Treating Traumatic Brain Injury

Past failures guide start-ups that seek to develop drugs for this silent epidemic, but will investors follow?

Nearly every day American soldiers in Iraq incur combat head wounds. Whether the injury is penetrating or closed, the forward medics have no way of diagnosing the extent of the trauma to the soldiers’ brains. After evacuation, the base hospital can offer no treatments except boring a hole in their skulls to relieve swelling. The same bleak scenario holds true at the scene of a traffic accident or when a child falls on her head. Yet every year in the US at least 1.4 million people suffer traumatic brain injuries (TBIs), some 50,000 resulting in death and another 80,000 leading to long-term disabilities.

For the TBI patient, the pharmaceutical industry can offer no help. TBI may have a singular record of failure. To date, some 200 clinical trials of TBI agents have failed. With a batting average like that, any player taking to the TBI field better have something special up his sleeve if he hopes to make it in the big leagues. In fact, a handful of companies—including three profiled here—think they do. All those past failures may have provided them with insights into better pathways to developing treatments for TBI.

Not surprisingly, TBI-focused companies have faced stiff resistance from private equity investors and pharmaceutical dealmakers. Most of those clinical trials have been conducted in academic or grant-sponsored settings. Reflecting on the abysmal success rate to date, Ronald L. Hayes, PhD, director of the Center for Traumatic Brain Injury Studies at the McKnight Brain Institute of the University of Florida, deadpans, "This has discouraged people." That’s a gross understatement by the founder of Banyan Biomarkers Inc. (Also see "Banyan Biomarkers Inc." - Scrip, 1 Jan, 2007.), a company profiled in this issue. Although the lack of successful precedents sends most investors running the other way, they are missing an enormous, completely unserved pharmaceutical market where even a glimmer of hope could send a stock soaring.

The Silent Epidemic

TBI is often called "the silent epidemic" because few are aware that so many people annually suffer brain injuries in the US, resulting in more than 230,000 hospitalizations, along with the deaths and long-term disabilities. About 50,000 to 75,000 TBI victims suffer a posttraumatic coma lasting for at least two weeks. In addition, a pool of patients remains in a state of decreased consciousness.

If a brain trauma patient does not exit a coma for more than four weeks, the prognosis for recovery is poor: 33% die within a year and only 7% have a good recovery. It is estimated that there are up to 200,000 patients living in a persistent vegetative or minimally conscious state in facilities and homes in the US. Compounding the tragedy, many patients who sustain TBI are young—some 50% of TBIs are transportation related. TBI is a leading cause of death and the greatest cause of disability in people under 24 years old, resulting in lifelong medical costs estimated at more than $1 million per patient. Currently, an estimated 5.3 million Americans live with TBI-related disabilities, more than the 4 million disabled by Alzheimer's disease.

Those statistics do not include military casualties. TBI is also one of the most frequent causes of morbidity and mortality on the modern battlefield. Nearly half of all combat deaths result from injuries to the head, and these injuries are among the most frequent causes of persistent disability for survivors. Improved forward medical care has increased the number of US casualties in Iraq suffering and surviving TBI than in previous wars. Recent assessments indicate that about two-thirds of Iraq casualties are coming home with brain injuries.

One important stumbling block in the effort to develop therapies has been the lack of reliable diagnostic tools for TBI. The vast majority of TBIs, between 75% and 90%, are mild or moderate (MTBI). MTBI produces a number of imprecise perceptual symptoms without diagnosable objective structural brain alterations, making it challenging to detect with computer tomography (CT) scans or magnetic resonance imaging (MRI). Depending on the timing of the CT scan or MRI, it may pick up brain swelling, bruising, and gross cell death. But imaging technology cannot rule out even severe brain damage, which is often invisible and develops over time. A loss of consciousness leading to coma may occur many hours after the initial injury.

That is because the mechanical injury initiates a cascade of inflammatory and intracellular responses, resulting in progressive further damage and death of brain tissue. Without markers to measure and characterize the injury’s progression and to localize damage sites, sorting out heterogeneous patient populations and their TBIs has proven impossible.

In any case, few experts believe that traditional pharmaceutical approaches of developing single-agent regimens with single mechanisms of action will be likely to work. The damage involves both gray and white matter—the neurons and the axonal connections. Halting the cellular damage and rebuilding severed links involve very different biological mechanisms. Alan Faden, MD, a leading TBI investigator at Georgetown University Medical Center and an advisor to RemeGenix Inc. (Also see "RemeGenix Inc." - Scrip, 1 Jan, 2007.), profiled here, says, "Traumatic brain injuries are multifactorial processes. Interfering with one part of the process is not likely to be effective. You need either multiple drugs, like drug cocktails used in cancer, or single drugs with multiple actions (pluripotential drugs) to modify multiple pathways in the injury cascade."

Harry Tracy, PhD, publisher of NeuroInvestment, which covers the neuropharmaceuticals field, agrees. "We already have compounds that if combined into a cocktail I suspect would have additive effects." However, to develop such a cocktail for TBI would require "a change in regulatory climate" to convince the Food and Drug Administration, which would first want proof of each component’s effectiveness as a monotherapy, to set a baseline against which to compare any polyagent treatment approach—a dauntingly costly development program for any small firm to take on.

Single Drugs, Multiple Pathways

Perhaps the most established company in the TBI field, Neuren Pharmaceuticals Inc., a University of Auckland spin-off (traded publicly on the Australian Exchange), is trying to get around this barrier by developing a drug that acts on multiple brain pathways. In collaboration with the US Army, the company is developing a compound, Glypromate, and several of its derivatives as a neuroprotectant for treating acute TBI and other brain-impairing conditions. The agent is a peptide fragment of IGF-1, which acts as an endogenous neuroprotectant that gets released by the injured brain and appears to work on multiple pathways. Glypromate entered Phase III testing this past quarter for preventing neurocognitive disturbance and loss of brain function following coronary artery bypass graft (CABG) surgery and following out-of-hospital cardiac arrest. The company is also testing another, related compound, NNZ-2566, for TBI in acute penetrating head wounds. "Neuren’s data," opines Tracy, "look better, and with those two compounds—and others in development—they have more potential than anyone else."

Sharing the Neuren strategy, RemeGenix plans to put a series of cyclic dipeptides structurally related to the major metabolic product of TRH (thyrotropin-releasing hormone) into humans for TBI and related disorders. The drugs down-regulate several major injury pathways while up-regulating endogenous neuroprotective pathways.

However, they still face the challenge of establishing a human testing protocol that gives their clinical trials a reasonable chance of achieving acceptable end points. "People," finds Tracy, "don’t know the right way to do this." Many prior attempts to control the heterogeneity among patients in clinical trials have failed. Tracy points to the monumental 2004 failure of Israel’s Pharmos Corp.’s Phase III dexanabinol TBI trial. One of the largest placebo-controlled TBI trials ever undertaken to that point—treating 428 patients with the nonpsychotropic cannabinoid NMDA receptor antagonist versus 418 treated with placebo—it was done under close supervision by the American and European Brain Injury Consortiums. The investigators attempted to control patient type by choosing only those judged by both a poor Glasgow Coma Score (the standard observational measure of consciousness) and a CT scan to have sustained severe brain injury, and to administer the drug within six hours of injury. Despite the drug’s highly promising Phase II data, the study’s results failed to reach any primary or secondary end points.

As hope for Pharmos’ drug rose, its stock soared, reaching a high of more than $21. News of the drug’s failure cost shareholders dearly. The company has since given up all attempts to pursue TBI and related indications. Today shares trade at around $2.

A still larger study had hoped to demonstrate the cognition benefits of corticosteroids—commonly given to reduce potentially lethal intracranial swelling. The trial had enrolled 10,000 patients at 239 hospitals in 40 countries when investigators found evidence in 2004 that the drugs actually increased mortality and ended the study.

However, the Franco-American company Xytis Inc. is working closely with that study’s head, Ian Roberts, PhD, of the London School of Hygiene and Tropical Medicine, to design similarly large-scale trials for a novel TBI treatment. Instead of trying to control subjects as precisely by type of injury, condition, and therapeutic window, the Xytis team will attempt to overcome TBI patient heterogeneity with brute force. The company recently began enrolling patients in a 400-patient Phase IIa study of its compound XY 2405 anatibant, a small-molecule antagonist of the bradykinin B2 receptor in-licensed from Fournier Pharma. If proof-of-concept is achieved, which according to CEO Vincent Simmon, PhD, should be known in the first quarter of 2008, Xytis anticipates undertaking a Phase III program incorporating as many as 5,000 severe and moderate TBI subjects. (See "Xytis Pharmaceuticals Ltd.," START-UP, April 2005 (Also see "Xytis Pharmaceuticals Ltd." - Scrip, 1 Apr, 2005.).)

Simmon says the hope is to show safety and a modest trend toward improvement in the current trial, which will provoke interest in backing from pharmaceutical partners or investors for the final study. Although he says there is already interest from potential partners, he knows how much resistance he will encounter. "People are afraid of doing another trial that, at the end of the day, will not show benefit. A large simple trial and an effective molecule are parts of the answer," he says.

Knowing Where to Begin

Trial design remains a stumbling block for any company pursuing neuroprotective strategies. Elkan Gamzu, PhD, a member of the Pharmos board of directors and a longtime clinical research director in the field, disagrees with those who think the lack of adequate clinical trial protocols accounts for the many TBI drug failures. "The trials were as well-conducted as possible," he says of the Pharmos and other prominent failed TBI drug programs. He has quite a bit of experience with failed neuroprotective agents. While CEO of Cambridge Neuroscience Inc., he oversaw Phase III studies of aptiganel (Cerestat) for stroke, which was halted because of unanticipated dose-related side effects; and TBI, also halted for absence of effect in an interim analysis, though no side effects were seen relative to placebo. Now also chair of NeuroHealing Pharmaceuticals Inc. ’s board of directors and head of its clinical trials program, he suggests that rehabilitation may be a more promising path for success in improving brain function than acute treatment of TBI. TBI and stroke victims often require years of rehabilitation and many never recover full functionality. NeuroHealing believes that drug therapy can expedite and improve the rehabilitation of physical and cognitive functionality in TBI and stroke survivors. (See "NeuroHealing Pharmaceuticals Inc.," START-UP, May 2005 (Also see "NeuroHealing Pharmaceuticals Inc." - Scrip, 1 May, 2005.).)

The company’s lead compound, NH001 is a direct-acting dopamine agonist. Dopamine is one of the central nervous system’s most potent stimulatory neurotransmitters and is known to play a crucial role in various aspects of learning, memory, and attention, some of the processes that characterize neuronal plasticity. As such, the company believes NH001 could help patients emerge more rapidly and thoroughly from a coma. NeuroHealing has tested NH001 in an open-label study. The first patient treated had been in a stable vegetative state for more than three months. After two weeks of treatment with NH001, he fully exited the vegetative state and is now making progress in physical recovery. "Our clinical advisors had never seen as rapid a response as this," says NeuroHealing’s CEO Neal Farber, PhD. "The patient had previously failed two other drug regimens." Similar exceptional benefits were seen in three other tested patients.

The company recently received FDA approval for a 76-patient, double-blind, placebo-controlled Phase II trial of NH001 on posttraumatic brain injury patients in a vegetative or minimally conscious state, which it hopes to begin in the near future. Not surprisingly, the company has been "inundated" with requests for patients to be entered into the trial, which should report results in early 2008.

For acute TBI patients, the lack of any reliable biological markers makes it nearly impossible to design trials with any precision. "If there were highly predictive surrogate markers," says Gamzu, recalling the problems encountered with aptiganel, "you could do better dose-response work." But to date, the only standard makers are cerebral profusion pressure factors, and, he says, "maybe they’re not good enough." NeuroInvestment’s Tracy agrees: "You need a biological instrument to measure improvement." That is where Banyan Biomarkers comes in.

Banyan believes it may hold the key to successful development of TBI drugs with its diagnostic blood test–based biomarkers for calpain and caspase—enzymes released by dissolving dead and dying brain cells into the blood. The markers will be employed in battlefield-ready handheld instruments that will detect TBI in patients without other anatomic evidence and provide information on the injury mechanism, mode of cell death (necrosis or apoptosis), cell type and subcellular localization of injury, and anatomic locations of injury. The company already has alliances to generate biomarkers for other companies’ organ-injury drug development programs and is developing its own compounds to inhibit enzymatic action in the brain as a way of halting cellular death.

Drugs targeting TBI tend to be part of a neuroprotection franchise in development. Many TBI compounds in development are also being optimized for other brain disorders, from Alzheimer’s disease and stroke to amyotrophic lateral sclerosis (ALS). "There are more similarities than differences between traumatic brain injury and other neurodegenerative diseases," says Georgetown’s Faden. Any approved TBI drug, whether for acute or chronic conditions, will very likely vault to blockbuster status. According to Xytis’ Simmon, "If you can keep people functional in society following injury, you’ve got a billion-dollar product, maybe two billion."

Although the past presents little basis for hope for those daring to venture into the field, Faden is optimistic that chances for success have improved with advancing knowledge of TBI, availability of more effective multi-potential drugs, and improved clinical trial design. "There is beginning to be a ray of light," he contends.—Marc Wortman