A groundbreaking Phase 3 clinical trial in Gabon has demonstrated that a single-dose malaria treatment combining four existing antimalarial drugs achieves cure rates equivalent to standard multi-day therapy, offering a potential solution to two critical challenges plaguing malaria control efforts: drug resistance and poor treatment adherence.
The study, presented at the 2025 Annual Meeting of the American Society of Tropical Medicine and Hygiene (ASTMH), involved more than 1,000 patients with uncomplicated malaria, half of them under 10 years old. Results showed that 93% of patients receiving the single-dose treatment were parasite-free after 28 days, compared to 90% of those who received the standard three-day artemether-lumefantrine (AL) regimen.
Novel Four-Drug Combination Targets Multiple Parasite Vulnerabilities
The single-dose regimen, known as SPAP, combines sulfadoxine-pyrimethamine (SP) with artesunate-pyronaridine (AP), creating a four-drug assault on malaria parasites. "We found that our single-dose treatment was just as effective as the standard course that typically requires taking six doses spaced out over three days, which many patients never complete," said Dr. Ghyslain Mombo-Ngoma, lead author of the study and head of clinical operations at the Medical Research Center of Lambaréné, Gabon (CERMEL).
The multi-drug approach may prove more effective against drug-resistant parasites than conventional treatments, which typically use only two drugs. By forcing the pathogen to fight on multiple fronts simultaneously, the strategy mirrors successful approaches used against drug-resistant tuberculosis.
Addressing Critical Treatment Adherence Crisis
The innovation directly tackles a persistent problem in malaria management: treatment completion rates. According to the study findings, one-third or more of malaria patients fail to complete the standard three-day course of treatment. This incomplete treatment allows parasites to linger in the body, potentially developing mutations that overcome current artemisinin combination therapies (ACTs) while risking progression to severe, life-threatening disease.
"Another challenge is that artemisinin combination therapies (ACTs) must be taken for three days to clear parasites from infected patients, and a third or more of malaria patients don't complete the full course," Mombo-Ngoma explained. This treatment failure contributes to the alarming rise of drug-resistant malaria and allows curable cases to intensify.
Urgent Need Amid Stalled Progress
The breakthrough comes at a critical time for malaria control efforts. After dramatic reductions from 2000 to 2015, malaria infections and deaths have plateaued and begun increasing. World Health Organization data shows that in 2023, there were 263 million cases and 597,000 deaths, compared with 216 million cases and 445,000 deaths in 2016. Sub-Saharan Africa accounts for 95% of the world's malaria infections and deaths, with children under 5 years old bearing the highest mortality burden.
The trial, conducted from May 2024 to October 2025, treated 539 patients with the single-dose SPAP regimen while 442 patients received the standard AL treatment. Importantly, researchers reported no serious adverse events related to the study drugs in any patients.
Practical Implementation Advantages
The treatment offers significant practical advantages for implementation across Africa. "Another key advantage is that our single-dose cure was accomplished with drugs that are currently available to malaria treatment programs across Africa—and relatively affordable as well," Mombo-Ngoma noted. The sulfadoxine-pyrimethamine combination is already manufactured as a generic drug in several African countries, while artesunate-pyronaridine will become available as a generic by early 2026.
Discussions are already underway with drug manufacturers to produce SP and AP as a single capsule or sachet, and malaria researchers in Mali, Ghana, Kenya and Mozambique have expressed interest in testing the single-dose approach.
Bridge to Future Treatments
While new compounds capable of defeating drug-resistant parasites are under development, they remain years away from widespread availability in Africa. "I'm a malaria researcher, but I'm also a doctor treating a lot of malaria patients, and I need new options now," Mombo-Ngoma emphasized. "What I hope is that, if we continue to have success with this single-dose cure, it can serve as a bridge to the new treatments now under development—something we can deploy very soon while we await the arrival of other options."
ASTMH President David Fidock praised the research approach, stating: "It's exciting to see our members pursuing innovative ways of fighting drug-resistant malaria while also seeking solutions to treatment-adherence challenges, which is a pervasive problem in the management of many diseases."
