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

Abstract

Current mass drug administration (MDA) programs for the treatment of human river blindness (onchocerciasis) caused by the filarial worm Onchocerca volvulus rely on ivermectin, an anthelmintic originally developed for animal health. These treatments are primarily directed against migrating microfilariae and also suppress fecundity for several months, but fail to eliminate adult O. volvulus. Therefore, elimination programs need time frames of decades, well exceeding the life span of adult worms. The situation is worsened by decreased ivermectin efficacy after long-term therapy. To improve treatment options against onchocerciasis, a drug development candidate should ideally kill or irreversibly sterilize adult worms. Emodepside is a broad-spectrum anthelmintic used for the treatment of parasitic nematodes in cats and dogs (Profender and Procox). Our current knowledge of the pharmacology of emodepside is the result of more than 2 decades of intensive collaborative research between academia and the pharmaceutical industry. Emodepside has a novel mode of action with a broad spectrum of activity, including against extraintestinal nematode stages such as migrating larvae or macrofilariae. Therefore, emodepside is considered to be among the most promising candidates for evaluation as an adulticide treatment against onchocerciasis. Consequently, in 2014, Bayer and the Drugs for Neglected Diseases initiative (DNDi) started a collaboration to develop emodepside for the treatment of patients suffering from the disease. Macrofilaricidal activity has been demonstrated in various models, including Onchocerca ochengi in cattle, the parasite most closely related to O. volvulus. Emodepside has now successfully passed Phase I clinical trials, and a Phase II study is planned. This Bayer–DNDi partnership is an outstanding example of “One World Health,” in which experience gained in veterinary science and drug development is translated to human health and leads to improved tools to combat neglected tropical diseases (NTDs) and shorten development pathways and timelines in an otherwise neglected area.

Effect of a single dose of 8 mg moxidectin or 150 μg/kg ivermectin on O. volvulus skin microfilariae in a randomized trial: Differences between areas in the Democratic Republic of the Congo, Liberia and Ghana and impact of intensity of infection

“…Expert consultations and detailed analyses of available data spearheaded by APOC concluded that alternative treatment strategies (ATS), including those with more effective drugs than ivermectin, are needed to eliminate parasite transmission in many areas [ 22 ]. Research into different types of ATS [ 23 ] is ongoing, including discovery and development of more effective drugs [ 24 – 26 ], identification of effective, affordable, and sustainable complementary vector control strategies [ 27 ] and studies for implementation of new ‘test-and-not-treat’ or ‘test-and-treat’ strategies for Loa-loa co-endemic areas [ 28 – 32 ]. Furthermore, research for a vaccine is continuing [ 33 ].…”

Spatial transcriptomics reveals antiparasitic targets associated with essential behaviors in the human parasite Brugia malayi

“…Bma-glc-3 and Bma-glc-4 channel subunits are more enriched in the head and may also play a role in macrocyclic lactone responses. Bma-slo-1 , a putative target of emodepside, an emerging candidate adulticide for treatment of river blindness [ 38 ], is more highly expressed in the body. Conversely, the likely β-tubulin target of albendazole ( Bma-btub-1 ), based on homology to Caenorhabditis elegans ben-1 , is head-enriched.…”

Adoptive Transfer of Immune Cells Into RAG2IL-2Rγ-Deficient Mice During Litomosoides sigmodontis Infection: A Novel Approach to Investigate Filarial-Specific Immune Responses

“…In general, adoptive transfer experiments using RAG2IL-2Rγ-deficient C57BL/6 mice provide an optimal platform to decipher cell subsets and their corresponding immune responses that are crucial for anti-filarial immunity. Since our recent studies already showed that RAG2IL-2Rγ-deficient C57BL/6 mice are susceptible to the human filaria Loa loa ( 35 , 66 , 74 ), this platform is not restricted to rodent filariae but will also be a suitable tool for in-depth research on human filariae and preclinical research, especially might allow the identification of essential immunological component(s) and accurate predictions of the efficacy of macrofilaricidal drugs, like flubendazole ( 75 ), oxfendazole ( 76 ) or emodepside ( 77 ).…”