Caroline Boulton, Global Program Head Malaria at Novartis, currently leads the development of the antimalarial portfolio at Novartis, including next-generation malaria treatment ganaplacide/lumefantrine. As antimalarial drug resistance grows, the treatment’s entirely new mechanism of action represents a powerful new tool to help outpace evolving malaria parasites. We spoke with Caroline about the nearly 17-year journey from discovering the novel ingredient in ganaplacide/lumefantrine in the lab to announcing promising Phase III trial results in November 2025.

First, what is antimalarial drug resistance and why is it a growing concern?

BOULTON: Antimalarial drug resistance occurs when the plasmodium parasites responsible for malaria evolve so that they can survive antimalarial therapy. Those parasites then spread through the population.

Antimalarial drugs have two components, and resistance will generally develop to one of the components first. That then puts extra pressure on the other antimalarial component to the extent that it also develops resistance. When there is resistance to both components, you get treatment failure. And that’s what we saw at the end of the 1990s, when drugs were failing because the parasites had mutated to become resistant — and, tragically, patients died because of that. 

We’re now seeing early signs of resistance to one of the components currently used in antimalarial therapies. Artemisinin-based therapies are the standard of care, and at the moment, we’re seeing partial resistance to artemisinin. Those mutations have been confirmed in several countries in Africa and they are suspected in several others. That’s the first signal that we need to be really concerned about the evolution of resistance, particularly in sub-Saharan Africa where the burden of malaria due to plasmodium falciparum, the deadliest form of the disease, is highest. 

That context is important, particularly as we consider Novartis’ recent announcement regarding its next-generation malaria treatment, ganaplacide/lumefantrine. How is ganaplacide/lumefantrine different than current standard treatments? 

BOULTON: Ganaplacide [the novel ingredient in ganaplacide/lumefantrine] was specifically developed to address the resistance threat with artemisinin. It’s a member of a brand-new non-artemisinin class of antimalarial which parasites in the environment have never been exposed to. That means there shouldn’t be any pre-resistance to ganaplacide. We also know that ganaplacide is highly effective at clearing the parasites that have the mutation responsible for partial artemisinin resistance. 

It also has several other advantages: not only does it clear blood stage infection, which is responsible for the malaria symptoms everyone recognizes, like fever and chills, but ganaplacide is also highly effective at clearing the sexual stages of malaria infection. That means it should reduce the possibility of the infection being spread further. That’s really important, especially in places where resistance is present. 

It’s also combined with a new formulation of lumefantrine. One of the components of conventional antimalarial drugs, lumefantrine is generally used twice a day, but we’ve redeveloped lumefantrine so that it can be given just once a day. That should make it easier for patients to take their treatments in the way they’re intended.

It must have been quite a journey to reach this point. Can you briefly trace the process from discovering ganaplacide in the lab to running clinical trials? 

BOULTON: Ganaplacide was first made a project back in 2008 when it was discovered in our labs in San Diego. We screened over 2 million different potential candidates before identifying ganaplacide, which performed extremely well in initial testing. From there, we have taken it through a full battery of clinical trials, from healthy volunteers to monotherapy trials in patients with malaria — where we really showed it’s an effective antimalarial and clears resistance mutations — and then we evaluated it in combination trials with lumefantrine. So it’s been a near 17-year journey, and we’ve had a lot of barriers and hurdles along the way — from making sure trial sites were open at the right times in the right places, especially where malaria is seasonal, to managing the consequences of severe floods that impacted one of our trial sites, to delays caused by COVID lockdowns, and military coups in four West African countries where we conducted one of our Phase II trials. 

But the team at Novartis together with our partners at Medicines for Malaria Venture (MMV) and the WANECAM2 Consortium funded by EDCTP, who co-developed ganaplacide-lumefantrine, managed to overcome these challenges. It’s been a very complex journey to get to this stage in the development of ganaplacide/lumefantrine, but we got here together. 

It really is an impressive feat to reach this point. Congratulations to you and the entire team. Can you expand upon the latest Phase III trial results to help our readers understand why they are so promising?

BOULTON: We conducted a very large Phase III controlled study, comparing ganaplacide/lumefantrine to the existing gold standard therapy, artemether-lumefantrine. We enrolled over 1600 patients, both adults and children, with uncomplicated malaria. 

What we saw was that ganaplacide/lumefantrine was not only non-inferior to the standard of care, but it was also numerically superior — there was a treatment difference in favor of ganaplacide/lumefantrine. And when we conducted a per-protocol analysis, which is the usual method used to assess the efficacy of new agents in malaria trials, ganaplacide/lumefantrine achieved a 99.2% PCR corrected cure rate at Day 29. Artemether-lumefantrine still had good efficacy with a cure rate of 96.7%. And that was not an isolated result, because in one of our Phase II trials, we also saw a 99% cure rate with ganaplacide/lumefantrine, so we’re observing consistently strong efficacy.

And when we looked into the data, it was very clear that not only did ganaplacide/lumefantrine reduce the number of re-infections, it also reduced the number of new infections across that 29-day period compared to artemether-lumefantrine, which is highly encouraging. 

But coming back to the reason that ganaplacide/lumefantrine was developed, we also looked at patients with parasites carrying mutations responsible for partial artemisinin resistance. And what we saw was that ganaplacide/lumefantrine cleared those parasites with a very similar time course to parasites that don’t have the mutation. Whereas when we looked at the artemether-lumefantrine group, we could see a delay in the clearance of the parasites carrying the mutation compared to normal parasites. So that really demonstrates the value of ganaplacide/lumefantrine in situations where resistance is developing to artemisinin. 

The clinical data also demonstrated that ganaplacide/lumefantrine cleared gametocytes in the majority of patients within 72 hours. So that means that if those patients are subsequently bitten by a mosquito, the infection will not be transmitted to another patient. For the standard of care, gametocytes were still present for much longer. That gives us great confidence that ganaplacide/lumefantrine will make a big difference not only to treating malaria but to help to reduce the burden of disease.  

99.2% is incredible, it must have been thrilling when those results came in. What are the next steps to getting ganaplacide/lumefantrine to market? When do you think it could potentially be available?

BOULTON : We’re working hard on preparing the regulatory submissions. And we hope that will result in approval to market ganaplacide/lumefantrine in some countries within sub-Saharan Africa within the next 18 months to two years.

Ganaplacide/lumefantrine has a really interesting profile with its ability to treat infection, including resistant parasites and its transmission blocking activity. And that gives us great confidence that ganaplacide/lumefantrine will make a big difference in the fight against malaria when it becomes available to health systems and patients.