Concussion drug therapies on the horizon

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Michael Wyand, PhD, Chief Executive Officer/Director, Oxeia Biopharmaceuticals explains why there’s a need for new drugs to treat traumatic brain injuries.

Whereas once it was thought that mild traumatic brain injuries were harmless and symptoms would disappear after a few days of rest, we now know that rest is not enough – these are   a major and ongoing public health issue.

Traumatic brain injuries (TBI) can range from mild to severe. They can be the result of a blow to the head or a rapid acceleration – deceleration of the head or blast injuries. Those surviving moderate and severe brain injuries may have long-lasting – even life-long – disabilities. Mild brain injuries, commonly known as concussions, are generally associated with short-term symptoms but in fact, may have long-lasting neurologic effects known as post-concussive syndrome.

There are an estimated seven to 21 million reported and unreported concussions patients annually in the US. The World Health Organization estimates that there are 69 million traumatic brain injuries annually worldwide. The vast majority of these, 56 million, are classified as concussions. 20% or more of concussion patients continue to have post-concussive symptoms for weeks, month or even years after the initial injury.

Many still believe that impact sports such as football, rugby, hockey and boxing, are the leading cause of concussions. The media have done an excellent job focusing attention on brain injuries at all levels of sports from recreational to professional. Lesser understood is that most TBIs are sustained from falls – especially among the elderly. Motor vehicle accidents, workplace accidents, blast injuries in the military, recreational activities and domestic abuse are also major causes of concussion that are just beginning to penetrate our collective consciousness. In a March 2022 report by the New York Times, Eve M. Valera, an Associate Professor of Psychiatry at Harvard University and a leading researcher on traumatic brain injuries among survivors of domestic violence, estimated that while hundreds of concussions occur in the NFL each year, there could be nearly 1.6 million annual brain injuries among survivors of domestic abuse in the US alone.  

A range of symptoms are associated with post-concussion symptoms (PCS). These include chronic and often debilitating headaches, depression, cognitive, memory, vision and balance issues, as well as sleep and other psychiatric disorders, such as PTSD. A recent study found that only 27% of studied PCS patients fully recovered. In other words, the vast majority of these patients (73% ) had symptoms that never resolved. Even among the 27% who did recover, one-third took longer than a year1.  

Over the past 20 years research has increasingly linked concussions to neurogenerative conditions, including dementia, Alzheimer’s disease and CTE, a degenerative brain disease.  

A number of studies of US service men and women give a good picture of links between concussion and subsequent diagnoses. More than 413,000 service members were diagnosed with a TBI between 2000 and Q3 of 2019. Over 80% of these were concussions. Studies have shown that veterans and service members who have had a concussion: 

  • Are more than twice as likely to be diagnosed with dementia than those without a history of concussion2. 
  • Have a 56% increased risk of Parkinson’s diagnosis3. 
  • Face cognitive impairment long after experiencing a concussion, raising questions about performance after being cleared to return to duty4.
  • Are more vulnerable to marriage and work instability5. 
  • Are more likely to suffer PTSD6.
  • Have an increased lifetime risk of suicide7.

Mild traumatic brain injuries or concussions are characterised by a lack of visible changes on CT or MRI scanning modalities used in clinic. The shockwaves that pass through the brain because of a direct or indirect blow to the head or body cause a rapid depletion of energy reserves available to the neurons in the brain. This leads to dysfunction of neurons and generation of toxic reactive energy species that can damage neurons, result in cell death and lead to inflammation. In addition, the movement of the brain within the skull at the time of injury creates cytoskeletal and axonal alterations that can lead to impairment of neurotransmission. Collectively, this is referred to as the Neurometabolic Cascade of Concussion8.   

Currently there are no biomarkers or blood tests to aid in the diagnosis of concussion. Although not a test to diagnose concussion, a biomarker test developed by Abbott Laboratories helps to determine whether a patient should receive a CT scan to rule out haemorrhage. The current diagnostic criteria for a patient with a history of a direct or indirect blow to the head include Patient Reported Symptoms related to how a patient feels and/or functions. The symptoms are assessed across cognitive, emotional and physical domains. Several tools assessing the concussive symptoms patients are experiencing have been extensively used to evaluate both athlete and non-athlete populations. The list includes the Post-Concussion Symptom Scale (PCSS), the Sport Concussion Assessment tool (SCAT), and the Rivermead Post-Concussion Symptom Questionnaire. 

Given the increased awareness of concussion and the associated long-term sequela from concussive injury it is imperative that we accelerate drug development efforts to find an effective therapy. Existing therapies for concussion consist of various forms of physical therapy such as vestibular, visual and cognitive therapies along with standard drug treatments for headache and nausea. While those therapies provide some relief to concussed patients, 20% or more continue to have persistent symptoms for weeks to months to years after injury. Tremendous strides have been made with other diseases, yet there are still no FDA-approved drug therapies for TBI.  

Historically, drug development efforts have focused on moderate to severe traumatic injuries. Concussive injuries have been overlooked and as a consequence, clinical trials for novel therapeutic approaches are just starting to appear. The majority of these programmes are in pre-clinical or Phase I studies. The current understanding of the Neurometabolic Cascade of Concussion provides relevant targets for drug developers spanning mitochondrial function, oxidative damage, neuro inflammation and effects on connectivity. There are a number of companies currently developing concussion drug therapies. For example, Astrocyte Pharma is developing AST-004 to harness the neuroprotective effects related to stimulation of astrocyte mitochondrial metabolism. Neuronasal is studying N-acetyl cysteine, a known antioxidant which has shown promise in early trials of mild TBI.  Oragenics is the clinic with ONP-002 and NeurAegis is at the pre-clinical stage.

Oxeia Biopharma is developing OXE103 (ghrelin), a synthetic peptide hormone with pleiotropic activity including enhanced mitochondrial ATP production, reduction of oxidative damage, and increased long-term potentiation of axons. In a Phase IIa exploratory trial with OXE103 at Kansas University Medical Center, OXE103 decreased overall symptom burden compared to standard of care. The results showed an 85% response rate in those treated with OXE103, versus a 33% response rate in those who received standard of care.

Until recently most studies have focused on moderate to severe brain injuries. Concussion treatment has received less attention and has focused on rest as a first line therapy.

With the growing understanding of the ramifications of this ‘mild injury’ to civilian, athlete and military populations, the need for effective drug therapies for this silent epidemic has become evident. Success in developing effective drug therapies and meeting this unmet medical need are advancing through collaborations among developers, investors and academic researchers. It’s an exciting time in the field of concussion drug development.

DDW Volume 25 – Issue 2, Spring 2024

References:

  1. https://www.braininjuryaustralia.org.au/research-recovery-concussion/
  2. https://jamanetwork.com/journals/jamaneurology/article-abstract/2679879
  3. https://www.neurology.org/doi/10.1212/wnl.0000000000005522
  4. https://www.nature.com/articles/s41598-018-22825-5
  5. https://pubmed.ncbi.nlm.nih.gov/12802224/
  6. https://jamanetwork.com/journals/jamapsychiatry/fullarticle/1785175
  7. https://jamanetwork.com/journals/jamapsychiatry/article-abstract/1688032
  8. Giza paper

Michael WyandAbout the author:

Dr Wyand’s decades of experience managing and building life science companies includes roles as CTO and President/COO, Epirus Biopharmaceuticals; R&D head at Percivia, BioAssets Development and Therion Biologics; and President/CSO, Mason Laboratory. Wyand trained in comparative pathology at Harvard Medical School and holds DVM, PhD in Pathology and BS degrees. 

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