MMV390048 is a novel
antimalarial compound that inhibits Plasmodium phosphatidylinositol-4-kinase. The safety, tolerability, pharmacokinetic profile, and
antimalarial activity of
MMV390048 were determined in healthy volunteers in three separate studies. A first-in-human, double-blind, randomized, placebo-controlled, single-ascending-dose study was performed. Additionally, a volunteer
infection study investigated the
antimalarial activity of
MMV390048 using the Plasmodium falciparum induced blood-stage
malaria (IBSM) model. Due to the high pharmacokinetic variability with the
powder-in-bottle formulation used in both of these studies, a third study was undertaken to select a
tablet formulation of
MMV390048 to take forward into future studies.
MMV390048 was generally well tolerated when administered as a single oral dose up to 120 mg, with rapid absorption and a long elimination half-life. Twelve adverse events were considered to be potentially related to
MMV390048 in the first-in-human study but with no obvious correlation between these and
MMV390048 dose or exposure. Although
antimalarial activity was evident in the IBSM study, rapid recrudescence occurred in most subjects
after treatment with 20 mg
MMV390048, a dose expected to be subtherapeutic. Reformulation of
MMV390048 into two
tablet formulations (
tartaric acid and Syloid) resulted in significantly reduced intersubject pharmacokinetic variability. Overall, the results of this study suggest that
MMV390048 is well tolerated in humans, and the pharmacokinetic properties of the compound indicate that it has the potential to be used for
antimalarial prophylaxis or inclusion in a single-dose cure.
MMV390048 is currently being tested in a phase 2a study in Ethiopian adults with acute, uncomplicated falciparum or
vivax malaria monoinfection. (The three clinical trials described here were each registered with ClinicalTrials.gov as follows: first-in-human study, registration no. NCT02230579; IBSM study, registration no. NCT02281344; and formulation optimization study, registration no. NCT02554799.).