Last September, the Fédération Internationale de Football Association (FIFA) and the World Health Organization launched the “Suspect and Protect” concussion awareness campaign. In the past few years, the U.S. Department of Defense, the National Hockey League, and the National Football League each introduced plans to minimize concussions, including updating their concussion protocols. And large pharmaceutical companies have done…little.
For companies active in this space, their slow progress may be more related to investors’ misperceptions of the topic than the science itself.
“People have scars from pharmaceutical development in this area in the 1990s and 2000s,” William Korinek, PhD, CEO of Astrocyte Pharmaceuticals, says. At that time, trials generally focused on severe brain injury. “Unfortunately [they were] enrolling heterogeneous patient groups. Therefore, there was a lack of success, and a lot of the bigger companies moved away. When that happens, the funding tends to follow.”
Additionally, Vishal Bansal, MD, co-founder and CSO of Oxeia Biopharmaceuticals, says that in talking with professional sports organizations, “We’re finding a lot of excitement over diagnostics, and a lot of skepticism over the potential for actual treatments.”
The treatment of choice, therefore, remains rest, gradually followed by aerobic exercise. For many patients, however, rest isn’t enough. “If patients are having significant or long-term symptoms, it sometimes takes several weeks to months—and sometimes up to a year—to recover to baseline,” Bansal points out. So, “we’re trying to hasten recovery.”
Nonetheless, as an industry, “we’re losing ground in concussion therapy,” Bansal says, speculating that will change only after the first drug is approved.
Meanwhile, nearly five million people are treated for concussions in hospital emergency rooms each year in the United States. Globally, 60 million people are thought to experience mild or severe traumatic brain injuries. According to the Centers for Disease Control & Prevention, “Current data sources may capture only 1 out of every 9 concussions across the nation.”
“This is a silent epidemic,” Ryan Kole, CEO of Beyond Barriers Therapeutics, tells GEN. “Concussion R&D, in general, is a black hole.”
With Brain Injury Awareness Month coming up in March, a handful of pharmacologic therapies are in the clinic, with a few more in preclinical development. Oxeia and Astrocyte (both of which delayed last year’s trials to raise additional funds), Beyond Barriers Therapeutics, and Oragenics each plan to launch Phase II clinical trials in 2025.
Astrocyte used 2024 to refine its clinical strategy for its novel drug AST-004 adjusting the trial design to study a more enriched and homogenous concussion population. AST-004 works by enhancing the healing mechanisms of astrocytes, the caretaker cells in the brain.
In 2025, the company is expecting additional grant funding to support the trial. Korinek says he anticipates launching the Phase II trial this summer, treating athlete concussions in Australia. A related trial evaluating its efficacy as an acute stroke treatment is planned in the United States later in the year.
Why Australia? “Australia’s level of collective awareness of concussion probably exceeds that of the U.S.,” Korinek speculates. Sports Medicine Australia, in concert with the Australia Institute of Sport, issued new guidelines last year mandating a minimum 21-day resting time before junior and community athletes could return to competition after a concussion.
Another approach, in development at Oxeia, uses synthetic human ghrelin to restore normal energy metabolism in the hippocampus. Its Phase II/b clinical trial, planned for later this year, aims to speed recovery. “We currently are involved in discussions [about] potential partnerships with various pharmaceutical companies,” notes Bansal.
“We don’t know how much [we can speed recovery],” he continues. “We do know that in 30 days from drug treatment, those who have received OXE103 have roughly 40 to 50 percent fewer symptoms than those who did not.”
Intranasal options
Beyond Barriers Therapeutics and Oragenics are each developing an intranasal concussion therapy. Beyond Barriers anticipates the launch of a Phase Ib/IIa investigator-initiated trial in the United States in early 2025.
“We’re repurposing an FDA-approved therapeutic to help reduce inflammation and oxidative stress in the brain [by replenishing glutathione] for mild traumatic brain injury, also known as concussions,” Beyond Barriers’ Kole tells GEN. Code-named BBT-101, the drug [which Kole prefers not to publicly identify], is a small-molecule antioxidant that may help reduce the short- and long-term side effects of concussions.
The compound works by “donating an electron to reactive oxygen species, which cause cellular damage after a head injury,” Kole explains. “We’re trying to reduce cell death by scavenging free radicals so they are no longer reactive.”
“By administering BBT-101 intranasally, we’re avoiding first-pass metabolism by the liver,” he continues. With oral administration, only about nine percent of the drug is bioavailable but, with nasal administration, approximately 90 percent goes to work in the body.
“Furthermore, it should act four times faster.” Kole says the nasal format also may “reduce or prevent the gastrointestinal side effects the oral version may cause. The drug showed signs of efficacy in a study in the military, when given orally,” he points out. “Beyond Barriers is confident the results will be more robust when delivered intranasally.”
Using a repurposed drug lets the company pursue the 505(b)(2) FDA approval pathway, which Kole says, “has a three-fold better chance of success of approval than the traditional 505(b)(1) route and is less expensive and time-intensive.”
Administration doses and schedules are to be determined, but early research suggests the administration window may be as long as 72 hours after injury.
Oragenics’ candidate, ONP-002, is a neurosteroid for moderate to severe concussions. A Phase I study indicates the treatment is safe and well-tolerated. Preclinical research suggests the compound enhanced neuronal survival and connectivity, and shows “positive effects on oxidative stress, swelling, cell clean-up, blood-brain barrier integrity, and inflammation following brain injury,” according to a corporate presentation. The company anticipates launching Phase IIa and IIb studies in the United States in 2025.
“We’re starting to see new and innovative biotech companies making tangible clinical progress in the field,” Korinek says, “but we’re still waiting to see the large pharma companies and big venture capital groups apply their resources into the space.” Therefore, much of the work involving pharmacologic treatments is being advanced with academic centers and government grants.
Challenges aplenty
Between five and seven percent of athletes experience a concussion in any given sports season, in the United States, according to University of Michigan Health data. For adults, concussions are evaluated in approximately two percent of emergency room visits.
“There is tremendous interest in concussions, and it’s been a particularly challenging space to come up with solutions because there are a couple different problems,” Samuel Browd, MD, medical director of the concussion program at Seattle Children’s, tells GEN.
“One is the immediacy of getting a diagnosis,” points out Browd. The few approved biomarker-based assays are only approved for use in emergency rooms to minimize the use of computed tomography scans, “but [concerned about the assays’ sensitivity], a lot of clinicians are worried they will miss something.” Consequently, despite FDA clearance of blood tests to diagnose concussions for Banyan Biomarkers in 2018, and BioMerieux and Abbott in 2024, demand is low.
“If anything, saliva assays would be best suited for potential sideline assessments…but the concern is how quickly they would become positive,” Browd adds. Ultimately, they may be more useful in determining when a player can return to play after a diagnosis, he speculates.
The good news, for patients, is that most will recover without serious side effects. But, as Korinek explains, “As 10 to 15 percent of patients continue to have post-concussion symptoms at three months, there is a clear clinical need and commercial opportunity for new treatments.”
Developers of concussion therapies each generally advocate early treatment. “If a patient waits to see if he or she recovers naturally,” Kole says, “it may be too late to stop any side effects if they occur. Although not everyone needs a therapeutic after an injury…limiting the damage after the first concussion may lessen the side effects from the next.”
More funding needed
Korinek says most investors he has talked with understand the commercial potential for concussion therapeutics but need to know that definitive trials can be conducted in heterologous populations, how expensive they will be, and whether big pharma is willing to acquire emergent programs.
“The lack of success in neuroprotective R&D in the 1990s and 2000s generated a lot of skepticism for developing brain injury therapeutics,” Korinek acknowledges.
Locating and enrolling the right population fast enough for a therapy to be effective were major hurdles, he explains. Not surprisingly, those highly heterologous trials failed, driving the larger players from the field and chilling funding for the remaining researchers. Trials planned now, have been designed to be more homogenous to show whether the pharmacologic intervention delivers patient benefit.
To deliver those benefits to patients, however, companies will still need “bigger investments from professional biopharma investors, venture capital funds, and from government agencies, and in an expedited manner,” Bansal says.
“Investors like a benchmark set forth by the FDA and the validation that a drug has an approval pathway,” he says, which helps them understand the risks and a drug’s chances of being approved.
That leaves developers in a “Catch-22” situation. The concussion space needs more capital to prove a concussion therapeutic can work and be commercially viable, while investors need success to spur fresh outlays of funds. Results from clinical trials scheduled to begin this year may show the clear benefits investors and big pharma need. And, Kole adds, “The payoff for investors will be large for those first to market, while also providing a huge benefit to society.”
In the meantime, with athletes at all levels, sporting associations, and parents recognizing the danger of concussion and calling for action, “perhaps there should be more people advocating to allocate capital to finding a solution,” Korinek says. “We have cancer moon shots…so why not a concussion moon shot?”
