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. 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. 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. 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. Boehringer Ingelheim.

中文翻译：

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皮下注射司匹索利单抗预防全身性脓疱型银屑病发作的功效和安全性 (Effisayil 2)：一项国际、多中心、随机、安慰剂对照试验

Spesolimab 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。我们的目的是评估 spesolimab 预防 GPP 耀斑的有效性和安全性。这项多中心、随机、安慰剂对照 2b 期试验在 20 个国家的 60 家医院和诊所进行。符合资格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 GPP 病史，过去至少有两次 GPP 发作病史，且 GPP 医师全球评估 (GPPGA) 评分为筛选和随机分配时为 0 或 1。患者被随机分配（1:1:1:1）接受皮下注射安慰剂、皮下注射低剂量斯佩索利单抗（300 mg 负荷剂量，随后每 12 周 150 mg）、皮下注射中剂量 spesolimab（600 mg 负荷剂量，随后 300 mg）。 mg 每 12 周），或皮下注射高剂量 spesolimab（600 mg 负荷剂量，随后每 4 周 300 mg）超过 48 周。主要目标是证明主要终点（首次 GPP 耀斑时间）的非平坦剂量反应曲线。从2020年6月8日到2022年11月23日，筛查了157名患者，其中123名被随机分配。92 名患者被分配接受 spesolimab 治疗（30 名高剂量、31 名中剂量和 31 名低剂量），31 名接受安慰剂。所有患者均为亚洲人（123 名患者中的 79 名 [64%]）或白人（44 名 [36%]）。患者组在性别分布（76 [62%] 女性和 47 [38%] 男性）、年龄（平均 40·4 岁，SD 15·8）和 GPP 医师总体评估评分方面相似。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 spesolimab 组 31 名患者中有 7 名 (23%)，中剂量 spesolimab 组 31 名患者中有 9 名 (29%)，高剂量 spesolimab 组 30 名患者中有 3 名 (10%)，以及 16 名患者(52%) 安慰剂组 31 名患者。在主要结局 GPP 发作时间（风险比 [HR]=0·16，95% CI 0·05–0·54；p=0·0005）终点方面，高剂量斯培索利单抗显着优于安慰剂。低剂量斯培索利单抗组的 HR 为 0·35（95% CI 0·14–0·86，名义 p=0·0057），HR 为 0·47（0·21–1·06，p=0·027）在中等剂量 spesolimab 组中。与安慰剂相比，我们建立了 spesolimab 的非平坦剂量反应关系，每个预定义模型的 p 值具有统计显着性（线性 p=0·0022、emax1 p=0·0024、emax2 p=0·0023 和指数 p =0·0034）。各治疗组的感染率相似；没有死亡，也没有导致停药的过敏反应。高剂量斯培索利单抗在预防 GPP 耀斑方面优于安慰剂，显着降低了 48 周内 GPP 耀斑和耀斑发生的风险。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，最终可能会改善患者的发病率和生活质量。勃林格殷格翰。