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The malaria parasite Plasmodium falciparum is becoming increasingly resistant to the artemisinin-based combination therapies (ACTs) currently in use. Researchers at the Bernhard Nocht Institute for Tropical Medicine (BNITM) have tested two new drug combinations in a DZIF-funded study.
Most malaria drugs are combination therapies based on artemisinin, an active ingredient derived from the medicinal plant Artemisia annua (sweet wormwood). The malaria parasite Plasmodium falciparum is becoming increasingly resistant to this type of treatment. New combinations of approved malaria drugs could provide a solution. Researchers at the Bernhard Nocht Institute for Tropical Medicine (BNITM) have tested two new drug combinations (artesunate/pyronaridine-atovaquone/proguanil and artesunate-fosmidomycin-clindamycin) in a DZIF-funded phase II clinical trial in Gabon and Ghana for safety, tolerability, and efficacy in cases of uncomplicated malaria. The promising results were recently published in the journal Lancet Microbe.
Parasites of the genus Plasmodium cause the tropical disease malaria in humans. Every year, more than 200 million people worldwide contract the disease, most of them in sub-Saharan Africa. The Plasmodium falciparum parasite is particularly dangerous; if left untreated, the malaria tropica it causes can be fatal.
The World Health Organization (WHO) recommends artemisinin-based combination therapies (ACTs) as the standard treatment for malaria. These drugs work quickly and reliably because they combine artemisinin with a longer-acting agent to prevent relapses. Common ACTs include the combination of artesunate (an artemisinin derivative) and pyronaridine. In some regions, particularly in Southeast Asia and increasingly in Africa, partial resistance to artemisinin and its derivatives has been observed - meaning that artemisinin and its derivatives are no longer fully effective there. Resistance is also developing to the combined active ingredients in ACTs.
Why are two-drug combination therapies not sufficient to fight malaria?
One reason for resistance is that the two active substances break down at different rates in the body. Once the artemisinin derivative artesunate has disappeared, the other active ingredient, pyronaridine, remains alone. This is precisely what allows the malaria parasite to develop resistance. Scientists from the Clinical Research department at BNITM (https://www.tropmed-hamburg.de/en/clinical-research) tested new triple combinations with a better-matched duration of action as part of the DZIF-funded MultiMal project (https://www.bnitm.de/forschung/forschungsgruppen/patient/abteilung-klinische-for...). Together with cooperation partners at two of the DZIF's four African Partner Institutions (https://www.dzif.de/en/infrastructure/african-partner-institutions) in Lambaréné, Gabon, at the Centre de Recherches Médicales de Lambaréné (CERMEL, https://www.dzif.de/en/partner/centre-de-recherches-medicales-de-lambarene-cerme...) and in Kumasi, Ghana, at the Kumasi Centre for Collaborative Research in Tropical Medicine (KCCR, https://www.dzif.de/en/partner/kumasi-centre-collaborative-research-kccr), they investigated two new forms of therapy: artesunate/pyronaridine-atovaquone/proguanil (APAP) and artesunate-fosmidomycin-clindamycin (AFC). "Our goal is to find out how well these new drug combinations work and whether they can help to stop the development of resistance in the long term and improve the treatment of malaria in Africa," explains Dr. Johannes Mischlinger (https://www.bnitm.de/en/research/research-groups/klinische-forschung/abteilung-k...), laboratory group leader at BNITM and last author of the study.
Different targets of the triple combination
Combination therapies with more than two active substances are still a relatively new treatment concept. The researchers chose the already approved malaria drug artesunate/pyronaridine, which is used as standard therapy for uncomplicated malaria in endemic areas. They supplemented the treatment with the active ingredients atovaquone, which impairs the parasites' energy production, and proguanil, which disrupts the parasites' DNA synthesis. Atovaquone/proguanil is also used to treat malaria, including for prophylaxis.
The researchers also tested two antibacterial antibiotics (fosmidomycin and clindamycin) in combination with the artemisinin derivative artesunate. Fosmidomycin inhibits a metabolic pathway that is not present in humans but is present in malaria parasites. Clindamycin inhibits protein synthesis in a parasitic organelle that is important for the survival of the malaria parasite.
"With the combined active substances, we attack different vital processes in the parasite at the same time in order to slow down the development of resistance. We also consider the combination of an antimalarial drug with antibiotics to be promising. Malaria often cannot be clinically distinguished from bacterial diseases, and laboratory diagnostics are usually not available in malaria-endemic regions. Treatment with a drug that targets malaria and also many types of bacteria could therefore be beneficial in these regions," says Mischlinger.
The new drug combinations are safe, well tolerated, and effective against malaria
The randomized, controlled Phase II trial included 100 patients infected with Plasmodium falciparum who had uncomplicated malaria. Forty people received the new antimalarial combination APAP, another 40 received the new combination AFC (antimalarial and antibiotic), and for comparison, 20 people received the antimalarial drug artesunate/pyronaridine (AP). Both the patients and the researchers knew which person was receiving which drug (an open-label study). The researchers observed the subjects for 42 days. Among other things, they took blood samples at various times to measure the malaria parasite load microscopically and by PCR (to detect parasite DNA).
Mischlinger and his team measured how many patients recovered after treatment, i.e. no longer showed any symptoms of malaria and no longer had any pathogens in their blood. 28 days after treatment, the scientists found that all patients treated with the new triple combination APAP and the conventional AP had recovered. Among patients treated with the new drug combination AFC, 97% were malaria-free after 28 days. By day 42, the values had fallen slightly in the experimental groups (APAP and AFC), but also in the AP control group. That means that in some patients, new malaria infections occurred, or previous infections flared up again. "These values mean that the three different treatments were equally effective against malaria," Mischlinger explains. "Further tests also showed that our newly tested drug combinations are safe and well tolerated. Our study shows that they are promising candidates for further Phase III clinical trials."
Prof. Dr. Michael Ramharter
Bernhard Nocht Institute for Tropical Medicine
michael.ramharter@ctm.bnitm.de
Dr. Johannes Mischlinger
Bernhard Nocht Institute for Tropical Medicine
mischlinger@bnitm.de
https://doi.org/10.1016/j.lanmic.2025.101245
https://www.dzif.de/en/powerful-medicines-against-malaria-resistance Original press release with picture
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