CNTO6785，一种完全人源抗白细胞介素 17 单克隆抗体，用于甲氨蝶呤治疗应答不足的类风湿关节炎患者：一项随机、安慰剂对照、Ⅱ期、剂量范围研究。

CNTO6785, a Fully Human Antiinterleukin 17 Monoclonal Antibody, in Patients with Rheumatoid Arthritis with Inadequate Response to Methotrexate: A Randomized, Placebo-controlled, Phase II, Dose-ranging Study.

机构信息

From the Swedish Medical Center and University of Washington, Seattle, Washington; Janssen Research and Development LLC, Spring House, Pennsylvania, USA; Department of Rheumatology and Connective Tissue Diseases, 2nd University Hospital, CM UMK, Bydgoszcz, Poland; Centro de Reumatologia y Ortopedia, Universidad Metropolitana, Barranquilla, Colombia; Rajavithi Hospital, Bangkok, Thailand; Division of Rheumatology, Department of Internal Medicine, Chiang Mai University, Chiang Mai, Thailand; Institute of Rheumatology, Prague, Czech Republic; Clinical Rheumatology Hospital #25, St. Petersburg, Russia; Head Rheumatology Unit, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; Janssen (China) Research and Development Center, Beijing, China.

P.J. Mease, MD, Swedish Medical Center and University of Washington; S. Jeka, Professor, MD, Department of Rheumatology and Connective Tissue Diseases, 2nd University Hospital, CM UMK; J.J. Jaller, MD, Scientific Director, Centro de Reumatologia y Ortopedia, Docente Investigador, Universidad Metropolitana; T. Kitumnuaypong, MD, Rajavithi Hospital; W. Louthrenoo, MD, Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University; H. Mann, MD, Institute of Rheumatology; G. Matsievskaia, MD, Chief of Rheumatology Department, Clinical Rheumatology Hospital #25; E.R. Soriano, MD, MSc, Head Rheumatology Unit, Hospital Italiano de Buenos Aires; B. Jia, PhD, Janssen (China) Research and Development Center; C. Wang, MD, Immunology Therapeutic Area Head, Janssen (China) Research and Development Center; J. Nie, PhD, Senior Manager, Clinical Pharmacology, Janssen (China) Research and Development Center; E. Hsia, MD, MSCE, Janssen Research and Development LLC.

出版信息

J Rheumatol. 2018 Jan;45(1):22-31. doi: 10.3899/jrheum.161238. Epub 2017 Nov 1.

DOI:10.3899/jrheum.161238

PMID:29093159

Abstract

OBJECTIVE

To evaluate the efficacy, safety, pharmacokinetics, and immunogenicity of CNTO6785, a fully human monoclonal antibody that binds to human interleukin 17A, in patients with active rheumatoid arthritis (RA) with inadequate response to methotrexate (MTX) therapy.

METHODS

This randomized, double-blind, placebo-controlled, dose-ranging study enrolled patients aged 18 to 80 years (inclusive) with active RA (≥ 6/66 swollen and ≥ 6/68 tender joints) who were refractory to MTX treatment (7.5-25 mg weekly, inclusive). The study duration was 38 weeks, containing a 10-week safety followup. Patients were randomized 1:1:1:1:1 to receive CNTO6785 15, 50, 100, or 200 mg every 4 weeks + MTX or placebo + MTX. The primary endpoint was American College of Rheumatology 20 (ACR20) response at Week 16.

RESULTS

There were no significant differences from placebo in the proportion of patients treated with CNTO6785 in the primary endpoint of ACR20 response at Week 16. There were no significant findings in any additional efficacy variables through Week 32. No dose-response relationships or specific patterns were observed in adverse event profiles among CNTO6785 treatment groups. Infections occurred with similar frequency across all groups, and injection site reactions were mild or moderate and did not demonstrate a dose-response relationship. Median serum CNTO6785 concentration increases through Week 38 were about dose-proportional; the incidence of neutralizing antidrug antibodies was 19.4% and was not associated with study drug dose level.

CONCLUSION

CNTO6785 was well tolerated, but did not demonstrate clinical efficacy in patients with active RA with inadequate response to MTX.

摘要

目的

评估 CNTO6785 的疗效、安全性、药代动力学和免疫原性，CNTO6785 是一种与人白细胞介素 17A 结合的全人源单克隆抗体，用于治疗对甲氨蝶呤（MTX）治疗反应不足的活动性类风湿关节炎（RA）患者。

方法

这项随机、双盲、安慰剂对照、剂量范围研究纳入了年龄在 18 至 80 岁（含）之间的活动性 RA（≥ 6/66 个肿胀关节和≥ 6/68 个压痛关节）且对 MTX 治疗（7.5-25mg/周，含）无反应的患者。研究持续 38 周，包括 10 周的安全性随访。患者按 1:1:1:1:1 的比例随机分为 5 组，分别接受 CNTO6785 15、50、100、200mg 每四周一次+MTX 或安慰剂+MTX。主要终点是第 16 周时美国风湿病学会 20（ACR20）应答率。

结果

在第 16 周时，接受 CNTO6785 治疗的患者在 ACR20 应答的主要终点方面与安慰剂相比没有显著差异。在第 32 周之前，任何其他疗效变量均无显著发现。在 CNTO6785 治疗组的不良事件谱中，没有观察到剂量反应关系或特定模式。所有组的感染发生率相似，注射部位反应为轻度或中度，与剂量无相关性。第 38 周时，血清 CNTO6785 浓度中位数的增加与剂量呈比例关系；中和抗体的发生率为 19.4%，与研究药物剂量水平无关。