Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose–Efficacy Modeling

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 MartínezSolange 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

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1002138
JournalPLoS Medicine
Volume13
Issue number10
DOIs
StatePublished - Oct 2016

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Antimalarials
Plasmodium falciparum
Plasmodium vivax
Plasmodium berghei
Parasites
Malaria
Rodentia
Confidence Intervals
Pharmacologic Actions
Southeastern Asia
Oocysts
Falciparum Malaria
Life Cycle Stages
Culicidae
Germ Cells
Inhibitory Concentration 50
Area Under Curve
Healthy Volunteers
Pharmacokinetics
Safety

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Le Bihan, A., de Kanter, R., Angulo-Barturen, I., Binkert, C., Boss, C., Brun, R., ... Wittlin, S. (2016). Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose–Efficacy Modeling. PLoS Medicine, 13(10), [e1002138]. https://doi.org/10.1371/journal.pmed.1002138

Characterization of Novel Antimalarial Compound ACT-451840 : Preclinical Assessment of Activity and Dose–Efficacy Modeling. / Le Bihan, Amélie; de Kanter, Ruben; Angulo-Barturen, Iñigo; Binkert, Christoph; Boss, Christoph; Brun, Reto; Brunner, Ralf; Buchmann, Stephan; Burrows, Jeremy; Dechering, Koen J.; Delves, Michael; Ewerling, Sonja; Ferrer, Santiago; Fischli, Christoph; Gamo–Benito, Francisco Javier; Gnädig, Nina F.; Heidmann, Bibia; Jiménez-Díaz, María Belén; Leroy, Didier; Martínez, Maria Santos; Meyer, Solange; Moehrle, Joerg J.; Ng, Caroline L.; Noviyanti, Rintis; Ruecker, Andrea; Sanz, Laura María; Sauerwein, Robert W.; Scheurer, Christian; Schleiferboeck, Sarah; Sinden, Robert; Snyder, Christopher; Straimer, Judith; Wirjanata, Grennady; Marfurt, Jutta; Price, Ric N.; Weller, Thomas; Fischli, Walter; Fidock, David A.; Clozel, Martine; Wittlin, Sergio.

In: PLoS Medicine, Vol. 13, No. 10, e1002138, 10.2016.

Research output: Contribution to journalArticle

Le Bihan, A, de Kanter, R, Angulo-Barturen, I, Binkert, C, Boss, C, Brun, R, Brunner, R, Buchmann, S, Burrows, J, Dechering, KJ, Delves, M, Ewerling, S, Ferrer, S, Fischli, C, Gamo–Benito, FJ, Gnädig, NF, Heidmann, B, Jiménez-Díaz, MB, Leroy, D, Martínez, MS, Meyer, S, Moehrle, JJ, Ng, CL, Noviyanti, R, Ruecker, A, Sanz, LM, Sauerwein, RW, Scheurer, C, Schleiferboeck, S, Sinden, R, Snyder, C, Straimer, J, Wirjanata, G, Marfurt, J, Price, RN, Weller, T, Fischli, W, Fidock, DA, Clozel, M & Wittlin, S 2016, 'Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose–Efficacy Modeling', PLoS Medicine, vol. 13, no. 10, e1002138. https://doi.org/10.1371/journal.pmed.1002138
Le Bihan, Amélie ; de Kanter, Ruben ; Angulo-Barturen, Iñigo ; Binkert, Christoph ; Boss, Christoph ; Brun, Reto ; Brunner, Ralf ; Buchmann, Stephan ; Burrows, Jeremy ; Dechering, Koen J. ; Delves, Michael ; Ewerling, Sonja ; Ferrer, Santiago ; Fischli, Christoph ; Gamo–Benito, Francisco Javier ; Gnädig, Nina F. ; Heidmann, Bibia ; Jiménez-Díaz, María Belén ; Leroy, Didier ; Martínez, Maria Santos ; Meyer, Solange ; Moehrle, Joerg J. ; Ng, Caroline L. ; Noviyanti, Rintis ; Ruecker, Andrea ; Sanz, Laura María ; Sauerwein, Robert W. ; Scheurer, Christian ; Schleiferboeck, Sarah ; Sinden, Robert ; Snyder, Christopher ; Straimer, Judith ; Wirjanata, Grennady ; Marfurt, Jutta ; Price, Ric N. ; Weller, Thomas ; Fischli, Walter ; Fidock, David A. ; Clozel, Martine ; Wittlin, Sergio. / Characterization of Novel Antimalarial Compound ACT-451840 : Preclinical Assessment of Activity and Dose–Efficacy Modeling. In: PLoS Medicine. 2016 ; Vol. 13, No. 10.
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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. 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.",
author = "{Le Bihan}, Am{\'e}lie and {de Kanter}, Ruben and I{\~n}igo Angulo-Barturen and Christoph Binkert and Christoph Boss and Reto Brun and Ralf Brunner and Stephan Buchmann and Jeremy Burrows and Dechering, {Koen J.} and Michael Delves and Sonja Ewerling and Santiago Ferrer and Christoph Fischli and Gamo–Benito, {Francisco Javier} and Gn{\"a}dig, {Nina F.} and Bibia Heidmann and Jim{\'e}nez-D{\'i}az, {Mar{\'i}a Bel{\'e}n} and Didier Leroy and Mart{\'i}nez, {Maria Santos} and Solange Meyer and Moehrle, {Joerg J.} and Ng, {Caroline L.} and Rintis Noviyanti and Andrea Ruecker and Sanz, {Laura Mar{\'i}a} and Sauerwein, {Robert W.} and Christian Scheurer and Sarah Schleiferboeck and Robert Sinden and Christopher Snyder and Judith Straimer and Grennady Wirjanata and Jutta Marfurt and Price, {Ric N.} and Thomas Weller and Walter Fischli and Fidock, {David A.} and Martine Clozel and Sergio Wittlin",
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month = "10",
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journal = "PLoS Medicine",
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TY - JOUR

T1 - Characterization of Novel Antimalarial Compound ACT-451840

T2 - Preclinical Assessment of Activity and Dose–Efficacy Modeling

AU - Le Bihan, Amélie

AU - de Kanter, Ruben

AU - Angulo-Barturen, Iñigo

AU - Binkert, Christoph

AU - Boss, Christoph

AU - Brun, Reto

AU - Brunner, Ralf

AU - Buchmann, Stephan

AU - Burrows, Jeremy

AU - Dechering, Koen J.

AU - Delves, Michael

AU - Ewerling, Sonja

AU - Ferrer, Santiago

AU - Fischli, Christoph

AU - Gamo–Benito, Francisco Javier

AU - Gnädig, Nina F.

AU - Heidmann, Bibia

AU - Jiménez-Díaz, María Belén

AU - Leroy, Didier

AU - Martínez, Maria Santos

AU - Meyer, Solange

AU - Moehrle, Joerg J.

AU - Ng, Caroline L.

AU - Noviyanti, Rintis

AU - Ruecker, Andrea

AU - Sanz, Laura María

AU - Sauerwein, Robert W.

AU - Scheurer, Christian

AU - Schleiferboeck, Sarah

AU - Sinden, Robert

AU - Snyder, Christopher

AU - Straimer, Judith

AU - Wirjanata, Grennady

AU - Marfurt, Jutta

AU - Price, Ric N.

AU - Weller, Thomas

AU - Fischli, Walter

AU - Fidock, David A.

AU - Clozel, Martine

AU - Wittlin, Sergio

PY - 2016/10

Y1 - 2016/10

N2 - 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.

AB - 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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