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.