Wisconsin Alumni Research Foundation

By “starving” seizure-causing neurons, startup Hexokine Therapeutics takes fresh aim at an old problem.

For the approximately 156,000 people each year in the U.S. who suffer severe seizures lasting five minutes or more – a medical emergency called status epilepticus – the damage can be debilitating. Even fatal.

Only about 25 percent of these patients suffer from underlying epilepsy. Most cases are triggered by other factors such as head trauma, stroke or infections. But no matter how or why it started, the longer an episode goes on, the more dangerous and difficult to treat it becomes.

It can be a terrible and terrifying thing to behold, says Dr. Nathan Fountain, an epilepsy specialist and professor at the University of Virginia School of Medicine.

Fountain has spent much of his career designing and running clinical trials around epilepsy. A former chair of the FDA Advisory Committee for Central and Peripheral Nervous System Drugs, he has seen proposed solutions wax and wane.

“I have a somewhat unique confluence of clinical experience and regulatory experience, but I was never interested in the business aspects,” he says.

A conversation with a colleague from UW-Madison was destined to change all that.

A Dormant Idea Comes to Life

A generation ago, it was incidentally noted that depriving seizure-causing neurons of energy could stop the seizure. A compound with a clumsy name and an elegant mechanism of action – a compound called 2-deoxy-D-glucose – stopped seizures in rodent models of status epilepticus. It was an interesting observation, somewhat obscure and soon forgotten.

“No one noticed it back then because the compound [abbreviated 2DG] was used as a diagnostic imaging agent rather than as a therapy,” says Fountain.

Interest “lay dormant” until the early 2000s, when UW-Madison neurologist Tom Sutula and collaborators in the Department of Neurology recognized that 2DG had potentially therapeutic actions against acute seizures and chronic epilepsy. He approached Fountain as a collaborator in an NIH National Center for Advancing Translational Sciences program, “Bridging Interventional Development Gaps (NIH-NCATS-BrIDGs), which supports translation of basic observations toward commercialization and market introduction.

In partnership with WARF and NIH-NCATS-BrIDGs, they found that while chronic usage carried side effects, as a targeted intervention 2DG could be a game-changer in the field. The two physicians soon realized that moving 2DG to the clinic would take the next level of investment.

“The light bulb went off for us. I realized that venture capital groups and others were investing in ideas that were much less mature than ours and have lower chance of success than we have,” Fountain says. “We have something here that’s much more than an idea. It’s almost to the finish line.”

Fountain and Sutula launched their biotech, called Hexokine Therapeutics, in fall 2021 and within a few months acquired seed funding.

Looking ahead, they expect animal studies to conclude by early next year. This will pave the way to an FDA submission and clinical trials using intravenous 2DG to treat status epilepticus.

Fountain envisions 2DG as a second-line therapy to treat the 50 percent or so of patients who fail to respond to initial intervention.

“What makes 2DG so exciting is that it works differently from virtually any other drug currently on the market for treating seizures, epilepsy or neurological disorders generally,” says Rafael Diaz, WARF licensing manager. “We’re excited to partner with Hexokine in this endeavor to bring UW-Madison research closer to patients.”

By blocking uptake of glucose, 2DG literally starves seizure-causing neurons of energy. 2DG is potentially the first drug of its kind for treating status epilepticus.

The field is poised for innovation. Existing first-line therapies (e.g., benzodiazepines such as Valium) have been the go-to solution for decades, Fountain says. These drugs, known as GABA agonists, are effective for many patients. Still, thousands of others fail to respond or even develop resistance to the treatment.

It is compelling to note that 2DG is routinely administered in small amounts during PET scans and has been safely used in this way in millions of patients. Of course, how the compound is tolerated as an acute, intravenous treatment for status epilepticus is another story waiting to be told.

“The steady support of WARF through processes of IP protection, advice about commercialization and regulatory challenges, and engagement with funding opportunities has been invaluable,” Sutula says. “We would not be where we are now without it.”

For Fountain – the once reluctant entrepreneur – this unexpected journey ends with a powerful vision.

“We’ll define success when we can sit next to the first person whose ongoing seizure we can stop with 2DG,” Fountain says. “That’s what we’re most looking forward to.”