IκB kinase inhibition as a potential treatment of osteoarthritis - results of a clinical proof-of-concept study
IκB kinase inhibition as a potential treatment of osteoarthritis - results of a clinical proof-of-concept study
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DOI：
10.1016/j.joca.2016.08.010
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发表时间：
2017-01-01
影响因子：
7
通讯作者：
Rudolphi, K.
中科院分区：
文献类型：
--
作者：
Grothe, K.;Flechsenhar, K.;Rudolphi, K.
目的：本出版物总结了化合物SAR113945的临床发展，SAR113945是一种I κ B激酶抑制剂，以缓释制剂关节内注射治疗症状性膝关节骨关节炎（OA）患者。结果：体外实验显示对I κ B激酶复合物具有特异性抑制作用。SAR113945对激酶、酶和离子通道的分析支持了临床开发的启动。细胞分析系统也显示抑制白细胞介素1 β，肿瘤坏死因子α (TNF α)和前列腺素E2 （PGE）的合成(2)。体内研究表明SAR113945对热性和机械性痛感过敏有积极作用，甚至比曲安奈德更有优势。药代动力学测量显示溶解的SAR113945在局部持续释放，支持膝关节相对较高的暴露，同时支持较低的全身暴露。三个剂量递增设计的1期研究证实了SAR113945的安全性和耐受性。在这些研究中，SAR113945对WOMAC评分呈阳性趋势。概念验证或2a期研究未能显示在主要终点（第56天的WOMAC疼痛亚评分）的总体招募研究参与者组中有任何效果，但在基线时出现积液的患者亚组中显示有统计学意义上的差异。结论：抑制NF κ B信号通路是治疗骨性关节炎症状和体征的有效方法。临床前工作和1期研究的结果似乎有望进行全面的临床开发，然而，概念验证研究未能在更大的患者样本量中显示出疗效。(C) 2016国际骨关节炎研究学会。Elsevier Ltd.出版。版权所有。
Objective: This publication summarizes the clinical development of the compound SAR113945, an I kappa B kinase inhibitor injected intra-articularly in a slow-release formulation to treat patients with symptomatic osteoarthritis (OA) of the knee.Results: In vitro experiments demonstrated a specific inhibition of the I kappa B kinase complex. Profiling of SAR113945 on kinases, enzymes and ion channels supported the initiation of a clinical development. Cellular assay systems also revealed an inhibition in the synthesis of interleukin 1 beta, tumor necrosis factor alpha (TNF alpha) and the prostaglandin E2 (PGE(2)). In vivo studies demonstrated positive effects of SAR113945 on thermal and mechanical hyperalgesia and even showed superiority in comparison with triamcinolone. Pharmacokinetic measurements showed a sustained release of dissolved SAR113945 locally supporting a comparably high exposure in the knee joint combined with a low systemic exposure. Three phase 1 studies with a dose-escalating design confirmed safety and tolerability of SAR113945. In those studies SAR113945 showed a positive trend on the WOMAC scores. The proof-of-concept or phase 2a study failed to show any effect in the overall group of recruited study participants for the primary endpoint, the WOMAC pain subscore at day 56, but showed a statistically significant difference in a subgroup of patients who had presented with effusion at baseline.Conclusion: Inhibiting the NF kappa B signaling pathway is an attractive method to treat patients with signs and symptoms of OA. The preclinical work and the results of the phase 1 studies appeared promising for a full clinical development, however, the proof-of-concept study failed to show efficacy in a larger patient sample size. (C) 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.