MICA: Pre-Clinical Development of a Small Molecule anti-Wolbachia Candidate Macrofilaricide Drug

Lead Research Organisation: Liverpool School of Tropical Medicine
Department Name: Parasitology

Abstract

Lymphatic filariasis (elephantiasis) and onchocerciasis (river blindness) are two important neglected tropical diseases that cause severe disability and affect more than 157 million people globally. Control efforts are hindered by the lack of a safe macrofilaricidal (adult parasite killing) drug. Targeting the Wolbachia bacterial endosymbionts in these parasites with doxycycline leads to a macrofilaricidal outcome, but protracted treatment regimens and contraindications restrict its widespread implementation. As part of an ongoing macrofilaricide drug discovery project we have successfully completed a lead optimisation programme to deliver a pre-clinical candidate anti-Wolbachia based macrofilaricide. The candidate AWZ1066S shows superior efficacy compared to doxycycline in a range of validated animal infection models, meets all current Target Candidate Profile characteristics (including extensive non-GLP safety/pharmacology and DMPK evaluation) and is positioned for onward development. We now request funding to support the critical formal pre-clinical development programme in order to progress AWZ1066S to the first into man transition.

Technical Summary

Lymphatic filariasis (elephantiasis) and onchocerciasis (river blindness) are neglected tropical diseases that cause severe disability and affect more than 157 million people globally. Both diseases are caused by parasitic filarial nematode infections and control efforts are hindered by the lack of a safe macrofilaricidal drug. Current drug regimens principally target the microfilarial stage of the parasites, thus requiring long treatment periods with high coverage to counter the long lifespan (10-14 years) of adult worms. A validated approach for delivering macrofilaricidal activity is to target the Wolbachia bacterial endosymbiont of these nematodes. These bacteria are essential for multiple components of the nematode life-cycle including larval growth, development, embryogenesis and, ultimately, survival of the adult worm, making Wolbachia a valuable chemotherapeutic target. Targeting Wolbachia in these parasites with tetracycline antibiotics such as doxycycline leads to a macrofilaricidal outcome, but protracted treatment regimens and contraindications restrict its widespread implementation. As part of an ongoing macrofilaricide drug discovery project we have successfully completed a lead optimisation programme to deliver a pre-clinical candidate anti-Wolbachia based macrofilaricide. The candidate AWZ1066S shows superior efficacy compared to doxycycline in a range of validated animal models of infection, meets all current Target Candidate Profile characteristics, including extensive non-GLP safety pharmacology and DMPK evaluation, and is positioned for onward development. We now request funding to support the critical formal pre-clinical development programme in order to progress AWZ1066S to the first into human transition.

Planned Impact

Lymphatic filariasis (elephantiasis) and onchocerciasis (river blindness) are neglected tropical diseases that cause severe disability and affect more than 157 million people globally, ranking filariasis as one of the leading causes of global morbidity. Both diseases are caused by parasitic filarial nematode infections and control efforts are hindered by the lack of a safe macrofilaricidal drug (a drug to kill adult parasites). Global programmes for control and elimination have been developed to provide sustained delivery of drugs to affected communities in order to interrupt transmission of disease and ultimately eliminate this public health burden. Existing drugs principally target the microfilarial stage of the parasites and so require sustained and prolonged delivery with high treatment coverage to endemic communities in order to break the transmission cycle of the long-lived (onchocerciasis 10-14 years, LF 5-8 years) adult worms. Seventeen countries in hard-to-reach areas, including post-conflict countries, have still not implemented MDA against LF 12 years after the Global Programme to Eliminate Lymphatic Filariasis (GPELF) was launched. In some of these countries, interruption of transmission will not be achieved using the current strategy alone. The growing evidence for resistance to ivermectin and safety constraints in areas co-endemic with L. loa has re-focused the need and urgency for new safe macrofilaricidal drugs and regimes to achieve control programme goals within existing timeframes.
Anti-Wolbachia therapy delivers safe macrofilaricidal activity with superior therapeutic outcomes compared to all standard anti-filarial treatments, with the added benefit of substantial improvements in clinical pathology. The use of doxycycline as a macrofilaricidal therapy has been established as proof-of-concept in an extensive series of field trials, but its widespread use in community-based control is constrained by the logistics of a relatively lengthy course of treatment (4-6 weeks) and contraindications in children under eight years and in pregnancy. These barriers highlight the need for new drug discovery projects with the potential to generate new anti-wolbachial chemotypes for eventual deployment as a macrofilaricide monotherapy (although deployment in combination would remain an option).
A short course an anti-Wolbachia based macrofilaricide has the potential to significantly impact elimination time frames for these important diseases, potentially reducing elimination timeframes from decades to years. Our macrofilaricide drug discovery project has successfully completed a lead optimisation programme to deliver a pre-clinical candidate anti-Wolbachia based macrofilaricide. The candidate AWZ1066S shows superior efficacy compared to doxycycline in a range of validated animal disease models, meets all current Target Candidate Profile characteristics, including extensive non-GLP safety pharmacology and DMPK evaluation and is positioned for onward development. Funding for this programme from the MRC DPFS will support the critical formal pre-clinical chemistry, analytical, toxicology and safety pharmacology development programme in order to progress AWZ1066S to the first into human transition.

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