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

Germanus S Bah,David D Ekale,Helena Fieseler,Vincent N Tanya,Sebastian Schneckener,Lucien Rufener,Nicolas H Bayang,Carsten Terjung,Youssouf M Mfopit,Steffen R Hahnel,John Graham-Brown,Gabriele M Schmuck,Ralph Krebber,Martin Glenschek-Sieberth,Anouk Sarr,Daniel Kulke,Benjamin L Makepeace,Henrietta F Ngangyung

doi:10.1371/journal.ppat.1009601

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.

Highlights

Onchocerciasis is a neglected tropical disease caused by a parasitic worm, Onchocerca volvulus, which belongs to the vector-transmitted superfamily Filarioidea
Onchocerciasis, 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
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

Summary

Introduction

Onchocerciasis is a neglected tropical disease caused by a parasitic worm, Onchocerca volvulus, which belongs to the vector-transmitted superfamily Filarioidea (the filarial nematodes). In most endemic foci in sub-Saharan Africa, IVM is distributed once annually, killing the first-stage larvae (microfilariae, Mf) in the skin and preventing disease manifestations. This regimen suppresses the release of new Mf from the adult female worm for several months [4]. The current World Health Organization (WHO) strategy is to eliminate onchocerciasis by MDA, modelling suggests that IVM alone cannot achieve elimination until the 2040s rather than 2025 [8], the target date of the Mectizan Donation Program [9] This sole reliance on IVM has other drawbacks, including the emergence of suboptimal responses to the drug in some O. volvulus populations in Ghana and Cameroon [10,11] and IVM contraindications in people

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