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

项目摘要 土壤传播蠕虫（STH），包括鞭虫，感染了全球超过15亿人， 但不幸的是，标准的驱虫药[阿苯达唑（ALB），400毫克，一次给药， 口服]的治愈率仅为43.6%。毛尾丝虫，增加了在面对 在现有驱虫药的基础上开展全球驱虫工作。最近的研究反驳了流行的观点， 驱虫药物主要通过胃肠道直接接触蠕虫， 表明在T.猪鞭虫（猪鞭虫类似物）是高度（r = 0.001）的。 0.93）和显著（P = 0.0007）与感染猪的奥芬达唑血浆水平相关，提示 OXF通过血肠细胞界面到达蠕虫。重要的是，单次口服剂量的OXF 最近证明可以完全消除T.猪，以及其他蠕虫的存在，在所有的猪测试。 综上所述，这些新的发现支持了这样的假设，即与ALB相反，OXF将是一种高度依赖性的蛋白质。 有效治疗人类T.鞭毛虫感染，以及目前治疗不善的蛔虫， 钩虫 重要的是，OXF即将成功完成首次人体研究（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 （NCT 02234570），并且迄今为止进展至15 mg/kg的剂量而没有遇到任何显著的 毒性尽管由于监管要求，尚未获得详细的药代动力学数据， 所有数据都要进行质量控制，数据库在任何分析之前都要冻结，很明显， OXF暴露正在发生。 本申请支持规划OXF的第二阶段概念验证研究（与 ALB）治疗成人T.鞭虫和蛔虫或钩虫共同感染。基于 根据临床前数据，OXF作为驱虫药物可能是广泛有效的。治疗T.毛尾 被选为第一个OXF疗效研究的主要目标，因为现有的效果不佳， 治疗这种蠕虫，因为在这种寄生虫的疗效终点快速读出。成功 完成这项II期研究将使研究进展到多中心（南美、非洲、东南 亚洲）的III期研究，以支持注册/批准的OXF的真正有效的治疗T。毛尾类， 蛔虫和钩虫遍布全球。

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.