A concussion pill has eluded drug developers for decades.
Researchers have conducted hundreds of animal studies and more than 30 clinical trials covering thousands of patients. Yet not a single medicine has been shown to protect the brain from the destruction wrought in the hours and days after a blunt head trauma.
There’s no pill to stop neurons from dying. No treatment to prevent inflammation in the brain. Nothing to pull patients more quickly out of the fog that can descend after a concussion.
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“Sisyphus — that’s what we feel like,” said Dr. David Wright, a neurologist at the Emory University School of Medicine, who led a recent study that ended in failure. “We constantly are pushing the rock up the hill, and it continuously rolls back down.”
The most recent high-profile failure came in late 2014, after the publication of two large trials that tested the hormone progesterone as a treatment for people with moderate or severe brain injuries. The drug had shown promise in earlier human studies. But the new research, reported in the New England Journal of Medicine, found that progesterone infusions were no more effective than a placebo.
The string of setbacks can be explained, in part, by the complexity of the disease — and the complexity of the brain itself.
“Every region has a different function, and the connectivity between them is so elegant,” said Dr. Patrick Kochanek, a brain injury expert at the University of Pittsburgh Medical Center.
Scientists are beginning to understand how healthy brains function, but they don’t yet have a handle on all the cellular and molecular mechanisms that come into play after an injury occurs. Nor do they fully understand how the brain recovers. Some patients with traumatic brain injury, or TBI — which includes concussions — receive drugs to reduce brain swelling and limit seizures. But there is no evidence those help the patient regain cognitive or motor skills.
In some instances, “the abnormalities are spread widely throughout the brain, so it’s hard to see how the reparative process is going,” said Dr. Walter Koroshetz, director of the National Institute of Neurological Disorders and Stroke.
What’s more, TBI isn’t a single ailment. A hard hit on the football field can prompt a brain injury. But so too can a gunshot wound, a car crash, or a fall from a ladder. Inside the skull, there might be bruising, bleeding, or swelling. In some cases, the long, connective fibers of the brain tear or stretch.
Most drug trials don’t account for this diversity, though. TBIs are classified according to their severity — mild, moderate, or severe — and trials tend to lump everyone in the same subtype together with little regard for the kind of damage inflicted.
That’s a problem because what works for one type of brain injury might not work for another.
“No wonder the clinical trials failed,” said Dr. Alan Faden, a neurologist at the University of Maryland School of Medicine. “How can you mix apples, oranges, and pears, and compare treatments that affect grapes and expect it to work?”
Dr. Geoffrey Manley, a neurosurgeon at the University of California, San Francisco, points to another issue: Investigators don’t have a good way to measure improvement in human studies.
Many trials rely on an eight-point scale that asks questions like, “Can the patient obey simple commands?” and “Is the patient able to work?” The higher the score, the better the brain function. But there are a multitude of reasons why someone might not be able to return to work. “This is a very crude disability measure,” Manley said.
Taken together, these problems make it hard to tell whether a trial failed because the drug was not effective or because of fatal flaws in the study design.
“I still think progesterone probably does something,” Wright said. “We just haven’t been able to measure it in the human clinical model.”
Improvements could be on the way. In 2007, the Department of Defense began pouring hundreds of millions of dollars into TBI research — and some of that money is funding efforts aimed at improving clinical trials. Manley, for example, is leading a military-backed project to find better ways to measure cognitive improvement.
The National Institutes of Health invests another $90 million per year on basic and clinical studies of TBI.
“Finally, funding agencies get it,” Wright said. “We need to do a little bit more legwork before we jump into clinical trials.”
A handful of small biotechs are jumping into the field as well. Astrocyte Pharmaceuticals, for example, launched last year in Cambridge, Mass., to advance a TBI drug that aims to activate cells that regulate neuron health. (Wright is a company advisor.)
“We’re in a time where we’re starting to understand more of the underlying pathways,” said Astrocyte Chief Executive William Korinek. “There are more intelligent drugs being designed.”
But after so many missteps, few large pharmaceutical firms seem willing to invest in TBI again — at least, not just yet. And experts say the federal funding isn’t enough.
“None of us should be surprised that we’re not further along,” Manley said.