From Innovaderm Research, Montreal (R.B.), McMaster University and Dermatrials Research, Hamilton, ON (R.V.), Alliance Clinical Trials and Probity Medical Research, Waterloo, ON (K.P.), and the Division of Dermatology, Department of Medicine, University of Toronto, Toronto (K.P.) - all in Canada; Goethe University Frankfurt, Frankfurt am Main (A.P.), and the Center for Inflammatory Skin Diseases, University Medical Center Schleswig-Holstein Campus Kiel, Kiel (S.G.) - both in Germany; the University of Pittsburgh, Pittsburgh (L.K.F.), and Janssen Research and Development, Spring House (M.M., Y.-K.S., A.K., S.L., C.D.) - both in Pennsylvania; and Oregon Dermatology and Research Center, Portland (P.R.).
N Engl J Med. 2024 Feb 8;390(6):510-521. doi: 10.1056/NEJMoa2308713.
The use of monoclonal antibodies has changed the treatment of several immune-mediated inflammatory diseases, including psoriasis. However, these large proteins must be administered by injection. JNJ-77242113 is a novel, orally administered interleukin-23-receptor antagonist peptide that selectively blocks interleukin-23 signaling and downstream cytokine production.
In this phase 2 dose-finding trial, we randomly assigned patients with moderate-to-severe plaque psoriasis to receive JNJ-77242113 at a dose of 25 mg once daily, 25 mg twice daily, 50 mg once daily, 100 mg once daily, or 100 mg twice daily or placebo for 16 weeks. The primary end point was a reduction from baseline of at least 75% in the Psoriasis Area and Severity Index (PASI) score (PASI 75 response; PASI scores range from 0 to 72, with higher scores indicating greater extent or severity of psoriasis) at week 16.
A total of 255 patients underwent randomization. The mean PASI score at baseline was 19.1. The mean duration of psoriasis was 18.2 years, and 78% of the patients across all the trial groups had previously received systemic treatments. At week 16, the percentages of patients with a PASI 75 response were higher among those in the JNJ-77242113 groups (37%, 51%, 58%, 65%, and 79% in the 25-mg once-daily, 25-mg twice-daily, 50-mg once-daily, 100-mg once-daily, and 100-mg twice-daily groups, respectively) than among those in the placebo group (9%), a finding that showed a significant dose-response relationship (P<0.001). The most common adverse events included coronavirus disease 2019 (in 12% of the patients in the placebo group and in 11% of those across the JNJ-77242113 dose groups) and nasopharyngitis (in 5% and 7%, respectively). The percentages of patients who had at least one adverse event were similar in the combined JNJ-77242113 dose group (52%) and the placebo group (51%). There was no evidence of a dose-related increase in adverse events across the JNJ-77242113 dose groups.
After 16 weeks of once- or twice-daily oral administration, treatment with the interleukin-23-receptor antagonist peptide JNJ-77242113 showed greater efficacy than placebo in patients with moderate-to-severe plaque psoriasis. (Funded by Janssen Research and Development; FRONTIER 1 ClinicalTrials.gov number, NCT05223868.).
单克隆抗体的使用改变了几种免疫介导的炎症性疾病的治疗方法，包括银屑病。然而，这些大蛋白必须通过注射给药。JNJ-77242113 是一种新型的、口服的白细胞介素-23 受体拮抗剂肽，可选择性阻断白细胞介素-23 信号传导和下游细胞因子的产生。
在这项 2 期剂量探索试验中，我们将中重度斑块状银屑病患者随机分为 JNJ-77242113 组，接受 25mg 每日 1 次、25mg 每日 2 次、50mg 每日 1 次、100mg 每日 1 次、100mg 每日 2 次或安慰剂治疗，疗程为 16 周。主要终点为第 16 周时，与基线相比，患者的银屑病面积和严重程度指数（PASI）评分至少下降 75%（PASI75 应答；PASI 评分范围为 0 至 72，评分越高表示银屑病的范围或严重程度越大）。
共 255 名患者接受了随机分组。基线时平均 PASI 评分为 19.1。平均银屑病病程为 18.2 年，所有试验组中 78%的患者既往接受过系统治疗。第 16 周时，与安慰剂组（9%）相比，接受 JNJ-77242113 治疗的患者中 PASI75 应答率更高（25mg 每日 1 次组、25mg 每日 2 次组、50mg 每日 1 次组、100mg 每日 1 次组和 100mg 每日 2 次组分别为 37%、51%、58%、65%和 79%），且存在显著的剂量反应关系（P<0.001）。最常见的不良事件包括新型冠状病毒肺炎（安慰剂组 12%，JNJ-77242113 各剂量组 11%）和鼻咽炎（各 5%和 7%）。联合 JNJ-77242113 剂量组（52%）和安慰剂组（51%）中至少有 1 例不良事件的患者比例相似。JNJ-77242113 剂量组间未发现不良事件与剂量相关的增加。
接受每日 1 次或 2 次口服 JNJ-77242113 治疗 16 周后，与安慰剂相比，白细胞介素-23 受体拮抗剂肽 JNJ-77242113 在中重度斑块状银屑病患者中的疗效更优。（由杨森研发公司资助；FRONTIER1 临床试验.gov 编号，NCT05223868。）
