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Phase III Study Investigates Dexanabinol Use For Traumatic Brain Injury
The first patient in the U.S. was enrolled at Penn State Milton S. Hershey Medical Center in Hershey, Pennsylvania. The trial at that location is under the direction of Principal Investigator Kevin Cockroft, M.D., assistant professor, Department of Neurosurgery, and Associate Investigator Jonas Sheehan, M.D., assistant professor, Department of Neurosurgery. Raj K. Narayan, M.D., Chairman of the American Brain Injury Consortium (ABIC), Chairman of the Department of Neurosurgery at University of Cincinnati and a member of the dexanabinol study safety committee said, "Neurosurgeons and their patients as well as all other emergency medical personnel are in serious need of an effective medication that can protect the brain from severe damage in injured patients and thereby improve neurological outcome. The principal investigators participating in this study are very enthusiastic about having a product available to treat this significant problem. The initiation of patient enrollment in this trial may also raise public awareness over the magnitude and devastating impact of brain injury, thereby lending a voice to what has been referred to as a silent epidemic."
The expansion of the study to the U.S. follows FDA authorization of Pharmos' Investigational New Drug application. All of the U.S. centers are following the same protocol used internationally and will comply with ABIC procedural guidelines in clinical head injury trials. "We are happy to join efforts with our U.S. colleagues in the development of a product that is needed all over the world," said Dr. Graham Michael Teasdale, Chairman of the European Brain Injury Consortium (EBIC).
Haim Aviv, Ph.D., Pharmos Chairman and CEO, said, "Our goal in this trial -- to prove a significant clinical benefit for TBI patients -- is backed by favorable Phase I and II clinical data and solid results from our extensive research into the unique mechanism of action displayed by this compound. If this drug is successful, it will be the only approved drug to treat this condition and will represent a substantial commercial opportunity for Pharmos."
TBI is a leading cause of death and disability in industrialized societies. Annually within the U.S. there are about 1.5 million head injuries, roughly 300,000 hospital admissions for head trauma, nearly 52,000 deaths and approximately 80,000 cases of severe long-term disability. The annual cost of acute care and rehabilitation in the U.S. for new cases is estimated to be as high as $10 billion. At present, there are an estimated 5.3 million Americans living with disabilities resulting from TBI. The annual market potential for the first FDA-approved drug treating TBI victims in the U.S. is estimated to be over $500 million. The worldwide market potential may exceed $1 billion.
The incidence of TBI is highest among young men as victims of automobile accidents and the elderly who are prone to falls. TBI occurs in two stages, the first of which is characterized by the initial impact on, or rapid internal shifting of, the brain, resulting in skull fractures and bruising. Without treatment, these primary effects trigger secondary processes in which neurotoxic chemicals are released in the brain and destroy healthy cells. Dangerous inflammatory processes may also develop, ultimately causing the most severe and long-lasting damage suffered by those who survive. Current therapy is limited to emergency medical and rehabilitative care, leaving TBI victims a totally unserved market globally.
Dexanabinol possesses several characteristics that make it an ideal candidate to treat TBI, and the trial has been designed to prove the clinical benefits of this unique molecule. First, dexanabinol appears to have a relatively long therapeutic window that may result from its unique combination of certain potent neuro-protective mechanisms that work at different intervals from the time of insult. Second, toxicological studies and Phase I and Phase II clinical trials demonstrated dexanabinol to be safe and well tolerated in animals and in healthy and sick patients. Third, in Phase II clinical development, dexanabinol demonstrated significant efficacy in preventing the elevation of intracranial pressure and in orientation and memory, and a trend toward efficacy in the primary neurological outcome. Pharmos notes that its clinical protocol strongly adheres to and reflects all its pre-clinical and clinical findings.
Dexanabinol's neuro-protective properties result from its unique combination of three critical mechanisms of action. Dexanabinol is an anti-inflammatory compound that may block the synthesis of pro-inflammatory cytokines in the injured brain, significantly slowing the breakdown of the blood-brain barrier and cellular death via apoptosis and necrosis. It is also an NMDA antagonist that prevents the lethal massive influx of calcium ions into the cells of the injured brain. Finally, the compound works as an anti- oxidant, acting to protect the brain by scavenging free radicals that are formed when the brain sustains an injury. Dexanabinol is the only compound possessing these multiple mechanisms of action that has been tested in the treatment of TBI.
About the Trial
The purpose of the pivotal Phase III study is to determine the safety and efficacy of dexanabinol in severe TBI patients. Total enrollment of approximately 900 multinational severe TBI patients is now expected in the double blind, randomized, placebo controlled trial, representing a small increase from the original estimate. To date more than 630 patients have been enrolled in over 60 participating trauma centers in Europe, Israel, Australia and the U.S. The primary endpoint for the study will be patient outcome as measured on the Glasgow Outcome Scale - Extended (GOSE) six months after injury. In order to maximize the opportunity to measure a drug effect with statistical significance, enrollment of patients into the study is carefully controlled by a series of detailed, rigid inclusion and exclusion criteria.
Patients enrolled in the study are given a single dose of 150mg dexanabinol or (placebo) vehicle within six hours after injury. Standard care is provided to all patients consistent with protocols developed by ABIC and EBIC. Intracranial pressure is monitored until stabilized at a medically acceptable level. Patients are evaluated at three and six months according to GOSE. The goal of the study is to observe at six months a statistically meaningful difference in outcome in the number of dexanabinol-treated victims as compared to the placebo group.
Source: Pharmos Corporation