背景:我们评估了中重度掌plant脓疱病(PPP)患者的抗白介素36受体抗体spesolimab。
方法:该IIb期试验包括负荷剂量期至第(W)4周,然后维持给药至W52。患者被随机分为2:1:1:1:2,皮下spesolimab3000mg至W4,然后每4周600mg(q4w),spesolimab3000毫克到W4,然后300毫克q4w,spesolimab1500毫克到W4,然后600毫克q4w,spesolimab1500毫克至W4,300毫克q4w至W16,然后每8周300毫克(q8w),或安慰剂在W16时切换到spesolimab600mgq4w。主要疗效终点是W16时掌足底脓疱面积和严重程度指数(PPPASI)相对于基线的百分比变化。次要终点包括掌足底脓疱医生的全球评估(PPPPGA)评分为0/1。安全性(包括不良事件[AE],局部耐受性)进行评估。
结果:152例患者接受治疗。未达到主要终点;spesolimab与安慰剂的平均差异为-14.6%(95%置信区间[CI]:-31.5%,2.2%)至-5.3%(95%CI:-19.1%,8.6%);均未达到显著性。在W16,spesolimab和安慰剂组的23(21.1%)和两名(4.7%)患者,分别,实现PPPPGA0/1(平均差16.4%;95%CI:3.8%,25.7%),在W52时增加到59名(54.1%;联合使用spesolimab)和12名(27.9%;安慰剂转换为spesolimab)患者。非亚洲患者的主要终点(平均差异-17.7%;名义P=0.0394)和W16的PPPPGA0/1与spesolimab相比安慰剂有显着改善。对于spesolimab和安慰剂,AE和AE相关的停药率相似。spesolimab的局部耐受性事件和注射部位反应比安慰剂更频繁。
结论:未实现证明非平坦剂量反应关系和概念验证的主要目标;spesolimab在次要终点和非亚洲患者中出现改善,表明潜在的适度好处。Spesolimab通常耐受性良好(ClinicalTrials.govNCT04015518)。
spesolimab治疗掌plant脓疱病的临床试验。掌plant脓疱病(PPP)是一种痛苦的,在患者的手掌和脚掌上发现的难以治疗的皮肤病。在这个临床试验中,我们研究了一种名为spesolimab的注射药物,用于治疗PPP患者。患者分为五组;四组接受不同剂量的spesolimab,一组接受安慰剂(不注射spesolimab)。16周后,接受安慰剂的患者改用spesolimab.我们测量了受PPP影响的身体面积以及在第16周PPP的严重程度。患者的医生还评估了受PPP影响的皮肤。治疗16周后,spesolimab和安慰剂在PPP影响面积和严重程度方面无显著差异.然而,与安慰剂相比,使用spesolimab的患者皮肤清晰或几乎清晰。在非亚洲患者中,与安慰剂组相比,spesolimab组的PPP有更多的改善;亚洲患者的情况并非如此.服用spesolimab或安慰剂的患者报告有副作用,其中最常见的是感冒,疼痛和头痛。与安慰剂相比,更多接受spesolimab的患者在注射部位报告了反应。我们对病人进行了长达1年的监测,结果仍然相似。我们表明,spesolimab可能对受PPP影响的身体区域有适度的影响,以及PPP的严重性,似乎没有比安慰剂引起更多的副作用,除了注射部位的反应。
BACKGROUND: We evaluated the anti-interleukin-36 receptor antibody spesolimab in patients with moderate-to-severe palmoplantar pustulosis (PPP).
METHODS: This phase IIb trial comprised a loading dose period to week (W) 4, then maintenance dosing to W52. Patients were randomised 2:1:1:1:2 to subcutaneous spesolimab 3000 mg to W4 then 600 mg every 4 weeks (q4w),
spesolimab 3000 mg to W4 then 300 mg q4w,
spesolimab 1500 mg to W4 then 600 mg q4w,
spesolimab 1500 mg to W4, 300 mg q4w to W16 then 300 mg every 8 weeks (q8w), or placebo switching to spesolimab 600 mg q4w at W16. The primary efficacy endpoint was percentage change from baseline in Palmoplantar Pustular Area and Severity Index (PPP ASI) at W16. Secondary endpoints included a Palmoplantar Pustular Physician\'s Global Assessment (PPP PGA) score of 0/1. Safety (including adverse events [AEs], local tolerability) was assessed.
RESULTS: 152 patients were treated. The primary endpoint was not met; mean differences for spesolimab versus placebo ranged from - 14.6% (95% confidence interval [CI]: - 31.5%, 2.2%) to - 5.3% (95% CI: - 19.1%, 8.6%); none reached significance. At W16, 23 (21.1%) and two (4.7%) patients in the combined spesolimab and placebo groups, respectively, achieved PPP PGA 0/1 (mean difference 16.4%; 95% CI: 3.8%, 25.7%), increasing to 59 (54.1%; combined spesolimab) and 12 (27.9%; placebo switch to
spesolimab) patients at W52. Non-Asian patients had significant improvements in the primary endpoint (mean difference - 17.7%; nominal P = 0.0394) and PPP PGA 0/1 at W16 with spesolimab versus placebo. Rates of AEs and AE-related discontinuations were similar for spesolimab and placebo. Local tolerability events and injection-site reactions were more frequent with spesolimab than placebo.
CONCLUSIONS: The primary objective to demonstrate a non-flat dose-response relationship and proof-of-concept was not achieved; improvements with spesolimab occurred in secondary endpoints and in non-Asian patients, indicating potential modest benefits.
Spesolimab was generally well tolerated (ClinicalTrials.gov NCT04015518).
A clinical trial of spesolimab for patients with palmoplantar pustulosis. Palmoplantar pustulosis (PPP) is a painful, difficult-to-treat skin disease that is found on patients’ palms and the soles of their feet. In this clinical trial, we studied an injected medicine called spesolimab for treating patients with PPP. Patients were split into five groups; four groups received different doses of spesolimab and one received placebo (an injection without
spesolimab). After 16 weeks, patients receiving placebo switched to
spesolimab. We measured the body area affected by PPP and how severe PPP was at week 16. Patients’ doctors also assessed skin affected by PPP. At 16 weeks of treatment, there was no significant difference between spesolimab and placebo in terms of the PPP-affected area and severity. However, more patients had clear or almost clear skin with spesolimab than placebo. Among non-Asian patients, more showed an improvement in their PPP with spesolimab than with placebo; this was not the case with Asian patients. Patients taking spesolimab or placebo reported side effects, of which the most common were colds, aches and headaches. More patients receiving spesolimab reported a reaction at the injection site compared with placebo. We monitored patients for up to 1 year, and results remained similar. We showed that spesolimab may have a modest effect on the body area affected by PPP, as well as the severity of PPP, and did not seem to cause more side effects than placebo, except for reactions at the injection site.