K. Wasan, C. Leiper, S. Leiper, J. Kim
University of British Columbia,
Canada
Keywords: nanomedicines, drug delivery, leishmaniasis, oral
Summary:
Introduction: Visceral leishmaniasis (VL) is a severe and often fatal infection with an annual incidence rate of 50,000 to 90,000 (WHO). VL can lead to death in over 95% of cases if not treated. There are a few, mostly old and increasingly less-efficacious treatments for VL. But the global consensus treatment is liposomal amphotericin B (AmB). Unfortunately, the 2-hour IV infusion for at least 7 days, the high cost and much-criticized limited access in LMICs mar meaningful real-world impact. A widely distributed oral form of AmB prescribed as a take-home self-medication regimen would enable treatment access to the most remote locations in LMICs without the need for specialized IV administration facilities and repeated clinical visits. Purpose: Our goal was to develop a cost-effective, safe, tropically stable and accessible oral amphotericin B formulation that was effective in validated animal models of visceral leishmaniasis and has safety in a human phase I clinical study. Methods: Extensive pre-clinical and clinical research has been completed on the development of our oral AmB product which has led to over 20 peer- reviewed publications and several issued patents in many jurisdictions. This includes developing a tropically stable formulation with over 24 months of stability in developing world conditions (following ICH guidelines), testing of this formulation in validated VL animal models for efficacy and toxicity and completing a human phase 1a/1b safety study. Results: Anti-leishmanial activity at non-toxic doses of our oral AmB formulation was observed in a murine model of VL, where <99% reduction in parasitic infection was achieved following 5 days of treatment with 10 mg/kg p.o. b.i.d. and 95% inhibition following treatment with 20 mg/kg p.o. q.d. for 5 days, relative to the control. In our phase 1a single dose human clinical study, the primary endpoint of safety and tolerability of our oral amphotericin B formulation following administration of all single ascending doses were met including no signs of kidney, liver and GI toxicities of note. In our phase 1b multiple dose human clinical study all repeated doses of our oral amphotericin B formulation were well tolerated with no serious adverse events including no signs of GI, kidney, and liver toxicities. Conclusions: We have developed a novel oral amphotericin B formulation that is cost-effective, safe, tropically stable and accessible with activity in VL animal models and a positive human safety profile. Future studies will include efficacy studies in epidemic areas.