Traumatic brain injury (TBI), a form of acquired brain injury, occurs when a sudden trauma causes damage to the brain. TBIs can result when the head suddenly and violently hits an object, or when an object pierces the skull and enters brain tissue.
According to the CDC, approximately 2.87 million cases of TBI occurred in the U.S. in 2014 with over 837,000 cases occurring amongst children. An estimated 13.5 million individuals live with a disability due to traumatic brain injury in the U.S. alone. Unintentional falls, being unintentionally struck by or against an object, and motor vehicle crashes were the most common causes of injury resulting in a TBI diagnosis in the Emergency Department (ED). These three causes of injury accounted for 47.9%, 17.1%, and 13.2%, respectively, of all TBI-related ED visits.
In 2014, an average of 155 people in the United States died each day from injuries that include a TBI. Those who survive a TBI can face effects that last a few days, or the rest of their lives. Effects of TBI can include impairments related to thinking or memory, movement, sensation (e.g., vision or hearing), or emotional functioning (e.g., personality changes, depression). These issues not only affect individuals but also can have lasting effects on families and communities.
A concussion is a type of traumatic brain injury caused by a blow to the head or by a hit to the body that causes the head and brain to move rapidly back and forth. This sudden movement can cause the brain to bounce around or twist in the skull, creating chemical changes in the brain and sometimes stretching and damaging brain cells.
Cognitive impairments are a common consequence of TBI. Disruptions in acetylcholine neurotransmission after TBI contribute to many of the cognitive impairments reported and numerous studies show injury-related reduction in ACh turnover and release, and decreased expression of nicotinic ACh receptors. In addition, the hippocampus, a region in the brain that plays a key role in the formation of memories is highly vulnerable to TBI. The alpha-7 nicotinic acetylcholine receptor is highly active in this region and reduced function of the receptor is linked with cognitive impairment. Together, these observations have led to the study of AChEIs in the treatment of TBI. Galantamine, unlike other AChEIs, has been shown to improve function in the hippocampus, improve cognition, learning and memory in animal models of concussion. It is believed the dual mechanism of action of galantamine, acetylcholine esterase inhibition and enhancement of alpha-7 nicotinic receptor function, contributes to its therapeutic effect.
ALPHA-1062 intranasal delivery for treatment of TBI
ALPHA-1062 is being developed for the acute treatment of TBI. The intranasal route of delivery has unique benefits compared to oral administration that may result in greater effectiveness. Animal models studying the pharmacokinetics of intranasal ALPHA-1062 show a 10-fold increase in concentration of galantamine in the brain compared to oral administration of galantamine.
ALPHA-1062 has been studied in single and multiple dose studies in humans and has shown significantly reduced GI side-effects when compared to similar doses of galantamine. Phase 2 studies of ALPHA-1062 in patients with TBI are planned to be initiated in late 2021.