Safety, Tolerability, Pharmacokinetics, and Antimalarial Activity of the Novel Plasmodium Phosphatidylinositol 4-Kinase Inhibitor MMV390048 in Healthy Volunteers

Abstract

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.)

A Phase 1, Placebo-controlled, Randomized, Single Ascending Dose Study and a Volunteer Infection Study to Characterize the Safety, Pharmacokinetics, and Antimalarial Activity of the Plasmodium Phosphatidylinositol 4-Kinase Inhibitor MMV390048

“…A single dose of MMV390048 tablets was administered fasted when parasitemia reached approximately 5000 parasites/mL. The doses of MMV390048 selected were predicted to be subtherapeutic based on preclinical modeling [ 4 ] and PK data obtained in previous clinical studies [ 6 ], and thus chosen to facilitate modeling to estimate the PK/PD relationship. Subjects received a standard course of artemether/lumefantrine 25 days postdosing, or earlier if recrudescence occurred.…”

“…PI4K is a particularly attractive target for antimalarial drug development because it is required across all Plasmodium lifecycle stages [ 5 ]. A powder-in-bottle and 2 tablet formulations (tartaric acid and Syloid) of MMV390048 have been tested in 3 phase 1 studies [ 6 ]. MMV390048 was well tolerated in healthy subjects up to a single dose of 120 mg.…”

An Update on Development of Small-Molecule Plasmodial Kinase Inhibitors

“…MMV048 showed high selectivity over human and other plasmodial kinases, a good ADME profile and an acceptable preclinical safety profile in various animal species (mice, rats, dogs and monkeys) [155,158]. Phase I clinical trials for MMV048 were recently completed (ClinicalTrials.gov: NCT02230579; NCT02281344; NCT02554799) [159]. A single oral dose of up to 120 mg was generally well tolerated in healthy volunteers and adverse events were mild to moderate.…”

Recent Highlights in Anti‐infective Medicinal Chemistry from South Africa

“…The most promising of this selection ( 83 ), had previously been identified in a similar screen as a hit against L. donovani . However, most importantly, it had also been identified by Chibale and co‐workers as a potent anti‐plasmodial hit compound, whose optimisation into clinical candidate MMV39008 ( 31 ) as well as preclinical candidate 84 , resulted in the generation of a medium sized library of related compounds. In a follow‐up study, this anti‐plasmodial optimisation library, was screened against T. b. brucei , which allowed for the determination of important anti‐trypanosomal SAR details for this class, with compounds 85 and 86 emerging as promising sub‐micromolar inhibitors of T. b. brucei …”

“…In the South African context, vast biological diversity and extensive bodies of traditional remedies have meant that both terrestrial and marine natural products have been the dominant force in the search for bioactive chemical compounds, with several notable successes . However, while natural products continue to play a pivotal role in South African drug discovery, modern approaches to medicinal chemistry are making an ever‐increasing footprint in South Africa, particularly within organic chemistry circles; this is possibly best exemplified by the recent success in the discovery of antimalarial MMV390048 . Accordingly, in this review, we discuss some recent highlights in medicinal chemistry research (2016–2020) in which researchers based in South Africa have made a significant contribution through medicinal chemistry methodology.…”