New Novartis drug aims to tackle parasite resistance to antimalarials

Global pharmaceutical company Novartis is working on several new drugs to treat malaria and its severe forms, and address emerging parasite resistance to current treatments. The most advanced in clinical development is Ganaplacide, a novel antimalarial drug that has the potential to clear infection and kill the sexual transmission stages of the parasite, helping stop further transmission of malaria. In trials, the drug in combination with the antimalarial drug lumefantrine has also shown to clear preexisting parasites that have developed partial resistance to artemisinin, a key anti-malarial drug, according to Caroline Boulton, global program head for malaria at Novartis. At present, the drug is in phase 3 trials in several African countries to compare its efficacy with Coartem, the current drug of choice for treating uncomplicated malaria across sub-Saharan Africa where the deadly malaria parasite Plasmodium falciparum is most prevalent. Novartis expects the trials to conclude in 2025. There’s also an ongoing phase 2 trial for the drug covering adolescents and children down to 6 months of age. Novartis expects to complete this trial within the next two months. “WHO has a standard that they want to see new drugs achieving over 95%, we’ll call it cure for simplicity. … And we achieved that in our phase 2 trial [for Ganaplacide],” Boulton told Devex. Why is this important: The World Health Organization currently recommends six combination drug treatments for uncomplicated malaria, including Coartem, but they all rely on artemisinin, the wonder malarial drug that is now under threat due to emerging parasite resistance. The drug remains effective, but partial parasite resistance to artemisinin, or the delay in the clearance of malaria parasites from the bloodstream of patients taking this treatment, has been observed in several African countries, including in Eritrea, Rwanda, and Uganda. Ganaplacide-lumefantrine, if successful, could help tackle parasite resistance by offering a new treatment option that’s not artemisinin based. “We see early signs of resistance which gives us a great sense of urgency to develop the next generation of antimalarials,” said Dr. Lutz Hegemann, president of global health at Novartis. “I feel much more comfortable now that we have a drug candidate that addresses resistance in the last phase of clinical trials. … And I would feel comfortable with the current data package that we have to use this medicine in an emergency similar to what we did with COVID medicines for emergency use,” he added. But what about pregnant women? Pregnant women are among those at higher risk of severe malaria, and getting infected puts them at risk of complications, such as premature birth and miscarriage. In 2020, over 11 million pregnant women in sub-Saharan Africa were at risk of such complications because of malaria. But they are often excluded from clinical trials due to safety concerns, leaving them at the tail end of benefitting from new drug treatments. Case in point: WHO only recommended the use of artemether-lumefantrine among pregnant women in their first trimester in 2022, despite the drug being used to treat uncomplicated malaria for more than two decades. Before this, the drug was only recommended for women in their second and third trimesters of pregnancy. Boulton said they are discussing clinical trials for pregnant women with different experts, but they need more safety data. What’s the plan for access? Patients who have completed the phase 3 trial successfully are eligible to take part in an extension study, where they will continue to have access to the drug if they become ill with malaria again. This would help show how safe and efficacious the drug is over a period of time in communities where people can suffer from malaria infections multiple times a year, Boulton said. But broadly, Boulton said they’re looking at different ways to ensure the drug becomes accessible to everyone irrespective of their socioeconomic or geographical location. They are currently in discussions with procurement agencies, such as The Global Fund to Fight AIDS, Tuberculosis and Malaria, for example. But to get there, they need to establish the drug’s efficacy. They also need to get it approved by stringent health authorities, or prequalified by WHO, which are part of the Global Fund’s eligibility requirements for procurement. Boulton said they don’t enforce patents on their products in sub-Saharan Africa, and they will be open to working with reputable organizations in terms of procurement of their antimalarial drugs. “We will work with whichever partners are most appropriate to work with to make sure that we fulfill that mandate of making sure that patients can have access to our medications,” Boulton said. What else is in the pipeline: Novartis has other novel drugs in phase 2 clinical development, including a drug called Cipargamin for the treatment of severe malaria via intravenous infusion. According to Novartis, the drug has shown “extremely rapid parasite clearance in patients,” which is critical in severe malaria patients. At present, there’s only one recommended drug available to treat severe malaria, artesunate given intravenously, followed by a full treatment course of artemisinin-based combination therapy. However, it suffers from partial resistance. If it progresses to full resistance, there will be limited options to treat severe malaria. Another drug in phase 2 clinical trials is known as INE963. It doesn’t have a name yet, but Novartis said it’s a “fast-acting and long-lasting antimalarial with a high barrier to resistance,” based on in vitro experiments Novartis has done to date. “There has never been a compound which is really irresistible to malaria parasites because of the way it manages to adapt itself. … But we're hoping that this one at least has an extremely high barrier to resistance in the future. And these are exactly the type of tools that we need to take us through to elimination,” Boulton said while noting that treatments are just one part of interventions needed to reach malaria elimination.