KAF156 is the first compound to progress into clinical development from the novel imidazolopiperazine class of antimalarial molecules. A key strength of the drug is its potential to both treat and prevent malaria, including resistant strains. Phase IIa studies have demonstrated that KAF156 rapidly kills both P. vivax and P. falciparum malaria parasites. In 2017, Novartis, in partnership with MMV, initiated a phase IIb study to evaluate the combination of KAF156 plus a new formulation of lumefantrine. David Hughes, Senior Global Program Head, Anti-infectives, Novartis Pharma talks about the benefits of the KAF156/lumefantrine combination and how it could help malaria-endemic countries move towards malaria elimination. 

1. What advantages does this new combination have over current treatment?

The first advantage of this combination is its activity in drug-resistant parasites. This was demonstrated preclinically and then in our proof-of-concept study, where we saw many patients who were infected with strains of parasites that possessed markers of resistance or reduced sensitivity to artemisinin. KAF156 monotherapy was able to clear these parasites from the patients. 

The phase IIb study is investigating KAF156 in combination with a new formulation of lumefantrine. The combination is currently being evaluated as a single dose, administered for 1, 2 and 3 days. At the moment, it holds great potential in being effective as a one-day regimen. Compared with today’s treatment options, the KAF156/lumefantrine combination’s easier dosing schedule could increase patient compliance, and subsequently reduce the emergence of resistance.

2. What are the phase IIb study objectives?

The overarching objectives are to characterize the activity, efficacy and toxicity of the combination of KAF156 and lumefantrine. The dosage and ratio of the partner drugs, as well as duration of therapy, are being evaluated in adults, children and infants, all in one complex study. We are looking for a therapy that is adapted to children’s needs, with the shortest possible treatment regimen. We will then take this forward into phase III studies.

3. How might these considerations change should we see an increase in artemisinin drug-resistance?

The global community is actively monitoring for artemisinin resistance. So far, no confirmed cases have been detected in Africa, but we are seeing cases of delayed parasite clearance in Asia. If full resistance develops and spreads, as we’ve seen with other antimalarial treatments in the past, then we will consider modifying our programme as quickly as possible to make the drug available in areas where resistance has emerged. We will of course be following recommendations from regulatory authorities to ensure we are doing the right thing for patients.

4. How is the phase IIb programme progressing?

Despite the trial complexity, the phase IIb study is progressing very well. It is being run in various sites across nine countries – seven in Africa and two in Asia. A run-in cohort of 12 patients was completed in September 2017, and as of March 2018, more than 100 adults and adolescents have been enrolled in Part A of the study. We expect to complete the interim analysis in early 2019 and then quickly move to Part B, which will evaluate the optimized drug combinations and treatment durations in patients aged 2–12 years.

5. What do each of the partners bring to the table?

The partnership between Novartis and MMV has been great! There is tremendous wisdom and power within the team, bringing a wide range of experience and diversity in terms of the overall strategy and design of the studies. MMV is able to anticipate the operational challenges we might face through their prior experience with other partners and running studies in malaria-endemic countries. Together with the interests and legacy of Novartis in this field, we can put together the best people on the project, who are experienced and motivated.

6. What are Novartis' future priorities in antimalarial drug development?

Our priority will be to continue to advance research for new active antimalarials, especially against resistant strains, to secure the gains made in the fight against malaria and progress toward elimination. We will also be focusing on drugs that block malaria transmission by targeting drug candidates that are active against gametocytes. Our aim is to ensure our new medicines are designed to benefit the populations with the greatest disease burden and needs: women who are pregnant or with child-bearing potential, and children. Developing medicines that are 'friendly' to these vulnerable populations is a high priority, as is including these populations in our trials as early as we can.

David Hughes, Senior Global Program Head, Anti-infectives, Novartis Pharma