Making the most of existing antimalarial medicines: a single dose cure with sulfadoxine–pyrimethamine plus artesunate–pyronaridine

(2025) 24:300 Mombo‑Ngoma et al. Malaria Journal https://doi.org/10.1186/s12936-025-05559-4 Malaria Journal Open Access PERSPECTIVE Making the most of existing antimalarial medicines: a single dose cure with sulfadoxine– pyrimethamine plus artesunate–pyronaridine Ghyslain Mombo‑Ngoma1,2,3*, Michael Ramharter1,3,4, Rella Zoleko Manego1,3,4, Bertrand Lell1,5, Quique Bassat6,7,8,9,10, Pedro Aide7, Oumou Maiga Ascofare3,11,12, Timothy N. C. Wells13, Abdoulaye Djimde14,15, Francine Ntoumi16,17 and Peter G. Kremsner1,17,18 Abstract Malaria remains a preventable and treatable disease; however, recent efforts to reduce mortality have plateaued. Although artemisinin-based combination therapy demonstrates high efficacy in controlled clinical settings, its realworld effectiveness is often compromised by suboptimal patient adherence. Specifically, the artemether–lumefan‑ trine regimen, administered twice daily over 3 days, has been associated with reduced compliance due to its com‑ plexity. Simplified therapeutic regimens that enhance adherence could, therefore, play a critical role in reinvigorating progress toward malaria elimination. Over the past decade, substantial progress has been made in the discovery and development of new chemical entities for malaria treatment, although the most advanced candidate still requires a 3-day dosing regimen. Treatment shortening most likely requires multiple drug combinations. Multi-drug regimens, such as artemether–lumefantrine–amodiaquine appear to be well tolerated, but these are under development to address emerging resistance to lumefantrine and will be unlikely to improve compliance. Sulfadoxine–pyrimeth‑ amine was originally developed as a single-dose curative treatment for malaria, and although use was curtailed early due to rapid selection for resistance, it continues to be deployed as a single therapy or in combination with other medicines, in treatment and in prevention. Combining with artemisinin-based combinations would be an option for potential treatment shortening. Of the registered antimalarial treatments, only a few of the artemisinin-based combinations are suitable. Mefloquine is excluded for tolerability concerns, amodiaquine because of its use in sea‑ sonal malaria chemoprevention, and lumefantrine and piperaquine due to concerns of emerging resistance. Pyrona‑ ridine–artesunate emerges as a promising candidate for association with sulfadoxine–pyrimethamine. A four-drug, single-dose antimalarial regimen would transform compliance, and play a major role in disease elimination. However, to ensure its success it will be important to assess the safety and tolerability of the novel association and understand its efficacy in regions with evolving resistance to sulfadoxine–pyrimethamine. Clinical studies need to assess the risk for selection of strains with novel resistance mechanisms against artesunate or pyronaridine. Importantly, a compre‑ hensive clinical evaluation will generate valuable real-world insights into community acceptance and operational feasibility. This information will be an important foundation for future design of single dose malaria therapies involv‑ ing new chemical entities. *Correspondence: Ghyslain Mombo‑Ngoma Full list of author information is available at the end of the article © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Mombo‑Ngoma et al. Malaria Journal (2025) 24:300 Page 2 of 8 Keywords Malaria eradication, Compliance, Effectiveness, Existing antimalarial medicines, Malaria, Sulfadoxine– pyrimethamine, Artesunate–pyronaridine, Single-dose cure Background The 2023 burden of malaria was reported globally to an estimated 263 million cases, and an estimated 597,000 deaths [1]. These estimates suggest an overall increase of 11 million cases from the previous year. Africa continues to carry the heaviest burden of morbidity and mortality, accounting for about 95% of malaria cases and estimated malaria deaths. Plasmodium falciparum is the major parasitic species affecting humans in Africa. The most effective way to manage an uncomplicated case or to avoid progression to severe disease and death is through early diagnosis and prompt and efficacious treatment. Artemisinin-based combination therapy (ACT), given for 3 days, show efficacy often far above the World Health Organization (WHO) recommended minimum threshold of 95% adequate clinical and parasitological response (ACPR) at day 28 during clinical studies. However, artemisinin-based combinations show lower effectiveness in real-world practice [2, 3], because of many system-specific issues. These include suboptimal intervention access, diagnostic shortcomings, incomplete provider compliance, but most importantly client adherence to the course of therapy. Many studies have shown that compliance rates with the 3-day ACT regimens are highly variable, but as low as 40% [4, 5]. With the development of antimalarial resistance to both artemisinins and many of the partner drugs, there is an urgent need for new therapies with new modes of action [6–8]. The first new approach was the development of synthetic peroxides. Arterolane (OZ277/ Rbx11160) was successfully developed as a 3-day medicine, Synriam, in combination with piperaquine and has been widely used in India. Based on this success, the next generation artefenomel (OZ439) was developed as a potential single dose cure in combination with ferroquine. This only achieved 91% efficacy in a phase 2 study, and had significant galenic or formulation issues leading to poor tolerability in small infants [9, 10]. After this, the current most advanced new molecule is a formulation of ganaplacide (KAF156) and lumefantrine, which showed 92–94% efficacy in phase 2 as a single dose [11, 12]. Given the 100% cure rates with 3 days of dosing, this combination has now been tested in phase 3 as a 3-day dosing [13]. However, its potential for treatment shortening by adding a third drug is in early clinical exploration [14]. The other single-dose combinations that are still in early phases include cabamaquine (M5717) + pyronaridine [15], and ZY19489 + ferroquine [16], both of which are exploring both (...truncated)