Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, United States.
Jackson Health System, Miami, FL, United States.
Front Immunol. 2024 Jul 22;15:1359481. doi: 10.3389/fimmu.2024.1359481. eCollection 2024.
Generalized pustular psoriasis (GPP) is a chronic, rare, and potentially life-threatening inflammatory disease, characterized by the rapid and widespread eruption of small, sterile pustules with surrounding skin erythema. Abnormal signaling of the interleukin-36 (IL-36) pathway appears to have a central role in GPP immunopathology, and provides a rational therapeutic target. Spesolimab is a first-in-class humanized monoclonal antibody that binds specifically to the IL-36 receptor, and antagonizes IL-36 signaling. Spesolimab obtained regulatory approval in the United States (US) in September 2022 for use in the treatment of GPP flares in adults, and was subsequently approved for GPP flare treatment in many other countries across the world. Recently, regulatory approval was granted for subcutaneous dosing of spesolimab for treatment of GPP when not experiencing a flare. Here, we review data from two key clinical trials that supported the initial US regulatory approval; namely, the phase 1 proof-of-concept trial (ClinicalTrials.gov ID, NCT02978690), and Effisayil 1 (NCT03782792), which remains the largest and only randomized clinical trial in patients experiencing GPP flares published to date. In the phase 1 proof-of-concept trial, a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 0 or 1 (clear or almost clear skin) was attained in 5/7 (71%) patients by week 1 and in all 7 patients by week 4; and the mean percent improvement in the Generalized Pustular Psoriasis Area and Severity Index (GPPASI) score from baseline was 59.0% at week 1, 73.2% at week 2, and 79.8% at week 4. In Effisayil 1, a GPPGA pustulation subscore of 0 (no visible pustules) was achieved in 19/35 (54%) patients receiving spesolimab at the end of week 1, versus 1/18 (6%) receiving placebo (difference, 49 percentage points; 95% confidence interval [CI], 21 to 67; P<0.001); and a GPPGA total score of 0 or 1 was achieved by 15/35 (43%) patients in the spesolimab group, versus 2/18 (11%) patients in the placebo group (difference, 32 percentage points; 95% CI, 2 to 53; P = 0.02). Infections at week 1 were reported in 6/35 (17%) patients receiving spesolimab and in 1/18 (6%) patients receiving placebo. These data demonstrate the efficacy and safety of spesolimab in providing rapid and sustained clinical improvement for patients with GPP flares, which translates into improved quality of life, by offering a targeted therapy for GPP.
全身性脓疱性银屑病（GPP）是一种慢性、罕见且潜在危及生命的炎症性疾病，其特征为迅速广泛出现小而无菌的脓疱，周围皮肤红斑。白细胞介素-36（IL-36）通路的异常信号似乎在 GPP 免疫病理学中起核心作用，并提供了合理的治疗靶点。Spesolimab 是一种首创的人源化单克隆抗体，特异性结合 IL-36 受体，拮抗 IL-36 信号。Spesolimab 于 2022 年 9 月在美国获得监管批准，用于治疗成人 GPP 发作，随后在世界许多其他国家/地区批准用于 GPP 发作治疗。最近，皮下给药 spesolimab 治疗非发作期 GPP 获得监管批准。在此，我们回顾了支持最初美国监管批准的两项关键临床试验数据；即，1 期概念验证试验（ClinicalTrials.gov ID，NCT02978690）和 Effisayil 1（NCT03782792），这是迄今为止发表的 GPP 发作患者中最大且唯一的随机临床试验。在 1 期概念验证试验中，7 名患者中有 5 名（71%）在第 1 周达到全身性脓疱性银屑病医生全球评估（GPPGA）评分 0 或 1（皮肤清晰或几乎清晰），所有 7 名患者在第 4 周达到该评分；从基线到第 1 周 GPPASI 评分的平均改善百分比为 59.0%，第 2 周为 73.2%，第 4 周为 79.8%。在 Effisayil 1 中，接受 spesolimab 治疗的 35 名患者中有 19 名（54%）在第 1 周末达到全身性脓疱性银屑病脓疱评分 0（无可见脓疱），而接受安慰剂治疗的 18 名患者中仅有 1 名（6%）达到该评分（差异，49 个百分点；95%置信区间 [CI]，21 至 67；P<0.001）；spesolimab 组中有 15 名（43%）患者达到 GPPGA 总评分 0 或 1，而安慰剂组中有 2 名（11%）患者达到该评分（差异，32 个百分点；95%CI，2 至 53；P = 0.02）。在第 1 周，接受 spesolimab 治疗的 35 名患者中有 6 名（17%）和接受安慰剂治疗的 18 名患者中有 1 名（6%）报告出现感染。这些数据表明 spesolimab 能迅速和持续改善 GPP 发作患者的临床症状，改善生活质量，为 GPP 提供了一种靶向治疗。
