Collaborative drug discovery: an update on the progress of such initiatives
Despite the ever increasing efforts being expended for drug discovery purposes, the number of approved drugs remains relatively static. A variety of explanations have been provided to explain this observation and initiatives to remedy this situation have been implemented. Many of these initiatives are still works-in-progress and whether these will yield a return-on-investment and ultimately be successful based upon their mandates is still unclear. A progress report for two of the major initiatives from the National Institute of Health and European Union are provided herein.
The National Institute of Health Molecular Libraries Program and the National Center for Advancing Translational Sciences
The National Institute of Health Molecular Libraries Program (MLP) was one of the earliest (established in 2004) and largest state-funded initiatives that intended to implement early stage drug discovery. There was a particular focus upon assay development and the screening of such assays against small molecule libraries, in a manner similar to that implemented within the pharmaceutical industry1. The initial plan of the MLP was to build a library of compounds and establish screening centres outside the pharmaceutical industry where many of these activities historically took place. The capital and resources required were significant and the vision was to perform two very different kinds of screens, namely functional screening where compounds would be evaluated against known targets as well as phenotypic screening where unbiased testing of compounds would take place in cell based assays without knowing their targets. This was a reasonable strategy as both types of approaches complement one another and a recent publication has highlighted the value of the more risky phenotypic screening approach2.
A notable effect of the MLP was to embed drug discovery within academia. The most significant findings of the MLP have been published in high ranking journals and compounds that have progressed in the drug discovery value chain, notably the publication of a chemically tractable new mechanism for controlling the cytokine storms that prove so deadly in pandemic influenza3, description of a novel, tractable mechanism for the treatment of type 2 diabetes4, elucidation of a high-resolution crystal structure of the S1P1 receptor5 and production of over 250 probes (small molecules that can be used as research tools to interrogate previously inaccessible targets, if not as drugs themselves), directly responsibility for at least 342 scientific publications6. The screening results have been deposited in a publicly available database, PubChem, which is accessed by a large number of users and is a valuable resource of assays and screens and associated data7. A side-effect of the MLP is that most major universities now have internal drug discovery centres that attempt to translate basic research findings into the drug discovery value chain8. Despite these successes, a notable downside of the MLP is that the attrition of projects was significant in terms of delivering compounds that would be considered to meet the criteria for progression within the pharmaceutical industry9. The outputs of the MLP are valuable and publically available and include, full reports of the probes that have been delivered10, detailed reports of projects e.g. caspase-111 and 12-lipoxygenase12 and publically available peer-reviewed publications e.g. assays to search for inhibitors of Schistosoma mansoni thioredoxin glutathione reductase13-15.
The MLP has now been replaced by the National Center for Advancing Translational Sciences (NCATS)16 whose mission statement is to catalyse the generation of innovative methods and technologies that will enhance the development, testing and implementation of diagnostics and therapeutics across a wide range of human diseases and conditions17. A number of exciting and challenging initiatives have been created within NCATS18 e.g. the Clinical and Translational Science Awards Program19 (infrastructure grants awarded to academic medical institutions to facilitate translational research), Components of the MLP20 (supports centres that provide access to large-scale screening, medicinal chemistry, and informatics for the identification of therapeutic and experimental chemical entities), Therapeutics for Rare and Neglected Diseases21 (drug-development pipeline within the NIH used for research collaborations with academic scientists, non-profit organisations and companies working on rare and neglected illnesses), Rapid Access to Interventional Development22 (a competitive granting program that provides resources for the development of new therapeutic agents), Office of Rare Diseases Research23 (a multifunctional NIH office that serves as a focal point for rare diseases), NIH-FDA Regulatory Science Initiative24,25 (a competitive grant program that funds regulatory science) and Cures Acceleration Network26 (a competitive grant program to fund translational solutions to high-need medical problems).
The European Union Innovative Medicines Initiative
The European Union Innovative Medicines Initiative (IMI) is the world’s largest public-private partnership in health research and development27. The IMI is improving the environment for pharmaceutical innovation in Europe by engaging and supporting networks of industrial and academic experts in collaborative research projects. The European Union contributes one billion euros to the IMI research programme, which is matched by in kind contributions worth at least another one billion euros from the member companies of the European Federation of Pharmaceutical Industries and Associations (EFPIA). The IMI covers a wide range of areas and is particularly well thought out as each project involves stakeholders from a range of backgrounds including academia, Small and Medium Enterprises (SMEs) and the EFPIA which has a very important role in this initiative. The EFPIA brings together European national pharmaceutical industry associations as well as leading companies undertaking research, development and the manufacture in Europe of medicinal products for human use and they include research-based pharmaceutical companies, developing and manufacturing medicines in Europe for human use – called corporate members; and those organisations representing pharmaceutical manufacturers at the national level.
A major goal of the IMI is to improve pharmaceutical R&D in Europe and to speed up the development of more effective and safer medicines for patients, and it does this by creating networks of innovation in pharmaceutical R&D. A large number of ongoing projects covering a wide range of pharmaceutical R&D areas have been approved by the IMI and EFPIA and these have generated a number of peer-reviewed publications in high ranking journals and useful drug discovery IT tools that are publically available28. Examples of the IMI funded projects and their main tasks are listed below.
eTOX
Integration of bioinformatics and chemoinformatics approaches for the development of expert systems allowing the in silico prediction of toxicities
Development of innovative strategies and novel software tools to better predict the safety and the side-effects of new candidate medicines for patients. A library of public resources has been created that collates from the literature and the internet relevant data related to drug toxicity29,30.
Open PHACTS
The open pharmacological concepts triple store
Development of an open access innovation platform via a web approach that is comprised of data, vocabularies and infrastructure needed to accelerate drug-oriented research. The aim is to develop an enabling resource for drug discovery projects which is open to all users and freely available in the public domain31.
eTRIKS
Delivering European translational information and knowledge management services
Development of an open, sustainable translational research informatics / knowledge management platform based on agreed standards.
EMIF
European Medical Information Framework
Development of an information framework of patient-level data that will link up and facilitate access to diverse medical and research data sources, opening up new avenues of research for scientists with the initial focus on obesity and Alzheimer’s disease.
EHR4CR
Electronic health records systems for clinical research
Development of a platform to enable the use of electronic health records that would allow for more efficient medical research and run pilots e.g. security, data quality and data storage solutions.
Conclusion
Collectively, it is anticipated that the above initiatives will increase the number of the compounds that successfully alleviate diseases in clinical trials and subsequently obtain regulatory approval. In particular, the main challenges these are expected to address includes attrition at all stages of drug development (a majority of both Phase II and Phase III trials evaluating novel mechanism of action compounds fail due to inadequate clinical efficacy and safety)32-34; early target de-risking (investigate novel targets i.e., first in class over improved drugs for existing targets i.e., best in class), however, this comes with a high attrition rate; improve new target validation methodologies to uncover tractable targets more readily and earlier in the drug discovery process; avoid repeating work on failed targets e.g. expand precompetitive space and avoid duplicative attempts at target validation on failed / difficult targets.
References
- Big Plans for Small Molecules: NIH Launches Chemical Genomics Initiative. Garber K. Journal of the National Cancer Institute, 95, 2003, 1740-1741
- How were new medicines discovered? Swinney DC, Anthony J. Nature Reviews Drug Discovery, 10, 2011, 507-519
- Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection. Teijaro JR, Walsh KB, Cahalan S, Fremgen DM, Roberts E, Scott F, Martinborough E, Peach R, Oldstone MB, Rosen H. Cell, 146, 2011, 980-991
- Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation. Choi JH, Banks AS, Kamenecka TM, Busby SA, Chalmers MJ, Kumar N, Kuruvilla DS, Shin Y, He Y, Bruning JB, Marciano DP, Cameron MD, Laznik D, Jurczak MJ, Schürer SC, Vidović D, Shulman GI, Spiegelman BM, Griffin PR. Nature, 477, 2011, 477-481
- Crystal structure of a lipid G protein-coupled receptor. Hanson MA, Roth CB, Jo E, Griffith MT, Scott FL, Reinhart G, Desale H, Clemons B, Cahalan SM, Schuerer SC, Sanna MG, Han GW, Kuhn P, Rosen H, Stevens RC. Science, 335, 2012, 851-855
- National prescription for drug development. Wadman M. Nature Biotechnology, 30, 2012, 309-312
- http://pubchem.ncbi.nlm.nih.gov/.
- HTS and hit finding in academia-from chemical genomics to drug discovery. Frearson JA, Collie IT. Drug Discovery Today, 14, 2009, 1150-1158
- Believe it or not: how much can we rely on published data on potential drug targets? Prinz F, Schlange T, Asadullah K. Nature Reviews Drug Discovery, 10, 2011, 712
- http://mli.nih.gov/mli/mlp-probes
- http://www.ncats.nih.gov/files/Caspase1_Project_Page.pdf
- http://www.ncats.nih.gov/files/12hLO_Project_Page.pdf
- 1,536-well-based kinetic HTS assay for inhibitors of Schistosoma mansoni thioredoxin glutathione reductase. Lea WA, Jadhav A, Rai G, Sayed AA, Cass CL, Inglese J, Williams DL, Austin CP, Simeonov A. Assay Drug Development Technologies, 6, 2008, 551-555
- Quantitative high-throughput screen identifies inhibitors of the Schistosoma mansoni redox cascade. Simeonov A, Jadhav A, Sayed AA, Wang Y, Nelson ME, Thomas CJ, Inglese J, Williams DL, Austin CP. PLoS Neglected Tropical Diseases, 2, 2008, e127
- Identification of oxadiazoles as new drug leads for the control of schistosomiasis. Sayed AA, Simeonov A, Thomas CJ, Inglese J, Austin CP, Williams DL. Nature Medicine, 14, 2008, 407-412
- http://www.ncats.nih.gov
- http://www.ncats.nih.gov/about/mission.html
- Reengineering Translational Science: The Time Is Right. Collins FS. Science Translational Medicine, 3, 2011, 1-7
- Working with the CTSA Consortium: What we bring to the table. Steele SJ. Science Translational Medicine, 2, 2010, 63mr5
- Molecular Libraries Program. NIH, http://mli.nih.gov/mli
- Therapeutics for Rare and Neglected Diseases, NIH. http://trnd.nih.gov
- NIH Rapid Access to Interventional Development. http://commonfund.nih.gov/raid
- Office of Rare Diseases Research, NIH. http://rarediseases.info.nih.gov
- The NIH Common Fund, Regulatory Science, NIH. http://commonfund.nih.gov/regulatoryscience
- FDA-NIH Joint Leadership Council Charter, FDA. http://www.fda.gov/scienceresearch/specialtopics/regulatoryscience/ucm201654.htm
- On board with the Cures Acceleration Network. Nabel EG. Science Translational Medicine, 2, 2010, 32ed2
- http://www.imi.europa.eu
- http://www.imi.europa.eu/content/ongoing-projects
- http://cadd.imim.es/etox-library
- The eTOX Library of Public Resources for in Silico Toxicity Prediction. Cases M, Pastor M, Sanz F. Molecular Informatics, Special Issue: Advances in Computational Toxicology, 32, 2013, 24-35
- Open PHACTS: semantic interoperability for drug discovery. Williams AJ, Harland L, Groth P, Pettifer S, Chichester C, Willighagen EL, Evelo CT, Blomberg N, Ecker G, Goble C, Mons B. Drug Discovery Today. 17, 2012, 1188-1198
- Trial watch: Phase III and submission failures: 2007–2010. Arrowsmith J. Nature Reviews Drug Discovery 10, 2011, 87
- Trial watch: Phase II failures: 2008–2010. Arrowsmith J. Nature Reviews Drug Discovery 10, 2011, 328-329
- Trial Watch: Phase II and Phase III attrition rates 2011-2012. Arrowsmith J, Miller P. Nature Reviews Drug Discovery 12, 2013, 569
About the author
Sheraz Gul is Head of Assay Development & Screening, Fraunhofer Institute for Molecular Biology and Applied Ecology – ScreeningPort, Hamburg, Germany. He is responsible for the management and development of Medium and High Throughput Screening activities for academic partners across Europe. He has 12 years research and development experience in both academia (University of London) and industry (GlaxoSmithKline Pharmaceuticals). This has ranged from the detailed study of catalysis by biological catalysts (enzymes and catalytic antibodies) to the design and development of assays for High Throughput Screening for the major biological target classes. He is the co-author of numerous papers, chapters and the Enzyme Assays: Essential Data handbook.
