spesolimab治疗泛发性脓疱型银屑病的试验

摘 要

背景

泛发性脓疱型银屑病是一种罕见且危及生命的炎症性皮肤病，其特征为广泛的无菌脓疱。白介素-36信号通路与该疾病的发病机制相关。spesolimab是人源化的抗白介素-36受体单克隆抗体，正被研究用于治疗GPP发作。

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.

方法

在一项2期试验中，我们以2:1的比例将GPP发作患者随机分组，两组分别接受单次900 mg spesolimab或安慰剂静脉给药。两组患者均可在第8日接受开放标签spesolimab，在第8日之后接受作为挽救用药的开放标签spesolimab，或者两者均接受，并接受随访至第12周。主要终点是第1周结束时，GPPGA（泛发性脓疱型银屑病医师总体评估，Generalized Pustular Psoriasis Physician Global Assessment）的脓疱分项评分为0分（范围，0[无可见脓疱]~4分[重度脓疱]）。关键次要终点是第1周结束时，GPPGA总分为0或1分（皮损清除或基本清除）；评分范围为0~4分，评分较高表示疾病较严重。

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.

结果

共计53例患者被纳入研究：35例被分配接受spesolimab，18例接受安慰剂。基线时，spesolimab组46%患者和安慰剂组39%患者的GPPGA脓疱分项评分为3分，两组分别有37%和33%患者的脓疱分项评分为4分。第1周结束时，spesolimab组35例患者中的19例（54%）脓疱分项评分为0分，而安慰剂组为18例患者中的1例（6%）（差异，49个百分点；95%置信区间[CI]，21~67；P<0.001）。spesolimab组35例患者中的15例（43%）的GPPGA总分为0或1分，而安慰剂组为18例患者中的2例（11%）（差异，32个百分点；95% CI，2~53；P=0.02）。spesolimab组2例患者报告了药物反应，其中1例合并药物性肝损伤。在被分配至spesolimab组的患者中，第1周期间，35例中的6例（17%）发生了感染；在试验期间任何时间接受了spesolimab的患者中，第12周时，51例中的24例（47%）发生了感染。在接受了至少1剂spesolimab的50例患者中，有23例（46%）检出抗药物抗体。

Result

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.

结论

在对GPP患者进行的此项2期随机试验中，白介素-36受体抑制剂spesolimab组在1周时的皮损清除率高于安慰剂组，但spesolimab组发生了感染和全身性药物反应。我们需要开展更长时间、更大规模的试验来确定spesolimab对脓疱型银屑病患者的疗效和风险。（由勃林格殷格翰资助；Effisayil 1在ClinicalTrials.gov注册号为NCT03782792。）

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.)

Hervé Bachelez, Siew-Eng Choon, Slaheddine Marrakchi, et al. Trial of Spesolimab for Generalized Pustular Psoriasis. DOI: 10.1056/NEJMoa2111563