特索利单抗治疗泛发性脓疱型银屑病的试验。
Trial of Spesolimab for Generalized Pustular Psoriasis.
机构信息
From Service de Dermatologie, Assistance Publique-Hôpitaux de Paris Hôpital Saint-Louis, and INSERM Unité 1163, Imagine Institute of Genetic Diseases, Université de Paris - both in Paris (H.B.); the Department of Dermatology, Hospital Sultanah Aminah Johor Bahru, Clinical School Johor Bahru, Monash University Malaysia, Subang Jaya, Malaysia (S.-E.C.); the Dermatology Department, Hedi Chaker University Hospital, Sfax, Tunisia (S.M., H.T.); the Institute of Infection, Immunity, and Inflammation, University of Glasgow, Glasgow, United Kingdom (A.D.B.); the Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan (T.-F.T.); the Department of Geriatric and Environmental Dermatology, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan (A.M.); the Department of Dermatology, University Hospital Basel, Basel, Switzerland (A.A.N.); the Department of Dermatology, Second Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou (M.Z.), and the Department of Dermatology, Huashan Hospital, Fudan University (J.X.), and Boehringer Ingelheim (China) Investment Company (H.H.), Shanghai - all in China; Washington University School of Medicine, Division of Dermatology, St. Louis (M.J.A.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (S.R., D.H.); Boehringer Ingelheim International, Ingelheim (S.D.V., K.T.), the Medical Clinic, Department of Sports Medicine, University of Tuebingen, Tuebingen (K.T.), and Boehringer Ingelheim International, Biberach (C.T.) - all in Germany; and the Icahn School of Medicine at Mount Sinai, New York (M.G.L.).
出版信息
N Engl J Med. 2021 Dec 23;385(26):2431-2440. doi: 10.1056/NEJMoa2111563.
BACKGROUND
Generalized pustular psoriasis (GPP) is a rare, life-threatening, inflammatory skin disease characterized by widespread eruption of sterile pustules. Interleukin-36 signaling is involved in the pathogenesis of this disorder. Spesolimab, a humanized anti-interleukin-36 receptor monoclonal antibody, is being studied for the treatment of GPP flares.
METHODS
In a phase 2 trial, we randomly assigned patients with a GPP flare in a 2:1 ratio to receive a single 900-mg intravenous dose of spesolimab or placebo. Patients in both groups could receive an open-label dose of spesolimab on day 8, an open-label dose of spesolimab as a rescue medication after day 8, or both and were followed to week 12. The primary end point was a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (range, 0 [no visible pustules] to 4 [severe pustulation]) at the end of week 1. The key secondary end point was a GPPGA total score of 0 or 1 (clear or almost clear skin) at the end of week 1; scores range from 0 to 4, with higher scores indicating greater disease severity.
RESULTS
A total of 53 patients were enrolled: 35 were assigned to receive spesolimab and 18 to receive placebo. At baseline, 46% of the patients in the spesolimab group and 39% of those in the placebo group had a GPPGA pustulation subscore of 3, and 37% and 33%, respectively, had a pustulation subscore of 4. At the end of week 1, a total of 19 of 35 patients (54%) in the spesolimab group had a pustulation subscore of 0, as compared with 1 of 18 patients (6%) in the placebo group (difference, 49 percentage points; 95% confidence interval [CI], 21 to 67; P<0.001). A total of 15 of 35 patients (43%) had a GPPGA total score of 0 or 1, as compared with 2 of 18 patients (11%) in the placebo group (difference, 32 percentage points; 95% CI, 2 to 53; P = 0.02). Drug reactions were reported in 2 patients who received spesolimab, in 1 of them concurrently with a drug-induced hepatic injury. Among patients assigned to the spesolimab group, infections occurred in 6 of 35 (17%) through the first week; among patients who received spesolimab at any time in the trial, infections had occurred in 24 of 51 (47%) at week 12. Antidrug antibodies were detected in 23 of 50 patients (46%) who received at least one dose of spesolimab.
CONCLUSIONS
In a phase 2 randomized trial involving patients with GPP, the interleukin-36 receptor inhibitor spesolimab resulted in a higher incidence of lesion clearance at 1 week than placebo but was associated with infections and systemic drug reactions. Longer and larger trials are warranted to determine the effect and risks of spesolimab in patients with pustular psoriasis. (Funded by Boehringer Ingelheim; Effisayil 1 ClinicalTrials.gov number, NCT03782792.).
背景
泛发性脓疱型银屑病（GPP）是一种罕见的、危及生命的炎症性皮肤病，其特征为广泛出现无菌脓疱。白细胞介素-36 信号参与了这种疾病的发病机制。Spesolimab 是一种人源化抗白细胞介素-36 受体单克隆抗体，目前正在研究用于治疗 GPP 发作。
方法
在一项 2 期试验中，我们以 2:1 的比例随机分配 GPP 发作的患者接受单次 900mg 静脉注射 spesolimab 或安慰剂。两组患者均可在第 8 天接受 spesolimab 的开放标签剂量，在第 8 天后使用 spesolimab 作为抢救药物，或同时使用，并随访至第 12 周。主要终点是第 1 周结束时广义脓疱性银屑病医生总体评估（GPPGA）脓疱评分达到 0（范围：0[无可见脓疱]至 4[严重脓疱]）。关键次要终点是第 1 周结束时 GPPGA 总评分达到 0 或 1（清除或几乎清除皮肤）；评分范围为 0 至 4，评分越高表明疾病严重程度越高。
结果
共纳入 53 例患者：35 例接受 spesolimab 治疗，18 例接受安慰剂治疗。基线时，spesolimab 组 46%的患者和安慰剂组 39%的患者 GPPGA 脓疱评分均为 3，分别有 37%和 33%的患者脓疱评分达到 4。第 1 周结束时，spesolimab 组 35 例患者中有 19 例（54%）脓疱评分达到 0，而安慰剂组有 1 例（6%）（差异：49 个百分点；95%置信区间[CI]：21 至 67；P<0.001）。第 1 周结束时，spesolimab 组 15 例（43%）患者 GPPGA 总评分达到 0 或 1，而安慰剂组有 2 例（11%）（差异：32 个百分点；95%CI：2 至 53；P = 0.02）。接受 spesolimab 治疗的 2 例患者出现药物反应，其中 1 例同时发生药物性肝损伤。在接受 spesolimab 治疗的患者中，第 1 周感染发生在 35 例患者中的 6 例（17%）；在整个试验中任何时候接受 spesolimab 治疗的患者中，第 12 周时 51 例患者中有 24 例（47%）发生感染。接受至少一剂 spesolimab 的 50 例患者中有 23 例（46%）检测到抗药物抗体。
结论
在一项涉及 GPP 患者的 2 期随机试验中，白细胞介素-36 受体抑制剂 spesolimab 在第 1 周时使病变清除的发生率高于安慰剂，但与感染和全身药物反应有关。需要进行更长和更大规模的试验来确定 spesolimab 在脓疱性银屑病患者中的疗效和风险。（由 Boehringer Ingelheim 资助；Effisayil 1 临床试验.gov 编号，NCT03782792）。
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