Evaluation of a novel chemokine receptor 2 (CCR2)-antagonist in painful diabetic polyneuropathy

Background and aims: Preclinical data suggest that the chemokine receptor 2 (CCR2) is involved in the pathophysiology of neuropathic pain through modulation of neuronal excitability, synaptic transmission and activation of spinal cord microglia. CCR2-antagonists have shown to be effective in preclinical models of neuropathic pain. The aim of this study was to evaluate the analgesic ef?cacy, safety and tolerability of a novel CCR2-antagonist, AZD2423, in patients with painful diabetic neuropathy (PDN). Methods: This was a double-blind, randomized, parallel-group, multi-center study in patients with sym- metric distal sensory polyneuropathy due to type 1 or 2 diabetes and duration of neuropathic pain between 3 months and 5 years. Concomitant treatment with neuropathic pain medications (e.g. anticon- vulsants, tricyclic antidepressants, serotonin-noradrenaline uptake inhibitors, opioids, topical lidocaine or capsaicin) was not allowed. 134 patients with PDN were equally randomized to 28 days oral admin- istration of 20 mg AZD2423, 150 mg AZD2423, or placebo. The primary ef?cacy variable was the change of average pain score from 5-days baseline to the last 5 days of treatment, measured with numerical rating scale (NRS, 0–10). The secondary ef?cacy measures included NRS worst pain scores, patient global impression of change, pain interference on sleep and activity, and neuropathic pain symptom inventory (NPSI). Results: The change of NRS average pain score was not signi?cantly different between treatment groups (AZD2423 20 mg: -1.50; AZD2423 150 mg: -1.35; placebo: -1.61). The NPSI total score and three out of ?ve subscores (evoked pain, pressing/deep pain and paresthesia/dysesthesia) tended to be reduced more by AZD2423 150 mg than by placebo. No other secondary ef?cacy variables differed between treatment groups. The frequency and type of adverse events for AZD2423 were similar to placebo. The achieved plasma levels of AZD2423 in the two dose groups were in line with predictions from pharmacokinetic data previously obtained in healthy volunteers. Dose-dependent increase of plasma levels of the ligand of CCR2 (CCL2; chemokine ligand 2) and decrease of the mean levels of monocytes (-27% by AZD2423 150 mg) suggested that the administrated doses of AZD2423 interacted with the CCR2 target. Conclusion: The CCR2-antagonist AZD2423 showed no analgesic ef?cacy in PDN based on NRS average pain scores and global and functional pain outcome measures. The NPSI data suggested possible effects on certain sensory components of pain. There were no major safety or tolerability concerns. Overall design: RNA-seq profiling of blood samples.

研究背景与目的：临床前数据表明，趋化因子受体2（chemokine receptor 2, CCR2）可通过调节神经元兴奋性、突触传递以及激活脊髓小胶质细胞参与神经病理性疼痛的病理生理过程。CCR2拮抗剂已在神经病理性疼痛的临床前模型中显示出有效性。本研究旨在评估新型CCR2拮抗剂AZD2423治疗痛性糖尿病周围神经病变（painful diabetic neuropathy, PDN）患者的镇痛疗效、安全性与耐受性。

研究方法：本研究为一项双盲、随机、平行分组、多中心临床试验，纳入因1型或2型糖尿病导致对称性远端感觉性多发性神经病，且神经病理性疼痛病程为3个月至5年的患者。禁止合并使用神经病理性疼痛治疗药物（如抗惊厥药、三环类抗抑郁药、5-羟色胺-去甲肾上腺素再摄取抑制剂、阿片类药物、外用利多卡因或辣椒素）。共134例PDN患者被均等随机分配至28天口服给药组，分别接受20mg AZD2423、150mg AZD2423或安慰剂治疗。主要疗效指标为基于数字评定量表（numerical rating scale, NRS，0~10分）测量的、从5天基线期至治疗最后5天的平均疼痛评分变化。次要疗效指标包括NRS最严重疼痛评分、患者整体变化印象、疼痛对睡眠与活动的干扰程度，以及神经病理性疼痛症状量表（neuropathic pain symptom inventory, NPSI）。

研究结果：各组间NRS平均疼痛评分变化无显著差异（AZD2423 20mg组：-1.50；AZD2423 150mg组：-1.35；安慰剂组：-1.61）。与安慰剂组相比，150mg AZD2423组的NPSI总分及5个亚项中的3项（诱发性疼痛、压迫/深部疼痛以及感觉异常/感觉迟钝）评分降低趋势更为明显。其余次要疗效指标在各组间均无显著差异。AZD2423的不良事件发生频率与类型均与安慰剂组相似。两个给药组中达到的AZD2423血浆浓度与此前在健康志愿者中获得的药代动力学数据预测结果一致。CCR2配体（chemokine ligand 2, CCL2）的血浆浓度呈剂量依赖性升高，而单核细胞平均水平降低（150mg AZD2423组降低27%），提示本次给药剂量的AZD2423可与CCR2靶点结合。

研究结论：基于NRS平均疼痛评分以及整体与功能性疼痛结局指标，CCR2拮抗剂AZD2423在PDN患者中未表现出镇痛疗效。NPSI数据则提示其可能对疼痛的部分感觉成分存在作用。未观察到严重的安全性或耐受性问题。

整体研究设计：血液样本RNA测序（RNA-seq）转录组分析。