Emodepside targets SLO-1 channels of Onchocerca ochengi and induces broad anthelmintic effects in a bovine model of onchocerciasis

Onchocerciasis (river blindness), caused by the filarial worm Onchocerca volvulus, is a neglected tropical disease mostly affecting sub-Saharan Africa and is responsible for >1.3 million years lived with disability. Current control relies almost entirely on ivermectin, which suppresses symptoms caused by the first-stage larvae (microfilariae) but does not kill the long-lived adults. Here, we evaluated emodepside, a semi-synthetic cyclooctadepsipeptide registered for deworming applications in companion animals, for activity against adult filariae (i.e., as a macrofilaricide). We demonstrate the equivalence of emodepside activity on SLO-1 potassium channels in Onchocerca volvulus and Onchocerca ochengi, its sister species from cattle. Evaluation of emodepside in cattle as single or 7-day treatments at two doses (0.15 and 0.75 mg/kg) revealed rapid activity against microfilariae, prolonged suppression of female worm fecundity, and macrofilaricidal effects by 18 months post treatment. The drug was well tolerated, causing only transiently increased blood glucose. Female adult worms were mostly paralyzed; however, some retained metabolic activity even in the multiple high-dose group. These data support ongoing clinical development of emodepside to treat river blindness. Author summary Onchocerciasis (river blindness), caused by the parasitic worm Onchocerca volvulus, is a devastating neglected tropical disease affecting sub-Saharan Africa with an overall impact of >1.3 million years lived with disability. Current control relies mainly on a single drug, ivermectin, which suppresses symptoms caused by the first-stage larvae (microfilariae) but does not kill the long-lived adults. The identification of a drug that can safely eliminate adult worms (i.e., a macrofilaricide) is a major research objective for onchocerciasis. We evaluated the anthelminthic activity of emodepside, a veterinary wormer, in cattle infected with a close relative of O. volvulus (Onchocerca ochengi) before conducting pharmacokinetic modelling to estimate drug distribution in humans. Emodepside as single or 7-day treatments at two doses produced rapid activity against O. ochengi microfilariae, prolonged suppression of female worm fecundity, and paralysed most female worms by 18 months, although some remained metabolically active even in the multiple high-dose treatment group. The drug was well tolerated, causing only transiently increased blood glucose. Thus, emodepside shows slow but significant efficacy against adult O. ochengi in naturally infected cattle, meeting the criteria for a safe macrofilaricidal drug. Our data support the ongoing clinical development of emodepside for the treatment of human onchocerciasis.