两项度普利尤单抗治疗特应性皮炎的 3 期临床试验。

Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis.

机构信息

From the Department of Dermatology, Oregon Health and Science University (E.L.S.), and Oregon Medical Research Center (A.B.) - both in Portland; the Department of Dermatology and Allergy, University of Bonn, Bonn (T.B.), the Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, Berlin (M.W.), and the Department of Dermatology and Allergy, Ludwig-Maximilian University, Munich (A.W.) - all in Germany; the Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York (E.G.-Y.), the Department of Dermatology, University of Rochester Medical Center, Rochester (L.A.B.), and Regeneron Pharmaceuticals, Tarrytown (Y.S., N.M.H.G., B.A., V.M., A.G., N.S., G.D.Y., M.A.) - all in New York; the Dermatology Research Unit, University of Sheffield Medical School, Sheffield, United Kingdom (M.J.C.); the Department of Dermatology, Preventive Medicine and Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago (J.I.S.); the Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark (M.D.); the Department of Dermatology, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Habikino, Osaka, Japan (Y.K.); the Department of Dermatology, University Hospital of Nice, Nice (J.-P.L.), and Sanofi, Chilly-Mazarin (L.E.) - both in France; the Clinic of Dermatology, Tartu University Hospital, Tartu, Estonia (K.K.); the Department of Medicine, Université Laval, Hôpital Hôtel-Dieu de Québec, Quebec, QC, Canada (Y.P.); and Sanofi, Bridgewater, NJ (G.P., H.S.).

出版信息

N Engl J Med. 2016 Dec 15;375(24):2335-2348. doi: 10.1056/NEJMoa1610020. Epub 2016 Sep 30.

DOI:10.1056/NEJMoa1610020

PMID:27690741

Abstract

BACKGROUND

Dupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, inhibits signaling of interleukin-4 and interleukin-13, type 2 cytokines that may be important drivers of atopic or allergic diseases such as atopic dermatitis.

METHODS

In two randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1 and SOLO 2), we enrolled adults with moderate-to-severe atopic dermatitis whose disease was inadequately controlled by topical treatment. Patients were randomly assigned in a 1:1:1 ratio to receive, for 16 weeks, subcutaneous dupilumab (300 mg) or placebo weekly or the same dose of dupilumab every other week alternating with placebo. The primary outcome was the proportion of patients who had both a score of 0 or 1 (clear or almost clear) on the Investigator's Global Assessment and a reduction of 2 points or more in that score from baseline at week 16.

RESULTS

We enrolled 671 patients in SOLO 1 and 708 in SOLO 2. In SOLO 1, the primary outcome occurred in 85 patients (38%) who received dupilumab every other week and in 83 (37%) who received dupilumab weekly, as compared with 23 (10%) who received placebo (P<0.001 for both comparisons with placebo). The results were similar in SOLO 2, with the primary outcome occurring in 84 patients (36%) who received dupilumab every other week and in 87 (36%) who received dupilumab weekly, as compared with 20 (8%) who received placebo (P<0.001 for both comparisons). In addition, in the two trials, an improvement from baseline to week 16 of at least 75% on the Eczema Area and Severity Index was reported in significantly more patients who received each regimen of dupilumab than in patients who received placebo (P<0.001 for all comparisons). Dupilumab was also associated with improvement in other clinical end points, including reduction in pruritus and symptoms of anxiety or depression and improvement in quality of life. Injection-site reactions and conjunctivitis were more frequent in the dupilumab groups than in the placebo groups.

CONCLUSIONS

In two phase 3 trials of identical design involving patients with atopic dermatitis, dupilumab improved the signs and symptoms of atopic dermatitis, including pruritus, symptoms of anxiety and depression, and quality of life, as compared with placebo. Trials of longer duration are needed to assess the long-term effectiveness and safety of dupilumab. (Funded by Sanofi and Regeneron Pharmaceuticals; SOLO 1 ClinicalTrials.gov number, NCT02277743 ; SOLO 2 ClinicalTrials.gov number, NCT02277769 .).

摘要

背景

度普利尤单抗是一种针对白细胞介素-4 受体α的人源单克隆抗体，可抑制白细胞介素-4 和白细胞介素-13 的信号传导，这两种细胞因子可能是特应性皮炎等特应性或过敏性疾病的重要驱动因素。

方法

在两项设计相同的随机、安慰剂对照、3 期临床试验（SOLO1 和 SOLO2）中，我们招募了患有中重度特应性皮炎的成年人，这些患者的疾病经局部治疗控制不佳。患者以 1:1:1 的比例随机分配，接受为期 16 周的皮下注射度普利尤单抗（300mg）或安慰剂，每周一次或每两周一次交替给予度普利尤单抗和安慰剂。主要终点是在第 16 周时，同时达到研究者总体评估（Investigator's Global Assessment）得分为 0 或 1（清除或几乎清除）和该评分较基线降低 2 分或更多的患者比例。

结果

我们在 SOLO1 中招募了 671 名患者，在 SOLO2 中招募了 708 名患者。在 SOLO1 中，主要终点发生在 85 名（38%）接受每两周一次度普利尤单抗治疗的患者和 83 名（37%）接受每周一次度普利尤单抗治疗的患者中，而接受安慰剂治疗的患者中仅有 23 名（10%）（与安慰剂相比，两者均 P<0.001）。SOLO2 的结果相似，主要终点发生在 84 名（36%）接受每两周一次度普利尤单抗治疗的患者和 87 名（36%）接受每周一次度普利尤单抗治疗的患者中，而接受安慰剂治疗的患者中仅有 20 名（8%）（与安慰剂相比，两者均 P<0.001）。此外，在这两项试验中，与接受安慰剂治疗的患者相比，接受度普利尤单抗每种治疗方案的患者在基线至第 16 周时，湿疹面积和严重程度指数（Eczema Area and Severity Index）至少改善 75%的患者比例显著更高（所有比较均 P<0.001）。度普利尤单抗还与其他临床终点的改善相关，包括瘙痒和焦虑或抑郁症状的减轻以及生活质量的改善。与安慰剂组相比，度普利尤单抗组更常发生注射部位反应和结膜炎。

结论

在两项设计相同的 3 期临床试验中，与安慰剂相比，度普利尤单抗改善了特应性皮炎的体征和症状，包括瘙痒、焦虑和抑郁症状以及生活质量。需要更长时间的试验来评估度普利尤单抗的长期疗效和安全性。（由 Sanofi 和 Regeneron Pharmaceuticals 资助；SOLO1 临床试验.gov 编号，NCT02277743；SOLO2 临床试验.gov 编号，NCT02277769）。