1. Introduction
Onchocerciasis (“river blindness”) is a neglected tropical disease caused by Onchocerca volvulus , a parasitic nematode transmitted to humans through the bite of the blackfly.1 The larvae mature into reproductively competent adults within 1 year. Adult worms have a lifespan of 9-11 years and reside primarily in subcutaneous and deep-tissue nodules where they produce progeny (microfilariae). The disease results from the death of the microfilariae, which prompts an inflammatory response, causing skin rash and lesions, including skin depigmentation, and unbearable itching. Microfilariae also migrate to the eye, causing local inflammation and other complications, including eye lesions, often leading to blindness.2Onchocerciasis is endemic in 27 countries mainly in sub-Saharan Africa, as well as in Yemen and Latin America.1
Onchocerciasis treatment and control currently rely on mass drug administration (MDA) of ivermectin (Mectizan®, Merck & Co. Inc.),3 which targets the microfilarial stage of the parasite and temporarily sterilises, but does not kill, the adult worms. MDA programmes must therefore be repeated at regular intervals for many years, which represents a considerable economic and logistical burden in endemic countries. There is also mounting evidence of potential resistance to ivermectin.4 Another avermectin parasiticide, moxidectin, was approved in 2018. Like ivermectin, it targets only microfilariae.5
Thus, there is an urgent need for new agents against onchocerciasis. Ideally, such agents should have activity against multiple life-stages of the parasite, a good safety profile and a long-lasting effect with a relatively simple dosing regimen.
Emodepside, a semi-synthetic cyclo-octadepsipeptide, is active across multiple nematode species.6 Like ivermectin and moxidectin,7,8 emodepside was originally developed as an anthelmintic for veterinary use. It was first marketed as Profender® (Bayer AG, Leverkusen, Germany) in 2005, in combination with praziquantel, and subsequently as Procox® (Bayer AG, Leverkusen, Germany), in combination with toltrazuril.
Because of its unique mechanism of action relative to other anthelmintics, emodepside is active at various stages in the nematode life-cycle.9,10 Pre-clinical pharmacology studies using in-vitro and in-vivo models of human filarial infections, including onchocerciasis, showed that emodepside is a potential candidate for human use.11,12 A concentration of 100 ng/mL (10-7 M) of emodepside was found to be consistently active on parasites across several filarial species and stages, and a minimum inhibitory concentration of 10-7 M was chosen as the target effective concentration in humans.
Here we report the pharmacokinetics (PK) and safety of emodepside after single and multiple doses in healthy male subjects, as well as the bioavailability of various tablet formulations.