KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission

Abstract

Renewed global efforts toward malaria eradication have highlighted the need for novel antimalarial agents with activity against multiple stages of the parasite life cycle. We have previously reported the discovery of a novel class of antimalarial compounds in the imidazolopiperazine series that have activity in the prevention and treatment of blood stage infection in a mouse model of malaria. Consistent with the previously reported activity profile of this series, the clinical candidate KAF156 shows blood schizonticidal activity with 50% inhibitory concentrations of 6 to 17.4 nM against P. falciparum drug-sensitive and drug-resistant strains, as well as potent therapeutic activity in a mouse models of malaria with 50, 90, and 99% effective doses of 0.6, 0.9, and 1.4 mg/kg, respectively. When administered prophylactically in a sporozoite challenge mouse model, KAF156 is completely protective as a single oral dose of 10 mg/kg. Finally, KAF156 displays potent Plasmodium transmission blocking activities both in vitro and in vivo. Collectively, our data suggest that KAF156, currently under evaluation in clinical trials, has the potential to treat, prevent, and block the transmission of malaria.

FIG 1

Chemical structure of KAF156.

FIG 2

Drug sensitivity of P. vivax (○) and P. falciparum (●) clinical isolates to chloroquine, artesunate, and KAF156. An ex vivo schizont maturation assay was used to measure the drug sensitivity of clinical isolates in Thailandfor P. vivax (n = 10) and P. falciparum (n = 13) isolates (A) and in Indonesia for P. vivax (n = 20) and P. falciparum (n = 26) (B). The horizontal bar represents the median IC₅₀, and its numerical value is indicated above (nM).

FIG 3

KAF156 is fully protective in a causal prophylactic mouse model of malaria. Mice (n = 5) were infected with P. berghei sporozoites intravenously on day 0 and administered a single dose of compound 2 h before parasite inoculation. Mice were monitored over 30 days for parasitemia. Vehicle used for compound administration was a suspension formulation of 0.5% (wt/vol) methylcellulose and 1% (wt/vol) Solutol HS15. The data represent the numbers of live mice at the indicated day postinfection.

FIG 4

KAF156 inhibits gametocyte development and blocks parasite transmission to mosquitoes. Three (A and B) or two (C) independent experiments were carried out, and the mean values are reported on bar graphs with the standard error of the mean indicated. (A) Cultures of immature stage II gametocytes were treated with various concentrations of KAF156 on days 8 to 12 after the induction of gametocytogenesis. The negative control (KAF156 concentration = 0 nM) cultures were treated with DMSO (vehicle) at a 0.1% final concentration. The total number of mature stage V gametocytes (males and females) per 5,000 erythrocytes was assessed by microscopy on day 13 for each experiment. (B) An SMFA was used to evaluate the transmission potential of parasites cultures treated on days 8 to 12. (C) Viable and fully mature stage V gametocytes (males and females) were treated with KAF156 on day 15 after induction and fed through SMFA to mosquitoes. For both panels B and C, no toxicity to mosquitoes was observed at any of the compound concentrations, and the number of oocysts in the midgut of an infected mosquito was counted for at least 20 infected mosquitoes for each independent experiment. An asterisk (*) indicates that the mean is significantly different (P < 0.05) from the untreated control in a one-way analysis of variance, followed by a Dunnett's multiple-comparison test.