Time to rethink our approach to neglected tropical disease drug discovery?

Flaws in the neglected tropical disease drug discovery model and what needs to change

Go to the profile of James Mckerrow
Jan 19, 2016
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To help coordinate neglected tropical disease (NTD) drug discovery efforts, and reduce the duplication of research, there has recently been an introduction of open source drug discovery platforms, and data sharing frameworks. These are logical tools that should be widely used to facilitate research on neglected tropical diseases and prevent duplication of efforts. Preventing redundancy in tropical disease research is a key aim, because these are disease targets with little or no commercial value. Unfortunately the success of open source drug delivery platforms has been limited. There are two obstacles. Some companies have entered the field, graciously providing compound libraries for screens against neglected tropical disease pathogens. Largely due to the culture of restricted intellectual property required for commercial ventures, results from these screens have too often been shielded from the NTD community as a whole. This is a major hindrance to nonprofit disease research because negative results can be as important as the few instances in which only the positive hits have been published. A second, surprising obstacle to the success of open source platforms has been the reluctance of even some nonprofit funding agencies to release data from the research centers they fund. As a result, multiple screening centers around the world have spent precious, limited funding and labor on screening the same small compound collections. A common excuse for this practice has been that a new drug could not be developed without industry participation, and that requires clear intellectual property. In fact funding for much of late stage drug development, and clinical trials for NTDs, has become the responsibility of philanthropic foundations or government agencies.

Another unfortunate challenge to the rapid development and launch of new drugs, vaccines, or diagnostics for neglected tropical diseases has been the transfer of a restrictive industry culture to research and development in the neglected tropical disease arena. Perhaps this is not surprising given that most scientific advisory boards of international nonprofit agencies, centers, and foundations are made up of retired pharmaceutical company managers, scientists, and executives. These individuals bring with them the mantra of “kill early kill often” to prevent costly downstream development. In the arena of neglected tropical disease, the mantra should probably be "leave no stone unturned”. The drug development pipelines for almost all neglected diseases are woefully thin. Drug screening and even hit to lead chemistry has generally not been limiting. Elimination of compounds with covalent reactivity, protein binding problems, or Lipinski Rules issues is appropriate for a drug that one would expect to take for the rest of their life to “ manage" a disease rather than cure it. This is not an appropriate strategy for NTD drugs that would be taken much like an antibiotic with courses of 3 to 20 days. Many parasitic organisms use host proteins as a key nutrient source so protein binding becomes a delivery system rather than an albatross. If one ranks the efficacy of anti-parasitic drugs, for example those used against Leishmania, drugs with the highest protein binding often rank the highest.

I have observed the field of neglected tropical disease research for over 25 years. We have no effective anti-parasitic vaccines and there are woefully few true breakthroughs in drug development or new diagnostic tests. We can all bemoan the lack of funding for this field but perhaps we should also remember that we are not looking for a new drug for diabetes, asthma or hypertension. We are looking for a curative drug given for a short course. That implies a very different safety profile. Restrictive prescreening has failed, let’s try something different.

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