The losses to trypanosomosis or Nagana are not limited to but are most heavily felt by the poorest livestock keepers. In 2011, UK Department for International Development asked GALVmed to seek new trypanocides, vaccines and diagnostics to help control this disease. During Phase 1 of the programme that ended December 2013, GALVmed developed partnerships to establish test systems to evaluate available technologies. Laboratory testing was carried out primarily at SwissTPH and then, with formulation support from the University of Greenwich, compounds were progressed and further testing occurred at sites in Mozambique (University Eduardo Modlane), South Africa (ClinVet) and Burkino Fassau (CIRDES). Although none of the potential vaccines were shown to work in a rigorous model, good progress was made in identifying new diagnostics and trypanocidal compounds. This work is continuing in Phase 2. This article describes our strategy, some of the challenges faced and progress made towards identifying new trypanocides.
Trypanocides are available both to treat (Diminazene), and prevent (Isometamidium, Homidium) trypanosomosis in cattle and other livestock. Indeed, trypanocides represent one of the largest segments of the animal health market in Africa with estimated sales of branded and generic products estimated at around $100 million. However, these compounds are over 50 years old and not only do they have narrow therapeutic margins but field resistance to these compounds is growing steadily. Unfortunately, the potential value of this market has been reduced by widespread availability of sub-standard and fake products. The lack of understanding of the disease, poor diagnosis and poor efficacy of current products due to drug resistance or intentional and accidental underdosing, coupled with inconvenient to use formulations, means that usage of trypanocides is much lower than required to tackle the disease. This market risk has resulted in a reluctance of the animal health companies to invest precious research and development funding in the search for new trypanocides.
In contrast, a partnership of academics, pharma companies and not-for-profit PDPs, such as DNDi, has made great progress in addressing human African trypanosomiasis (HAT) or Sleeping Sickness caused by related species,T.brucei rhodesiense and gambiense. As well as declining cases, there is now a strong pipeline of new, highly-effective drug candidates in development, e.g. fexinidazole and SCYX7158.
GALVmed has adopted a strategy to build on the discoveries made by these groups to leverage their compounds for potential application to animal trypanosomosis. Our Phase 1 work leveraging the human candidate programmes almost achieved our goal of identifying a development candidate. AN7973 from Anacor was shown to be very safe and could cure cattle infected with T.congolense by a single 10mg/kg injection. Unfortunately, T.vivax proved less susceptible to this compound and could not be treated by an economic dose.
Through support from our joint funders, the Bill & Melinda Gates Foundation and the UK Government, we have been encouraged to expand our efforts for Phase 2 to leverage the human research with additional collaborations. Many of the drugs identified for HAT failed due to lack of efficacy against Stage 2 of the disease in which the parasite enters the central nervous system where it is harder to access with the drug. Other lead compounds failed to provide activity by oral dosing. Neither of these features are required for a treatment of Animal African Trypanosomosis where the parasites largely live in the peripheral tissues and bloodstream and treatment is more convenient by injection. We need a compound that is potent and long-lasting so that it can cure or provide prophylaxis by a single injection. It also needs to be very safe both to the animal and to humans who might wish to subsequently eat the animal or use its milk.
GALVmed has developed screening partnerships with more than a dozen academic and industry groups who have been active in seeking treatments for HAT. Our partnerships span the globe and include the Universities of Dundee, Strathclyde, Cape Town, Washington, North Eastern (U.S.), Monash (Aus.), research institutes e.g. Broad, St. Jude Children’s Hospital, and companies such as Novartis, Anacor and Celgene. We have been testing their compounds in the laboratory against the livestock trypanosomes, T. vivax and T.congolense and we have identified a number of very exciting lead structures. We have already commenced lead optimisation programmes with Anacor, University of Dundee and Celgene Global Health to seek close analogues of these lead compounds that might have the ideal combination of properties to make them candidates for development. The best of these compounds are now being progressed to cattle studies and we have very encouraging results – so watch this space!