Biomarkers in discovery, development and safety testing

By Christina Shasserre

Christina Shasserre of EMD Chemicals sheds light on new multiplex assays for detection of biomarkers to help improve the drug discovery and development process.

“Biomarkers play an increasingly important role at the global level for a more informed development of new medicines, and it is expected that they will contribute to an increased rate of success in making new medicines available to the public”
-European Medicines Agency, www.emea.europa.eu

As the North American affiliate of Merck KGaA, Darmstadt, Germany, EMD Chemicals shares in more than 340 years of experience and excellence in the development and manufacture of specialty chemicals. Merck KGaA is a global pharmaceutical and chemical company with total revenues of € 7.6 billion in 2008, a history that began in 1668 and a future shaped by approximately 33,000 employees in 60 countries. In 1917, the U.S. subsidiary Merck & Co. was expropriated and has been an independent company ever since. The origins of EMD Chemicals trace back to 1970 when Merck KGaA established EM Laboratories, Inc. in Elmsford, N.Y. EMD Chemicals offers the markets' most innovative solutions and products in six areas:  Biosciences, Life Science Solutions, Analytics & Reagents, Industrial Pigments, Liquid Crystals and Crop Bioscience.

The worldwide headquarters for the Merck KGaA/EMD Chemicals Biosciences business in San Diego, Calif., offers innovative solutions to scientists at the cutting edge of research sold under the product brands Calbiochem®, Novagen® and Novabiochem®. The products are used worldwide in disease-related life sciences research at pharmaceutical and biotechnology companies. With a keen eye on scientific and market trends, the Biosciences division has made numerous investments into the area of biomarker analysis. Using the internal expertise in the U.S. and Germany, EMD Chemicals has developed some of the most innovative and relevant multiplex assays on the market today. To further expand the multiplex portfolio, the Biosciences division has also formed partnerships with other leading suppliers of biomarker reagents and services to commercialize assays for drug safety testing, cardiovascular and cancer research.

Biomarkers in drug development

The use of biomarkers in pre-clinical drug development is becoming increasingly prevalent. In the research environment, the use of single and multiplex technologies is critical to the success of most projects. The analysis of key biomarkers involved in specific biological pathways or processes gives researchers a rapid and accurate snapshot of the disease state and whether a candidate compound is effective. More detailed applications can give rise to mechanistic insights on the mode of action of compounds, as well as the condition itself. In the area of cardiovascular disease therapies, drug developers are aware that a specific condition, such as high blood pressure, will have a high probability of being accompanied by additional disorders such as atherosclerosis, diabetes or high cholesterol. In these situations, it is advantageous to determine the effects of the therapeutic not only on biomarkers for the target condition, but also to see whether the potential treatment has secondary affects on biomarkers for of these associated complaints. By observing modulations in the levels of biomarkers pre- and post-administration, researchers can develop a larger network picture of effects for their therapeutics. In many cases, use of a more general suite of biomarkers is used. The cytokines and chemokines induced as part of the inflammatory process can be used to give a high-altitude view of general dysfunction - allowing biomarkers to be used in a more general, screening mode.

Recent EMD Chemicals R&D activities have created eight Widescreen™ Multiplex assays for the detection of 53 key biomarkers associated with cardiovascular and metabolic conditions, including diabetes, high cholesterol, atherosclerosis, inflammation and markers for heart muscle damage. This suite of tests can be used to obtain a more complete understanding of the effect a test compound has on a variety of biological systems and processes. A selection of the WideScreen Assay is the result of an ongoing collaboration between EMD Chemicals and Rules Based Medicine (RBM). A portfolio of products has been developed containing specific multiplex panel kits that utilize assays validated and used in the Human-MAP® and RodentMAP® service portfolio from RBM. Panels focus on specific therapeutic areas or disease states and allow data generated in discovery and preclinical stages to be correlated to data from later phases of drug development.

Biomarkers in safety profiling

The determination of the safety liabilities of candidate compounds is an essential component of drug development. Testing compounds earlier in the process is becoming more common, as the benefits of dropping potentially hazardous candidates sooner are realized. Multiple organ and system toxicities, including hepatotoxicity, cardiotoxicity, immunotoxicity and nephrotoxicity, need to be evaluated prior to use of a potential therapy in humans. Existing tests are often seen as cumbersome and lack the specificity and sensitivity that would allow researchers to make the confident decisions. Due to their potential utility, the use of biomarkers in drug safety testing was adopted as several projects under the auspices of the Critical Path Institute (CPI).

Working with the public-private Predictive Safety Testing Consortium (PSTC), C-Path initiated a program to develop improved testing methods to identify drug-induced renal damage. RBM collaborated with the PSTC by developing assays and providing data on thousands of rat urine samples submitted for analysis by Novartis AG. The results of the PSTC study were submitted to the FDA and EMEA in 2008, leading to the listing of seven urinary kidney damage biomarkers. Subsequently, EMD Chemicals and Rules Based Medicine have collaborated to develop these assays as commercially available kits, to support preclinical rat nephrotoxicity studies. Traditional tests for nephrotoxicity, including blood urea nitrogen and serum creatinine levels, provide only limited information days or weeks after kidney damage has occurred. In contrast, the WideScreen Rat Kidney Toxicity Panels provide researchers with a tool to detect biomarkers that may be up-regulated and reveal damage within hours, allowing drugs to be efficiently and rigorously tested before human testing begins.

Using a combination of internal expertise and key partnerships, EMD Chemicals will continue to build on its investment and develop new and relevant multiplex assays for the detection on biomarkers for use in drug discovery, development and safety evaluation. Next steps include assays for the detection of compound-induced mitochondrial toxicity, expanding the safety testing portfolio.

Christina Shasserre is General Manager and Head of Global Biosciences at EMD Chemicals, an international organization serving the global market by providing specialty chemicals for pharmaceutical, biotech, cosmetic, automotive, plastics and various industrial applications.