Date Published: October 4, 2016
Publisher: Public Library of Science
Author(s): Amélie Le Bihan, Ruben de Kanter, Iñigo Angulo-Barturen, Christoph Binkert, Christoph Boss, Reto Brun, Ralf Brunner, Stephan Buchmann, Jeremy Burrows, Koen J. Dechering, Michael Delves, Sonja Ewerling, Santiago Ferrer, Christoph Fischli, Francisco Javier Gamo–Benito, Nina F. Gnädig, Bibia Heidmann, María Belén Jiménez-Díaz, Didier Leroy, Maria Santos Martínez, Solange Meyer, Joerg J. Moehrle, Caroline L. Ng, Rintis Noviyanti, Andrea Ruecker, Laura María Sanz, Robert W. Sauerwein, Christian Scheurer, Sarah Schleiferboeck, Robert Sinden, Christopher Snyder, Judith Straimer, Grennady Wirjanata, Jutta Marfurt, Ric N. Price, Thomas Weller, Walter Fischli, David A. Fidock, Martine Clozel, Sergio Wittlin, Matthew H. Todd
Abstract: BackgroundArtemisinin 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 FindingsThe 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.ConclusionThe 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.
Partial Text: Malaria caused 438,000 deaths worldwide in 2015, of which 70% were in children under the age of 5 y . Between 2000 and 2015, strategies for malaria control and eradication reduced the incidence of malaria by 48% in the WHO African Region. The upscaled interventions consisted of increased accessibility to long-lasting insecticidal bed nets, protection of the population at risk by indoor residual spraying, and increased access to rapid diagnostic tests and artemisinin-based combination therapies. However, with the detection of parasite resistance to artemisinin, the core compound of artemisinin-based combination therapies, in five countries of Southeast Asia, the availability of efficacious combination therapies is under threat . Additionally, not a single new chemical class of antimalarials has been registered since 1996 , and the current global portfolio of antimalarial compounds in late clinical development relies largely on novel combinations of existing drugs, not novel compounds . These elements highlight the critical and urgent need for new drugs to treat malaria.
This report presents results from vitro and in vivo experiments to preclinically characterize a novel antimalarial compound (ACT-451840). The data shown here indicate that ACT-451840 shares many of the favorable MMV TCP1 properties of artemisinin and its derivatives, such as its potency against P. falciparum and P. vivax, fast onset of action, activity against all asexual erythrocytic stages, and PRR of >4 log per cycle of asexual blood stage forms. In addition, although the potency observed in the standard membrane feeding assay was 10-fold lower than the potency of the compound against asexual blood stage parasites, ACT-451840’s gametocytocidal activity blocks transmission, fulfilling the properties requested for a TCP3b .