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High throughput screening: A partnership for academics within the pharma industry

By: Roche Life Science

Posted: April 21, 2016 | Lab Life - High Throughput

Large pharmaceutical companies pioneered high-throughput screening (HTS) for drug discovery in the early 1990s. As a result of significant technological advancements in automated biotechnology and combinatorial chemistry and automation. Together with a rapid rise in screening capacity, these advances resulted in the development of drug libraries and databases containing compounds in the multi-millions.

This methodology required biotechnological advances in automation and step-wise miniaturization of assay samples, as illustrated by the development of automated commercial systems processing 384- and 1536-well plates in a variety of chemical and cellular HTS assays. However, while HTS may identify hundreds of lead compounds from a library screen, only a minute fraction will ever be tested in clinical trials, and an even smaller fraction, if any, will reach Food and Drug Administration (FDA) approval. These developments highlight the exceptional cost and lengthy journey of the drug discovery process, often requiring many years and multi-million dollar investments to reach a marketable outcome.

Developments in HTS

Pharmaceutical profits over the past decade have reflected these difficulties, with a sharp decline in profits from new drugs since 2004, according to a recent study from the MIT Sloan School of Management.1 This article additionally reported that pharmaceutical research and development (R&D) costs exceeded earned revenue for new drugs from 2005-2009. These changes meant R&D investment was viewed as a significant financial risk, resulting in massive cutbacks during a time when companies were preparing for the "patent cliff" - when groups of high-revenue mainstream drugs would lose patent protection against a surge of generic competitors.2

Together, the decline in new drug revenue and financial strain of drug R&D over the previous decade resulted in a growing partnership between pharmaceutical industries and academic laboratories to accelerate enhanced productivity in HTS and early drug discovery. This resulted in shunting much of the early phases of target identification and testing R&D to academic laboratories,3 allowing pharmaceutical industries to focus on early efficiency and cost reduction by providing resources at subsequent assay development and testing stages.

How funding factors in

Importantly, these partnerships arose at time when research labs across the country were facing a rapid decline in federal funding with depleted research budgets. Thus, the partnership between academia and industry came at an opportune time, with the coincident decline in pharmaceutical R&D highlighting the importance of finding innovative and sustainable methods for financial stability in drug discovery research. Indeed, the role of academia in HTS/drug discovery partnerships with industry continues to evolve, and there remain significant challenges to creating a successful partnership between academia and industry.

Traditionally, academic laboratories contributed predominantly in target identification and validation, with strengths in dissecting the mechanisms of disease and identifying therapeutic targets for drug discovery. Thus, laboratories relied on industry for the development and clinical testing of chosen targets. At times, this has been thought to result in an emphasis on development of more marketable drug targets. However, over the past decade, there has been enormous financial investment in the development of HTS capabilities and medicinal chemistry expertise for early drug discovery at U.S. academic centers. This was done in part through increased federal support for translational medicine and declining costs of automated screening systems.4 The investments included the creation of the NIH Chemical Genomic Center, among others, and funding for development of assays with testing against a central database and publicly available results. In 2008, the NIH Roadmap initiative designated approximately $70 million to the Molecular Libraries Program, providing funds to a number of comprehensive screening centers across the country to facilitate probe discovery using advanced methodologies with cutting-edge assay technology.4

New developments in HTS

The development of academic-driven HTS has resulted in a shift in assay focus. According to a 2011 survey of 78 academic or non-profit U.S. drug discovery centers, while cancer and infectious diseases were the most common therapeutic areas for academic drug discovery, as expected (at 86 and 71 percent, respectively), diseases prevalent in less developed countries and orphan diseases were also a major focus (30 and 36 percent, respectively).5

There was a wide range of reported drug targets tested, including protein kinases and G-protein coupled receptors, as well as non-classical targets such as non-enzymatic proteins and phenotypic assays lacking an identified target. Interestingly, 72 percent of centers reported capabilities for hit-to-lead medicinal chemistry, while only 51 percent reported capabilities for testing efficacy in vivo and 42 percent for testing drug metabolism and pharmacokinetics. With regard to questions comparing academic versus industrial drug discovery, academia was perceived to have greater strength in disease biology expertise and innovation, while industry was felt to have greater strength in assay development, screening, and medicinal chemistry.5

However, given the evolving role for academic laboratories in early HTS and drug discovery processes, there remain significant challenges in partitioning responsibilities, sharing risks and the rights to intellectual property. Both parties must share a clear project goal with a mutual understanding of risk sharing (and benefits sharing). There must be as much upfront transparency as possible with regard to intellectual property while maintaining respect for academic freedom and welcoming innovative ideas from both partners. Understandably, the last thing either party wants is a drawn-out legal battle after years of collective hard work and innovation.

In summary, the scope of academic research in HTS and drug discovery has significantly expanded from systems biology and target discovery to advanced assay design and probe discovery, chemical genomics, as well as primary and secondary screening of vast compound libraries. As a consequence, there have been dynamic changes in the relationship between academia and industry, with pharmaceutical companies increasing support of open innovation strategies and academics enhancing discovery potential and fueling the drug discovery pipeline. And while there remain a number of challenges in optimizing these partnerships, the continued sharing of risks and rewards in a mutually beneficial manner, while maintaining common goals, will continue to facilitate scientific successes.

1. http://mitsloan.mit.edu/newsroom/press-releases/mit-sloan-research-shows-sharp-decline-in-economic-returns-of-new-drugs/

2. http://www.nature.com/news/2011/110209/full/470154a.html

3. http://www.nature.com/news/2011/110622/full/474433a.html

4. Baker M. Academic screening goes high-throughput. Nature Methods 2010: 7, 787–792.

5. Frye S et al. US academic drug discovery. Nat Rev Drug Discov. 2011 Jun;10(6):409-10.

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