Probing the future of KAF156/Ganaplacide, a next-generation replacement for artemisinin in antimalarial combination therapy

KAF156/Ganaplacide (Novartis) is a promising antimalarial, with one-digit nanomolar IC50s against Plasmodium falciparum, planned as a longer half-life replacement of artemether in combination with lumefantrine (LUM). It will hit the field by the second half of the 2020s. P. falciparum can develop resistance against KAF156 in vitro, through mutations in a new transporter, pfCARL.

We will explore KAF156 resistance with the objective of predicting its future clinical impact, and gather knowledge supporting mitigating measures.Workplan:To develop KAF156 resistance in vitro, followed by whole genome sequencing to identify causal mutations.To test the resistant parasites reproducing the patient real-life KAF156 pharmacokinetics.

Resistance defined by the parasite capacity to recrudesce, as in vivo - an objective link between in vitro drug resistance data and in vivo reality.To explore the pharmacodynamics characteristics of KAF156 in combination with LUM (isobolgrams), and probe mechanisms of resistance with putative inhibitors.To explore SNP selection upon treatment: (a) Are pfcarl mutations selected in vivo by the KAF156/LUM combination?

Does KAF156-LUM select LUM resistance associated pfmdr1 mutations?

We will analyze the first African large phase III KAF156-LUM efficacy trial, to be performed in 2022-2025 in Mali. (b) In parallel, archive Artemether-Lumefantrine (AL) trials will be revisited: can LUM select for pfcarl mutations by itself?