广义脓疱型牛皮癣(3GPP)是一种慢性、罕见,和可能危及生命的炎症性疾病,其特点是迅速而广泛的小喷发,无菌脓疱,周围皮肤红斑。白细胞介素-36(IL-36)途径的异常信号传导似乎在3GPP免疫病理学中起着核心作用,提供合理的治疗靶点。Spesolimab是一类中的人源化单克隆抗体,与IL-36受体特异性结合,并拮抗IL-36信号传导。Spesolimab于2022年9月在美国(US)获得了监管批准,用于治疗成人的3GPP耀斑,并随后在世界许多其他国家/地区被批准用于3GPP耀斑治疗。最近,在未出现耀斑的情况下,给予spesolimab皮下给药用于治疗3GPP的监管部门批准.这里,我们审查了两项支持美国监管机构最初批准的关键临床试验的数据;即第一阶段概念验证试验(ClinicalTrials.govID,NCT02978690),和Effisayil™1(NCT03782792),这仍然是迄今为止发表的针对有GPP耀斑患者的最大也是唯一的随机临床试验.在第一阶段概念验证试验中,5/7(71%)患者在第1周时和所有7例患者在第4周时获得了0或1分(透明或几乎透明的皮肤)的广义脓疱型银屑病医师全球评估(GPPGA);与基线相比,广义脓疱型银屑病面积和严重程度指数(GPPASI)评分在第1周时为59.0%,第2周时为73.2%,第4周为79.8%。在Effisayil™1中,在第1周结束时接受spesolimab的19/35(54%)患者的GPPGA脓疱子评分为0(无可见脓疱),与接受安慰剂的1/18(6%)相比(差异,49个百分点;95%置信区间[CI],21至67;P<0.001);spesolimab组中15/35(43%)患者的GPPGA总分为0或1,安慰剂组的2/18(11%)患者(差异,32个百分点;95%CI,2至53;P=0.02)。在接受spesolimab的6/35(17%)患者和接受安慰剂的1/18(6%)患者中报告了第1周的感染。这些数据证明了spesolimab的有效性和安全性,可以为有GPP耀斑的患者提供快速和持续的临床改善。这意味着生活质量的提高,通过为3GPP提供靶向治疗。
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.