In the summer of 2019, Dr. Linda Dwoskin and her team at the Universities of Kentucky and Arkansas felt they were in a promising place in their decades-long search for a treatment for the 700,000 Americans with methamphetamine use disorder: They had solved a nagging problem for their most promising compound, JPC-077—namely, that most of the compound was broken down in the body before it could reach the systemic circulation, resulting in a low bioavailability of only 3 percent. After modifying the compound to increase its bioavailability, Dr. Dwoskin estimated that it would take perhaps only 2 more years of work in the laboratory before clinical trials could begin. Her wild ride of medication development, which was detailed in Parts 1, 2, 3, and 4 of this article series, appeared to have entered a period of smoother sailing. What she did not anticipate, however, was a storm called COVID-19.
To understand the status of Dr. Dwoskin’s research—and her frustration with the new hurdle—it is useful to recount how her methamphetamine project came to life. Dr. Dwoskin started her first independent position at the College of Pharmacy at the University of Kentucky in 1988, and by 1999, she was promoted to full professor. During this time, she quickly learned that the path toward a viable, approved medication to treat a substance use disorder is labor intensive and not for the impatient, nor the faint of heart. The world of biomedical research is devoid of instant gratification, and the development of a single medication may span a person’s entire career from a wide-eyed post doc to a seasoned, gray-haired Associate Vice President for Research. Thousands of promising compounds may have to be synthesized, modified, optimized, tested, and tweaked.
Dr. Dwoskin’s journey toward a medication for methamphetamine use disorder began in 1994, when she studied a natural product called lobeline that showed promise for smoking cessation. During this research, she noted that—similar to the drug methamphetamine—lobeline interacts with the intracellular protein ventricular monoamine transporter 2 (VMAT2), but unlike the drug, it does not cause euphoria or reward. She hypothesized that lobeline might block methamphetamine’s access to VMAT2 and so prevent the drug’s rewarding effects.
Thus began a quest to find a molecule that would maintain lobeline’s ability to inhibit the target VMAT2, but would be safe and effective for human use. Also, the researchers sought a compound that could be taken orally. Over the years, however, the team’s path was littered with frustrating results for their potential candidate molecules. One molecule showed poor bioavailability; another one was chemically unstable. Still others showed only weak interactions with VMAT2 or caused adverse effects such as cardiotoxicity or liver toxicity. There was particular disappointment with a molecule named GZ-793A, which seemed to check all the boxes but was then shown to change ion flow through a cardiac protein pore called the hERG channel, potentially sparking cardiac arrythmia.
Nevertheless, these early tests yielded valuable information—for example, ruling out unwanted effects. “At first, it was confusing for staff and students because nothing was happening in some of the off-target assays that they were performing,” Dr. Dwoskin reminisces. “But sometimes finding nothing is a good thing. It means a compound has good selectivity for the target and theoretically has no side effects. Over time, you learn that drug discovery is a high-risk, high-gain sort of effort.”
Again and again, the team created new, modified compounds to circumvent issues with the existing ones. Much like a crowded family tree, each subsequent generation of molecules maintains a piece of the original structure. However, whereas human generational transitions are typically left to chance, scientists can pick and choose which elements of a molecule to keep and which to eliminate, all while retaining the pharmacophore—the part that is needed for the desired activity at the molecule’s target. “There are parts of the molecule that you can kind of play around with and manipulate to deal with whatever problem you’re having,” Dr. Dwoskin notes. Over the years, their molecules of interest became distant cousins to lobeline, but were still related to it to some degree.
Former NIDA Notes Editor David Anderson began this Narrative of Discovery series in 2015. Just before he retired last year, he asked Dr. Dwoskin to take a philosophical look back at what she had accomplished so far. Could she claim success when there is still no approved medication? Dr. Dwoskin admits that she has not yet achieved her primary goal—helping people who are struggling with their destructive use of methamphetamine. However, she points out, you can identify incremental victories that result from her research, including a better understanding of the scientific process needed for medication development as well as valuable new knowledge about VMAT2.
Also, technological advances along the way have increased the efficiency of her team’s research. For example, computer simulations and systems such as artificial neural networks can more quickly identify sets of structural features of their candidate molecules that are associated with the desired effects, enabling more accurate predictive programming. Still, the medicinal chemists on Dr. Dwoskin’s team also continue to rely on classical, tried-and-true methods of chemical synthesis and biological testing.
Another successful outcome of the decades of research are the many careers that have been launched from this journey of medication development and that help to disseminate insights gained from the project throughout the biomedical community. Of the dozens of research assistants and post docs who have passed through her lab, some have continued in academia and are now associate or full professors. Others have joined government agencies, and still others are now working in the biotech and pharmaceutical industries. Through their involvement in the methamphetamine project, these investigators have learned to think scientifically within a drug discovery framework in an academic environment. “They’ve all been contributors, and they’ve all gained tremendously from the experience,” explains Dr. Dwoskin.
Some of these collaborations have become lasting friendships. Dr. Dwoskin points to Gabi Deaciuc, a Research Analyst Principal who has been with her for more than 20 years, saying, “Gabi has conducted countless assays; prepares the compounds for evaluation; and keeps the lab functioning and in regulatory order. She goes above and beyond and is a supportive and understanding mentor of our junior investigators. Plus, Gabi has a great sense of humor and is deeply kind. The lab wouldn’t be ‘the lab’ without Gabi.”
Dr. Dwoskin acknowledges that she herself also has grown into a different scientist over the years. “Starting out, my research was more of an academic scientific pursuit to understand mechanisms underlying how the brain works. But along the way, my research became more goal directed and my emphasis has been to improve human health and help those with a substance use disorder. This is on the forefront in my mind as I focus on the bigger picture that has become more important.”
And, she has developed a greater serenity over time in dealing with the stops and starts of the research. “Early on, when things were looking good and then there was a problem that wasn’t anticipated, it was really disheartening, just a true up and down on a rollercoaster. But as you go, there’s less up and down and more, ‘Okay, we’re going to deal with this. We can fix this’,” she explains.
Navigating the Regulatory Side of Science
Through her project, Dr. Dwoskin also has learned that it is not just the science that presents hurdles. Medication development also necessitates a skillful understanding of regulatory requirements, data thresholds, drug-development milestones, intellectual property regulations, and piles of forms and paperwork that must be completed to get university and federal support to obtain continued funding and cross the bridge to the commercial application of the academic research.
As her expertise grew in the business side of research, Dr. Dwoskin was promoted to Associate Dean and, more recently, to Associate Vice President for Research at the University of Kentucky. She also assumed an additional role directing one of five new, NIH-supported Research Evaluation and Commercialization Hubs (REACH), the Kentucky Network for Innovation & Commercialization (KYNETIC). KYNETIC is led by Dr. Dwoskin, Dr. Paula Bates at the University of Louisville, and the Kentucky Cabinet for Economic Development, with support from the Kentucky Commercialization Ventures program. In this role, Dr. Dwoskin mentors young faculty and other academic colleagues on how to identify an unmet clinical need, establish collaborations, design relevant experiments and milestones, secure grants, navigate the intellectual property landscape, devise a regulatory strategy, and formulate a commercialization pathway. “I don’t know if people really go into this kind of research knowing what they’re getting into, because it’s a very long and complex road,” she notes.
Dr. Dwoskin is by now listed as the inventor on more than 25 patents, including many related to the methamphetamine project. She knows the process. The first step is the university “disclosure,” when scientists are confident that the molecule under investigation is finally mature enough to convert it into an intellectual property. This disclosure prompts the university to request and secure the patent needed to bring a product to market. Eventually, this is followed by the search for a contract research organization (CRO) certified by the U.S. Food and Drug Administration (FDA) to help with synthesis of the most promising molecule in a human dosage form. This formulation must be approved by FDA for clinical trials, followed by the trials themselves and the rigorous documentation needed for final FDA market approval. Finally, the researchers must identify a commercial partner willing to license the patent and share the risk associated with jumping the hurdles to get the compound to market and to those individuals who need it.
With these administrative demands as well as the supervision of the actual research, much of Dr. Dwoskin’s work week is spent on the methamphetamine project. And although she still has time for other research endeavors, including one looking at the long-term impact of taking stimulants for attention-deficit hyperactivity disorder, it is the discovery and development of a methamphetamine therapeutic that has shaped the trajectory of her research career at the university.
Only 50 Molecules Away
Fast-forward to the end of 2019. When JPC-077 had to be placed on the backburner because of its rapid metabolism, another series of molecules dubbed the GZ series seemed more favorable. In particular, the compound GZ-11608 decreased methamphetamine’s effects—a finding that Dr. Dwoskin and her team reported in a paper in November 2019. But the pattern of two steps forward, one step back unfortunately continued: Despite its many advantages, GZ-11608 also suffered poor oral bioavailability.
By the time we spoke with Dr. Dwoskin again this spring, the team had moved on to a new, exciting lead they have named STK-5-25. Not only does STK-5-25 interact potently with VMAT2, it has met all other milestones, such as no detectable hERG interaction, indicating a low probability of cardiotoxicity, and an oral bioavailability of 30 percent. Of critical importance, in mid-April 2020, they learned that the United States Patent and Trademark Office had approved the patent for the series that includes the STK-5-25 structure. And, there was more good news: A small biotech company is interested in taking the lead in bringing the molecule to market. Dr. Dwoskin now believes, “We are only 50 molecules and about 3 months away from identifying the right compound.”
But just as the patent and commercialization infrastructure were being put into place, COVID-19 exploded across the globe. All lab activities were first paused and then practically closed down as only essential research was allowed. A few technicians were able to continue to maintain the instruments and the cell lines that need weekly feeding, but all other work had to be put on hold. Would this new roadblock derail the promising developments? Although the situation is difficult for everyone, Dr. Dwoskin doesn’t give up hope. She has been busier than ever, coordinating and chairing the committee responsible for devising a plan to resume research at the university. Meanwhile, her team works from home, doing what they can—analyzing data and designing new molecules. More recently, research is beginning to resume, and work schedules in the lab are staggered to allow for social distancing. To Dr. Dwoskin, the glass is still half full. “I feel pretty confident, as optimistic as I did in the beginning. We’re going to make it work,” she believes. “But maybe with the wise understanding that it takes a lot of effort to get there, which I didn’t understand at the beginning.”
While she waits for the university to resume full research capacity, she has secured some additional funding for the project and identified a CRO that can rapidly do the labor-intensive work of lead molecule optimization, which could shorten a 12-month stretch of work at the university to an outsourced but intensive 3-month project.
Dr. Dwoskin had previously noted that serendipity had been her friend. And now? “I’m hoping we’re still having a good relationship,” she says. When the optimized lead compound is identified and scaled up, her team will evaluate it for oral bioavailability and efficacy against methamphetamine in behavioral assays. If all works well, she will secure additional funding to do the final preclinical work to bring the compound to an Investigational New Drug status and clinical trials. “We are all doing our best to try and make this happen,” she says, adding, “And if it doesn’t happen, I don’t have any regrets because I’ve done the best I could.”