Artemether/Lumefantrine

Novartis plans to seek approval for GanLum, which has a fast track designation from the FDA, as soon as possible. \n A phase 3 trial of Novartis’ next-generation malaria treatment has met its primary endpoint, positioning the drugmaker to seek approval of a therapy with the potential to kill drug-resistant parasites.The World Health Organization (WHO) has sounded the alarm in recent years about the rise of partial resistance to artemisinin, the mainstay of malaria treatment in Africa. Researchers have found mutations linked to partial resistance in multiple regions of Africa. Some studies have reported higher levels of treatment failure. In 2022, the WHO hailed Novartis’ GanLum as the most promising non-artemisinin-based combination. The Swiss drugmaker validated the promise Wednesday evening by reporting that GanLum performed as well as the standard-of-care treatment Coartem.Investigators studied 1,688 adults and children across 34 sites in 12 African countries to assess the effect of GanLum, a combination of lumefantrine and the novel non-artemisinin antimalarial ganaplacide. The cure rate in people who took a sachet of GanLum granules daily for three days was 97.4% or 99.2%, depending on the analysis. The Coartem results were 94% and 96.7%, respectively. Those figures represent people who were free from clinical symptoms and baseline parasites 28 days after the start of treatment. Patients with new infections were included in the cure rate. Excluding those patients, Novartis reported cure rates of 85.3% for GanLum, compared to 82.1% for the standard of care. GanLum’s safety profile was similar to standard of care, according to the drugmaker.Novartis said additional analysis indicated GanLum was highly effective against mutant malaria parasites associated with partial drug resistance. The Swiss drugmaker also noted a rapid response against mature gametocytes, the sexual stage of the parasite’s life cycle responsible for onward transmission. GanLum showed high efficacy against multiple forms of the parasite, Abdoulaye Djimdé, Ph.D., professor of parasitology and mycology at the University of Science, Techniques and Technologies of Bamako, Mali, said in a statement. Novartis’ press release lacks a close look at how GanLum performed against the five parasitic Plasmodium species that infect humans. The drugmaker plans to seek approval for GanLum, which has a fast track designation from the FDA, as soon as possible. Novartis said the drug would represent the first major innovation in malaria treatment since it brought Coartem to market in 1999. While GanLum could mitigate the threat of artemisinin resistance, its use of lumefantrine leaves the drug combination exposed to another potential risk. Lumefantrine is used in Coartem. The WHO has said resistance to lumefantrine would represent a major setback in recent research and development efforts. 

Novartis reported positive late-stage findings for its investigational antimalarial treatment KLU156 (ganaplacide/lumefantrine, or GanLum), with the non-artemisinin combination meeting its key goal of non-inferiority to the standard of care Coartem (artemether/lumefantrine) in patients with acute, uncomplicated malaria due to Plasmodium falciparum.According to the company, the therapy pairs ganaplacide — an imidazolopiperazine class compound that disrupts the parasite's internal protein transport systems essential for its survival in host red blood cells — with a new once-daily formulation of lumefantrine. An earlier Phase II study in 524 participants had met its primary endpoint, showing efficacy of the combination in adults and children.Highlighting the threat of drug-resistant parasites, Novartis’ Chief Medical Officer Shreeram Aradhye, said “we’ve gone further to develop a new class of antimalarial with an entirely new mechanism of action, which has the potential to both treat the disease and block transmission.”The Phase III KALUMA trial — conducted in partnership with the WANECAM 2 consortium with financial support from the EU — enrolled 1,688 adults and children weighing ≥10 kg with P. falciparum infection across 12 African countries. Patients were randomised to receive either GanLum granules once daily or Coartem twice-daily for three days. Cure rate was the proportion of patients without clinical symptoms or parasites 28 days after treatment initiation, regardless of whether recurrence stemmed from recrudescence or new infection.The findings, presented Wednesday at the American Society of Tropical Medicine and Hygiene annual meeting, showed the study’s primary endpoint was met, with GanLum achieving a non-inferior PCR-corrected cure rate of 97.4% using an estimand framework against Coartem’s 94.0%, equating to cure rates of 99.2% and 96.7% respectively, under conventional per protocol analysis.Additional analyses demonstrated high efficacy of GanLum against mutant malaria parasites associated with partial drug resistance, as well as rapid response against mature gametocytes responsible for onward transmission. Meanwhile, the experimental combination’s safety profile matched the standard of care, with adverse events consistent with malaria itself.Granted Fast Track and Orphan Drug Designations by the FDA in 2022, Novartis plans to seek regulatory approvals for GanLum at the earliest.