From the Department of Dermatology, University of Rochester Medical Center, Rochester (L.A.B.), Regeneron Pharmaceuticals, Tarrytown (J.D.H., N.M.G., H.R., R.K., M.A., S.P.W., M.D.H., N.S., G.D.Y., A.R.R.), the Department of Dermatology and the Immunology Institute, Icahn School of Medicine at Mount Sinai (E.G.-Y.), the Laboratory for Investigative Dermatology (E.G.-Y., M.S.-F.) and the Center for Clinical and Translational Science (M.S.-F.), Rockefeller University, New York - all in New York; the Department of Dermatology, Allergology, and Venereology, Universität zu Lübeck, Lübeck (D.T.), and the Department of Dermatology and Allergology, University of Bonn, Bonn (T.B.) - both in Germany; Sanofi, Bridgewater, NJ (R.R., J.E.M., G.P.); and the Department of Dermatology, Oregon Health and Science University, Portland (E.S.).
N Engl J Med. 2014 Jul 10;371(2):130-9. doi: 10.1056/NEJMoa1314768.
Dupilumab, a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13, has shown efficacy in patients with asthma and elevated eosinophil levels. The blockade by dupilumab of these key drivers of type 2 helper T-cell (Th2)-mediated inflammation could help in the treatment of related diseases, including atopic dermatitis.
We performed randomized, double-blind, placebo-controlled trials involving adults who had moderate-to-severe atopic dermatitis despite treatment with topical glucocorticoids and calcineurin inhibitors. Dupilumab was evaluated as monotherapy in two 4-week trials and in one 12-week trial and in combination with topical glucocorticoids in another 4-week study. End points included the Eczema Area and Severity Index (EASI) score, the investigator's global assessment score, pruritus, safety assessments, serum biomarker levels, and disease transcriptome.
In the 4-week monotherapy studies, dupilumab resulted in rapid and dose-dependent improvements in clinical indexes, biomarker levels, and the transcriptome. The results of the 12-week study of dupilumab monotherapy reproduced and extended the 4-week findings: 85% of patients in the dupilumab group, as compared with 35% of those in the placebo group, had a 50% reduction in the EASI score (EASI-50, with higher scores in the EASI indicating greater severity of eczema) (P<0.001); 40% of patients in the dupilumab group, as compared with 7% in the placebo group, had a score of 0 to 1 (indicating clearing or near-clearing of skin lesions) on the investigator's global assessment (P<0.001); and pruritus scores decreased (indicating a reduction in itch) by 55.7% in the dupilumab group versus 15.1% in the placebo group (P<0.001). In the combination study, 100% of the patients in the dupilumab group, as compared with 50% of those who received topical glucocorticoids with placebo injection, met the criterion for EASI-50 (P=0.002), despite the fact that patients who received dupilumab plus glucocorticoids used less than half the amount of topical glucocorticoids used by those who received placebo plus the topical medication (P=0.16). Adverse events, such as skin infection, occurred more frequently with placebo; nasopharyngitis and headache were the most frequent adverse events with dupilumab.
Patients treated with dupilumab had marked and rapid improvement in all the evaluated measures of atopic dermatitis disease activity. Side-effect profiles were not dose-limiting. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT01259323, NCT01385657, NCT01639040, and NCT01548404.).
度普利尤单抗是一种完全人源化的单克隆抗体，可阻断白细胞介素-4 和白细胞介素-13，已显示出在哮喘和嗜酸性粒细胞水平升高的患者中的疗效。度普利尤单抗阻断这些 2 型辅助 T 细胞 (Th2) 介导炎症的关键驱动因素，有助于治疗相关疾病，包括特应性皮炎。
我们进行了随机、双盲、安慰剂对照试验，纳入了接受局部糖皮质激素和钙调磷酸酶抑制剂治疗后仍有中重度特应性皮炎的成年人。度普利尤单抗在两项为期 4 周的试验中作为单药治疗进行了评估，在一项为期 12 周的试验中进行了评估，并在另一项为期 4 周的研究中与局部糖皮质激素联合使用。终点包括湿疹面积和严重程度指数 (EASI) 评分、研究者整体评估评分、瘙痒、安全性评估、血清生物标志物水平和疾病转录组。
在 4 周的单药治疗研究中，度普利尤单抗迅速且呈剂量依赖性改善临床指标、生物标志物水平和转录组。为期 12 周的度普利尤单抗单药治疗研究结果再现并扩展了 4 周的发现：与安慰剂组的 35%相比，度普利尤单抗组的 85%患者 EASI 评分降低 50%（EASI-50，EASI 评分越高表示湿疹越严重）（P<0.001）；与安慰剂组的 7%相比，度普利尤单抗组的 40%患者研究者整体评估评分达到 0 至 1（表示皮损清除或接近清除）（P<0.001）；瘙痒评分下降（表示瘙痒减轻），度普利尤单抗组下降 55.7%，安慰剂组下降 15.1%（P<0.001）。在联合研究中，与接受安慰剂加局部皮质类固醇注射的患者相比，度普利尤单抗组的 100%患者符合 EASI-50 标准（P=0.002），尽管接受度普利尤单抗加皮质类固醇的患者使用的局部皮质类固醇量不到接受安慰剂加局部皮质类固醇的患者的一半（P=0.16）。皮肤感染等不良事件在安慰剂组中更为常见；鼻咽炎和头痛是度普利尤单抗最常见的不良事件。
接受度普利尤单抗治疗的患者在所有评估的特应性皮炎疾病活动指标上均有显著且快速的改善。副作用谱不是剂量限制因素。（由再生元制药公司和赛诺菲资助；临床试验.gov 编号，NCT01259323、NCT01385657、NCT01639040 和 NCT01548404）。
