Efficacy, Safety, Tolerability, and Pharmacokinetics of MMV390048 in Acute Uncomplicated Malaria

Abstract

An open label, phase IIa study conducted in Ethiopia evaluated the efficacy, safety, tolerability, and pharmacokinetics of a single 120-mg dose of the phosphatidylinositol 4-kinase inhibitor MMV390048 in Plasmodium vivax malaria. The study was not completed for operational reasons and emerging teratotoxicity data. For the eight adult male patients enrolled, adequate clinical and parasitological response at day 14 (primary endpoint) was 100% (8/8). Asexual parasites and gametocytes were cleared in all patients by 66 and 78 hours postdose, respectively. There were two recurrent P. vivax infections (days 20 and 28) and a new Plasmodium falciparum infection (day 22). MMV390048 exposure in P. vivax patients was lower than previously observed for healthy volunteers. Mild adverse events, mainly headache and gastrointestinal symptoms, were reported by eight patients. Single-dose MMV390048 (120 mg) rapidly cleared asexual parasites and gametocytes in patients with P. vivax malaria and was well tolerated.

Advances in malaria pharmacology and the online guide to MALARIA PHARMACOLOGY: IUPHAR review 38

“…A number of other scaffolds potently inhibiting this kinase have also been reported, including the quinoxaline BQR695 (McNamara et al, 2013), BRD73842 (Kato et al, 2016), imidazopyridazines (Cheuka et al, 2021; McNamara et al, 2013), naphthyridines (MMV024101) (Kandepedu et al, 2018), bipyridine‐sulfonamides (CHMFL‐PI4K‐127) (Liang et al, 2020), Torin 2 derivatives (NCATS‐SM3710) (Krishnan et al, 2020) and the anticancer mTOR inhibitor sapanisertib (Arendse et al, 2022). PI4Kβ inhibition leads to a moderately slow rate of parasite kill in vitro (Paquet et al, 2017), although it should be noted that MMV390048 displayed fast killing kinetics in the clinic (Mohammed et al, 2023; Sinxadi et al, 2020). MMV390048 and other PI4Kβ ATP‐competitive inhibitors show a moderate propensity to generate de novo resistance as demonstrated in vitro , where a higher number of parasites in culture is needed to raise resistance compared to other drugs known to be highly mutable such as atovaquone (Brunschwig et al, 2018; Paquet et al, 2017).…”

“…The most advanced Plasmodium PI4Kβ inhibitor, the 2-aminopyridine MMV390048, was developed from a whole-cell, phenotypic screening approach without prior knowledge of the target (Paquet et al, 2017). MMV390048 progressed to Phase 2a clinical trials where a single oral of 120 mg rapidly cleared asexual parasites and gametocytes in eight patients with P. vivax malaria and was well tolerated (Mohammed et al, 2023). However, clinical development was stopped due to teratoxicity concerns based on data emerging from studies in rats (Demarta-Gatsi et al, 2022).…”

A Plethora of Functions Condensed into Tiny Phospholipids: The Story of PI4P and PI(4,5)P2

“…PI4KIIIα, PI3Ks >150 [76] in vitro cancer [67] inflammation [72] IN-10 3.6 [15] PI4KIIIα, PI3Ks >720 [15,33] in vitro inflammation [72] T-00127-HEV1 60 [32] PI4KIIIα, PIK3CD 10 000 [32] in vitro viral infection [77][78][79] in vivo [78] BF738735 5.7 [32] PI4KIIIα 1700 [33] in vitro viral infection [79,80] Enviroxime 120 [32] PI4KIIIα 1400 [32] discontinued in phase II clinical trials viral infection [15,81] Plasmodium falciparum PI4KIIIβ MMV390048 28 [82] no off-targets, highly selective terminated phase II clinical trials parasitic infection [15,83] PI4P5KIα ISA-2011B n.d. [15] p110α n.d. [15] in vitro inflammation [84] cancer [85,86] in vivo cancer [85,86] PI4P5KIγ UNC3230 51 (K d ) [15] PI5P4Kγ 4 (K d ) [15] in vitro cancer [87]…”