P. falciparum PfATP4 Multi-Drug Resistance to KAE609 (Cipargamin) is Present in Africa

The PfATP4 (PF3D7 1211900) multi-drug resistance mutation G223R is found in Africa by genetically analyzing 2640 worldwide Plasmodium falciparum blood stage isolates (the MalariaGen Pf3k resource). This mutation confers an approximate 8 fold [4] increase in the PfATP4 IC50 of Spiroindolones (KAE609 & KAE678) [14],[16],[4],[10] and Aminopyrazoles (GNF-Pf4492) [4]. It is postulated that the G223R mutation may be a consequence of the drug resistant Southeast Asian Dd2 genotype becoming more dominant in Africa [3]. The presence of this mutation has important policy implications for the eventual general deployment of the Spiroindolone KAE609 (Cipargamin) which is currently undergoing stage 2 clinical trials.