Breakthrough Clinical Results
TauGen, LLC, in collaboration with CereMark Pharma, has filed a US patent application for a new class of drug candidates targeting traumatic brain injury (TBI). These compounds aim to mitigate the downstream pathological mechanisms of TBI, specifically focusing on the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress, key factors in secondary brain injury. The innovative approach addresses ER stress, a well-recognized contributor to secondary brain injury, offering potential therapeutic solutions for both acute and chronic TBI-associated neurodegeneration. This patent application highlights TauGen's commitment to advancing innovative therapies for TBI.
Key Highlights
- US patent application filed for novel drug candidates targeting TBI.
- Compounds focus on mitigating downstream pathological mechanisms of TBI, specifically targeting the unfolded protein response.
- The approach addresses ER stress, a key factor in secondary brain injury.
- Potential therapeutic solutions for both acute and chronic TBI-associated neurodegeneration.
Incidence and Prevalence
Global Estimates of Traumatic Brain Injury Incidence and Prevalence
Traumatic brain injury (TBI) is a major public health problem worldwide that affects all age groups. According to the most recent data (2019), more than 50 million people worldwide sustain a traumatic brain injury annually, making it a leading cause of death and disability and a major global health concern.
In the United States, approximately 1.7 million people sustain a TBI each year, of whom 52,000 die and 275,000 are hospitalized. The US reports approximately 50,000 deaths from severe traumatic brain injuries annually, with societal costs totaling at least $10 billion.
TBI is often referred to as a 'silent epidemic' as society remains largely unaware of the magnitude of the problem. It is a complex injury with a broad spectrum of symptoms and disabilities, causing patients to experience a range of physical, mental, cognitive and social problems.
Regional Variations and Demographics
Studies show significant geographical heterogeneity in road injury outcomes despite improved mortality rates in recent decades. The Global Burden of Disease (GBD) 2017 study reported that 1,243,068 people died from road injuries in 2017 out of 54,192,330 new cases.
Age-standardized incidence rates of road injuries increased between 1990 and 2017, while mortality rates decreased globally. Regionally, age-standardized mortality rates decreased in all but two regions: South Asia and Southern Latin America.
In Pakistan and many developing countries, road traffic accidents are the predominant cause of TBI, with motorbike accidents being a major contributor to severe cases. Studies indicate the most commonly affected age group is 21 to 30 years (34.1%) with a male to female ratio of 3.3:1.
A 2018 study from Tehran, Iran found the highest rate of TBIs occurred in age categories 21‒30 (31.5%), 31‒40 (19.2%) and 41‒50 (12.3%) years, with transport accidents being the most common cause (76.4%).
In Botswana, a 2021 study found high TBI prevalence with the majority (83.2%) being male with a mean age of 34.5 years. Most cases (54%) were due to road traffic accidents, with a mortality rate of 35%.
Mechanisms of Injury and Risk Factors
Injuries are predominantly caused by road traffic accidents (62.6%), followed by falls (31.7%) and assault (5.5%). A 2024 study of patients with mild TBI found 66.6% were associated with falls.
Independent risk factors for death in TBI include: age over 60 years, falling and motorcycle accidents, intracranial hemorrhage accompanied by brain contusion, subdural bleeding, a Glasgow Coma Scale (GCS) of less than 9, and need for intensive care unit admission.
In prison populations, the prevalence rates of history of TBI range from 9.7% to 100%, with an average of 46%.
TBI remains a significant global health challenge, particularly affecting young adults in their most productive years, with substantial regional variations in incidence, mechanisms of injury, and outcomes.
Economic Burden
Economic Burden of Treating Traumatic Brain Injury in USA and Europe
United States
The economic costs of traumatic brain injuries (TBI) in the United States in 2010 were estimated at $76.5 billion, including $11.5 billion in direct medical costs and $64.8 billion in indirect costs such as lost wages, productivity, and nonmedical expenditures. These figures underestimate the national burden as they exclude TBIs managed in nonhospital settings and over 31,000 military personnel treated in Department of Defense or Veterans Administration medical systems.
A 2012 study revealed that for a 20-year-old with severe TBI, aggressive care costs approximately $1,264,000 ± $118,000 compared to routine care at $1,361,000 ± $107,000 when all costs are considered.
Earlier research from 2003 found that hospitalization costs averaged $8,189 for moderate, $14,603 for serious, $16,788 for severe, and $33,537 for critical TBI. Costs varied by injury mechanism: $20,084 for gunshot wounds, $20,522 for motor vehicle crashes, $15,860 for falls, and $19,949 for blows to the head.
Europe
In the Netherlands, a 2020 study found that in-hospital costs per TBI patient averaged €11,920 with costs primarily driven by admission (66%) and surgery (13%). The length of stay (8±13 days) and costs increased with higher TBI severity, presence of intracranial abnormalities, extracranial injury and surgical intervention.
In Finland, a 2013 study determined that median treatment costs per TBI patient were €5,429, with surgery costing €1,600 and other costs €3,651. The same study estimated median production losses due to early retirement at €1.19 million per TBI patient, significantly lower among less severe than among severe cases.
Global Perspective
A 2017 systematic review of in-hospital costs for patients with severe TBI found that costs per patient ranged from $2,130 to $401,808, with significant variation between studies.
In 2023, a study in Iran found that 45.5% of households experienced TBI-related catastrophic costs, highlighting the significant economic impact on families.
Key Insights
Indirect productivity losses form the majority of the overall economic burden of TBI to society, while direct treatment costs in tertiary level hospitals also impose a considerable burden on the healthcare sector. The economic impact varies significantly based on injury severity, treatment approach, and healthcare system, with both patients and healthcare systems bearing substantial financial burdens.
Emerging Mechanism of Action
Emerging Mechanisms of Action for Traumatic Brain Injury
Neuroinflammatory Pathways
Recent research has identified several key neuroinflammatory mechanisms in TBI. Parthenolide (PTN) demonstrates anti-inflammatory, anti-apoptotic, and anti-oxidative effects by impeding microglial activation and hindering STAT3/NF-κB and inflammasome activation. Imipramine, an ASMase inhibitor, reduces ceramide formation and prevents cognitive dysfunction. HDAC inhibitors mitigate neuroinflammatory responses and alleviate oxidative stress. PKM2 inhibition with shikonin and TEPP-46 effectively inhibits microglial inflammation after TBI.
Neurovascular Pathways
Erythropoietin (EPO) has shown beneficial effects in clinical trials by decreasing cytotoxic brain edema and preserving the blood-brain barrier. EPO preserves astrocyte function under ischemic conditions and causes a Na,K-ATPase-dependent increase in glutamate uptake. 10-hydroxy-2-decenoic acid (10-HDA) reduces copper accumulation in the brain after TBI by regulating copper transport-related proteins.
Neurometabolic Pathways
PKM2, a key glycolytic enzyme, regulates microglial activation during TBI. TEPP-46 promotes PKM2 tetramerization, enhances interaction between PKM2 and MFN2, and improves mitochondrial function. EPO increases NADH production in both astrocytes and neurons.
Cellular Signaling Mechanisms
TGF-β superfamily signaling is upregulated following TBI, with increased levels of phosphorylated Smads. TGF-β1 and BMP-4 shift reactive glia towards anti-inflammatory and tissue reparatory phenotypes. Progranulin (PGRN) deficiency promotes persistent microgliosis and astrocytosis. PGAM5 acts as a mitochondrial sensor for brain injury, activating mitophagy to remove damaged mitochondria.
Neuroprotective Mechanisms
Edaravone attenuates neurological impairment by elevating expression of BDNF and TrkB while decreasing apoptosis-related proteins. Deferoxamine (DFO) attenuates TREM2 expression and up-regulates autophagy. Adenosine A2A Receptor antagonists reverse cognitive deficits through control of degenerative proteins and synaptotoxicity. Amorfrutin B, a selective PPARγ modulator, compromises hypoxia/ischemia-induced activation of microglia and stimulates PPARγ signaling.
Innovative Approaches
Cerebrolysin as add-on therapy leads to significantly higher proportions of patients achieving favorable outcomes and shorter hospital stays. Combining repetitive transcranial magnetic stimulation (rTMS) with pharmacological interventions shows promise. Machine learning models can predict TBI outcomes with AUROCs ranging from 83.1% to 88.5%. Advanced neuroimaging techniques and brain injury biomarkers are increasingly used for goal-directed management and personalized patient care. Combined behavioral and pharmacological strategies appear essential for good patient recovery in TBI.