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.

Salinomycin and Other Ionophores as a New Class of Antimalarial Drugs with Transmission-Blocking Activity

“…Only primaquine is effective in reducing late-stage gametocytemia in vivo (48). In that respect, the ionophores, and salinomycin in particular, compare quite well with the most advanced new antimalarial drug candidates of the MMV portfolio, including the spiroindolone KAE609 (49), the imidazolopiperazine KAF 156, and the quinolone-3-diarylether ELQ-300 (50,51). All these compounds have been shown to inhibit early and late P. falciparum gametocytes at concentrations between 50 and 500 nM.…”

A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria

“…However, at higher concentrations, or in other strains, it was significantly more difficult to select for DSM265-resistant parasites, suggesting that overall it may be harder for resistance to DSM265 to emerge compared to atovaquone. Published data on chloroquine and KAF156 suggest a lower propensity to develop resistance than DSM265 (MIR of 10 8 in Dd2 using the same 3xEC 50 protocol) (22, 26). Similar data are not available for the ATP4 inhibitor (KAE609) in clinical development, although its target was identified through sequencing of resistant parasites (27).…”

Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic

“…Targeting more than one life stage would be advantageous, and KAF156, an imidazolopiperazine, is another promising agent that is active against each of the three parasite stages (liver, ABS and gametocyte) present in the human host 111,112 . This compound recently showed encouraging clinical efficacy, with 14 of 21 patients cured of acute uncomplicated P. falciparum malaria following treatment with a single dose 113 .…”