Standard malaria treatments use artemisinin-based combination therapies (ACTs), which pair an artemisinin derivative with a partner drug such as a quinine or chloroquine derivative. Coartem, the fixed-dose combination of artemether (artemisinin-derivative) and lumefantrine (chloroquine-derivative), is widely regarded as the global gold standard for uncomplicated Plasmodium falciparum malaria. Although the precise mechanism of action of artemisinin and related compounds is not fully understood, they are thought to generate damaging free radicals and inhibit essential parasite proteins, broadly disrupting metabolism and killing the parasite. The partner drugs (e.g. chloroquine) act differently: as weak bases, they concentrate in the parasite’s acidic food vacuole where hemoglobin digestion releases toxic heme that is normally detoxified into crystalline hemozoin. Chloroquine/quinine are believed to block hemozoin formation so that heme accumulates to toxic effect.
A second line of defense is provided by the malaria vaccines. The World Health Organization (WHO) has recommended two vaccines: RTS,S/AS01 (Mosquirix), which was introduced in 2019 and has moderate efficacy, and the newer R21/Matrix-M vaccine, recommended in 2023, which shows higher efficacy and affordability.
Malaria infections can be mild (uncomplicated malaria) characterized by non-specific flu-like symptoms without severe organ damage, allowing conscious patients to be treated with oral ACTs. In contrast, complicated (severe) malaria is a medical emergency defined by vital organ dysfunction or metabolic failure -- such as cerebral malaria, severe anemia, or respiratory distress -- caused by infected blood cells clogging small vessels. While uncomplicated cases are managed on an outpatient basis, severe malaria requires immediate hospitalization and aggressive treatment.
The ACTs (Artemisinin-based Combination Therapies), and specifically Coartem, have been the undisputed "gold standard" for malaria treatment for over two decades. Their success is attributed to their efficacy and speed. In regions without resistance, efficacy often exceeds 95-98%. ACTs work via a "one-two punch." The artemisinin component acts like a "bomb," reducing the parasite load in the body by a factor of 10,000 within the first 48 hours. The partner drug (lumefantrine) then wipes out the remaining survivors. Since the early 2000s, ACTs have been credited with saving millions of lives and significantly reducing the global malaria burden.
The emergence of partial artemisinin resistance, arising through a specific mutation in Plasmodium, has created a dangerous crack in this armor. As a result, there is delayed clearance of the resistant mutant taking approximately 71 hours instead of the expected <48 hours. Efficacy is decreased because the artemisinin component is not activated properly and fails to kill the bulk of the parasites quickly. As a result, the partner drug (e.g. lumefantrine) must act as the primary killing agent, but it is a less potent older generation drug, and more likely to fail on its own. In addition, there is increased transmission of resistant parasites because they linger in the blood for longer, which creates a wider window of opportunity for mosquitoes to bite the patient and spread the (resistant) disease to others. Thus although only partial, resistance can lead to serious complications in the control of malaria.
One way to circumvent these issues is to develop a drug with a significantly different chemical structure from artemisinin so that that the mutant cannot counteract the drug. GanLum (KLU156), developed by the pharmaceutical company Novartis, emerged from a massive phenotypic screen, thereby casting a much wider net compared to traditional target-based drug design. Researchers evaluated over two million chemical compounds to identify a molecule effective against both the blood and liver stages of the parasite, eventually isolating a novel imidazolopiperazine named ganaplacide (KAF156). Both its chemical structure and mechanism of action -- disrupting the parasite's endoplasmic reticulum and protein secretory pathway -- are very different from artemisinin. Ganaplacide was then paired with lumefantrine to create GanLum, which is administered orally once daily.
The next step was to evaluate the efficacy and safety of GanLum compared to Coartem. The Phase 3 KALUMA trial enrolled 1,688 (uncomplicated) malaria patients, including both adults and children. The study was conducted across 34 clinical sites in 12 countries in sub-Saharan Africa with some areas having up to 20% of patients infected by resistant Plasmodium. Patients received either a once-daily dose of GanLum (treatment group) granules for 3 days, or Coartem twice daily for 3 days (control group).
GanLum was highly effective and non-inferior to the current standard of care Coartem, achieving a PCR-corrected cure rate of 97.4% compared to 94.0% for Coartem at Day 29 after treatment. KALUMA was presumably a non-inferiority trial which aims to prove that the new drug is roughly as good as the current standard. In addition, GanLum cleared parasites with artemisinin-resistant mutations in ~47 hours (vs. 71 hours for standard care). The PCR-correction refers to a PCR test to distinguish between recrudescence, the original infection wasn’t fully cleared and comes back i.e. drug failure, and reinfection, the person gets bitten again and acquires a new infection during follow-up. Quite strikingly, the uncorrected numbers were 85.3% (GanLum) versus 82.1% (Coartem), which showed that more than 10% of participants had been re-infected by another mosquito bite by Day 29.
Beyond its high efficacy, the study highlighted GanLum's potential to reduce transmission by clearing the parasites faster and by eliminating the sexual gametocyte stages responsible for transmission. Importantly, the overall safety profile was comparable to existing therapies, although the trial identified a notable tolerability issue: nearly 20% of patients reported vomiting due to the formulation's bitter taste, resulting in a higher dropout rate than the control group. In the future, Novartis will strive to mitigate the dropout by improved administration protocols and taste masking.
The excitement surrounding GanLum goes beyond its modest statistical superiority (albeit very impressive cure rate), and instead is sparked by its status as the first new class of antimalarial drug in over 25 years, offering a critical defense against the looming threat of global artemisinin resistance. Unlike current therapies that are losing potency against mutated parasites, GanLum operates through a novel mechanism and chemical compound. Combined with a simplified once-daily dosing regimen that enhances patient compliance, it provides a vital insurance policy and a new strategic tool to prevent the catastrophic failure of existing treatments.
Figure 1. Estimated annual number of deaths from malaria from 2000 to 2020 (https://ourworldindata.org/malaria). Nearly all deaths occurred in Africa. The recent uptick in deaths in 2020 is likely due to Covid outbreak disrupting both treatment and vaccination efforts. Hopefully, GanLum along with the end of the Covid pandemic will cause the curve to start decreasing again.
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