KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission

Kelli L. Kuhen, Arnab K. Chatterjee, Matthias Rottmann, Kerstin Gagaring, Rachel Borboa, Jennifer Buenviaje, Zhong Chen, Carolyn Francek, Tao Wu, Advait Nagle, S. Whitney Barnes, David Plouffe, Marcus C.S. Lee, David A. Fidock, Wouter Graumans, Marga Van De Vegte-Bolmer, Geert J. Van Gemert, Grennady Wirjanata, Boni Sebayang, Jutta Marfurt & 18 others Bruce Russell, Rossarin Suwanarusk, Ric N. Price, Francois Nosten, Anchalee Tungtaeng, Montip Gettayacamin, Jetsumon Sattabongkot, Jennifer Taylor, John R. Walker, David Tully, Kailash P. Patra, Erika L. Flannery, Joseph M. Vinetz, Laurent Renia, Robert W. Sauerwein, Elizabeth A. Winzeler, Richard J. Glynne, Thierry T. Diagana

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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.

Original languageEnglish
Pages (from-to)5060-5067
Number of pages8
JournalAntimicrobial Agents and Chemotherapy
Volume58
Issue number9
DOIs
Publication statusPublished - 2014

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Antimalarials
Malaria
Sporozoites
Plasmodium
Life Cycle Stages
Pharmaceutical Preparations
Inhibitory Concentration 50
Parasites
Clinical Trials
KAF156
Infection
Therapeutics

Cite this

Kuhen, Kelli L. ; Chatterjee, Arnab K. ; Rottmann, Matthias ; Gagaring, Kerstin ; Borboa, Rachel ; Buenviaje, Jennifer ; Chen, Zhong ; Francek, Carolyn ; Wu, Tao ; Nagle, Advait ; Barnes, S. Whitney ; Plouffe, David ; Lee, Marcus C.S. ; Fidock, David A. ; Graumans, Wouter ; Van De Vegte-Bolmer, Marga ; Van Gemert, Geert J. ; Wirjanata, Grennady ; Sebayang, Boni ; Marfurt, Jutta ; Russell, Bruce ; Suwanarusk, Rossarin ; Price, Ric N. ; Nosten, Francois ; Tungtaeng, Anchalee ; Gettayacamin, Montip ; Sattabongkot, Jetsumon ; Taylor, Jennifer ; Walker, John R. ; Tully, David ; Patra, Kailash P. ; Flannery, Erika L. ; Vinetz, Joseph M. ; Renia, Laurent ; Sauerwein, Robert W. ; Winzeler, Elizabeth A. ; Glynne, Richard J. ; Diagana, Thierry T. / KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission. In: Antimicrobial Agents and Chemotherapy. 2014 ; Vol. 58, No. 9. pp. 5060-5067.
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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.",
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Kuhen, KL, Chatterjee, AK, Rottmann, M, Gagaring, K, Borboa, R, Buenviaje, J, Chen, Z, Francek, C, Wu, T, Nagle, A, Barnes, SW, Plouffe, D, Lee, MCS, Fidock, DA, Graumans, W, Van De Vegte-Bolmer, M, Van Gemert, GJ, Wirjanata, G, Sebayang, B, Marfurt, J, Russell, B, Suwanarusk, R, Price, RN, Nosten, F, Tungtaeng, A, Gettayacamin, M, Sattabongkot, J, Taylor, J, Walker, JR, Tully, D, Patra, KP, Flannery, EL, Vinetz, JM, Renia, L, Sauerwein, RW, Winzeler, EA, Glynne, RJ & Diagana, TT 2014, 'KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission', Antimicrobial Agents and Chemotherapy, vol. 58, no. 9, pp. 5060-5067. https://doi.org/10.1128/AAC.02727-13

KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission. / Kuhen, Kelli L.; Chatterjee, Arnab K.; Rottmann, Matthias; Gagaring, Kerstin; Borboa, Rachel; Buenviaje, Jennifer; Chen, Zhong; Francek, Carolyn; Wu, Tao; Nagle, Advait; Barnes, S. Whitney; Plouffe, David; Lee, Marcus C.S.; Fidock, David A.; Graumans, Wouter; Van De Vegte-Bolmer, Marga; Van Gemert, Geert J.; Wirjanata, Grennady; Sebayang, Boni; Marfurt, Jutta; Russell, Bruce; Suwanarusk, Rossarin; Price, Ric N.; Nosten, Francois; Tungtaeng, Anchalee; Gettayacamin, Montip; Sattabongkot, Jetsumon; Taylor, Jennifer; Walker, John R.; Tully, David; Patra, Kailash P.; Flannery, Erika L.; Vinetz, Joseph M.; Renia, Laurent; Sauerwein, Robert W.; Winzeler, Elizabeth A.; Glynne, Richard J.; Diagana, Thierry T.

In: Antimicrobial Agents and Chemotherapy, Vol. 58, No. 9, 2014, p. 5060-5067.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission

AU - Kuhen, Kelli L.

AU - Chatterjee, Arnab K.

AU - Rottmann, Matthias

AU - Gagaring, Kerstin

AU - Borboa, Rachel

AU - Buenviaje, Jennifer

AU - Chen, Zhong

AU - Francek, Carolyn

AU - Wu, Tao

AU - Nagle, Advait

AU - Barnes, S. Whitney

AU - Plouffe, David

AU - Lee, Marcus C.S.

AU - Fidock, David A.

AU - Graumans, Wouter

AU - Van De Vegte-Bolmer, Marga

AU - Van Gemert, Geert J.

AU - Wirjanata, Grennady

AU - Sebayang, Boni

AU - Marfurt, Jutta

AU - Russell, Bruce

AU - Suwanarusk, Rossarin

AU - Price, Ric N.

AU - Nosten, Francois

AU - Tungtaeng, Anchalee

AU - Gettayacamin, Montip

AU - Sattabongkot, Jetsumon

AU - Taylor, Jennifer

AU - Walker, John R.

AU - Tully, David

AU - Patra, Kailash P.

AU - Flannery, Erika L.

AU - Vinetz, Joseph M.

AU - Renia, Laurent

AU - Sauerwein, Robert W.

AU - Winzeler, Elizabeth A.

AU - Glynne, Richard J.

AU - Diagana, Thierry T.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

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KW - mefloquine

KW - piperazine derivative

KW - unclassified drug

KW - KAF156

KW - animal experiment

KW - animal model

KW - Anopheles

KW - antimalarial activity

KW - antimalarial drug susceptibility

KW - article

KW - controlled study

KW - disease elimination

KW - dose time effect relation

KW - drug dose comparison

KW - drug efficacy

KW - drug safety

KW - female

KW - genetic strain

KW - human

KW - human cell

KW - IC 50

KW - in vitro study

KW - in vivo study

KW - malaria control

KW - malaria falciparum

KW - mouse

KW - multiple drug dose

KW - nonhuman

KW - parasite clearance

KW - parasite transmission

KW - Plasmodium falciparum

KW - Plasmodium vivax malaria

KW - priority journal

KW - rodent malaria

KW - schizont

KW - single drug dose

KW - sporozoite

KW - treatment response

KW - animal

KW - drug effects

KW - IC50

KW - Institute for Cancer Research mouse

KW - Malaria, Falciparum

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KW - Animals

KW - Antimalarials

KW - Imidazoles

KW - Inhibitory Concentration 50

KW - Mice

KW - Mice, Inbred ICR

KW - Piperazines

KW - Sporozoites

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DO - 10.1128/AAC.02727-13

M3 - Article

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EP - 5067

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 9

ER -