组的 281 名患者中有 33.2%和安慰剂组的 146 名患者中有 10.8%达到主要终点（P<0.001）；EASI-75 应答分别为 52.1%和 18.1%（P<0.001）。瘙痒和瘙痒对睡眠的干扰评估表明 lebrikizumab 治疗有效。与安慰剂相比，接受 lebrikizumab 治疗的患者结膜炎发生率更高。诱导期的大多数不良事件为轻度或中度严重程度，并未导致试验中止。