title: KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission.
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.
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Kuhen
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: Arnab K
authors.initials: AK
authors.lastname: Chatterjee
authors.affiliation: Swiss Tropical and Public Health Institute, Parasite Chemotherapy, Basel, Switzerland University of Basel, Basel, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Rottmann
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Gagaring
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Borboa
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Buenviaje
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Francek
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: Advait
authors.initials: A
authors.lastname: Nagle
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: S Whitney
authors.initials: SW
authors.lastname: Barnes
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Plouffe
authors.affiliation: Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: Marcus C S
authors.initials: MC
authors.lastname: Lee
authors.affiliation: Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York, USA Division of Infectious Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Fidock
authors.affiliation: Radboud University Nijmegen Medical Center, Medical Microbiology Department, Nijmegen, The Netherlands.
authors.forename: Wouter
authors.initials: W
authors.lastname: Graumans
authors.affiliation: Radboud University Nijmegen Medical Center, Medical Microbiology Department, Nijmegen, The Netherlands.
authors.forename: Marga
authors.initials: M
authors.lastname: van de Vegte-Bolmer
authors.affiliation: Radboud University Nijmegen Medical Center, Medical Microbiology Department, Nijmegen, The Netherlands.
authors.forename: Geert J
authors.initials: GJ
authors.lastname: van Gemert
authors.affiliation: Global Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Australia.
authors.forename: Grennady
authors.initials: G
authors.lastname: Wirjanata
authors.affiliation: Eijkman Institute for Molecular Biology, Jakarta, Indonesia.
authors.forename: Boni
authors.initials: B
authors.lastname: Sebayang
authors.affiliation: Global Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Australia.
authors.forename: Jutta
authors.initials: J
authors.lastname: Marfurt
authors.affiliation: Laboratory of Malaria Immunobiology, Singapore Immunology Network, Agency for Science Technology and Research, Biopolis, Singapore.
authors.forename: Bruce
authors.initials: B
authors.lastname: Russell
authors.affiliation: Laboratory of Malaria Immunobiology, Singapore Immunology Network, Agency for Science Technology and Research, Biopolis, Singapore.
authors.forename: Rossarin
authors.initials: R
authors.lastname: Suwanarusk
authors.affiliation: Global Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Australia Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Ric N
authors.initials: RN
authors.lastname: Price
authors.affiliation: Shoklo Malaria Research Unit, Mae Sot, Tak, Thailand Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Francois
authors.initials: F
authors.lastname: Nosten
authors.affiliation: Department of Veterinary Medicine, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: Anchalee
authors.initials: A
authors.lastname: Tungtaeng
authors.affiliation: Department of Veterinary Medicine, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: Montip
authors.initials: M
authors.lastname: Gettayacamin
authors.affiliation: Entomology Department, AFRIMS, Bangkok, Thailand Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Jetsumon
authors.initials: J
authors.lastname: Sattabongkot
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Taylor
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Walker
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Tully
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Kailash P
authors.initials: KP
authors.lastname: Patra
authors.affiliation: Division of Pharmacology and Drug Discovery, University of California, San Diego, School of Medicine, La Jolla, California, USA.
authors.forename: Erika L
authors.initials: EL
authors.lastname: Flannery
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Vinetz
authors.affiliation: Laboratory of Malaria Immunobiology, Singapore Immunology Network, Agency for Science Technology and Research, Biopolis, Singapore.
authors.forename: Laurent
authors.initials: L
authors.lastname: Renia
authors.affiliation: Radboud University Nijmegen Medical Center, Medical Microbiology Department, Nijmegen, The Netherlands.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sauerwein
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California, USA Division of Pharmacology and Drug Discovery, University of California, San Diego, School of Medicine, La Jolla, California, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Winzeler
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Glynne
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore thierry.diagana@novartis.com.
authors.forename: Thierry T
authors.initials: TT
authors.lastname: Diagana
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000635:transmission*; D051379:Mice; D008813:Mice, Inbred ICR; D010879:Piperazines / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects; D034101:Sporozoites / Q000187:drug effects
chemical_list: D000962:Antimalarials; D007093:Imidazoles; D010879:Piperazines; C000599914:ganaplacide