New Drugs for Human African Trypanosomiasis: A Twenty First Century Success Story

Abstract

The twentieth century ended with human African trypanosomiasis (HAT) epidemics raging across many parts of Africa. Resistance to existing drugs was emerging, and many programs aiming to contain the disease had ground to a halt, given previous success against HAT and the competing priorities associated with other medical crises ravaging the continent. A series of dedicated interventions and the introduction of innovative routes to develop drugs, involving Product Development Partnerships, has led to a dramatic turnaround in the fight against HAT caused by Trypanosoma brucei gambiense. The World Health Organization have been able to optimize the use of existing tools to monitor and intervene in the disease. A promising new oral medication for stage 1 HAT, pafuramidine maleate, ultimately failed due to unforeseen toxicity issues. However, the clinical trials for this compound demonstrated the possibility of conducting such trials in the resource-poor settings of rural Africa. The Drugs for Neglected Disease initiative (DNDi), founded in 2003, has developed the first all oral therapy for both stage 1 and stage 2 HAT in fexinidazole. DNDi has also brought forward another oral therapy, acoziborole, potentially capable of curing both stage 1 and stage 2 disease in a single dosing. In this review article, we describe the remarkable successes in combating HAT through the twenty first century, bringing the prospect of the elimination of this disease into sight.

Keywords: acoziborole; chemotherapy; elimination; fexinidazole; human African trypanosomiasis; pafuramidine; sleeping sickness.

Figure 1

Different drugs have been used to treat HAT depending on the trypanosome subspecies causing the disease, and whether progression is at stage 1 or 2. For the past decade nifurtimox and eflornithine combination therapy has been the treatment of choice for stage 2 T. b. gambiense disease, and pentamidine for stage 1. For rhodesiense HAT, stage 2 is treated with melarsoprol and stage 1 with suramin.

Figure 2

Clinical trials with pafuramidine (DB289), which is the prodrug of furamidine (DB75), failed due to the appearance of renal toxicity during extended phase I safety profiling. The aza-derivatives including DB868—a prodrug of DB829, and DB844—a prodrug of DB820, also showed activity against stage 2 disease, but development was halted following identification of the toxicity associated with pafuramidine. Fexinidazole has been approved for use by the European Medicines Agency in 2018. The compound is converted to sulfoxide then sulfone derivatives after administration. Acoziborole is a benzoxaborole in clinical trials, where the efficacy of a single dosing of the drug as an oral medication against stage 2 disease is being assessed.