A Drug's Blueprint
Here’s a little known fact: many of the most popular medicines on the market were developed, approved and prescribed without scientists having a clue about exactly how they worked. For example, researchers know that the drug acetaminophen (also called Tylenol) elevates the pain threshold while also acting on the heat-regulating center of the brain, but precisely how it does that is still a mystery.
Though drug discovery continues to evolve, pharmaceutical companies have traditionally focused on one mission -- to develop compounds that could alleviate illnesses. The remaining question of how those agents specifically function at the cellular level can take years and years to unravel, and even then might only give a partial answer. So they often leave that to the academic scientists.
Here’s a little known fact: many of the most popular medicines on the market were developed, approved and prescribed without scientists having a clue about exactly how they worked. For example, researchers know that the drug acetaminophen (also known as Tylenol) elevates the pain threshold while also acting on the heat-regulating center of the brain, but precisely how it does that is still a mystery.
Though drug discovery continues to evolve, pharmaceutical companies have traditionally focused on one mission -- to develop compounds that could alleviate illnesses. The remaining question of how those agents specifically function at the cellular level can take years and years to unravel, and even then might only give a partial answer. So they often leave that to the academic scientists.
Harold Kohn, Ph.D., is one such academic. A Kenan Distinguished Professor of Pharmacy at UNC-Chapel Hill, Kohn focuses on the biological underpinnings of clinically approved and emerging drug candidates. He says that without understanding how a drug works in the first place, it can be extremely difficult to make the modifications necessary to improve it.
“Once you learn how a drug functions at the molecular level and you actually identify the drug’s target and understand the many ways the drug interacts within the cell, you can begin to dream of doing better,” said Kohn, an organic chemist by trade. “At least, that is my incentive.”
Kohn is a mild-mannered New York native, someone who will tell it like it is but softens the blows with quaint baseball metaphors. He is a scientist who has been in research long enough to evolve from that early enthusiastic naiveté, to knowledgeably jaded, and then back again to enthusiastic, though quietly so.
Over the course of his nearly 40-year career, Kohn has applied that enthusiasm to studying anti-cancer drugs, antibiotics and neurological agents. By studying the structures of a number of compounds, he delineated what he describes as a general “blueprint” for compounds that could treat disorders like epilepsy. While still in his former post at the University of Houston, Kohn discovered and subsequently tested one of these agents, a compound called lacosamide, in animal models with seizures. It worked. Today, the drug is being used in 24 countries to treat epilepsy, a disorder characterized by neurons that fire inappropriately.
When Kohn joined the UNC faculty in 1999, he wondered if he could make an even better drug. He knew that his old compound lacosamide and a new series of compounds reported in the literature – called safinamide and ralfinamide -- looked similar, but that they also possessed key structural differences that made them function quite differently. So he asked whether combining these two different parent molecules could create an entirely new breed of molecules more powerful in treating disorders characterized by neuronal hyperexcitability, such as epilepsy and neuropathic pain. Rather than use computer modeling -- which he joked he was “too old for” -- Kohn cut and pasted together his favorite chemical attributes using pencil and paper drawings. Then he generated the compound in the lab. Again, it worked.
Kohn turned to the North Carolina Translational and Clinical Sciences (NC TraCS) Institute to help him take his discovery even further. NC TraCS is home to UNC’s NIH Clinical and Translational Science Awards (CTSA), a national consortium tasked with speeding up the pace of translational research. NC TraCS awarded Kohn $10K and $50K pilot awards, which he used to get a more detailed understanding of his new compound. More recently, it awarded him a Carolina KickStart commercialization grant to help him form a company, NeuroGate Therapeutics.
“I would rather license the compound out to another company right from the get-go, because that would be the fastest way to get it into the clinic,” said Kohn. “But in the current economic climate, companies want data that reaches into phase I, almost phase II, and we didn’t have that. We were faced with the dilemma of whether to let the technology slip away or to start a company and to give the compound a chance. There is always a lifetime for a technology that is governed by your own interests, governed by the intellectual property, so there are time pressures on you. We could let it go and strike out or get up and try to get a hit, and we decided to do the latter.”
Since making that decision, Kohn sat in on a Launch the Venture course, built a business plan and looked at the costs of getting his discovery into clinical trials. He jokes that he now realizes he knows only a fraction of what he should know about starting a business. One thing he has learned is that you can never ignore the business aspect of your research, because eventually decisions hinge not so much on the science but on the demands of business. He credits this education to leaders within the commercialization sector of NC TraCS, Carolina KickStart.
“I can tell you clearly that NC TraCS has brought expertise to campus that did not exist before,” said Kohn. “They have provided support, both financial and emotional support, and have filled a void on campus. For example, entrepreneur-in-residence Joel Schaffer has been a very powerful mentor to me -- as old as I am, I can still use mentors. Don Rose [director of Carolina KickStart] has been a gem. He is a person who gives freely of his time and has made a difference here in terms of entrepreneurship. The whole TraCS team has provided sound advice and has been key to our success.”
Through collaborations with the National Institutes of Health, Indiana University School of Medicine, The Hamner Institute and other facilities, Kohn is getting as much data as possible on his new compound so they can move on to safety and toxicity studies. The substantial resources required to undertake that step, however, will require the buy-in of outside investors. Kohn is willing to stay in the game as long as it takes to get his drug into the hands of patients, even if that means becoming a full-blown entrepreneur.
“I think entrepreneurship has been going on in academia for a long time, and that is a good thing,” said Kohn. “Cisplatin, which is a very important anticancer drug, was designed at a university, not to mention lots of other drugs, new materials, and software, all coming out of universities. I think this activity has increased because companies have downsized their R&D efforts and thus there are less players in the field. As a result, the university is one of the last places where innovations can occur, and I am happy to be a part of that.”
