A world of discovery

A Roundtable with Cisbio Bioassays, Milabs, PerkinElmer and Roche NimbleGen

NGP. What challenges do life sciences companies currently face in the drug discovery process?
François Degorce. There are three major challenges today. The first is the need for more relevant assays. Cisbio is working on the development of cell-based and more physiological models in order to help minimize investigation of non-relevant targets.

The second is that researchers want and need to be able to study several parameters at the same time. While many technologies can simultaneously perform different measurements in a cell, the downside to this is that these measurements are not performed in a high throughput mode. Cisbio is currently focusing on the emergence of multiplexed functional assays, which will enable this simultaneous HTS measurement.

Finally, many companies are working to develop faster label-free technologies to speed up the high-throughput screening process as an alternative to current methods.

Prof. Frederik Beekman. Drug development needs to become much faster and effective by using tools that facilitate early selection of potentially successful drug leads. A high return on investment is only feasible by being on the market long before drug patent rights end.

Richard Eglen. An accelerating trend in drug discovery involves greater adoption of phenotypic HCS approaches. Biopharma researchers are now defining signalling pathway networks in cells, rather than single targets. Compound profiling in a range of assays rather than one specific assay is now widely used, resulting in early resolution of potential compound ADME/Tox issues.

There is therefore an increase in the use of cellular imaging techniques using HCS assays as a complementary approach to classical HTS assays. However, their implementation requires complex assay development, secondary screening and data interpretation. Data interpretation and archiving are emerging as key issues. Indeed, several solutions to the challenge of HCS data management are emerging, including Columbus, from PerkinElmer, which provides flexible, yet comprehensive, image data management and may set the industry standard in this area.

Gerd Maass. Life sciences companies need to understand and respond to many stakeholders in the drug development process. These stakeholders include patients, physicians, health insurance companies, regulators and politicians. From all these parties, there is an increasing pressure on research based pharmaceutical companies to develop drugs with high efficacy and an acceptable side effect profile. Therefore, including biomarker research and diagnostic tools in early phase Pharma R&D will help to better identify drug targets and select the right drug candidates to develop efficient and safe new medicines tailored for individual patients or patient groups.

NGP. Why is it important that the research process move swiftly?
FB. We face a kind of crisis in drug development due to the ever-increasing cost of the whole clinical process, which jeopardises both commercial and societal needs. At the same time society does not want the industry to take shortcuts and compromise on safety issues. One way forward to combine these needs is by a much tighter pre-selection of candidate molecules in a very early stage of development.

RE. Speed is critical since Biopharma companies are now under unprecedented pressure to deliver novel therapeutics. Consequently, increased regulatory safety hurdles, increased competition and the rise of generics require that Biopharma R&D performs at enhanced efficiency levels.

R&D groups also need to reduce attrition of compounds in the clinic, particularly early in the process, thereby ensuring that expensive resources are not deployed on suboptimal compounds. This ‘fail early, fail fast’ approach further requires that promising candidates that are identified are rapidly taken into clinical evaluation. Clearly, the growing number of in vitro toxicity studies presents a major challenge in terms of choice of cell models and data interpretation.

GM. Patent protection for new medicines is limited in time and the cost of development of even a single drug is staggering. Decreasing the drug development cycle helps the company to recoup these costs before its patent expires and generics reach the market. Safety is of key importance as drugs are being administered in dual and triple combinations, especially in oncology and virology. Safety issues are further heightened by treatments with multiple drugs due to different diseases in one and the same patient as well as the prevalent use of over the counter drugs and dietary supplements.

FD. R&D teams seek a powerful, reliable, sensitive technology, which will contribute to major reductions in development and screening time. A specific and robust technology is less prone to interference and therefore provides a more relevant hit selection after the first level of screening. Since a maximum of compounds are confirmed during this phase, drug developers can focus on these usable hits in secondary screening instead of on false positives that result when a less robust technology is used.

However, in addition to the speed factor, we cannot overlook the cost aspect involved in drug discovery. Processes that are fast yet economical are increasingly sought after by scientists who need to screen more and more compounds at a faster rate, without increasing the amount of reagents used or the cost involved.

NGP. What tools can life sciences companies use to assist them in achieving a drug discovery process that is fast?
RE. Many Biopharma R&D groups involved in target validation, lead identification and optimization activities require instrumentation and software that can be used in all phases of pre-clinical research. Such technologies, including many from PerkinElmer, utilise the latest developments in fluorescent or luminescent cellular reporters for cellular assays. Research is also encompassing optical techniques such as high-performance live cell microscopy (for example UltraVIEW VoX confocal microscope), fluorescence and luminescence plate readers, (for example the EnVision or ViewLux), as well as high content imaging devices (for example the Opera). All of these platforms can be fully integrated with liquid handling and automation systems using instruments such as the plate::explorer system.

Data analysis software must also be simple to learn and understand, yet be flexible enough to adapt to specific assay needs. The rapid analysis of large HCS datasets can now be performed with powerful software products (such as Acapella), and 3D/4D data can be easily analysed using Volocity rendering software. Integrated data storage and reanalysis systems such as the Columbus family of products now provide Biopharma with comprehensive methods of handling data from a variety of sources.

GM. Detection of new sensitive and specific biomarkers provides a powerful methodology to speed up drug development and to ensure efficacy, monitoring and safety. This capability enables researchers to monitor drug response and side effects, as well as explore rare events of toxicity.

Biomarkers can be detected from body fluids and tissue for example. In early clinical development, it is therefore important that collection and storage of those specimens from patients – based on their consent ­– are performed in order to apply the necessary biomarker assays. Biomarker assays also need to be developed on reliable platforms suitable for in vitro diagnostics (IVD) applications and global distribution.

FD. Cell-based assays and robust technologies are vital tools for speeding up the drug discovery process. Cisbio develops both fast and economical solutions for HTS based on our HTRF (Homogeneous Time Resolved Fluorescence) technology. HTRF is a robust and integrated technology platform that provides critical benefits to drug development customers in that it limits assay development time and helps create a homogenous assay format that is well suited to evolving HTS needs. Homogeneous technologies such as HTRF allow for exceptional miniaturization possibilities, which speed up the research process and reduce operational costs and staffing time. We have associated HTRF to cell-based formats and created new functional tools that can provide information about cell function in a high throughput mode, allowing for enhanced and more relevant results.

Cisbio has recently introduced a second generation HTRF technology based on a terbium cryptate, which allows for enhanced assay performance in terms of sensitivity, assay window and robustness. We are currently working on developing a full range of new applications that are based on this unique terbium chemistry and will provide alternatives to radioactive assays.

Another ‘tool’ per se, is outsourcing. Many pharmaceutical and biotechnology companies do not have the resources or capabilities to design specific assays and outsource certain elements of their research to partners, such as in the field of assay conversion to HTS-friendly formats. For a number of years, Cisbio has provided assay development and custom labelling services, so we have seen first hand the benefits such partnerships bring to researchers.

FB. Important tools are animal models of disease in combination with quantitative methods for in vivo imaging of molecule distributions like Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET). These devices visualise the radio labelled drug itself, or tracer molecules that show change of cell functions, as a result of drug administration for example. Cell function can be visualized at an early stage, often long before any anatomical change can be seen with anatomic modalities like X-ray CT or MRI or after sectioning.

The labour intensive process of ADME (absorption, distribution, metabolism and excretion) can be dramatically accelerated with SPECT and PET. SPECT and PET are complementary with regard to molecules that can be visualised. Today U-SPECT (MILabs, The Netherlands) can reach a much better resolution and associated quantitative accuracy than small animal PET. This allows one to monitor drug and tracer accumulation at sub-compartments of mouse organs, such as the brain and the heart, or in tiny parts of tumours. Many tracers are available as a kit for SPECT that are relevant to a wide variety of brain diseases, cardiac disease or cancer. Many other tracers can be readily labelled at the site without labour intensive and costly infrastructure like cyclotrons, which are needed for PET imaging. Investing in such tools for their research and development groups can be highly profitable investments for a drug company.

NGP. How do you see the drug discovery process developing in the future?
GM. Investigating the mode-of-action of targeted, non-toxic drugs will include a variety of diagnostic testing even at the preclinical stage. Scientists in drug development must have internal access and control of these diagnostic assays. The availability of new technologies and biomarker assays on platforms like 454 Sequencing, NimbleGen microarray technology, real-time PCR by LightCycler, and Ventana tissue diagnostics are a strong strategic advantage for the Roche group and will help us to systematically realize the potential of personalised healthcare.

FD. In the future, we will see more qualified assays using natural models. These formats will need to satisfy both sensitivity and cell handling. The introduction of cells into screening processes implies that cell production and quality can be closely monitored.

We will also see better throughput for in-cell analyses to eliminate the bottlenecks caused by the large amount of data, which these analyses generate.

FB. I see a rapid change from extremely labour intensive sectioning and complete ADME procedures to efficient ultra-high resolution molecular imaging techniques that provide quantitative information at the sub-half millimetre resolution level and that allow longitudinal studies and movies of drug-interaction. Since SPECT temporal and spatial resolution will improve dramatically over the next decade, life science companies need to hurry to get experience with this exciting new technology.

RE. There will clearly be a sustained role for classical biochemical and cellular plate reader approaches in HTS. In parallel, we expect significant growth in the use of HCS data collection and analysis techniques. In these studies, multiple parameters will be simultaneously collected from both live cells and tissues. Sophisticated software tools will also be needed to analyse, store and manage the complex and information-rich data generated in these studies. Collectively, these tools will accelerate research and provide novel drug candidates for many diseases.

About the Contributors

François Degorce is Head of Marketing at Cisbio Bioassays where he primarily directs the marketing for Cisbio Bioassays’ flagship technology, HTRF. He is responsible for all technology-related product development as well as establishing successful customer alliances with prominent drug development and instrumentation companies.

Professor Frederik Beekman is CEO and CSO of Milabs and has 17 years of experience in molecular imaging. He has co-authored eighty journal articles and 17 patents and he received several scientific awards for his contribution to SPECT technology. He collaborates with top groups in nuclear engineering, molecular imaging, image processing and tracer development.

Richard Eglen (Ph.D. Molecular Pharmacology) is currently President of Bio-discovery, at PerkinElmer. He has held numerous executive management positions in the Life Science industry. Eglen has worked extensively in the GPCR, kinase and ion channel fields, authored over 280 publications, book chapters and patents and serves on numerous NIH advisory, academic society and journal editorial boards.

Gerd Maass has worked for Roche since 1997 in several global programs in the field of cancer drug research and development. From 2001 to 2006, he was responsible for the management of the pharmaco-diagnostic programs in cancer, with the overall aim of providing diagnostic tool for patient-stratification (predict drug response). Between 2007 and July 2008, Maass was heading the research and development activities of Roche Applied Science, a business unit of Roche Diagnostics. Effective August 1st, 2008, he was appointed as President and CEO of Roche NimbleGen, located in Madison Wisconsin.