Advancement of Drugs for the Treatment of Repeated Mild Traumatic Brain Injury (mTBI)

Treating traumatic brain injury (TBI) remains one of the top priorities for the Department of Defense (DoD). In the last two decades, there have been approximately 420,000 documented incidents of Service members sustaining at least one TBI. Future combat operations are expected to result in an increase in time to evacuation, delaying TBI diagnosis and treatment during the most critical period after injury. The DoD and the military services require solutions to fill the capability gap to treat TBI as close to point of injury as possible, to reduce primary and secondary brain damage.

TBI has been shown to increase long-term mortality and reduce life expectancy. Furthermore, studies have shown that suffering from repeated mTBIs, or a single moderate or severe TBI increases the risk of developing pathological changes to the brain that are characteristics of Alzheimer’s disease (AD), an irreversible, progressive disease that negatively impacts memory, cognitive ability, and behavior. Some studies have shown that those who have experienced a TBI have had a significantly earlier onset of AD. The onset of dementia can even occur in patients who seemingly fully recover from their initial TBI.

For this RPP, repeated mTBIs are the focus. Military mTBI is typically caused from either concussive events or exposure to explosive blast injury, and results in physical changes to the brain. Since these changes associated with a single mTBI seem to be reversible, Warfighters often return to duty and risk exposure to repeated mTBIs. However, repeated mTBIs have been suggested to cause chronic traumatic encephalopathy (CTE) and the later onset of dementia or AD.

The estimated economic costs of care for TBI are >$75 Billion per year according to the Centers for Disease Control (CDC), which is on top of the $290 Billion in costs required to care for the 5. million Americans with dementia. The current standard of care for both TBI and AD remains supportive in nature, based on management of symptoms, with no drug therapies that address the brain damage. Despite numerous clinical trials on potential therapies, there is no U.S. Food and Drug Administration (FDA) approved drug therapy for the treatment of TBI. Therefore, it is important to develop a drug therapy for the treatment of repeated mTBI that will decrease lost military duty time of those in active service and support the long-term healthy aging of veterans (i.e., prevent the potential later onset of dementia).

The intent of this jointly funded program by MTEC and BrightFocus Foundation is to enable the advancement of candidate drugs into human clinical trials for the treatment of repeated mTBI. Many drugs have shown promising results in animal models. Despite this, the average rate of successful translation from animal models to human clinical trials is very low. This is largely due to the limited ability that animal models have in mimicking the complex processes of injury and disease that occurs in humans. To this end, human clinical studies are often required by the U.S. Food and Drug Administration (FDA) to determine the true benefit of the technology. Therefore, the goal of this RPP is to catapult drugs for the treatment of repeated mTBI with dual-use (military and civilian applications) toward human clinical trials to ensure that a pipeline of drug candidates is ready for safety and efficacy evaluation. Relevance to both the military and Alzheimer’s disease AD is an important aspect of this RPP.

The research project award recipients were selected from the Offerors who responded to MTEC’s Request for Project Proposals (20-16-mTBI).

Advancing the Promising Cerebroprotectant AST-004 to Human Traumatic Brain Injury Clinical Trials

Project Team: Astrocyte Pharmaceuticals
Award Amount: $500,000
Project Duration: 19 months
Project Objective: Astrocyte Pharmaceuticals has developed AST-004, a promising therapeutic for TBI. AST-004 has significant efficacy across a broad range of preclinical TBI models, demonstrating reductions in cell death, edema, and markers of neuronal and astrocyte injury. In a repetitive TBI mouse model, our treatment approach reduced long-term neurological deficits in motor coordination and anxiety. Importantly, AST-004 reduced edema and brain injury markers in a large animal porcine TBI model. AST-004 has shown preliminary efficacy in Alzheimer’s disease (AD) with increased brain cell viability in two AD mouse models. In this proposal, we will conduct a Pre-IND meeting with the FDA and manufacture the starting material to support oral formulation development for mild TBI. Thus, this support from MTEC and the BrightFocus Foundation can significantly accelerate the development of this novel and promising therapy for mild and severe TBIs that can limit the short and long-term negative effects associated with TBIs.

Mitochondrial Uncoupling Prodrug to Treat Repeated Mild Traumatic Brain Injury

Project Team: University of Kentucky Research Foundation
Award Amount: $500,000
Project Duration: 26 months
Project Objective: We seek to validate MP201’sefficacy in a military-relevant model of blast repeated mild traumatic brain injury (rmTBI), examining mitochondrial recovery and long-term behavioral improvements after rmTBI.