Professor Carolyn Fairbanks in the College of Pharmacy has spent three decades in pursuit of understanding how pain and opioid-induced tolerance and addiction work in the body, and in developing novel compounds that can block pain in the spinal cord that don’t develop tolerance or risk causing addiction.
Collaboration Explores Non-Addictive Pain Relief
Just before the turn of the century, Fairbanks and her mentor George Wilcox, a professor of neuroscience at the University of Minnesota Medical School, worked with colleagues in the Department of Medicinal Chemistry and the Center for Drug Design to develop a promising analgesic based on a novel neuromodulator that alleviates chronic pain without some of the difficult side effects of opioids.
The project was initially supported by internal University of Minnesota funds earmarked for the development of promising therapeutics. Unfortunately, once those funds were expended, the researchers could not secure additional funding to continue to demonstrate the compound’s use from either the National Institutes of Health (NIH) or from pharmaceutical companies, and Fairbanks and Wilcox had to largely shelve the idea of developing compounds based on a molecule called agmatine.
“At that time, our data was too preliminary to attract NIH therapeutic development funding or investment from drug companies,” said Fairbanks. “While George and I went on to new research questions on the parent molecule, agmatine, that could find support from NIH, these new compounds were never far from our minds.”
In the early 2010s as the nation grappled with an epidemic of opioid use disorder, a University of Minnesota alumnus who was interested in stimulating therapeutic solutions to opioid addiction approached the College of Pharmacy to support such research. Fairbanks’s pain therapeutic compounds happen to reduce maladaptive neuroplasticity, which is a common biological trigger of both chronic pain and addiction. If the small molecules that Fairbanks, Wilcox, and their team were investigating could interrupt the process causing pain, they might also reduce opioid addiction, aligning their work with the donor’s interests. The gift enabled Fairbanks to restart the project.
“That funding infusion was enough to get us back looking at these encouraging compounds and to produce some preliminary data,” Fairbanks said, “But it wasn’t enough to take it to the next stage of development.”
DoD Support Propels Research Forward
In 2014, when looking for alternative means of support, the researchers came across a call for proposals looking for new ideas in pain research from a DoD program called Congressionally Directed Medical Research Program (CDMRP). CDMRP allows members of Congress to designate areas of disease and health challenges for DoD to invest in, such as chronic pain. Unlike with a traditional NIH grant, but like many other DoD processes, the researchers submitted a short summary of their proposed work, and then were invited to submit a full proposal, which was well received and awarded.
“In 2011, the Institute of Medicine reported that up to 100 million Americans suffer from chronic pain, resulting in costs of up to $635 billion annually due to medical expenses and lost productivity,” said Fairbanks. “Congress and DoD were interested in novel pain treatments because studies showed that veterans and military service members had a high prevalence of pain and opioid use.”
With that grant and a follow-on CDMRP grant that together totaled $6 million, the researchers undertook a decade of preclinical work, the subsequent stage in drug development where crucial feasibility assessments, iterative evaluations, and drug safety data are typically gathered using laboratory animals.
Fairbanks and her team have now identified an agmatine-based molecule as a lead candidate to take forward, and they are completing some additional chemistry, stability, and safety work on that compound in preparation for an application to the Food and Drug Administration (FDA) for an Investigational New Drug (IND) designation. To grant an IND designation, the FDA conducts a comprehensive review of a potential drug’s pre-clinical data, and that designation opens the door to clinical trials with human subjects.
The Value of Dual Use Research
Technologies like therapeutics that have applications for both the military and for civilians are referred to as dual use technologies. Although they may be supported by and developed initially for the military or military personnel by DoD agencies, dual use products often offer significant benefits to people outside the military. Defense agencies will also support projects that are beyond the level of basic research but are not able to attract investment from industry.
“With something like pain relief, it’s easy to see the value of research supported by DoD to our broader society,” said Fairbanks. “It’s even more valuable for a potential pain relief medication that acts upon the central nervous system like ours does, because investing in pain medication development is considered high risk by the pharmaceutical industry.”
Fairbanks is appreciative of the ongoing relationship she has with her program officer and the CDMRP.
“They’ve been very engaged and supportive and responsive when we’ve faced new challenges, such as the COVID-19 epidemic, which disrupted and delayed our work for a while,” said Fairbanks. “On the whole it has made me a better principal investigator.”
That said, there are differences from more traditionally funded projects, notably more frequent reporting requirements.
“Often DoD grants require quarterly reporting on progress, at least initially,” Fairbanks said. “My experience is that DoD requires you to be very adherent to what its funding is for, versus, say, NIH’s typically more fluid approach, particularly for basic research, which enables a researcher to pivot more rapidly when needed.”
Still, Fairbanks, who also serves as the associate dean for research for the College of Pharmacy, encourages faculty within her college and across the University to look at potential funding from defense-related agencies. “Without DoD support, we wouldn’t be anywhere close to the point we are now with agmatine molecules,” she said. “That progress has great potential for relief from chronic pain and addiction among soldiers and veterans, but also among our wider civilian society.”