A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria

Margaret A Phillips; Julie Lotharius; Kennan Marsh; John White; Anthony Dayan; Karen L White; Jacqueline W Njoroge; Farah El Mazouni; Yanbin Lao; Sreekanth Kokkonda; Diana R Tomchick; Xiaoyi Deng; Trevor Laird; Sangeeta N Bhatia; Sandra March; Caroline L Ng; David A Fidock; Sergio Wittlin; Maria Lafuente-Monasterio; Francisco Javier Gamo Benito; Laura Maria Sanz Alonso; Maria Santos Martinez; Maria Belen Jimenez-Diaz; Santiago Ferrer Bazaga; Inigo Angulo-Barturen; John N Haselden; James Louttit; Yi Cui; Arun Sridhar; Anne-Marie Zeeman; Clemens Kocken; Robert W Sauerwein; Koen Dechering; Vicky M Avery; Sandra Duffy; Michael Delves; Robert Sinden; Andrea Ruecker; Kristina S Wickham; Rosemary Rochford; Janet Gahagen; Lalitha Iyer; Ed Riccio; Jon Mirsalis; Ian Bathhurst; Thomas Rueckle; Xavier Ding; Brice Campo; Didier Leroy; Susan Ann Charman

doi:10.1126/scitranslmed.aaa6645

A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria

Margaret A Phillips, Julie Lotharius, Kennan Marsh, John White, Anthony Dayan, Karen L White, Jacqueline W Njoroge, Farah El Mazouni, Yanbin Lao, Sreekanth Kokkonda, Diana R Tomchick, Xiaoyi Deng, Trevor Laird, Sangeeta N Bhatia, Sandra March, Caroline L Ng, David A Fidock, Sergio Wittlin, Maria Lafuente-Monasterio, Francisco Javier Gamo BenitoLaura Maria Sanz Alonso, Maria Santos Martinez, Maria Belen Jimenez-Diaz, Santiago Ferrer Bazaga, Inigo Angulo-Barturen, John N Haselden, James Louttit, Yi Cui, Arun Sridhar, Anne-Marie Zeeman, Clemens Kocken, Robert W Sauerwein, Koen Dechering, Vicky M Avery, Sandra Duffy, Michael Delves, Robert Sinden, Andrea Ruecker, Kristina S Wickham, Rosemary Rochford, Janet Gahagen, Lalitha Iyer, Ed Riccio, Jon Mirsalis, Ian Bathhurst, Thomas Rueckle, Xavier Ding, Brice Campo, Didier Leroy, Susan Ann Charman

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207 Citations (Scopus)

Abstract

Malaria is one of the most significant causes of childhood mortality, but disease control efforts are threatened by resistance of the Plasmodium parasite to current therapies. Continued progress in combating malaria requires development of new, easy to administer drug combinations with broad-ranging activity against all manifestations of the disease. DSM265, a triazolopyrimidine-based inhibitor of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH), is the first DHODH inhibitor to reach clinical development for treatment of malaria. We describe studies profiling the biological activity, pharmacological and pharmacokinetic properties, and safety of DSM265, which supported its advancement to human trials. DSM265 is highly selective toward DHODH of the malaria parasite Plasmodium, efficacious against both blood and liver stages of P. falciparum, and active against drugresistant parasite isolates. Favorable pharmacokinetic properties of DSM265 are predicted to provide therapeutic concentrations for more than 8 days after a single oral dose in the range of 200 to 400 mg. DSM265 was well tolerated in repeat-dose and cardiovascular safety studies in mice and dogs, was not mutagenic, and was inactive against panels of human enzymes/receptors. The excellent safety profile, blood- and liver-stage activity, and predicted long half-life in humans position DSM265 as a new potential drug combination partner for either single-dose treatment or once-weekly chemoprevention. DSM265 has advantages over current treatment options that are dosed daily or are inactive against the parasite liver stage.

Original language	English
Pages (from-to)	1-12
Number of pages	12
Journal	Science Translational Medicine
Volume	7
Issue number	296
DOIs	https://doi.org/10.1126/scitranslmed.aaa6645
Publication status	Published - 2015

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10.1126/scitranslmed.aaa6645

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Phillips, M. A., Lotharius, J., Marsh, K., White, J., Dayan, A., White, K. L., Njoroge, J. W., El Mazouni, F., Lao, Y., Kokkonda, S., Tomchick, D. R., Deng, X., Laird, T., Bhatia, S. N., March, S., Ng, C. L., Fidock, D. A., Wittlin, S., Lafuente-Monasterio, M., ... Charman, S. A. (2015). A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria. Science Translational Medicine, 7(296), 1-12. https://doi.org/10.1126/scitranslmed.aaa6645

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title = "A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria",

abstract = "Malaria is one of the most significant causes of childhood mortality, but disease control efforts are threatened by resistance of the Plasmodium parasite to current therapies. Continued progress in combating malaria requires development of new, easy to administer drug combinations with broad-ranging activity against all manifestations of the disease. DSM265, a triazolopyrimidine-based inhibitor of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH), is the first DHODH inhibitor to reach clinical development for treatment of malaria. We describe studies profiling the biological activity, pharmacological and pharmacokinetic properties, and safety of DSM265, which supported its advancement to human trials. DSM265 is highly selective toward DHODH of the malaria parasite Plasmodium, efficacious against both blood and liver stages of P. falciparum, and active against drugresistant parasite isolates. Favorable pharmacokinetic properties of DSM265 are predicted to provide therapeutic concentrations for more than 8 days after a single oral dose in the range of 200 to 400 mg. DSM265 was well tolerated in repeat-dose and cardiovascular safety studies in mice and dogs, was not mutagenic, and was inactive against panels of human enzymes/receptors. The excellent safety profile, blood- and liver-stage activity, and predicted long half-life in humans position DSM265 as a new potential drug combination partner for either single-dose treatment or once-weekly chemoprevention. DSM265 has advantages over current treatment options that are dosed daily or are inactive against the parasite liver stage.",

author = "Phillips, {Margaret A} and Julie Lotharius and Kennan Marsh and John White and Anthony Dayan and White, {Karen L} and Njoroge, {Jacqueline W} and {El Mazouni}, Farah and Yanbin Lao and Sreekanth Kokkonda and Tomchick, {Diana R} and Xiaoyi Deng and Trevor Laird and Bhatia, {Sangeeta N} and Sandra March and Ng, {Caroline L} and Fidock, {David A} and Sergio Wittlin and Maria Lafuente-Monasterio and {Gamo Benito}, {Francisco Javier} and {Sanz Alonso}, {Laura Maria} and Martinez, {Maria Santos} and Jimenez-Diaz, {Maria Belen} and {Ferrer Bazaga}, Santiago and Inigo Angulo-Barturen and Haselden, {John N} and James Louttit and Yi Cui and Arun Sridhar and Anne-Marie Zeeman and Clemens Kocken and Sauerwein, {Robert W} and Koen Dechering and Avery, {Vicky M} and Sandra Duffy and Michael Delves and Robert Sinden and Andrea Ruecker and Wickham, {Kristina S} and Rosemary Rochford and Janet Gahagen and Lalitha Iyer and Ed Riccio and Jon Mirsalis and Ian Bathhurst and Thomas Rueckle and Xavier Ding and Brice Campo and Didier Leroy and Charman, {Susan Ann}",

year = "2015",

doi = "10.1126/scitranslmed.aaa6645",

language = "English",

volume = "7",

pages = "1--12",

journal = "Science Translational Medicine",

issn = "1946-6234",

publisher = "American Association for the Advancement of Science (AAAS)",

number = "296",

}

Phillips, MA, Lotharius, J, Marsh, K, White, J, Dayan, A, White, KL, Njoroge, JW, El Mazouni, F, Lao, Y, Kokkonda, S, Tomchick, DR, Deng, X, Laird, T, Bhatia, SN, March, S, Ng, CL, Fidock, DA, Wittlin, S, Lafuente-Monasterio, M, Gamo Benito, FJ, Sanz Alonso, LM, Martinez, MS, Jimenez-Diaz, MB, Ferrer Bazaga, S, Angulo-Barturen, I, Haselden, JN, Louttit, J, Cui, Y, Sridhar, A, Zeeman, A-M, Kocken, C, Sauerwein, RW, Dechering, K, Avery, VM, Duffy, S, Delves, M, Sinden, R, Ruecker, A, Wickham, KS, Rochford, R, Gahagen, J, Iyer, L, Riccio, E, Mirsalis, J, Bathhurst, I, Rueckle, T, Ding, X, Campo, B, Leroy, D & Charman, SA 2015, 'A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria', Science Translational Medicine, vol. 7, no. 296, pp. 1-12. https://doi.org/10.1126/scitranslmed.aaa6645

TY - JOUR

T1 - A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria

AU - Phillips, Margaret A

AU - Lotharius, Julie

AU - Marsh, Kennan

AU - White, John

AU - Dayan, Anthony

AU - White, Karen L

AU - Njoroge, Jacqueline W

AU - El Mazouni, Farah

AU - Lao, Yanbin

AU - Kokkonda, Sreekanth

AU - Tomchick, Diana R

AU - Deng, Xiaoyi

AU - Laird, Trevor

AU - Bhatia, Sangeeta N

AU - March, Sandra

AU - Ng, Caroline L

AU - Fidock, David A

AU - Wittlin, Sergio

AU - Lafuente-Monasterio, Maria

AU - Gamo Benito, Francisco Javier

AU - Sanz Alonso, Laura Maria

AU - Martinez, Maria Santos

AU - Jimenez-Diaz, Maria Belen

AU - Ferrer Bazaga, Santiago

AU - Angulo-Barturen, Inigo

AU - Haselden, John N

AU - Louttit, James

AU - Cui, Yi

AU - Sridhar, Arun

AU - Zeeman, Anne-Marie

AU - Kocken, Clemens

AU - Sauerwein, Robert W

AU - Dechering, Koen

AU - Avery, Vicky M

AU - Duffy, Sandra

AU - Delves, Michael

AU - Sinden, Robert

AU - Ruecker, Andrea

AU - Wickham, Kristina S

AU - Rochford, Rosemary

AU - Gahagen, Janet

AU - Iyer, Lalitha

AU - Riccio, Ed

AU - Mirsalis, Jon

AU - Bathhurst, Ian

AU - Rueckle, Thomas

AU - Ding, Xavier

AU - Campo, Brice

AU - Leroy, Didier

AU - Charman, Susan Ann

PY - 2015

Y1 - 2015

N2 - Malaria is one of the most significant causes of childhood mortality, but disease control efforts are threatened by resistance of the Plasmodium parasite to current therapies. Continued progress in combating malaria requires development of new, easy to administer drug combinations with broad-ranging activity against all manifestations of the disease. DSM265, a triazolopyrimidine-based inhibitor of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH), is the first DHODH inhibitor to reach clinical development for treatment of malaria. We describe studies profiling the biological activity, pharmacological and pharmacokinetic properties, and safety of DSM265, which supported its advancement to human trials. DSM265 is highly selective toward DHODH of the malaria parasite Plasmodium, efficacious against both blood and liver stages of P. falciparum, and active against drugresistant parasite isolates. Favorable pharmacokinetic properties of DSM265 are predicted to provide therapeutic concentrations for more than 8 days after a single oral dose in the range of 200 to 400 mg. DSM265 was well tolerated in repeat-dose and cardiovascular safety studies in mice and dogs, was not mutagenic, and was inactive against panels of human enzymes/receptors. The excellent safety profile, blood- and liver-stage activity, and predicted long half-life in humans position DSM265 as a new potential drug combination partner for either single-dose treatment or once-weekly chemoprevention. DSM265 has advantages over current treatment options that are dosed daily or are inactive against the parasite liver stage.

AB - Malaria is one of the most significant causes of childhood mortality, but disease control efforts are threatened by resistance of the Plasmodium parasite to current therapies. Continued progress in combating malaria requires development of new, easy to administer drug combinations with broad-ranging activity against all manifestations of the disease. DSM265, a triazolopyrimidine-based inhibitor of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH), is the first DHODH inhibitor to reach clinical development for treatment of malaria. We describe studies profiling the biological activity, pharmacological and pharmacokinetic properties, and safety of DSM265, which supported its advancement to human trials. DSM265 is highly selective toward DHODH of the malaria parasite Plasmodium, efficacious against both blood and liver stages of P. falciparum, and active against drugresistant parasite isolates. Favorable pharmacokinetic properties of DSM265 are predicted to provide therapeutic concentrations for more than 8 days after a single oral dose in the range of 200 to 400 mg. DSM265 was well tolerated in repeat-dose and cardiovascular safety studies in mice and dogs, was not mutagenic, and was inactive against panels of human enzymes/receptors. The excellent safety profile, blood- and liver-stage activity, and predicted long half-life in humans position DSM265 as a new potential drug combination partner for either single-dose treatment or once-weekly chemoprevention. DSM265 has advantages over current treatment options that are dosed daily or are inactive against the parasite liver stage.

UR - http://stm.sciencemag.org.ezproxy.lib.monash.edu.au/content/scitransmed/7/296/296ra111.full.pdf

U2 - 10.1126/scitranslmed.aaa6645

DO - 10.1126/scitranslmed.aaa6645

M3 - Article

SN - 1946-6234

VL - 7

SP - 1

EP - 12

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 296

ER -

A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria

Abstract

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