Oxfendazole mediates macrofilaricidal efficacy against the filarial nematode Litomosoides sigmodontis in vivo and inhibits Onchocerca spec. motility in vitro

Author summary Onchocerciasis and lymphatic filariasis represent two debilitating filarial diseases that belong to the neglected tropical diseases. The current efforts to eliminate those diseases is hampered by the lack of short-course macrofilaricidal drugs, i.e. drugs that kill the adult worms, or regimens that are proven to be safe for both diseases. In the present study we demonstrate that the anthelmintic drug oxfendazole, currently used in veterinary medicine against intestinal helminths, has excellent efficacy in theLitomosoides sigmodontisrodent model of filariasis. Oxfendazole caused complete clearance of adult filariae after a short oral regimenin vivo. Oxfendazole was not directly active against the circulating filarial progeny, the microfilariae, suggesting that drug-induced serious adverse events due to the clearance of microfilariae are unlikely. Human dose was predicted based on the efficacy in the rodent model, the calculation estimated a low efficacious dose, which has already been shown to be safe in phase 1 clinical trials. Thus, oxfendazole represents a promising drug candidate for the treatment of human filarial diseases such as onchocerciasis and lymphatic filariasis. A major impediment to eliminate lymphatic filariasis and onchocerciasis is the lack of effective short-course macrofilaricidal drugs or regimens that are proven to be safe for both infections. In this study we tested oxfendazole, an anthelmintic shown to be well tolerated in phase 1 clinical trials.In vitro, oxfendazole exhibited modest to marginal motility inhibition of adult worms ofOnchocerca gutturosa, pre-adult worms ofOnchocerca volvulusandOnchocerca lienalismicrofilariae.In vivo, five days of oral treatments provided sterile cure with up to 100% macrofilaricidal efficacy in the murineLitomosoides sigmodontismodel of filariasis. In addition, 10 days of oral treatments with oxfendazole inhibited filarial embryogenesis in patentL.sigmodontis-infected jirds and subsequently led to a protracted but complete clearance of microfilaremia. The macrofilaricidal effect observedin vivowas selective, as treatment with oxfendazole of microfilariae-injected naive mice was ineffective. Based on pharmacokinetic analysis, the driver of efficacy is the maintenance of a minimal efficacious concentration of approximately 100 ng/ml (based on subcutaneous treatment at 25 mg/kg in mice). From animal models, the human efficacious dose is predicted to range from 1.5 to 4.1 mg/kg. Such a dose has already been proven to be safe in phase 1 clinical trials. Oxfendazole therefore has potential to be efficacious for treatment of human filariasis without causing adverse reactions due to drug-induced microfilariae killing.