Publication: Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling
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2016-10-01
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Public Library of Science
Abstract
Background
Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-
based combination therapy in endemic countries. Additionally, the diversity of chemical
mode of action in the global portfolio of marketed antimalarials is extremely limited.
Addressing the urgent need for the development of new antimalarials, a chemical class of
potent antimalarial compounds with a novel mode of action was recently identified. Herein,
the preclinical characterization of one of these compounds, ACT-451840, conducted in
partnership with academic and industrial groups is presented
Method and Findings
The properties of ACT-451840 are described, including its spectrum of activities against
multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine
malaria models that permit infection with the human and the rodent parasites P. falciparum
and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration
of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum
NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg
against P. falciparum (95% confidence interval: 3.3±4.9 mg/kg) and 13 mg/kg against P.
berghei (95% confidence interval: 11±16 mg/kg). ACT-451840 potently prevented male
gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89
nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito
with a 50% inhibitory concentration of 30 nM (range: 23±39). The compound's preclinical
safety profile is presented and is in line with the published results of the first-in-man study in
healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic
(PK/PD) modeling was applied using efficacy in the murine models (defined
either as antimalarial activity or as survival) in relation to area under the concentration versus
time curve (AUC), maximum observed plasma concentration (Cmax), and time above a
threshold concentration. The determination of the dose±efficacy relationship of ACT-
451840 under curative conditions in rodent malaria models allowed prediction of the human
efficacious exposure.
Conclusion
The dual activity of ACT-451840 against asexual and sexual stages of P. falciparum and
the activity on P. vivax have the potential to meet the specific profile of a target compound
that could replace the fast-acting artemisinin component and harbor additional gametocytocidal
activity and, thereby, transmission-blocking properties. The fast parasite reduction
ratio (PRR) and gametocytocidal effect of ACT-451840 were recently also confirmed in a
clinical proof-of-concept (POC) study.
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Bibliographic citation
Le Bihan A, de Kanter R, Angulo-Barturen I, Binkert C, Boss C, Brun R, et al. (2016) Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose±Efficacy Modeling. PLoS Med 13(10): e1002138.