Traumatic Brain Injury (TBI)
TBI is a major cause of death and disability affecting disproportionately a young male population, mostly victims of motor vehicle accidents. Children and adolescents, as well as the elderly are also affected, and falls are among the most frequent causes. Annually, within the US alone, head trauma is the cause of about two million emergency room visits, roughly 475,000 hospital admissions, nearly 52,000 deaths and approximately 80,000 cases of severe long-term disability (e.g. functional and cognitive disorders, learning disabilities). Direct costs attributed to the treatment of TBI exceed $10bn p.a. in the US alone. Current approaches to the treatment of acute TBI focus on short-term patient mortality and have no significant impact on ameliorating the long-term physical and cognitive deficits.
One of the most clearly identified consequences of acute TBI is a loss of the integrity of the Blood-Brain-Barrier (BBB). The BBB becomes permeable and allows blood constituents, such as immune cells, to easily enter the brain, which in turn triggers a cascade of detrimental physiological processes. These include the activation of inducible Nitric Oxide Synthase (iNOS) resulting in the formation of high levels of Nitric Oxide (NO) leading to damage in surrounding brain tissue.
The elevation of NO becomes detectable from 6 hours post-trauma and levels appear to remain significantly elevated for up to 7 days, with a peak described around 1-2 days. Thus, there is a substantial time-window for pharmacological intervention with a selective iNOS inhibitor.
VAS203 assumed mechanism in TBI
VAS203 is an allosteric iNOS inhibitor and rapidly lowers excessive production of NO resulting from acute iNOS activation. VAS203 does not materially affect the physiological production of NO by other constitutive enzymes, which are essential for brain function.
Pre-clinical, proof-of-principle studies using controlled cortical impact showed that VAS203 had significant and positive effects on elevated intracranial pressure (ICP), which contributes to the deleterious consequences of TBI, as well as on neurological outcome measured with behavioural tests.
By targeting both cerebral blood vessels and cerebral tissue in a region-specific manner VAS203 represents a completely novel pharmacological approach to TBI that can be administrated in addition to best standard of care. VAS203 could become the first therapy that addresses specifically post-traumatic inflammatory damage to brain tissue and the BBB. VAS203 may thereby ameliorate the persistent and debilitating injuries from moderate and severe closed head injuries, which affect several hundred thousand patients worldwide each year.
There is currently no proven effective pharmacological intervention for patients who sustain an acute closed head injury, albeit a substantial number of drug candidates that have been examined in clinical trials.