Patients with chronic pain syndromes, such as those with painful peripheral neuropathy due to diabetes mellitus, have limited treatment options and suffer ongoing attrition of their quality of life. Safer and more effective treatment options are needed. One therapeutic approach encompasses phenotypic characterization of the neuropathic pain subtype, combined with the selection of agents that act on relevant mechanisms. ISC 17536 is a novel, orally available inhibitor of the widely expressed pain receptor, transient receptor potential ankyrin 1, which mediates nociceptive signaling in peripheral small nerve fibers. In this randomized, placebo-controlled, proof-of-concept trial, we assessed the safety and efficacy of 28-day administration of ISC 17536 in 138 patients with chronic, painful diabetic peripheral neuropathy and used quantitative sensory testing to characterize the baseline phenotype of patients. The primary end point was the change from baseline to end of treatment in the mean 24-hour average pain intensity score based on an 11-point pain intensity numeric rating scale. The study did not meet the primary end point in the overall patient population. However, statistically significant and clinically meaningful improvement in pain were seen with ISC 17536 in an exploratory hypothesis-generating subpopulation of patients with preserved small nerve fiber function defined by quantitative sensory testing. These results may provide a mechanistic basis for targeted therapy in specific pain phenotypes in line with current approaches of “precision medicine” or personalized pain therapeutics. The hypothesis is planned to be tested in a larger phase 2 study.

患有慢性疼痛综合征的患者，例如因糖尿病而患有疼痛性周围神经病变的患者，治疗选择有限，并且生活质量持续下降。需要更安全、更有效的治疗方案。一种治疗方法包括神经性疼痛亚型的表型特征，并结合作用于相关机制的药物的选择。ISC 17536 是一种新型口服抑制剂，广泛表达的疼痛受体、瞬时受体电位锚蛋白 1，可介导外周小神经纤维中的伤害性信号传导。在这项随机、安慰剂对照、概念验证试验中，我们评估了 138 名慢性疼痛性糖尿病周围神经病变患者服用 ISC 17536 28 天的安全性和有效性，并使用定量感觉测试来表征患者。主要终点是基于 11 点疼痛强度数字评定量表的平均 24 小时平均疼痛强度评分从基线到治疗结束的变化。该研究未达到总体患者群体的主要终点。然而，在由定量感觉测试定义的保留小神经纤维功能的探索性假设生成患者亚群中，使用 ISC 17536 观察到具有统计学意义和临床意义的疼痛改善。这些结果可能为特定疼痛表型的靶向治疗提供机制基础，符合当前的“精准医学”或个性化疼痛治疗方法。该假设计划在更大规模的二期研究中进行测试。