Efficacy of oxfendazole treatment against infective larvae of Litomosoides sigmodontis

Filarial infections are prevalent worldwide and affect both humans and animals. Two filarial infections, lymphatic filariasis and onchocerciasis, are listed among the neglected tropical diseases by the WHO and targeted for their elimination via large-scale public health campaigns in the affected countries. New drugs are urgently needed to facilitate this goal, and the WHO has outlined the need to develop novel adult worm killing (=macrofilaricidal) compounds for onchocerciasis as one of the critical actions in their roadmap for neglected tropical diseases for 2020-2030. Oxfendazole (Oxf) is an anthelmintic benzimidazole that has been used in the veterinary field for decades and is currently being repurposed for human filarial infections. Previous work has shown that orally administered Oxf has a strong activity against the adult worms of Litomosoides sigmodontis. Based on these and other findings, Oxf was selected for further clinical development, and a phase I clinical trial conducted in 2019 reported no significant safety issues. Following these results, a multi-centric phase II basket trial was designed and is conducted by the eWHORM consortium (https://ewhorm.org/). In this study we investigated the efficacy of Oxf against the infective larval stage of L. sigmodontis in BALB/cJ mice. Female BALB/cJ mice were naturally infected and treated orally with Oxf starting 1 day after infection for up to 5 days. Mice were euthanized 35 days after infection and the number and length of worms were assessed ex vivo. Oxf treatment for 5 days led to near-complete clearance of worms (97.6% median reduction compared to vehicle control) while a 3-day treatment regimen demonstrated a dose-dependent reduction in recovered worms (up to 82.6%). The length of isolated worms was reduced to a similar degree irrespective of treatment duration. These results indicate that treatment with Oxf can clear early filarial infections in addition to its known macrofilaricidal activity.