REHOVOT, Israel The leading cause of death among youth in the Western world is not drug abuse, but the preventable neurological sequels of head trauma (mostly from traffic accidents), for which there is no approved treatment yet. Perhaps among the greatest of ironies, a marijuana analogue, the non-psychotropic derivative dexanabinoid, from Pharmos Corp., is now the first drug to definitively prevent brain damage, including death after head injury.
¿Dexanabinol is the most promising neuroprotective agent seen to date,¿ said Lawrence Marshall, a world authority on outcome after head trauma. Marshall is chief of neurological surgery at the University of California at San Diego.
¿Phase II clinical trial results present outstanding and objective evidence via a pattern of intracranial pressure reduction with significantly improved outcome in severe head injury,¿ said Marshall.
Two years ago, Pharmos mounted the Phase II clinical trials in six trauma centers in Israel. These double-blind, randomized, placebo-controlled studies examined 67 unconscious patients, mostly young men injured in traffic accidents. About half received dexanabinol and the remainder were given placebo, as per protocol, within six hours of injury.
¿Significant reduction in intracranial pressure below the damage threshold¿ a key predictor of neurological outcome without jeopardizing blood pressure was quite impressive in the dexanabinol-treated group,¿ Marshall said.
Numerous drugs and treatments have failed in Phase III trials or before. A handful of others now being tested in these big studies have yet to demonstrate decisive human benefit; these may still be stopped mid-trial like some of their predecessors if there is any hint of harm. Although each of these drugs is a star performer in laboratory studies, and each has a robust single mechanism of brain action, they have all failed in human studies.
Demand Difficult To Overstate¿
Dexanabinol is different from other drugs in that it has a triple mechanism of action, explained neuropharmacologist Anat Biegon, who is vice president of Pharmos research and development, in Rehovot. ¿It is not only a calcium uptake inhibitor and an anti-inflammatory, but it is also an antioxidant, all of which are needed to prevent the cascade of brain injury from spreading and irreversibly damaging surrounding brain tissue, the cause of death or untreatable central disability.¿
Nachshon Knoller, a neurosurgeon from the Sheba Medical Center, in Tel Hashomer, Israel, is the Phase II study¿s principal investigator. ¿Typically, an unconscious accident victim with head trauma, when admitted to an emergency room today, is likely to be given a cocktail of 20 to 30 different medications,¿ he said. ¿Each deals with different indications of head trauma, but none deals with the brain and nerve damage resulting from the injury. The demand for a product like dexanabinol is difficult to overstate.¿ This week, Knoller summarized the final Phase II study results before the National Neurotrauma Society, in Los Angeles.
In the U.S. alone, about 370,000 patients with severe head trauma are hospitalized every year, with the global incidence more than double that figure.
Pharmos managing director Michael Schickler ¿conservatively¿ estimates the potential market for dexanabinol in the treatment of severe head trauma at $500 million annually, but it could exceed $1 billion if other neurological conditions such as stroke and multiple sclerosis are treated with the drug.
Pharmos has demonstrated numerous other treatment possibilities in laboratory studies. For example, dexanabinol diminishes neural damage resulting from exposure to nerve gas in animals. ¿The market could be substantially bigger if the drug¿s special triple ability is commandeered to treat other illnesses,¿ Schickler said.
¿With the positive results of the Phase II clinical trials in hand, we are organizing to start Phase III clinical trials in 1999 in the U.S., Israel, and Europe,¿ said former Weizmann Institute molecular biologist Haim Aviv, who founded Pharmos and is its chairman and CEO. Pharmos anticipates submitting the drug to the FDA for approval in three to four years.
This rosy outlook contrasts markedly with the company¿s frustration just a few months ago, when the National Institutes of Health commanded massive media coverage, commandeering front-page news for Pharmos¿ so-called ¿scientific breakthrough¿ with a different marijuana-derivative that it found to be a powerful antioxidant in an in vitro model of animal cells, with the potential for treatment against head trauma and stroke.
¿There is little question that the Hebrew University dexanabinol and Pharmos research and development is years ahead for the same indication,¿ Schickler said. The company, led by Aviv, has developed a long-term strategy and is ¿looking at fulfilling or beating all set milestones well into the future,¿ he said.