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Aug 1, 2010 (Vol. 30, No. 14)

Wide-Ranging Applicability of Biomarkers Transforms Discovery

Early Use Can Mitigate Some Risks and Increase Likelihood of Compound Advancement

  • Genomic Considerations

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    The Covance Genomics Laboratory uses a range of technologies to assess gene expression and sequence variation in preclinical and clinical programs, including Illumina’s Duo SNP Array. Its primary service areas include gene-expression profiling, next generation and targeted sequencing, and genome-wide and targeted genotyping.

    The Covance Genomics Laboratory operates out of Rosetta’s former gene-expression lab and is expanding into the biomarker space. The company recently launched a new discovery and translational services group, which will integrate its discovery services, antibody products and immunology services, Biomarker Center of Excellence, and the Genomics Laboratory.

    Parrish said that genomics and protein biomarkers are complementary approaches. “You can certainly do one without the other, but you may find the protein biomarkers by way of the genomics. Proteomics is more specific. You don’t get a sense of how it works in the bigger picture unless you get a much better sense of how a compound will react in the pathways and systems.” Having diverse applications, robust platforms, and an innovative biomarker strategy is crucial to discovery, he added.

    Covance is attempting to become “an end-to-end company. In June, we opened a state-of-the-art biorepository facility at our Greenfield, IN location. The 20,000-sq-ft building is dedicated to long-term storage of clinical trial specimens and can store a wide range of specimens, including plasma, serum, whole blood, DNA, PBMC, and tissue. We’re integrating across sites so that chemists can send samples to one place. We’re trying to set this up so that it’s simple and streamlined for the client.”

  • Quantification Using LC-MS/MS

    Dr. Houghton and his co-workers have developed an LC-MS/MS method for the measurement of seven steroids in human urine and validated for use in a regulated bioanalytical arena as a biomarker for 11b-hydroxy steroid dehydrogenase enzyme activity. This project drew upon a surrogate matrix calibration strategy for the quantification of endogenous analytes.

    “Data generated using this method in support of two Phase I studies, with two different drugs, showed the power of pharmacodynamic data in supporting proof of concept, drug potency and kinetics, and evaluation of food-effect, said Dr. Houghton.

    While there is a particular focus on protein and peptides as pharmacodynamic biomarkers of therapeutic effect or disease indicators, in some instances, there may be endogenous small molecules that are appropriate, he reported. 

    “By measuring changes in the ratio of these endogenous metabolites, all within a single multiplex LC-MS/MS assay, it was possible to both prove the efficacy of the drug, as well as the potency. Steroids, by their very nature and diverse action around the body, may prove in some disease state to be excellent biomarkers and are relatively cheap and easy to measure.”

    One of the main challenges in the field, Dr. Houghton noted, is regulatory acceptance of biomarkers with clear guidance on validation and application in clinical trials and as diagnostics. “The FDA has recognized and is actively supporting this process, which should lead to more rapid acceptance of specific markers to particular disease states in the future.

    “The pharmaceutical industry needs to continue to work hand-in-hand with regulators to ensure biomarkers become an integral part of the drug-development process. However, regulators around the world also need to recognize the cost implications to pharma companies of companion diagnostics and ensure there is adequate return-on-investment opportunity for drug companies for the added R&D spend.”

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