5 min readThe Past, Present and Future of the European Drug Discovery

Increasing costs, a limited drug pipeline and the impeding loss of patent coverage for ‘blockbuster’ drugs are changing the landscape of pharmaceutical science. Certain business strategies will need to be employed to overcome these challenges. Factors such as the Human Genome Project, combinatorial chemistry, ongoing M&A activity and partnerships between pharmaceutical and biotechnology companies add to the scale and complexity associated with drug discovery (Fig. 1). It is staggering when one looks at the decline in the number of pharmaceutical companies over the past 15 years: from 42 companies in 1988 to 31 in 1996 and 15 in 2003. In addition, the growing number of smaller biotechnology and virtual pharmaceutical companies that have little or no in-house discovery capabilities will continue to drive demand for contract research and outsourcing to gain strategic benefits and not just to cut costs.

FIGURE 1. European Drug Discovery Market, 2007: SWOT analysis
Source: Frost & Sullivan

The introduction of high-throughput screening (HTS) in the 1990s sparked the interest of pharmaceutical, biotechnology and drug discovery companies to screen a large number of compounds using cell based assays. Cell based assays are an invaluable tool in basic research applications and drug screening techniques, having replaced the traditional enzyme- or antibody-based assays. Biochemical-based assays are simple, well-defined systems that use purified proteins and reagents. Despite having fewer variables and being quick to screen, they proved to be poor indicators of compound clinical efficacy. Consequently, such compounds that appeared to be effective based on primary and secondary screening failed during the late-stage drug testing.  Each year, HTS laboratories perform slightly more cell-based than the previous year. Cell-based assays represent about half of the screening conducted in HTS laboratories worldwide. The effect of a drug on an organism is complex and involves interactions at multiple levels that cannot be predicted using biochemical assays. Trying to understand this complexity has contributed to an increased use of cell-based assay as they offer a more accurate representation of the real-life cell model than the traditional biochemical assays.

The screening market (cell-based assays, HTS, secondary screening and ADME/Tox) is witnessing fast paced growth owing to the growing need to identify non-druggable targets early in screening. It represents the single largest cost-saving opportunity in the pharmaceutical industry as studies performed in animals are too slow to be used for real-time feedback in a drug discovery campaigns (Fig. 2). Using robotics, liquid handling devices, sensitive detectors, data processing and control software, HTS allows researchers to conduct millions of biochemical, genetic or pharmacological tests. The trends in HTS have been towards testing compounds in cell-based and biochemical assays and increasing rates and in small volumes. The proposed advantages are that more leads will be found in less time and with less reagent use and that larger libraries can be screened, thus increasing the information content of the screen and increasing the odds of finding good leads.

FIGURE 2. Contribution of the screening segment towards the European drug discovery market 2007
Source: Frost & Sullivan

The screening market was worth $10.01 billion during 2007. The market is expected to grow at an anticipated compound annual growth rate (CAGR) of 14.4 per cent, thereby yielding corresponding revenues of approximately $25.65 billion in 2014. The drug discovery process is currently on a steep growth curve both with respect to the number of targets and compounds to be screened and the complexity of the assays required. Increased numbers of targets and compounds call for increased throughput in screens. Furthermore, the expense and scarcity of targets and compounds have driven a trend towards smaller assay volumes through miniaturization. 

Life science companies such as Applied Biosystems, PerkinElmer, GE Healthcare, Invitrogen, Promega and many more have risen to the occasion with new offering, including new assays, new formats, new technologies and new instruments. Microfluidics technologies, for example, are being applied to the development of systems that consume nanolitre quantities of reagents. New alternative technologies and systems come at a cost and manufacturers are continually faced with assessing their true cost benefit ratios. In the summer of 2007, Millipore corporations announced the availability of the CellCiphr Cytotoxicity Profiling Assay Kit using human HepG2 cells. The assay is effective at detecting drug-induced hepatotoxicity and is expected to be used early in the drug discovery process. The assay was developed in collaboration with Cellumen and their proprietary Cellular Systems Biology approach investigating cytotoxicity. Tracking compounds with this assay takes advantage of the imaging, sensitivity and multiplexing capability of high content screening (HCS) instruments. The CellCiphr Panel provides multiplexed HCS analysis of eleven human cytotoxicity parameters, recognizing hepatotoxicity sooner in the drug discovery pipeline.

In recent years, PerkinElmer has significantly expanded its reagent portfolio and instrumentation platform in the area of drug discovery. Amongst other projects, PerkinElmer is researching on aequorin, a technology that allows cells to be suspended in a mix rather than attached to a plate. One of these reagents is Euroscreen Products-AqueoScreen platform, a functional homogeneous, generic, aequorin-based platform to detect GPCR activation. The company also introduced the instrument called LumiLux Cellular Screening Platform that integrates the liquid-handling manipulations, injection of the compounds and the detector that reads the reaction. The technology enables customers to reduce the time it takes to run the assays to about 30 per cent whilst increasing throughput.

Traditionally HTS has not delivered on its promise of increasing the numbers and quality of new drugs entering clinical trials. Structural space is significantly restricted in conventional HTS, in which the identified hits often are hydrophobic and possess relatively high molecular mass already. The lack of success is due in part to the complexity and the relatively large size of the compounds routinely being screened. This problem can be addressed by fragment based drug discovery (FBDD), an alternative approach, which uses as starting points very small, low molecular weight, drug fragments. These fragments have the potential to keep the overall complexity and molecular weight of each drug candidate low, a key factor in successful drug development. Astex’s Pyramid platform integrates biophysical techniques such as X-ray crystallography, nuclear magnetic resonance spectroscopy and isothermal calorimetry with fragment library design and a range of computational methodologies into a proprietary approach for fragment-based drug discovery.  The productivity of Pyramid has allowed the company to generate a robust pipeline of novel ‘best in class’ dug candidates against its in-house targets and those of its collaborators, such as Novartis and AstraZeneca and selected compounds from these programmes are now being progressed in or towards clinical trials. However, due to the limitations of HTS and the oversaturated market, Frost and Sullivan expect companies to devote much of their attention on areas such as FBDD and label free technologies in order to capitalize upon the current and future market opportunities.

Drug discovery is in the midst of revolutionary and very rapid changes and HTS cannot be considered in isolation from other aspects of drug discovery. These considerations will shape the long-term future of HTS. The field of HTS has generated several strategic alliances. The technology access agreement is a common mechanism whereby a large company gets to use a new technology and participate in its late-stage development. In 2007, Roche entered cell based assay platform market through biosensor alliance with Acea. The exclusive agreement called for Roche to market systems for real-time cellular analysis based on Acea’s impedence-based platform. The technology was designed for applications such as, measuring effects on GPCRs, to assays for cell proliferation, cytotoxicity and even cell migration and invasion. The consequence of this strategic alliance was to position Roche to compete against GE Healthcare and Thermo Fisher scientific, which already have strong cellular-analysis product lines. In 2007, further collaborations were made with the Life Science companies to expand their HTS technologies. Boehringer Ingelheim and Evotec collaboration involved the identification and development of small therapeutic molecules acting on selected GPCRs with a focus on CNS disease, by applying Evotec’s core competence in assay development and uHTs using a combination of its own and Boehringer Ingelheim’s screening libraries. The collaboration was aimed at increasing the product pipeline productivity as well as reducing R&D costs.

The future of HTS will be determined to a large extent by the level of funding committed to that activity by pharmaceutical companies. However, during the past few years the drug discovery task has shifted slightly from simply identifying promising leads to identifying dead-end leads as early in the process as possible. Advances made in the area of HCS, FBDD and label free technology will be the main driving factors for the growth of screening during the forecasting period.

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