AWZ1066S, a highly specific anti-Wolbachia drug candidate for a short-course treatment of filariasis
Hong WD., Benayoud F., Nixon GL., Ford L., Johnston KL., Clare RH., Cassidy A., Cook DAN., Siu A., Shiotani M., Webborn PJH., Kavanagh S., Aljayyoussi G., Murphy E., Steven A., Archer J., Struever D., Frohberger SJ., Ehrens A., Hübner MP., Hoerauf A., Roberts AP., Hubbard ATM., Tate EW., Serwa RA., Leung SC., Qie L., Berry NG., Gusovsky F., Hemingway J., Turner JD., Taylor MJ., Ward SA., O’Neill PM.
Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect ∼157 million people and inflict severe disability. Both diseases are caused by parasitic filarial nematodes with elimination efforts constrained by the lack of a safe drug that can kill the adult filaria (macrofilaricide). Previous proof-of-concept human trials have demonstrated that depleting >90% of the essential nematode endosymbiont bacterium, Wolbachia, using antibiotics, can lead to permanent sterilization of adult female parasites and a safe macrofilaricidal outcome. AWZ1066S is a highly specific anti-Wolbachia candidate selected through a lead optimization program focused on balancing efficacy, safety and drug metabolism/pharmacokinetic (DMPK) features of a thienopyrimidine/quinazoline scaffold derived from phenotypic screening. AWZ1066S shows superior efficacy to existing anti-Wolbachia therapies in validated preclinical models of infection and has DMPK characteristics that are compatible with a short therapeutic regimen of 7 days or less. This candidate molecule is well-positioned for onward development and has the potential to make a significant impact on communities affected by filariasis.