美国西奈山伊坎医学院Mark G Lebwohl课题组研究了皮下司柏索利单抗预防脓疱性银屑病的临床疗效和安全性。相关研究成果于2023年9月19日发表在《柳叶刀》杂志上。

司柏索利单抗是一种抗白细胞介素36受体单克隆抗体，被批准用于治疗泛发性脓疱性银屑病（GPP）发作。该研究旨在评估司柏索利单抗预防GPP发作的疗效和安全性。

这项多中心、随机、安慰剂对照的2b期临床试验在20个国家的60家医院和诊所进行。符合条件的研究参与者年龄在12至75岁之间，根据欧洲罕见和严重银屑病专家网络标准，有记录的GPP病史，至少有两次GPP发作史，在筛查和随机分配时，GPP医师全球评估（GPPGA）得分为0或1。将患者随机分配（1:1:1:1）在48周内接受皮下安慰剂、皮下低剂量司柏索利单抗（300 mg负荷剂量，然后每12周150 mg）、皮下中剂量司柏索利单抗（600 mg负荷剂量然后每12周300 mg）或皮下高剂量司柏索利单抗（600 mg负荷剂量，然后每隔4周300 mg）。主要目的为主要终点，即首次GPP发作的时间上证明非平坦的剂量-反应曲线。

从2020年6月8日到2022年11月23日，研究组共筛查了157名患者，其中123名被随机分配。92名被分配接受司柏索利单抗（30人高剂量，31人中剂量和31人低剂量），31人被分配接受安慰剂。所有患者要么是亚洲人（123人中有79人[64%]），要么是白人（44人[36%]）。患者组在性别分布（76名[62]女性和47名[38%]男性）、年龄（平均40.4岁）和GPP医师全球评估评分方面相似。在主要终点上建立了非平坦的剂量-反应关系。

到第48周，35名患者出现GPP发作；低剂量司柏索利单抗组31名患者中有7名（23%），中剂量司柏索利单抗组31例患者中有9名（29%），高剂量司柏索利单抗组30例患者中有3名（10%），安慰剂组31例患者中有16名（52%）。在GPP发作时间的主要结局终点方面，高剂量司柏索利单抗明显优于安慰剂组（危险比[HR]=0.16，p=0.0005）。低剂量司柏索利单抗组的HR为0.35，中剂量司柏索利单抗组的HRs为0.47（p=0.027）。与安慰剂相比，研究组建立了司柏索利单抗的非平坦剂量反应关系，每个预定义模型的p值具有统计学意义（线性p=0.0022，emax1 p=0.0024，emax2 p=0.0023，指数p=0.0034）。各治疗组的感染率相似；没有患者死亡，也没有导致停药的超敏反应。

研究结果表明，高剂量司柏索利单抗在预防GPP发作方面优于安慰剂，在48周内显著降低了GPP发作和发生的风险。鉴于GPP的慢性性质，预防发作的治疗是临床方法的重大转变，并可能最终改善患者的发病率和生活质量。

附：英文原文

Title: Efficacy and safety of subcutaneous spesolimab for the prevention of generalised pustular psoriasis flares (Effisayil 2): an international, multicentre, randomised, placebo-controlled trial

Author: Akimichi Morita, Bruce Strober, A David Burden, Siew Eng Choon, Milan J Anadkat, Slaheddine Marrakchi, Tsen-Fang Tsai, Kenneth B Gordon, Diamant Thai, Min Zheng, Na Hu, Thomas Haeufel, Christian Thoma, Mark G Lebwohl

Issue&Volume: 2023-09-19

Abstract:

Background

Spesolimab is an anti-interleukin-36 receptor monoclonal antibody approved to treat generalised pustular psoriasis (GPP) flares. We aimed to assess the efficacy and safety of spesolimab for GPP flare prevention.

Methods

This multicentre, randomised, placebo-controlled, phase 2b trial was done at 60 hospitals and clinics in 20 countries. Eligible study participants were aged between 12 and 75 years with a documented history of GPP as per the European Rare and Severe Psoriasis Expert Network criteria, with a history of at least two past GPP flares, and a GPP Physician Global Assessment (GPPGA) score of 0 or 1 at screening and random assignment. Patients were randomly assigned (1:1:1:1) to receive subcutaneous placebo, subcutaneous low-dose spesolimab (300 mg loading dose followed by 150 mg every 12 weeks), subcutaneous medium-dose spesolimab (600 mg loading dose followed by 300 mg every 12 weeks), or subcutaneous high-dose spesolimab (600 mg loading dose followed by 300 mg every 4 weeks) over 48 weeks. The primary objective was to demonstrate a non-flat dose-response curve on the primary endpoint, time to first GPP flare.

Findings

From June 8, 2020, to Nov 23, 2022, 157 patients were screened, of whom 123 were randomly assigned. 92 were assigned to receive spesolimab (30 high dose, 31 medium dose, and 31 low dose) and 31 to placebo. All patients were either Asian (79 [64%] of 123) or White (44 [36%]). Patient groups were similar in sex distribution (76 [62%] female and 47 [38%] male), age (mean 40·4 years, SD 15·8), and GPP Physician Global Assessment score. A non-flat dose-response relationship was established on the primary endpoint. By week 48, 35 patients had GPP flares; seven (23%) of 31 patients in the low-dose spesolimab group, nine (29%) of 31 patients in the medium-dose spesolimab group, three (10%) of 30 patients in the high-dose spesolimab group, and 16 (52%) of 31 patients in the placebo group. High-dose spesolimab was significantly superior versus placebo on the primary outcome of time to GPP flare (hazard ratio [HR]=0·16, 95% CI 0·05–0·54; p=0·0005) endpoint. HRs were 0·35 (95% CI 0·14–0·86, nominal p=0·0057) in the low-dose spesolimab group and 0·47 (0·21–1·06, p=0·027) in the medium-dose spesolimab group. We established a non-flat dose-response relationship for spesolimab compared with placebo, with statistically significant p values for each predefined model (linear p=0·0022, emax1 p=0·0024, emax2 p=0·0023, and exponential p=0·0034). Infection rates were similar across treatment arms; there were no deaths and no hypersensitivity reactions leading to discontinuation.

Interpretation

High-dose spesolimab was superior to placebo in GPP flare prevention, significantly reducing the risk of a GPP flare and flare occurrence over 48 weeks. Given the chronic nature of GPP, a treatment for flare prevention is a significant shift in the clinical approach, and could ultimately lead to improvements in patient morbidity and quality of life.

DOI: 10.1016/S0140-6736(23)01378-8

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01378-8/abstract