Awarded Amount$7,960,044DiseaseNTD (Lymphatic filariasis / Onchocerciasis)InterventionDrugDevelopment StageClinical Phase2Collaboration PartnersEisai Co., Ltd. , University of Liverpool , University of Buea (UoB) , University Hospital of Bonn (UKB) , Liverpool School of Tropical MedicinePast Project
Introduction and Background of the Project
Lymphatic filariasis (elephantiasis) and onchocerciasis (river blindness) are two neglected tropical diseases that are caused by parasitic worms. These diseases affect more than 86 million people globally. The international community agrees that these diseases should and could be eliminated with the correct tools and there are ongoing mass drug administration campaigns underway to achieve this goal. However, in the absence of a drug that can kill adult parasites, current programmes require many years of annual (or greater) rounds of drug administration to large populations in the rural communities blighted by these diseases. We have demonstrated that adult worms can be killed by eliminating a symbiotic bacterium that they contain called Wolbachia.
This approach has the potential to significantly reduce the timescale of elimination programmes, to provide alternatives to current drugs and to deliver an additional tool that can be used in areas where current approaches are failing or cannot be deployed. The antibiotic doxycycline works in this way and proof of concept has already been proven in human field trials. Results were excellent but required 4 to 6 weeks of daily treatment. Also, this drug cannot be used in children and pregnant women, who represent a large proportion of the target population.
We have identified a new drug candidate, AWZ1066S, that acts more quickly and efficiently than doxycycline and has been shown to be safe in pre-clinical testing and in the early stages of a Phase I clinical trial in healthy human volunteers.
2. Project objective
The objective of this project is to continue the development of this drug candidate further by completing a Phase II clinical trial to assess its effectiveness in patients suffering with onchocerciasis. This is an essential step in the development of a new drug and brings us closer to a new treatment for these diseases.
3. Project design
The project will involve:
• Completion of essential preclinical safety studies prior to the start of the clinical trial
• Completion and registration of the clinical trial protocol
• Completion of the Phase II trial in line with international requirement for the licensing of new drugs.
4. Specific roles and responsibilities of each and every Partner in this Project
The Liverpool School of Tropical Medicine (LSTM) is the designated coordination partner for the project and is responsible for the overall management of the project and will be the sponsor of the Phase II clinical trial. In the role as coordinator, the LSTM team, led by Prof Ward who has over 30 years experiences in research and development of new drugs for the treatments of NTDs, will liaise with all partners and the funder GHIT.
Eisai provides industry standard preclinical and clinical development expertise as we progress to the clinical development stage. The Eisai team, led by Dr Gusovsky, who has recently completed two stages of clinical development of an antimalarial candidate funded by GHIT, is responsible for coordinating the Eisai teams from the different sites. Eisai’s research facility will manufacture and test the material for use in the clinical trial. Eisai will work collaboratively with LSTM on the Regulatory and Clinical Strategy.
The UoL team, led by Prof O’Neill will help monitor and co-ordinate preclinical studies, and radiolabel synthesis and any chemistry route optimization strategies.
The University of Buea team, managed by Prof Wanji will co-lead Activities 13-18 with UKB with responsibility for trial site selection, community sensitization, patient recruitment, treatment allocation, adverse event reporting and management and follow-up sampling activities and primary endpoint analysis.
TThe University Hospital of Bonn (UKB) team, Prof Hoerauf and Dr Klarmann-Schulz, will work in partnership with the University of Buea team and LSTM to deliver the Phase II clinical trial activities. They will work together on trial site selection, community engagement, patient recruitment, treatment allocation, adverse event reporting and management and follow-up sampling activities. Primary endpoint analysis will be carried out by the University of Buea team, with secondary endpoint analysis of adult worm histology/immunohistochemistry to be carried out by the UKB and LSTM teams.
How can your partnership (project) address global health challenges?
Parasitic worm diseases inflict serious public health problems throughout tropical communities. Global programs for their control and elimination have been developed to provide sustained delivery of drugs to affected communities to interrupt transmission of disease and ultimately eliminate this public health burden. Existing drugs principally target the young worms and not the adult worms. This means that sustained and prolonged delivery with high treatment coverage to endemic communities is required to break the transmission cycle of the long-lived (onchocerciasis 10-14 years, lymphatic filariasis 5-8 years) adult worms. Seventeen countries in hard-to-reach areas, including post-conflict countries, have still not implemented mass drug administration against lymphatic filariasis 22 years after the Global Programme to Eliminate Lymphatic Filariasis (GPELF) was launched. In some of these countries, the growing evidence for resistance to the current drug ivermectin and safety constraints in areas co-endemic with a similar infection called Loa loa has re-focused the need and urgency for new safe drugs that kill adult worms and regimes to achieve elimination programme goals within existing timeframes.
Our approach of killing the symbiotic bacteria within the worms means that adult worms are killed. This leads to better therapeutic outcomes compared to all current treatments, with the added benefit of substantial improvements in disease progression. The use of doxycycline to kill adult worms 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 pregnant women. These barriers highlight the need for a new drug to overcome these problems and the current drug candidate, AWZ1066S, provides a unique opportunity to make a large contribution to communities affected by these diseases.
What sort of innovation are you bringing in your project?
The approach of killing the parasitic worm by targeting the essential Wolbachia bacteria within the worm is a totally unique approach and one that offers many advantages over drugs that target worms directly. Proof-of-concept clinical trials have already shown that this alternative approach works and can reduce elimination timeframes significantly. Our drug candidate also has the potential to be used in the whole population, including children and pregnant women.
Others (including references if necessary)
Johnston KL, Hong WD, Turner JD, O'Neill PM, Ward SA, Taylor MJ. (2021) Anti-Wolbachia drugs for filariasis. Trends in Parasitology. S1471-4922(21)00143-4.
Hong WD, Benayoud F, Nixon GL, Ford L, Johnston KL, Clare RH, Cassidy A, Cook DAN, Siu A, Shiotani M, Webborn PJH, Kavanagh S, Aljayyoussi G, Murphy E, Steven A, Archer J, Struever D, Frohberger SJ, Ehrens A, Hübner MP, Hoerauf A, Roberts AP, Hubbard ATM, Tate EW, Serwa RA, Leung SC, Qie L, Berry NG, Gusovsky F, Hemingway J, Turner JD, Taylor MJ, Ward SA, O'Neill PM. AWZ1066S, a highly specific anti-Wolbachia drug candidate for a short-course treatment of filariasis. Proc Natl Acad Sci U S A. 2019 Jan 22;116(4):1414-1419.
Phase II Clinical Development of AWZ1066S, a Small Molecule anti-Wolbachia Candidate Macrofilaricide Drug