The non-artemisinin antimalarial drugs under development: a review

In 2022, malaria caused approximately 249 million cases and 608,000 deaths, primarily in Africa. Current treatments target asexual blood-stage parasites, gametocytes, and liver hypnozoites. Standard guidelines recommend a 3-day course of artemisinin-based combination therapies as a first-line treatment of uncomplicated malaria and parenteral artesunate for severe malaria. However, the emergence of partial resistance to artemisinin derivatives threatens the treatment efficacy, highlighting the urgent need for novel antimalarial drugs.

This review summarizes recent progress in the clinical development of antimalarials particularly non-artemisinin compounds under target product profile-1.

Data were gathered from Medicines for Malaria Venture (MMV)'s portfolio and clinical trial databases between 2020 and 2024.

Sixteen clinical trials were reviewed, including safety and efficacy studies involving healthy volunteers, experimentally infected volunteers, asymptomatic Plasmodium falciparum carriers and malaria patients. Six trials evaluated the safety and tolerability of MMV533, ZY19489, INE963, GSK701/MMV367 and intravenous KAE609 in healthy volunteers. Efficacy trials involving experimentally infected volunteers assessed ZY19489 and GSK701/MMV367, whereas studies on asymptomatic carriers tested ZY19489/ferroquine and cabamiquine/pyronaridine. Trials on malaria patients investigated combinations of ganaplacide/lumefantrine-SDF, cabamiquine/pyronaridine, both oral and intravenous cipargamin and INE963.

Although attrition remains a possibility, several promising candidate drugs with novel modes of action are advancing through clinical development. Many are expected to become available for treating uncomplicated and severe malaria within the next decade. These new antimalarials could significantly enhance malaria treatment, reduce resistance, and support global health efforts towards malaria control, elimination and, potentially, eradication.