Enhancing pathways to therapeutic development with clinical biomarkers.

Therapeutic drug development, in its transition from an era of alchemy and empiricism to the modern age of molecular medicine, is experiencing an unusual paradox. Today, despite the pharmaceutical and biotechnology pipelines being filled with unparalleled opportunities to create tomorrow’s therapies, the R&D enterprise faces many new hurdles in reaching this objective. The rapid growth in knowledge about genetic and environmental links to human health has yielded thousands of strategically designed biomolecules to target the cellular cornerstones of disease pathways. Challenged with the prospect of a plethora of candidate compounds to evaluate but insufficient human and economic resources to test them all, leaders in therapeutic development point to defining precise and reliable clinical measurements as a key strategy toward overcoming this bottleneck. To this end, there is interest in using biomarkers, or measures of biological parameters of disease, to predict which new molecular entities will be effective and safe in treating patients. Diseases of aging, including cognitive and mood disorders, are among the therapeutic categories that can be augmented through the application of improved clinical measures, including biomarkers. Conceptually, biomarkers can streamline pathways for developing pharmaceuticals, cell-based therapies, vaccines, and diagnostics in several ways. Some examples include improving the pre-clinical selection of candidate compounds by measuring in vitro activity and demonstrating proof-of-concept, enhancing efficiency of early-phase clinical studies by informing dose-ranging studies, and reducing the numbers of human subjects needed by improving sensitivity and specificity of the measurements. In some cases, after extensive evaluation, biomarkers may be suitable for use as surrogates to clinical endpoints in clinical trials. This application is usually limited to disease states for which the clinical endpoint measures lack sensitivity and specificity or the clinical milestones take long periods of time to reach, and for those circumstances when the mechanism of drug action is well characterized and measurable. Such is the case with the application of imaging biomarkers in neurotherapeutics R&D. Notable examples of these include the use of radiotracers such as 2deoxy-2-[ 18 F]fluoro-D-glucose ( 18 FDG) to study dopamine transporters as biomarkers in the assessment of candidate therapies for Parkinson disease, and radioligands for serotonin receptor subtype binding affinity for psychoactive agents in schizophrenia and depression. Despite the lack of understanding about the specific etiology of many neuropsychiatric disorders, neuroimaging modalities, including functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and single photon-emission computed tomography (SPECT) provide quantitative information to index pharmacologic responses to experimental agents. In these cases, the tools measure physiological and biochemical biomarkers such as blood flow, oxygen utilization, and glucose uptake that are affected by the pathophysiology of the disorder and the treatment response. These biomarkers have been helpful in guiding the selection of candidates for larger-scale clinical trials and doses of neuroactive agents to use in them.