The Coordination, Rationalization, and Integration of anti-MALarial drug Discovery & Development Initiatives (CRIMALDDI) Consortium, funded by the EU Framework Seven Programme, attempted in 2009-2010, through a series of interactive and facilitated workshops, to develop priorities for research to expedite the discovery of new anti-malarials. Ian Boulton was the Project Leader for this initiative, responsible for facilitating the workshops as well as contributing to the development of the conclusions and recommendations. This is one of two papers published at the end of the project. It outlines the recommendations for the development of enabling technologies and the identification of novel targets.
Platform technologies and novel anti-malarial drug targets
Screening systems must be robust, validated, reproducible, and represent human malaria. They also need to be cost-effective. While such systems exist to screen for activity against blood stage Plasmodium falciparum, they are lacking for other Plasmodium spp. and other stages of the parasite’s life cycle. Priority needs to be given to developing high-throughput screens that can identify activity against the liver and sexual stages. This in turn requires other enabling technologies to be developed to allow the study of these stages and to allow for the culture of liver cells and the parasite at all stages of its life cycle.
As these enabling technologies become available, they will allow novel drug targets to be studied. Currently anti-malarials are mostly targeting the asexual blood stage of the parasite’s life cycle. There are many other attractive targets that need to be investigated. The liver stages and the sexual stages will become more important as malaria control moves towards malaria elimination. Sexual development is a process offering multiple targets, even though the mechanisms of differentiation are still not fully understood. However, designing a drug whose effect is not curative but would be used in asymptomatic patients is difficult given current safety thresholds. Compounds active against the liver schizont would have a prophylactic effect and Plasmodium vivax elimination requires effectors against the dormant liver hypnozoites. It may be that drugs to be used in elimination campaigns will also need to have utility in the control phase. Compounds with activity against blood stages need to be screened for activity against other stages.
Natural products should also be a valuable source of new compounds. They often occupy non-Lipinski chemical space and so may reveal valuable new chemotypes.
The Affordable Medicines Facility – malaria (AMFm) was an initiative piloted in Africa. Its main objective was to increase access to Quality Assured Artemisinin-containing Combination Treatments (QAACTs) through a co-payment mechanism. The co-payment was intended to reduce the end-user price of QAACTS to the same level as chloroquine or sulphadoxine-pyrimethamine. The pilot programmes ended in December 2012 and the Global Fund asked the Roll Back Malaria Partnership (RBM) to take leadership in planning for the transition in 2013 to the next phase of this initiative. The RBM Board discussed this issue at its May 2012 meeting.
To inform these discussions, the RBM Executive Committee (EC) commissioned from TropMed Pharma Consulting a facts-based situational analysis of:
- the role of the private sector in delivering high quality antimalarial diagnosis and treatment;
- the global experience of social marketing programmes and subsidies in increasing access to health related commodities, especially those related to malaria;
- the current situation of AMFm and what will be known about it at the end of the Phase I pilots.