Promising Non-Artemisinin Malaria Drug Succeeds in Phase III Trial

Globally, malaria remains one of the most persistent public health threats, with more than 250 million cases and over half a million deaths each year. With the growing threat of resistance to artemisinin-based combination therapies (ACTs) – the current gold standard treatments – new treatment options are urgently needed.

GanLum (ganaplacide/lumefantrine, or KLU156) is a combination of two compounds, attacking the malaria parasite on multiple fronts: ganaplacide, a novel non-artemisinin compound with an entirely new mechanism of action, and a new once-daily formulation of the existing antimalarial lumefantrine, a longer-acting drug. In the “KALUMA” trial, GanLum was evaluated in 1 688 adults and children across 34 sites in 12 African countries, achieving a PCR-corrected cure rate of 97.4 % using the regulatory estimand framework (versus 94.0 % for the current standard of care, artemether-lumefantrine) and 99.2 % vs. 96.7 % in the conventional per-protocol analysis. Notably, GanLum displayed high efficacy against parasite strains showing partial resistance to artemisinin derivatives and demonstrated activity against mature gametocytes, the sexual stage of the parasite’s lifecycle responsible for onward transmission. 

Swiss TPH’s contribution to a full innovation pipeline

Swiss TPH contributed to the discovery and development of GanLum across several stages of the R&D pathway [1] — from early scientific work to clinical validation. Our scientists supported the earliest phases of compound discovery and optimisation evaluated potential combination partners [2] and later confirmed evidence of the compound’s transmission-blocking potential.

“From early compound screening through optimisation, our aim has been to identify potent molecules with a novel mode of action that can overcome emerging resistance. This next-generation candidate reflects that goal and the strength of sustained scientific collaboration,” said Matthias Rottmann, Senior Scientific Project Leader at Swiss TPH.

During the clinical validation phase, Swiss TPH supported the conduct of a large Phase III trial in the Democratic Republic of the Congo, working closely with national partners to ensure rigorous study implementation in a high-burden setting. This included coordinating patient enrolment and follow-up, ensuring adherence to protocol and safety procedures, and overseeing data quality and monitoring processes. “Over the last 20 years, Swiss TPH has worked with national partners in endemic countries to co-developed clinical research capacity. Together, we have built regulatory-compliant trial sites that are transforming regions historically excluded from clinical research, ensuring that the communities most affected by neglected diseases can directly contribute to, and benefit from, breakthrough treatments,” said Elizabeth Reus, Head of the Clinical Operations unit at Swiss TPH. 

Swiss TPH also conducted advanced genotyping analyses to distinguish true treatment failures from re-infection during the trial and assess the impact of molecular markers of resistance on treatment outcomes. “It is reassuring to see that the new combination shows excellent efficacy in areas with high levels of partial artemisinin resistance, as we do not currently have any other option if artemisinin-based combination therapies (ACTs) start failing”, said Christian Nsanzabana, leader of the Genotyping Group, whose team performed the molecular analyses during the clinical trial.

Taken together, these contributions reflect Swiss TPH’s ability to support key stages of the research and validation process in close collaboration with national and international partners.

Why this matters for malaria control

The very high cure rate of GanLum and the novel mode of action of ganaplacide – which targets the parasite’s internal protein-transport systems – represent a critical advance in the malaria toolbox. With mounting evidence of partial resistance to artemisinin-based combination therapies (ACTs), the development of alternative therapies has become increasingly urgent. Moreover, the ability of GanLum to act on sexual stages of the parasite suggests a dual benefit of effective case-management plus potential interruption of transmission – supporting both treatment and elimination agendas.

Looking ahead

Novartis plans to submit regulatory applications for GanLum as soon as possible. If authorised, this therapy could become the first major malaria treatment advance since ACTs transformed malaria care more than 25 years ago. Swiss TPH will continue to work with partners and health systems in malaria-endemic regions to ensure that scientific progress contributes to future improvements in prevention, diagnosis and treatment.

Related publications

[1] Kuhen KL, Chatterjee AK, Rottmann M, et.al. KAF156 Is an Antimalarial Clinical Candidate with Potential for Use in Prophylaxis, Treatment, and Prevention of Disease Transmission. Antimicrobial Agents and Chemotherapy 2014, 58 (9). journals.asm.org/doi/10.1128/aac.02727-13

[2] Gal IR, Demarta-Gatsi C, Fontinha D, et al. Drug Interaction Studies of Cabamiquine:Ganaplacide Combination against Hepatic Plasmodium berghei. ACS Infectious Diseases Journal. 2025 Jan 10;11(1):69-79. https://pubmed.ncbi.nlm.nih.gov/39657997/