Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.
J Gastroenterol Hepatol. 2021 Aug;36(8):2180-2186. doi: 10.1111/jgh.15463. Epub 2021 Mar 31.
E6011 is a humanized monoclonal antibody targeting fractalkine (FKN), a CX3C chemokine, which regulates leukocyte trafficking during inflammation. We evaluated the safety and pharmacokinetic profile of E6011 in patients with Crohn's disease (CD) and also performed preliminary pharmacodynamic (PD) and efficacy assessments.
This study included a 12-week multiple ascending dose (MAD) phase (2, 5, 10, and 15 mg/kg intravenously every 2 weeks, n = 6, 8, 7, and 7, respectively) and a 40-week Extension phase (n = 12) at the same dose as the MAD phase. Serum E6011, serum total FKN (free soluble FKN and E6011-FKN complex) as a PD marker and CD activity index were evaluated. The primary outcome was safety assessment in the MAD phase.
Twenty-seven (96%) of 28 patients had previously been treated with anti-tumor necrosis factor α agents. During the MAD phase, adverse events (AEs) occurred in 18 (64%). The most common AE was nasopharyngitis (five patients, 18%). No severe AEs occurred. Serious AEs occurred in three patients, progression of CD in two, and anemia in one. Serum E6011 concentrations increased dose-dependently after infusion and reached a plateau around 4-6 weeks. Serum total FKN rose simultaneously. Five (18%) patients developed anti-E6011 antibodies during the study. Overall, clinical response and clinical remission were observed at Week 12 in 40% (10/25) and 16% (4/25) of active CD patients, respectively.
E6011 was well-tolerated and might be effective in CD patients. These findings need to be clarified in a randomized controlled study.
E6011 是一种针对趋化因子 fractalkine（FKN）的人源化单克隆抗体，FKN 是一种 CX3C 趋化因子，可调节炎症期间白细胞的迁移。我们评估了 E6011 在克罗恩病（CD）患者中的安全性和药代动力学特征，同时进行了初步的药效学（PD）和疗效评估。
本研究包括 12 周的多次递增剂量（MAD）阶段（2、5、10 和 15mg/kg 静脉注射，每 2 周一次，n=6、8、7 和 7）和 40 周的扩展阶段（n=12），剂量与 MAD 阶段相同。评估血清 E6011、血清总 FKN（游离可溶性 FKN 和 E6011-FKN 复合物）作为 PD 标志物和 CD 活动指数。主要终点是 MAD 阶段的安全性评估。
28 例患者中，27 例（96%）曾接受过抗肿瘤坏死因子 α 治疗。MAD 阶段发生不良事件（AE）18 例（64%）。最常见的 AE 是鼻咽炎（五例，18%）。无严重 AE 发生。严重 AE 发生于三例患者，CD 进展两例，贫血一例。输注后，血清 E6011 浓度呈剂量依赖性增加，约在 4-6 周达到平台期。血清总 FKN 同时升高。研究期间，五例（18%）患者产生抗 E6011 抗体。总体而言，在活动性 CD 患者中，12 周时 40%（10/25）和 16%（4/25）的患者分别出现临床应答和临床缓解。
E6011 耐受性良好，可能对 CD 患者有效。这些发现需要在随机对照研究中进一步证实。
