title: Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
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authors.initials: A
authors.lastname: Le Bihan
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Ruben
authors.identifier: http://orcid.org/0000-0001-7503-9776
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authors.lastname: de Kanter
authors.affiliation: GlaxoSmithKline, TresCantos Medicines Development Campus, Diseases of the Developing World, Tres Cantos, Madrid, Spain.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Angulo-Barturen
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Christoph
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authors.lastname: Binkert
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Christoph
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authors.lastname: Boss
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.|Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
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authors.lastname: Brunner
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
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authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
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authors.identifier: http://orcid.org/0000-0001-8448-6068
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authors.affiliation: TropIQ Health Sciences B.V., Nijmegen, The Netherlands.
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authors.lastname: Dechering
authors.affiliation: Department of Life Sciences, Imperial College London, SW7 2AZ, London, United Kingdom.
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authors.lastname: Delves
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
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authors.lastname: Ewerling
authors.affiliation: GlaxoSmithKline, TresCantos Medicines Development Campus, Diseases of the Developing World, Tres Cantos, Madrid, Spain.
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authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
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authors.affiliation: GlaxoSmithKline, TresCantos Medicines Development Campus, Diseases of the Developing World, Tres Cantos, Madrid, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Gamo-Benito
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Nina F
authors.identifier: http://orcid.org/0000-0002-8104-7032
authors.initials: NF
authors.lastname: Gnädig
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Bibia
authors.initials: B
authors.lastname: Heidmann
authors.affiliation: GlaxoSmithKline, TresCantos Medicines Development Campus, Diseases of the Developing World, Tres Cantos, Madrid, Spain.
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authors.initials: MB
authors.lastname: Jiménez-Díaz
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
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authors.lastname: Leroy
authors.affiliation: GlaxoSmithKline, TresCantos Medicines Development Campus, Diseases of the Developing World, Tres Cantos, Madrid, Spain.
authors.forename: Maria Santos
authors.initials: MS
authors.lastname: Martínez
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
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authors.lastname: Meyer
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Joerg J
authors.initials: JJ
authors.lastname: Moehrle
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Caroline L
authors.identifier: http://orcid.org/0000-0001-8267-8453
authors.initials: CL
authors.lastname: Ng
authors.affiliation: Eijkman Institute for Molecular Biology, Jakarta, Indonesia.
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authors.lastname: Noviyanti
authors.affiliation: Department of Life Sciences, Imperial College London, SW7 2AZ, London, United Kingdom.
authors.forename: Andrea
authors.identifier: http://orcid.org/0000-0003-3804-9670
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authors.lastname: Ruecker
authors.affiliation: GlaxoSmithKline, TresCantos Medicines Development Campus, Diseases of the Developing World, Tres Cantos, Madrid, Spain.
authors.forename: Laura María
authors.initials: LM
authors.lastname: Sanz
authors.affiliation: TropIQ Health Sciences B.V., Nijmegen, The Netherlands.
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authors.initials: RW
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authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
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authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
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authors.initials: S
authors.lastname: Schleiferboeck
authors.affiliation: Department of Life Sciences, Imperial College London, SW7 2AZ, London, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Sinden
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
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authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York, United States of America.
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authors.affiliation: Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia.
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authors.affiliation: Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia.
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authors.affiliation: Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia.|Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Ric N
authors.identifier: http://orcid.org/0000-0003-2000-2874
authors.initials: RN
authors.lastname: Price
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
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authors.lastname: Weller
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
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authors.lastname: Fischli
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York, United States of America.|Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: David A
authors.identifier: http://orcid.org/0000-0001-6753-8938
authors.initials: DA
authors.lastname: Fidock
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
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authors.initials: M
authors.lastname: Clozel
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
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mesh_terms: D000178:Acrylamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D008826:Microbial Sensitivity Tests; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects*; D010966:Plasmodium vivax / Q000187:drug effects*
chemical_list: D000178:Acrylamides; D000962:Antimalarials; D037621:Artemisinins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010879:Piperazines; C000619473:ACT-451840; C513498:Mdr1 protein, Plasmodium falciparum; C031327:artemisinin