The Future of Drug Development for Neglected Tropical Diseases: How the European Commission Can Continue to Make a Difference

sion. Monitoring how and where these filaments emerge, elongate, and recycle will certainly require future imaging adjustments to increase signal sensitivity, speed, and resolution. Thanks to the great achievement in generating a tool that all the community was waiting for, and in conjunction with photoactivation and inactivation-based approaches, and super-resolution live-cell imaging, the mystery of the actin contribution to the lytic cycle of tachyzoites might be finally elucidated in the near future.


EC FP7 Drug Discovery Projects
The EC has been notably successful in bringing together large, multinational research networks. Four such consortia, with the acronyms NMTrypI (http:// fp7-nmtrypi.eu), KINDReD (http:// kindred-fp7.com/), A-ParaDDisE (http:// a-paraddise.cebio.org/), and PDE4NPD (www.pde4npd.eu), involving more than 50 teams in Europe, Africa, India, South America, Australia, and the USA, were funded in the last call under FP7 related to drug development in neglected infectious diseases. The projects targeted the major chronic parasitic diseases leishmaniasis, Chagas disease, sleeping sickness, schistosomiasis, and malaria. Together, these diseases affect more than a billion people worldwide, cause hundreds of thousands of deaths, and are major contributors to the poverty trap in the countries concerned [2]. The projects were given the following objectives: To establish a common drug-discovery platform that should have the capacity to undertake screening of compound libraries, lead development.
To test validated hit compounds in relevant animal models as well as toxicology and safety testing of new drug candidates. The four projects pursued distinct strategies for drug discovery, involving both phenotypic screening, target-based methods, and repurposing of existing approved drugs, and have all made significant progress. Based on the criteria for the selection of 'hit' and 'lead' compounds, recently defined [3], well over 100 hits have been identified of which more than 10 can so far be defined as lead compounds with promising profiles in animal studies and significant potential for further development. These numbers will grow as the projects reach term. In addition, novel drug targets have been identified and validated for each of the parasites studied, homology models and crystal structures of target enzymes have been resolved, and new chemical entities identified as potential drugs of interest both in NTDs and other pathologies.
Importantly, as suggested by the EC at the time of funding, the four consortia have worked in close collaboration throughout the course of their projects under the umbrella of common 'Synergy' activities. These involved regular discussions, a joint symposium in 2016, common partner teams and/or external advisory board members, resource pooling, and a common data storage platform (https://fp7h-synergy.h-its.org/). This has enabled them to adopt a common strategy to face the challenge of ensuring that the advances made will not be lost once the current projects come to an end. Crucially, support is needed for developing hit and lead compounds from in vivo animal studies through preclinical testing up to and including phase I clinical trials. This involves rigorous pharmacokinetic, pharmacodynamic, and toxicity studies (Absorption, Distribution, Metabolism, Excretion, and Toxicity; ADMET) and drug production according to Good Laboratory Practice/Good Manufacturing Practice (GLP/GMP) standards ( Figure 1  appropriate funding: a pooled R&D fund has been proposed by the WHO [4] but this remains theoretical. The absence of such a large pooled funding mechanism and the fragmentation of current efforts are to be deplored [2,5].

How the EC Can Make a Difference
The considerable contribution of the ECfunded programmes to NTD research is not in question. It is also clear that emphasis has previously been placed on basic research, but that this should now shift in order to address the gaps in the pipelines for the development of drugs, vaccines, and diagnostics. The most obvious gap separates drug hit and lead development from the type of clinical trial funded by the EDCTP. The next logical step for the drug development investment strategy of the EU would be to fund a call within H2020, to build upon the synergy developed in the last FP7 call. This would enable continued interaction between academia and small and medium-sized enterprises by creating a platform to take on the task of bridging the gap between lead optimization and early-stage clinical trials (phases I-II). Lead compounds developed by the four consortia, but also from other sources (e.g., teams participating in the current EC-funded COST 1307 initiative) would feed the platform regardless of the parasitic disease targeted, overcoming the problem of fragmentation amongst groups in the field and removing replication of effort. While this should not replace funding of basic research, it would lead to an increase in the density of the different stages of preclinical testing and in the numbers of candidates entering phase I clinical trials. In this way the previous investment in NTD drug discovery would be consolidated.
While it is evident that no single funder can completely cover the whole drug development pipeline, targeted funding, as suggested here, could attract support from other sources, including industry, foundations, and nongovernmental organizations, and collaborations between these stakeholders should be sought. Finally, the cooperation of the pharmaceutical industry, whose expertise is essential for any drug to finally reach the clinic, could be engineered through the Innovative Medicines Initiative (IMI), cofunded by the EC and industry, by adding NTD drug development to the IMI remit.