Single-Dose Drug Acoziborole Shows Promise Against Both Forms of Sleeping Sickness

Sleeping sickness, one of Africa’s most feared tropical diseases, may finally be approaching its endgame. Human African trypanosomiasis, caused by single-celled parasites of the species Trypanosoma brucei and transmitted by tsetse flies, has haunted rural communities across sub-Saharan Africa for centuries. The disease is almost invariably fatal if left untreated, yet it has long proved difficult to diagnose and treat, particularly in the remote villages where it strikes. Now, a new laboratory study published in PLOS Neglected Tropical Diseases provides strong evidence that acoziborole, a drug already celebrated as a potential single-dose oral cure for the most common form of the disease, is likely to work just as well against the rarer and more aggressive eastern form caused by Trypanosoma brucei rhodesiense.

The significance of this finding lies in the peculiar epidemiology of sleeping sickness. Two subspecies of Trypanosoma brucei infect humans: Trypanosoma brucei gambiense, which accounts for more than 95 percent of all reported cases and is found primarily in West and Central Africa, and Trypanosoma brucei rhodesiense, which circulates in East and Southern Africa and also infects livestock and wild animals. Although gambiense sleeping sickness dominates the global case count, elimination of the disease as a public health problem requires confronting both parasites. A drug that works only against one subspecies would leave an entire region of the continent without a simple cure, undermining the ambitious elimination targets set by the World Health Organization and its partners.

Acoziborole, developed through a partnership led by the Drugs for Neglected Diseases initiative, represents a genuine breakthrough in chemotherapy for neglected diseases. Unlike earlier treatments for gambiense sleeping sickness, which required intravenous infusions of toxic compounds such as melarsoprol, or lengthy courses of oral drugs like fexinidazole, acoziborole is designed to be given as a single oral dose. The drug has already completed clinical development as a one-dose cure for Trypanosoma brucei gambiense infection, a milestone that could transform treatment programs by allowing community-level administration without the need for hospitalization or complex follow-up. But a single-dose strategy only delivers full elimination if it can be deployed against both subspecies of the parasite.

To address this gap, a team of researchers from the Swiss Tropical and Public Health Institute and the Drugs for Neglected Diseases initiative conducted an in-depth preclinical evaluation of acoziborole against bloodstream forms of all three Trypanosoma brucei subspecies, with particular attention to the rhodesiense parasite. The study, authored by Monica Cal, Sonja Keller, Romina Rocchetti, Stéphanie Braillard, Jean-Robert Ioset, Pascal Mäser and Marcel Kaiser, was designed to strengthen the drug’s preclinical dossier by systematically characterizing its potency, speed of action and killing profile across diverse parasite strains, including clinical isolates that had never been exposed to the compound in the laboratory.

The results were encouraging on every measure. Acoziborole displayed consistent and high activity against all tested strains of Trypanosoma brucei rhodesiense, with half-maximal inhibitory concentrations, or IC50 values, clustered around 600 nanomolar. This means that extremely low concentrations of the drug are sufficient to halve the growth of the parasite in vitro, a hallmark of a potent antitrypanosomal agent. Crucially, the activity was uniform across different strains, including a multidrug-resistant field isolate, suggesting that resistance mechanisms circulating in natural parasite populations are unlikely to compromise the drug’s effectiveness. For a disease whose control has repeatedly been set back by drug toxicity and emerging resistance, this consistency is a valuable asset.

Speed of kill is another critical parameter for any drug intended to cure a rapidly progressive infection, and here acoziborole also outperformed its closest oral competitor. The researchers found that acoziborole acts faster than fexinidazole, the ten-day oral treatment that has recently been introduced for both forms of sleeping sickness. More striking still, acoziborole exhibited irreversible cidality against Trypanosoma brucei rhodesiense at concentrations of 4.3 micromolar or higher, equivalent to 1.6 micrograms per milliliter, after just 15 hours of incubation. Irreversible cidality means that even after the drug is removed from the culture medium, the parasites cannot recover and resume growth. A compound that permanently disables the parasite within hours of exposure offers a substantial margin of safety in clinical practice, where drug levels in the blood fluctuate over time.

One nuance emerged from the side-by-side comparison of the two human-infective subspecies. At very short exposure times of eight hours or less, Trypanosoma brucei gambiense appeared to be more sensitive to acoziborole than its rhodesiense counterpart. In a conventional drug, such a difference in early kill kinetics might raise concerns about whether the same dosing regimen would suffice for both forms of the disease. However, the researchers argue that this discrepancy is clinically irrelevant, and the reasoning rests on a remarkable pharmacological property of the compound itself.

Acoziborole possesses an extremely long elimination half-life in the human body, meaning it persists in the bloodstream at active concentrations for weeks or even months after a single oral dose. This slow clearance is precisely what makes a one-dose cure possible: rather than requiring repeated administrations to maintain therapeutic levels, the drug lingers and continues to act on any parasites it encounters. Because patients effectively live with sustained drug exposure for extended periods, the modest difference in how quickly the two subspecies succumb during the first hours of contact becomes immaterial. Over the long residence time of acoziborole in the body, both parasites face the same relentless chemical assault, and both are expected to be eliminated.

Taken together, the laboratory findings support a confident conclusion: acoziborole is expected to be as effective against rhodesiense sleeping sickness, often abbreviated r-HAT, as it is against gambiense sleeping sickness, or g-HAT, in patient populations. This is more than a technical footnote. Rhodesiense sleeping sickness follows a more acute course than the gambiense form, with a shorter incubation period and faster progression to neurological disease, and it has historically been treated with the toxic arsenical melarsoprol, which itself kills a significant fraction of patients. A safe, single-dose oral alternative for this eastern form of the disease would eliminate one of the last justifications for using a nineteenth-century poison in modern medicine.

The broader context makes the timing of this work especially compelling. The incidence of sleeping sickness has fallen to a historic low, thanks to decades of sustained surveillance, vector control and treatment efforts, and the World Health Organization has recognized the disease as one of the very few infections targeted for elimination as a public health problem. Yet the endgame of any elimination campaign is the hardest phase: cases become rare, scattered and hard to find, and health systems in endemic regions struggle to justify maintaining specialized diagnostic and treatment capacity. A single-dose oral drug that works against both parasite subspecies could be administered presumptively or with minimal testing at the community level, closing the last gaps in coverage. With its clinical success against gambiense infection now backed by preclinical evidence of comparable activity against rhodesiense parasites, acoziborole stands as the most promising tool yet for delivering the final blow against a disease that has plagued tropical Africa for generations.

Subject of Research: Preclinical efficacy profiling of the antitrypanosomal drug acoziborole against Trypanosoma brucei rhodesiense and other African trypanosomes

Article Title: Winning the endgame against sleeping sickness: Efficacy profiling of acoziborole against African trypanosomes with the focus on Trypanosoma brucei rhodesiense

Article References: Cal, M., Keller, S., Rocchetti, R., Braillard, S., Ioset, J.-R., Mäser, P., & Kaiser, M. (2026). Winning the endgame against sleeping sickness: Efficacy profiling of acoziborole against African trypanosomes with the focus on Trypanosoma brucei rhodesiense. PLOS Neglected Tropical Diseases, 20(10), e0014762. https://doi.org/10.1371/journal.pntd.0014762

Image Credits: AI Generated

DOI: 10.1371/journal.pntd.0014762

Keywords: sleeping sickness, acoziborole, African trypanosomiasis, Trypanosoma brucei rhodesiense, Trypanosoma brucei gambiense, tsetse fly, neglected tropical diseases, drug resistance, fexinidazole, elimination, preclinical testing, antiparasitic drugs