Winning the endgame against sleeping sickness: Efficacy profiling of acoziborole against African trypanosomes with the focus on Trypanosoma brucei rhodesiense
- 1Swiss Tropical and Public Health Institute, Allschwil, Switzerland.
- 2University of Basel, Basel, Switzerland.
- 3Drugs for Neglected Diseases initiative, Geneva, Switzerland.
Abstract
Human African trypanosomiasis (HAT) is caused by two subspecies of Trypanosoma brucei, T. b. gambiense and T. b. rhodesiense, with the former accounting for over 95% of all cases. HAT is an elusive disease, which is fatal unless treated, with a focal prevalence in the rural areas of tropical Africa where the tsetse fly vectors are endemic. At the same time, HAT is one of the very few infectious diseases where global elimination seems possible. The incidence is at a historic low, and new orally bioavailable drugs have been developed that will expand the coverage of treatment in endemic regions. In particular, acoziborole has passed the clinical development as a single-dose oral cure of T. b. gambiense infection. However, to win the endgame against HAT, acoziborole also needs to be extended to T. b. rhodesiense. In order to strengthen the preclinical dossier of acoziborole, we conducted an in-depth evaluation of acoziborole against the bloodstream forms of all three T. brucei subspecies with a focus on T. b. rhodesiense. Acoziborole had consistent and high activity against different T. b. rhodesiense strains, including a multidrug-resistant field isolate, with IC50 values around 600 nM. Acoziborole is faster acting than fexinidazole, and it exhibits irreversible cidality against T. b. rhodesiense at concentrations of ≥4.3 μM (1.6 μg/ml) after 15 h of incubation. At very short exposure times (≤8 h), T. b. gambiense appeared to be more sensitive than T. b. rhodesiense. However, given the extremely long elimination half-life of acoziborole in the human body, this difference will be irrelevant for its trypanocidal action in patients. We therefore conclude that acoziborole is expected to be as effective against r-HAT as against g-HAT in patient populations. Author summary: Human African trypanosomiasis (HAT) is a neglected tropical disease that is found exclusively in sub-Saharan Africa. The causative agents are the parasites Trypanosoma brucei gambiense in West and Central Africa, and T. b. rhodesiense in East Africa. Once a devastating scourge across tropical Africa, HAT today is under control with fewer than 1000 reported cases per year. This low incidence raises hopes to reach the goal of zero transmission, particularly so since major breakthroughs have been achieved in the development of new, orally applicable drugs: fexinidazole in 2019, and acoziborole in 2026, have obtained positive opinion by the European Medicines Agency for the treatment of HAT. Whereas fexinidazole is registered for both T. b. rhodesiense and T. b. gambiense, acoziborole is only approved for the latter; the reason is that there are too few cases of T. b. rhodesiense to conduct a clinical trial. Yet, even though currently of lower medical importance than T. b. gambiense, T. b. rhodesiense will be more difficult to control in the long run because it is a zoonotic pathogen. Acoziborole as a single-dose cure would be a tremendous help in the therapy of sporadic cases or outbreaks. Here we provide an in-depth profiling of acoziborole against T. b. rhodesiense isolates, demonstrating its full effectivity at the clinically relevant levels. We hope these findings pave the way for the use of acoziborole also against the East-African pathogen T. b. rhodesiense.
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BibTeX
@article{cal2026winning,
title = {{Winning the endgame against sleeping sickness: Efficacy profiling of acoziborole against African trypanosomes with the focus on Trypanosoma brucei rhodesiense}},
author = {Monica Cal and Sonja Keller and Romina Rocchetti and Stéphanie Braillard and Jean-Robert Ioset and Pascal Mäser and Marcel Kaiser},
journal = {PLOS Neglected Tropical Diseases},
year = {2026},
month = oct,
doi = {10.1371/journal.pntd.0014762},
url = {https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0014762},
note = {CC BY},
}
RIS
TY - JOUR
TI - Winning the endgame against sleeping sickness: Efficacy profiling of acoziborole against African trypanosomes with the focus on Trypanosoma brucei rhodesiense
AU - Monica Cal
AU - Sonja Keller
AU - Romina Rocchetti
AU - Stéphanie Braillard
AU - Jean-Robert Ioset
AU - Pascal Mäser
AU - Marcel Kaiser
PY - 2026
DA - 2026/10/05
JO - PLOS Neglected Tropical Diseases
DO - 10.1371/journal.pntd.0014762
UR - https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0014762
AB - Human African trypanosomiasis (HAT) is caused by two subspecies of Trypanosoma brucei, T. b. gambiense and T. b. rhodesiense, with the former accounting for over 95% of all cases. HAT is an elusive disease, which is fatal unless treated, with a focal prevalence in the rural areas of tropical Africa where the tsetse fly vectors are endemic. At the same time, HAT is one of the very few infectious diseases where global elimination seems possible. The incidence is at a historic low, and new orally bioavailable drugs have been developed that will expand the coverage of treatment in endemic regions. In particular, acoziborole has passed the clinical development as a single-dose oral cure of T. b. gambiense infection. However, to win the endgame against HAT, acoziborole also needs to be extended to T. b. rhodesiense. In order to strengthen the preclinical dossier of acoziborole, we conducted an in-depth evaluation of acoziborole against the bloodstream forms of all three T. brucei subspecies with a focus on T. b. rhodesiense. Acoziborole had consistent and high activity against different T. b. rhodesiense strains, including a multidrug-resistant field isolate, with IC50 values around 600 nM. Acoziborole is faster acting than fexinidazole, and it exhibits irreversible cidality against T. b. rhodesiense at concentrations of ≥4.3 μM (1.6 μg/ml) after 15 h of incubation. At very short exposure times (≤8 h), T. b. gambiense appeared to be more sensitive than T. b. rhodesiense. However, given the extremely long elimination half-life of acoziborole in the human body, this difference will be irrelevant for its trypanocidal action in patients. We therefore conclude that acoziborole is expected to be as effective against r-HAT as against g-HAT in patient populations. Author summary: Human African trypanosomiasis (HAT) is a neglected tropical disease that is found exclusively in sub-Saharan Africa. The causative agents are the parasites Trypanosoma brucei gambiense in West and Central Africa, and T. b. rhodesiense in East Africa. Once a devastating scourge across tropical Africa, HAT today is under control with fewer than 1000 reported cases per year. This low incidence raises hopes to reach the goal of zero transmission, particularly so since major breakthroughs have been achieved in the development of new, orally applicable drugs: fexinidazole in 2019, and acoziborole in 2026, have obtained positive opinion by the European Medicines Agency for the treatment of HAT. Whereas fexinidazole is registered for both T. b. rhodesiense and T. b. gambiense, acoziborole is only approved for the latter; the reason is that there are too few cases of T. b. rhodesiense to conduct a clinical trial. Yet, even though currently of lower medical importance than T. b. gambiense, T. b. rhodesiense will be more difficult to control in the long run because it is a zoonotic pathogen. Acoziborole as a single-dose cure would be a tremendous help in the therapy of sporadic cases or outbreaks. Here we provide an in-depth profiling of acoziborole against T. b. rhodesiense isolates, demonstrating its full effectivity at the clinically relevant levels. We hope these findings pave the way for the use of acoziborole also against the East-African pathogen T. b. rhodesiense.
SN - 1935-2735
SN - 1935-2727
ER -