Oxfendazole as a Broad Spectrum Deworming Medicine in Humans: Phase II Efficacy Study in Geohelminths

项目摘要 土壤传播的蠕虫(STH)，包括鞭虫，感染着全世界超过15亿人， 但不幸的是，标准的护理驱虫药物[阿苯达唑(ALB)，400毫克，一次给药 对毛滴虫的治愈率仅为43.6%，增加了面对 基于现有驱虫剂的全球驱虫努力。最近的研究反驳了流行的观念，即 驱虫药物的作用主要是通过胃肠道直接接触蠕虫，通过 表明猪旋毛虫体内奥芬达唑(Oxf‘s)浓度很高(r= 0.93)，且与感染猪的奥芬达唑血浆浓度显著相关(P=0.0007)。 OXF通过血液-肠道细胞界面到达蠕虫体内。重要的是，口服单剂量的奥克沙星 最近证明，在所有测试的猪中，完全消灭了猪毛虫以及存在的其他蠕虫。 综上所述，这些新发现支持这样一种假设，即与白蛋白相比，OXF将是一种高度 有效治疗人类鞭虫感染，以及目前治疗不当的蛔虫和 钩虫。 重要的是，Oxf即将成功完成第一项人类研究(单次递增剂量安全性 和药代动力学研究)，在NIAID的主持下，在正常健康志愿者中进行 (NCT02234570)，到目前为止已经进展到15 mg/kg的剂量，没有遇到任何显著的 毒性。虽然详细的药代动力学数据尚未获得，因为监管要求 在任何分析之前，所有数据都要在冻结数据库的情况下进行质量控制，这显然具有重要意义 乐施会的风险暴露正在发生。 本申请是为了支持规划乐施会第二阶段概念论证研究(与 Alb)用于治疗感染鞭虫和混合感染蛔虫或钩虫的成人。基于 临床前数据显示，Oxf作为一种驱虫药物可能具有广泛的疗效。毛滴虫的治疗 被选为第一次乐施会功效研究的主要目标，原因是现有的 对这种蠕虫的治疗，因为在这种寄生虫的疗效终点快速读出。成功 这项第二阶段研究的完成将使多个地点(南美、非洲、东南部)的发展成为可能 亚洲)支持乐施会注册/批准真正有效治疗毛滴虫的第三阶段研究， 世界各地的蛔虫和钩虫。

Project Summary Soil transmitted helminths (STH), including Trichuris trichiura, infect more than 1.5 billion people world-wide, but unfortunately, the standard of care deworming medicine [albendazole (ALB), 400 mg, administered once orally] has a cure rate of only 43.6% for T. trichiura, increasing the risk of resistance development in the face of global deworming efforts based on existing anthelmintics. Very recent work counters the prevailing notion that deworming medicines work mainly by exposure directly to the worms via the gastrointestinal lumen, by demonstrating that oxfendazole's (OXF's) concentration in T. suis (the porcine Trichuris analog) is highly (r = 0.93) and significantly (P = 0.0007) correlated with oxfendazole plasma levels in the infected pigs, suggesting that OXF reached the worms via the blood-enterocyte interface. Importantly, a single oral dose of OXF was recently demonstrated to completely eliminate T. suis, as well as other helminths present, in all pigs tested. Taken together, these new findings support the hypothesis that, in contrast to ALB, OXF will be a highly effective treatment for human T. trichiura infection, as well as for the presently poorly treated Ascaris and hookworms. Importantly, OXF is nearing the successful completion of a First in Human study (single, ascending dose safety and pharmacokinetic study), conducted under the auspices of the NIAID, in normal healthy volunteers (NCT02234570) and has thus far progressed to a dose of 15 mg/kg without encountering any significant toxicity. Although detailed pharmacokinetic data are not yet available because of the regulatory requirement for all data to be quality controlled with the data base frozen prior to any analysis, it is apparent that significant OXF exposure is taking place. The present application is in support of planning a Phase II Proof of Concept study of OXF (in comparison to ALB) in the treatment of adults infected with T. trichiura and coinfected with Ascaris or hookworm. Based on preclinical data, OXF may well be broadly efficacious as a deworming medication. Treatment of T. trichiura was chosen as the primary target for the first OXF efficacy study because of the poor effect of existing therapies on this worm and because of the rapid read-out at an efficacy endpoint for this parasite. Successful completion of this Phase II study will enable progression to a multi-site (South America, Africa, South East Asia) Phase III study to support registration/approval of OXF for the truly effective treatment of T. trichiura, Ascaris and hookworm world-wide.