A compound with the potential to resist drug resistance

Dr Cornelis Winnips, Global Program Clinical Head, and Dr Anne Claire Marrast, Senior Medical Director, Novartis

1. What did the results reveal from the Phase IIb study of the novel ganaplacide-lumefantrine combination in young children with malaria?

Anne Claire Marrast: The Phase IIb study, completed in 2021, tested several dosing regimens of the combination of ganaplacide and a solid dispersible formulation of lumefantrine (also known as LUM-SDF) in adults and children.1 It allowed us to identify an efficacious dosing regimen with a good safety and tolerability profile, particularly in young children.

Cornelis Winnips: The study results showed that the efficacy of the ganaplacide and LUM-SDF combination against acute malaria in young children was comparable to what we would typically expect from a standard antimalarial treatment.

2. What is exciting about this combination?

CW: First, ganaplacide has the potential for excellent transmission-blocking activity, based on the in vitro results. Second, if it goes forward into Phase III, it will be the first non-artemisinin-based combination therapy (ACT) to be run in Phase III for treatment of P. falciparum malaria for over 20 years.

ACM: Both partner drugs have important characteristics. On the one hand, ganaplacide, which belongs to a new generation of compounds, chemically synthetized, with both pre-erythrocytic and blood-stage activity, allows for rapid clearance of parasites including those carrying the Kelch 13 mutation (a marker of artemisinin partial resistance). On the other hand, as an improved formulation of lumefantrine, LUMSDF allows for administration once a day rather than twice a day.

3. What additional challenges were posed by COVID-19?

CW: Due to COVID-related travel restrictions, we experienced operational challenges in terms of monitoring the studies, which had an impact on site engagement. On the operations side, we faced difficulties in getting materials in and out of countries for various reasons, such as shipping restrictions, priorities being focused on COVID-19 rather than on malaria, and reduced flights into each country. This caused delays, but progress was steady.

ACM: The COVID-19 pandemic delayed the start of the second part of the study which was aimed at evaluating efficacy, safety and tolerability in children aged 2 to 12 with several pre-selected dosing regimens based on the results of part 1 of the study.

4. What are the next steps?

CW: The next step is to select dosage for the final product. We will also decide on a recommendation regarding consumption of food with the drug. We will then test the final dose again in a Phase IIb study and gather efficacy, safety, tolerability and acceptability data in children all the way down to 6 months of age. While we initiate the Phase III trial programme, we will prepare for the commercial-scale manufacturing of the product in its final dose configuration and formulation suitable for both adults and children. This will happen in parallel over the next 3 years.

ACM: As Cornelis says, once the best dosing regimen is selected, the efficacy, safety and tolerability profile will be confirmed with a large Phase III programme including adults, adolescents and children of all endemic regions, with a particular focus on Africa.

5. What has it been like to work in partnership on this project?

ACM: Working with Novartis is great because of their professionalism. They see this as a true partnership and the collaboration allows us to bring together Novartis state-of-the-art drug development knowledge and MMV’s expertise in the field of malaria.

CW: Very positive. Novartis has had a collaboration with MMV for many years and on this project since 2016. We really benefit from the unique know-how and expertise of MMV in the field of malaria. It has helped us set up the study in a successful and scientifically sound way, fully meeting the needs of malaria physicians and patients.

1. Efficacy and Safety of KAF156 in Combination With LUM-SDF in Adults and Children With Uncomplicated Plasmodium Falciparum Malaria: https://clinicaltrials.gov/ct2/show/results/NCT03167242