Kevin K.W. Wang, PhD
Director, Program for Neurotrauma, Neuroproteomics & Biomarkers Research (NNBR), McKnight Brain Institute,
Associate Professor of Psychiatry, Neuroscience & Physiological Sciences
Affiliate Professor of Analytical Chemistry, Department of Chemistry
University of Florida
Blood-Based TBI Biomarkers as Tools to Support Therapeutic Development: from animal models to clinical studies.
In the United States, more than 320,000 US service members sustained TBI between 2000 and 2016. In addition, direct medical costs for treatment of TBI in the U.S. have been estimated to be $4 billion annually. Types of TBI include penetrating, blast-induced, single and repetitive brain injury. While to date there are still no FDA-approved therapies to treat any forms of TBI, there continues to be strong interests in new therapeutic development towards treating TBI. In parallel, an emerging body of data show that biofluid-based TBI biomarker tests can (i) diagnose the presence of TBI of different severities including even concussion, (ii) be correlated to injury severity and CT pathology, and (iii) predict outcome. Thus, we propose that the TBI field can benefit from regulatory endorsed tools in assisting in therapeutic or medical product development.
We systemically data-mined and analyzed a large number of animal and clinical observational and intervention studies. We identified that a number of TBI biofluid biomarker candidates (e.g. GFAP, UCH-L1, S100b and Tau) not only have potentials as in vitro diagnostic tests, but also as “theranostic” tools in facilitating new TBI therapy development and clinical trials. In multiple animal TBI model (controlled cortical impact, fluid percussion injury, penetrating ballistic-like brain injury, blast-like overpressure wave induced brain injury and repetitive close head injury), we observed that many of TBI biomarkers are elevated in blood in the acute and/or subacute phase post-injury. Furthermore, some of the same biomarkers also responsive to a number of therapeutic interventions.
On the clinical side, The FDA in fact has recently created a regulatory path called “Biomarker Qualification Program (BQP)” that serves to facilitate and ultimately endorse the use of such biomarkers in clinical studies for new TBI therapies if sufficient supportive evidence can be provided. Among the several FDA “Context of Use” biomarker categories, we identified that the current data point towards a blood-based TBI protein (such as GFAP and Tau) that can be used as Prognostic Biomarker in identifying and selecting patients with biomarker elevation above a predefined cutpoint that is prognostic of being more likely to progress to TBI-induced disability or to experience prolonged post-concussive symptoms. Thus, the intended use of such biomarker test(s) will be patient inclusion/enrichment to enable therapy trials more time- and cost-efficiency and to enhance likelihood of achieving quantifiable therapeutic efficacy. Thus, we and others are continuing our translational work in identification of the most promising biomarkers in alignment with future TBI drug development, and on collecting the analytic performance data and clinical evidence that support the use of such biomarker(s) in future TBI therapeutic trials.