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

Abstract

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.

Onchocerciasis drug development: from preclinical models to humans

“…Action on the SLO-1 K channel results in an inhibitory effect on motility, pharyngeal pumping and egg laying of nematodes. In addition to emodepside’s success as a veterinary anthelminthic, several experiments showed its effect on filarial nematodes in various models, including initial studies on L. sigmodontis in Mastomys (Zahner et al 2001 ) and recently O. ochengi in cattle (Bah et al 2021 ). These experiments showed macrofilaricidal efficacy after 5 consecutive doses of 5–100 mg/kg in rodents and 0.75 mg/kg in cattle.…”

Drug development for the treatment of onchocerciasis: Population pharmacokinetic and adverse events modeling of emodepside

“…Antiparasitic activity of emodepside in vivo was previously evaluated in an O . ochengi -infected cattle model [ 22 ] and an L . sigmodontis -infected rat model [ 28 ].…”

“…ochengi cattle model, a pronounced reduction in adult worm motility was observed if total plasma concentrations of emodespide were maintained above approximately 100 ng/mL for 7 days. In addition, emodepside showed embryotoxic effects and microfilaricidal activity with prolonged effects on adult female fecundicity [ 22 ]. Notably, the effect on adult worm motility and viability as well as microfilariae density in cattle was dose-dependent and multiple doses (0.75mg/kg for 7 days) tended to be more effective compared to a single dose of emodepside [ 22 ].…”

“…Dose-dependent inhibition of worm motility by emodepside after 3–5 days of incubation was observed across all tested filarial species and stages. Moreover, embryotoxic, microfilaricidal and partial macrofilaricidal activity of emodepside has been demonstrated in cattle infected with Onchocerca ochengi , the closest known relative of the human parasite [ 22 ]. Importantly, emodepside was also shown to be fully effective against nematodes in sheep and cattle that are resistant to other classes of anthelminthic drugs [ 23 ].…”

Development of emodepside as a possible adulticidal treatment for human onchocerciasis—The fruit of a successful industrial–academic collaboration

“…The motility of adult macrofilariae recovered from nodules was significantly affected over time at all emodepside doses for females, but only at the highest dose for males [97]. In 5 out of 7 cattle, including those with no microfilariae, the 7 × 0.75 mg/kg treatment scheme caused death or sterility of female worms, demonstrating slow-acting macrofilaricidal and sterilizing effects [98].…”