Dexanabinol for Traumatic Brain Injury
Pharmos' pivotal, Phase lll clinical trial of dexanabinol for TBI is in its final stage. As of mid-September 2003, more than 700 patients have been enrolled in over 70 medical centers in the US, Europe, Israel and Australia. Total patient enrollment of approximately 900 US and international patients is expected to be completed by early 2004 and results are expected in the second half 2004. In September 2003, the FDA granted dexanabinol designation as a fast track drug, a program codified under the FDA Modernization Act of 1997 to streamline development and expedite review of new drugs for serious life-threatening conditions such as TBI.
:: The Opportunity ::
TBI is a leading cause of death and disability in industrialized societies. Annually within the U.S., there are about two million emergency room visits for head injury, roughly 300,000 admissions for head trauma, nearly 52,000 deaths and approximately 80,000-90,000 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. Additionally, survivors of severe head injury often face five to ten years of intensive rehabilitative treatment and lifelong disability. Lifetime treatment costs can reach $4 million. A study by the National Foundation for the Brain estimates the annual societal cost in the U.S. for TBI is $48.3 billion.
The annual market potential for a drug treating new TBI victims in the U.S. is over $500 million. The worldwide market potential exceeds $1 billion. Currently there is no FDA approved product for the treatment of severe head injury.
For more information on traumatic brain injury, please visit:
Centers for Disease Control and Prevention National Center for Injury Prevention and Control Traumatic Brain Injury in the United States - A Report to Congress, December 1999
Brain Injury Association, Inc.
:: The Indication ::
Injury to the brain, by physical trauma, stroke, or other insult, triggers a complex network of cascades that magnify neuronal damage and death far beyond that caused by the initial insult. The physical insult causes rapid release of excitatory amino acid neurotransmitters from damaged brain cells. The sharp increase in extracellular neurotransmitters overwhelm ion channel receptors on nearby brain cells that have not been damaged by the physical injury, leading to a massive influx of calcium ions into the cells. The excessive intracellular calcium levels trigger a host of biochemical events that generate large amounts of toxic and pro-inflammatory molecules such as free radicals, nitric oxide, prostaglandins, tumor necrosis factor-alpha (TNF-a) and other inflammatory cytokines. The resulting inflammatory cascades lead to breakdown of the vasculature at the blood-brain barrier and to neuronal brain cell death via necrosis and apoptosis. Within hours of the initial insult, these cascades cause intracranial pressure (ICP) to rise, leading to expansion of ischemia and development of secondary brain damage. The secondary neurological damage increases the probability of a bad clinical outcome for the patient.
:: Preclinical Findings ::
In preclinical studies, dexanabinol exhibits significant neuroprotective activity with a six-hour therapeutic window in animal models of closed head injury. A single injection of dexanabinol given after the insult confers a significant increase in neuronal survival and long-term functional improvement.
Dexanabinol is unique among neuroprotective agents because it combines in one molecule three mechanisms of action that suppress toxic and inflammatory cascades induced by TBI:
Dexanabinol is a safe non-competitive NMDA antagonist that blocks NMDA stimulated calcium influx in primary neuronal culture and rat head injury.
Dexanabinol inhibits TNF alpha and other inflammatory cytokines produced in culture and in animal models of inflammation.
Dexanabinol scavenges free radicals in vitro and in vivo.
:: Clinical Findings ::
Phase I Clinical Trial - Safety in Volunteers
A Phase I open label study was conducted in 50 normal healthy male volunteers to evaluate the safety and tolerance of dexanabinol following a single intravenous administration over 15 minutes. For all doses tested (4 to 200 mg), there were no serious adverse events during the study. Particularly noteworthy, there were no hallucinations and no significant changes in cardiovascular, hemodynamic or hepatic functions.
Phase II Clinical Trial - Safety in Severe TBI Patients
A Phase II randomized, double blind, placebo-controlled clinical trial of dexanabinol was conducted in 6 neurosurgical centers. Included in the study were 101 patients who suffered a "severe" brain injury as defined by a Glasgow Coma Score (GCS) of 4 to 8 and who could be treated within six hours of injury. Patients were assessed according to the Glasgow Outcome Scale (GOS) at 10 days and 1, 3, and 6 months. The study demonstrated that:
1. Dexanabinol is safe and well tolerated by TBI patients. No significant drug-related adverse events were found.
2. ICP was better controlled in dexanabinol treated patients than in the control group.
3. Compared to control, a higher percentage of dexanabinol treated patients achieved the primary outcome of returning to normal life as measured by the GOS.
The clinical progression and the proposed benefit of treating TBI with dexanabinol are illustrated by the sequence of figures below. At the time of injury, the severe TBI victim suffers initial damage to the brain that cannot be treated with drugs. However, in the ensuing hours after injury, the brain swells (edema) and brain damage increases beyond the initial injury (sometimes more than six fold). Increased ICP decreases cerebral perfusion pressure, resulting in additional ischemia in the brain. In the initial days after injury, the amount of time that a patient's ICP is greater than 25 mm mercury is negatively correlated to good outcome as measured by the GOS.
Current standard of care (placebo-treated patients) in the study, as depicted by the teal bars in the above bar charts, leads to good outcome in about 1/3 of the patients (above left). In the more severely injured patients (GCS 4-6), only about 11% of patients achieve good outcome. However, dexanabinol-treated patients, depicted by the gold bars in the above right chart, showed significant attenuation of ICP in the days after injury, and improved outcome according to six-month GOS measurements. Among the more severely injured patients (GCS 4-6), the percentage of dexanabinol-patients achieving Good Outcome was even more dramatic.
Phase III Clinical Trial - Efficacy Assessment of Dexanabinol Treatment of TBI Victims
Dexanabinol's clinical plan has been carefully designed in collaboration with a panel of worldwide TBI experts to maximize the probability of detecting its clinical benefit in severe TBI patients. To ensure a common protocol for the multi-national trial, the panel is composed of members of the European Brain Injury Consortium (EBIC) and the American Brain Injury Consortium (ABIC).
Among the series of detailed, rigid inclusion and exclusion criteria determining patient enrollment in the Phase III trial, one of the most critical is that a patient must fall into the "severe" TBI category. While a number of criteria must be met to categorize a TBI patient as "severe," one major criterion is that a victim score between 4 and 8 on the GCS upon evaluation at the trauma center. Another absolute criterion for enrollment is that dexanabinol must be administered within six hours of injury, the therapeutic window determined in preclinical experiments.
Patients enrolled in the study are given a single dose of 150mg dexanabinol. ICP is monitored until stabilized at a medically acceptable level. Patients are evaluated using GOS at 10 days and at 1, 3, and 6 months.
The primary outcome for the study will be the GOS evaluation 6 months after injury. The goal of the study is to observe a statistically significant increase in the number of victims categorized in the top GOS category, return to normal life, in the drug treated group when compared to the placebo group.
Source Pharmos Corporation, all rights reserved.
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