Development of Acoziborole for the Treatment of Human African Trypanosomiasis

National Center For Advancing Translational Sciences

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Abstract

HAT is transmitted by a vector, the tsetse fly, which introduces trypanosomes free-living extracellular parasites into the bloodstream, body fluids, lymph and cerebrospinal fluid. The Trypanosoma brucei species is pathogenic to humans and endemic to sub-Saharan Africa. T.b. gambiense accounts for over 98% of cases of HAT (gHAT) and T.b. rhodesiense accounts for about 2% of cases (rHAT). The disease progresses through two stages of infection, first in the blood and lymph and then into the central nervous system (CNS). While in the blood and lymph, clinical signs and symptoms are mild and non-specific, including headaches, fatigue, and intermittent fevers. By contrast, infection in the CNS is marked by pronounced neuropsychiatric signs, including disrupted sleep/wake cycles, hallucinations and aggression, abnormal reflexes, seizures, and coma. Once infection has progressed to the CNS, HAT is more difficult to treat, requiring drugs to cross the blood-brain barrier, making early diagnosis and treatment imperative. Until recently, first-line treatment for late-stage HAT relied on a combination of two drugs (nifurtimox and eflornithine), administered over a course of 10 days, requiring intravenous injection in a clinical setting. To reach wider patient populations in poorer, more remote areas with little healthcare infrastructure, the lead collaborators developed fexinidazole, an oral therapy taken once daily for 10 days that can treat both early and late stages of infection. To further simplify the treatment regimen, the lead collaborators have now developed acoziborole, which also treats both stages of infection, but requires only a single oral dose in lieu of a multi-day course. TRND scientists have completed Good Laboratory Practice (GLP)-compliant nonclinical toxicology studies necessary to support the registration of acoziborole with health regulatory authorities to treat HAT patients in Africa.