Fexinidazole

Human African trypanosomiasis (HAT) is caused by two subspecies of Trypanosoma brucei, T. brucei gambiense and T. brucei rhodesiense, with T. brucei gambiense HAT accounting for ~97% of the total disease burden. Transmitted by the bite of an infected tsetse fly, HAT begins as a local infection at the bite site before disseminating throughout the blood and reticuloendothelial system (first or hemolymphatic stage) and eventually crossing the blood-brain barrier (second or meningoencephalitic stage). First stage T. brucei gambiense HAT is characterized by fever, headache, swollen lymph nodes, pruritus, and other non-specific symptoms. Progression to the second stage results in progressive deterioration of neurological function, including sleep disturbances (HAT is also referred to as sleeping sickness), tremors, ataxia, abnormal behaviour, confusion, and coma; myocarditis and endocrine hypothalamic-hypophyseal dysfunction may also be present. If left untreated, HAT is fatal.

Fexinidazole is the first all-oral treatment for T. brucei gambiense HAT. Both fexinidazole and its two main metabolites, a sulfoxide (M1) and sulfone (M2) metabolite, possess in vitro activity against T. brucei gambiense, T. brucei rhodesiense, and T. brucei brucei in the 0.2-0.9 μg/mL range. Further studies revealed in vivo efficacy in HAT animal models and acceptable toxicity profiles, both in animal and human subjects. Crucially, fexinidazole was shown to be non-inferior to existing nifurtimox/eflornithine combination therapy (NECT) in late-stage T. brucei gambiense infection.

The precise mechanism of action of fexinidazole remains unknown. However, it is suggested that bacterial-like nitroreductases encoded by trypanosomes activate fexinidazole and its M1/M2 metabolites through reduction to form reactive intermediates capable of damaging DNA and proteins. Whole-body autoradiography of [14C]-labelled fexinidazole in rats revealed broad distribution into all tissues, including an observed brain-to-blood concentration ratio of 0.4-0.6. Therefore, fexinidazole is capable of direct toxicity against trypanosomes throughout the body and in the brain, which is consistent with its efficacy against both early and late-stage infections.