Tylosin Analogue Macrofilaricides (TylAMac™)

Filarial Nematode

The Anti-Wolbachia Consortium (A·WOL) based at Liverpool School of Tropical Medicine is using innovative approaches to discover and develop drugs for the Neglected Tropical Diseases (NTDs) onchocerciasis and lymphatic filariasis. These diseases are caused by parasitic filarial nematode worms, leading to debilitating pathology resulting in profound disability, social stigma and economic loss. Global elimination efforts are hampered by the lack of a drug that kills adult worms (macrofilariae) relying instead on multiple rounds of mass drug administration with drugs that target the larval stage (microfilariae). Thus a high priority has been given to the identification of new agents that are macrofilaricidal.

A∙WOL is exploiting a novel aspect of parasite biology; the reliance of filarial nematodes on their bacterial endosymbiont Wolbachia. Elimination of Wolbachia arrests embryogenesis, prevents larval development, blocks transmission potential and leads to adult worm death. Targeting Wolbachia to develop a macrofilaricide demonstrates an ‘innovative solution to a problem within the health sector’. Clinical studies have validated this approach; daily treatment with doxycycline (≥four weeks) reduces Wolbachia to a threshold below which adult worm fertility and, ultimately, viability is not sustained. However, while doxycycline is an effective macrofilaricide its contraindications and treatment duration is unsuitable for a public health strategy. Agents with greater safety profiles and more rapid onset of action, providing ≤7 day regimens, are required.

Tylosin Analogue Macrofilaricides (TylAMac™) have been developed as part of A∙WOL’s partnership with AbbVie’s NTD programme. These novel macrolide based antibiotics are highly active anti- Wolbachia agents and are the first products ever to be designed specifically as macrofilaricidal agents. The two most potent have anti-parasitic efficacy, pharmacology, and safety profiles compatible with an oral treatment regimen of ≤7 days. Thus TylAMac™ have the potential to revolutionise current global filariasis elimination programmes.