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High-Throughput Screening Technique has the Potential to Enhance Neuro-pharmaceutical Drug Development

High-Throughput Screening Technique has the Potential to Enhance Neuro-pharmaceutical Drug Development

Dec 10, 2010

                Nearly all of the largest U.S. pharmaceutical companies are currently facing increasing pressure as they approach a steep ‘patent cliff’,  past which many of the most profitable drugs in their portfolios will lose patent protection and face aggressive competition from less expensive generic formulations.  Pfizer, for example, is one of the largest pharmaceutical companies in the world with just over $50 billion in revenues for the fiscal year ended December 2009.  Their top-selling drug, Lipitor, represented approximately 20% of Pfizer revenues as of year-end 2009, but is slated to lose patent protection in 2011.  With few (if any) strong candidates in line to fill their proprietary portfolios, Pfizer and many other large pharmaceutical companies have turned to layoffs, mergers and acquisitions in an attempt to enhance their business performance[1]. 


                Given the deep concern generated over the number of blockbuster drugs coming off patent, one might ask why these pharmaceutical companies, with some of the brightest minds in industry, have found themselves in such a tight spot.  Why haven’t they just tested and developed enough viable candidates to fill this potential void?  In order to begin to answer these questions, we need to turn to the process of drug discovery.


                Drug discovery is a labor- and cost-intensive process with a very long life cycle. Currently, advancing a drug candidate to regulatory approval takes roughly 12 to 15 years and costs an estimated $800 to $900 million, on average. While some products reach the market on a shorter timeline and at lower cost, others may churn through up to $2 billion dollars before approval[2]. In the traditional small molecule drug development paradigm this process runs from the initial basic research phase, in which thousands of compounds are tested, through testing of the drug in human clinical trials.  According to the American Association for Laboratory Animal Science (AALAS), early research and pre-human testing alone can take up to six years to complete[3].  At every stage of this costly development process, more and more compounds are discarded for various safety, efficacy or feasibility reasons, until development teams are left with a small number of viable lead candidates of the thousands from which they started.


                As it stands, a single drug may be under development for over a decade, representing a huge capital investment – and risk – for a pharmaceutical company.  Even in the early stages of development, the current small molecule screening process for neurological drugs has three primary steps that compound the time necessary for screening and identifying viable candidates.  First, in vitro testing, while labor intensive, often fails to accurately predict outcomes in animal (in vivo) models or later clinical trials.  Second, in vivo testing is time consuming, particularly when considering the standard mouse model.  With longer development periods and more complicated genetics, it takes a significant amount of lag time until a mouse is ready for testing.  Finally, most testing must be done through manual handling of test subjects, and is subject to both time constraints and human error.


               This is where the High-Throughput Neurotechnology Group at MIT, led by Mehmet Yanik, steps onto the scene.  Over the course of 2010, this group published a series of papers detailing an enhanced technology for neurological drug discovery using high-throughput testing of both vertebrates and invertebrates[4].  The automated in vivo screening technology developed by Yanik and colleagues at MIT pumps zebrafish larvae from reservoirs into a micro-fluid array, after which they undergo imaging and laser surgery at the cellular level[5].  The advantage of the microsurgery is that it expedites the in vivo screening process for libraries of potential drug candidates, saving time and money. In one study, for example, the zebrafish were exposed to a compound designed to stimulate axon regeneration and then evaluated for markers of efficacy.  The whole process takes approximately 20 to 30 seconds for one larva, degrees of magnitude less than the multiple minutes required with traditional manual handling[6].


                The High-Throughput Neurotechnology Group at MIT has made a big jump in the drug discovery process and their techniques should be highly enticing to the biopharmaceutical and academic industries.  With the enhanced speed of automated in vivo testing, Yanik’s lab has developed a solution that tackles two large bottlenecks in the screening and development process.  To capture the magnitude, consider for a moment the enhanced speed metrics.  Current manual testing processes can take approximately 10 minutes.[7]  Reducing the process down to 20 seconds represents 1/30th the time for manual inspection. Conceivably, one person could complete the job of thirty in the same time frame by simply monitoring the high-throughput device.


                On a broader scale, we know the pre-clinical process consumes three to six years of the drug development process and that an average drug may need $900 million invested over 15 years before reaching the market.  A portion of this time and money spent in the pre-clinical process is based on the in vivo animal testing necessary to check biological activity of a drug candidate.  With the speed gained from the Yanik lab’s new in vivo technology, it is highly likely that a pharmaceutical company may be able to save full a year in the pre-clinical process.  At $900 million per drug over 15 years, this could represent approximately a $60 million dollar saving per drug.  With 500 products in different stages of development in their pipeline, a $60 million dollar saving opportunity per product should certainly catch Pfizer’s eye.


[1] Pfizer to close 8 Plants, Cut Back Manufacturing (Update 3) http://www.businessweek.com/news/2010-05-18/pfizer-to-close-8-plants-cut-back-manufacturing-update3-.html Bloomberg BusinessWeek, May 18, 2010.

[2] The Drug Discovery Process www.aalas.org/doc/Sect-1_4.doc American Association for Laboratory Animal Science

[3] The Drug Discovery Process www.aalas.org/doc/Sect-1_4.doc American Association for Laboratory Animal Science

[4] Microfluidic immobilization of physiologically active C. elegans, Rohde, C. B., Gilleland, C., Zeng, F., Yanik, M. F., Nature Protocols, 5, 1888 (2010);  Large-scale in vivo femtosecond laser neurosurgery screen reveals small-molecule enhancer of regeneration, Samara, C., Rohde, C. B., Gilleland, C., Norton, S., Haggarty, S., Yanik, M. F., PNAS, Oct. 2010; High-throughput in vivo vertebrate screening, Pardo-Martin, C., Chang, T.-Y., Koo, B., Gilleland, C., Wasserman, S., Yanik, M. F., Nature Methods 7, 634 (July 19th 2010)

[5] Pardo-Martin, Carlos; Chang, Tsung-Yao; Koo, Bryan Kyo; Gilliland, Cody L; Wasserman, Steven C; Yanik, Mehmet Fatih.  High-Throughput in vivo vertebrate screening Nature Methods August 2010, volume 7, no 8, pp 634-636

[6] Tamplin, Owen J. and Zon, Leonard I.  Fishing at the Cellular Level Nature Methods August 2010, volume 7, no 8 pp 600-601

[7] MIT creates technology for high-speed study of zebrafish larvae MIT media relations July 2010.  http://web.mit.edu/press/2010/zebrafish.html