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

项目总结

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.