8

Workshop Reflections and Opportunities to Move Forward

Matthew Hayes began the final session by commenting that a wide range of perspectives were represented at the workshop, including government, academia, industry, and biotech. “It speaks volumes to me that so many stakeholders are showing interest in the repurposing of GLP-1Rs beyond their current approval for diabetes or obesity,” he said. Brian Fiske shared that the speakers in this session would synthesize the main topics from the workshop (see Box 7-1) and hear from a panel of diverse participants about their perception of the field and how it can move forward.

PANEL DISCUSSION

An Industry Perspective

Speaking from his perspective as a scientist, Matthew Coghlan said he very much appreciated hearing from Patricia Nece and Karen Glanz, participants with lived experiences. In addition, he spoke of some early experiences in the search for drugs that could treat diabetes and obesity. “I remember almost 20 years ago in one of my early companies, when we had the opportunity to license the original molecule, it was laughed out of the room,” he said. “Who would want an injectable?” This was exenatide, with the brand name Byetta, and it was the start of the GLP-1 revolution.

So it is great, he continued, to be in the field now as it experiences an inflection point, where new forms and new uses for this class of medicines are appearing rapidly. “I think it’s an exciting time,” he said.

“But what I’ve learned today,” he continued, “is we need more data,” particularly to understand the biological mechanisms underpinning the drugs’ clinical effects. This will help, for example, in determining which preclinical effects are likely to translate into the clinic, said Coghlan.

Finally, he said, the field needs to push forward on the “fantastic opportunities to expand into CNS [central nervous system] disorders and other areas of disease.” Coghlan highlighted that this will require preclinical

research to point the way to the treatments most likely to be useful in humans and, most important, getting data from clinical trials to determine conclusively which of these new drugs will be safe and effective in humans.

A Government Perspective

Iván Montoya began by offering some background information on the National Institute on Drug Abuse (NIDA) and its Division of Therapeutics and Medical Consequences at the National Institutes of Health, which works with academia and industry to develop medications and other therapeutics for the treatment of substance use disorders. The division supports research—including many of the studies presented at the workshop—through grants and contracts, he said.

Montoya said he was intrigued by the idea of an endogenous GLP-1 system. People in the substance use disorder field are familiar with the endogenous cannabinoid system and the endogenous opioid system, and this is an analogous concept. In particular, he is interested in the development of the GLP-1 system and what factors might shape it.

He drew a distinction between the work now being done with GLP-1R agonists to treat obesity and diabetes, with drugs that have received FDA approval, and the work on treating neuropsychiatric disorders, with drugs that have not. “There is no FDA [Food and Drug Administration] approval for any GLP-1 agonist for substance use disorders,” he said. As a result, the data concerning substance use disorders are very preliminary.

The individual differences in the response to GLP-1R agonists was another issue that caught his eye, he said. Although there are not enough data concerning the treatment of substance use disorders to conclusively say much about individual differences, differences in response are evident in the treatment of obesity and diabetes. Studies are needed to understand more about these differences, and they should take into account patients’ genetic, physical, and social characteristics, Montoya said.

Noting that one of the objectives of the workshop was to examine the clinical trial and regulatory considerations of GLP-1R agonists, Montoya said that this objective was not well addressed during the meeting. “I think we need to have more discussion about the clinical trial designs,” he said. For instance, he said, it is possible that GLP-1R agonists can be used for the treatment of polysubstance abuse—that is, the abuse of multiple substances, which is more prevalent than the abuse of single substances. But what sort of trial design should be used in addressing that question? The typical trial has one medication and one drug of abuse. Testing a GLP-1R agonist against polysubstance abuse would require a different design than usual. The FDA would need to be involved in determining what sort of designs

and endpoints would be acceptable to get a GLP-1R agonist approved for such a treatment, he noted.

He closed by reiterating the interest of NIDA in studying GLP-1R agonists. “We hope to continue working with academia and also with industry and the FDA to develop more protocols and to . . . fund research for more GLP-1R agonists for treatment of substance use disorders,” he concluded.

A Lived Experience Perspective on Public Understanding and Policy

Karen Glanz’s takeaways from the workshop highlighted the importance of public understanding and public policy. These two areas, she said, will play a role in how effective the GLP-1R agonists ultimately become in the overall population. Concerning public understanding, she said, it will be important for the media to get the message out to the public that the new uses for GLP-1R agonists will not be as straightforward as, for example, simply repurposing semaglutide for Parkinson’s disease or Alzheimer’s disease or substance use disorder. There is already a lot of discussion about these medications in the media, she added, and not all of it is accurate. More generally, Glanz said, public understanding will be crucial in situations where eye-catching research results appear, such as the potential connection between GLP-1R agonists and suicidal ideation; the public will need access to evidence-based information in such cases.

Switching to the topic of stigma, she said that while the workshop had included discussion of stigma in terms of obesity and obesity management treatment, there was little said about the stigma associated with CNS disorders such as substance use disorders, but individuals with those diseases face stigma when they seek treatment for them. For instance, she said, in many U.S. states a pregnant woman who is using illicit substances is treated as a criminal, “so how can she get adequate care?” This is compounded by the fact that many of the women facing this situation have a low socioeconomic status, live in rural areas, and are from underrepresented populations.

Although obesity is now widely understood to be a disease, she said, many people still see it as a moral failing. “I see those issues crossing over into some of the CNS disorders and into this class of drugs,” she continued, “and I think there is a lot of work to be done.”

A Real-World-Evidence Researcher’s Perspective

After first commenting that she agreed with everyone else about how exciting and promising GLP-1R agonists are for treating CNS disorders, Serena Jingchuan Guo cautioned that there are still many unknowns that

will require collecting more preclinical data, clinical trial data, and real-world data. “We still do not yet have a complete picture about the safety profiles, the drugs, and the efficacy profiles,” she said. This is particularly important, she added, because the new GLP-1 medicines are being hailed as miracle drugs, and they are being considered for treating many conditions even though there are not enough data on the possible consequences of such treatments. But with enough data, researchers and clinicians can do such things as disease phenotyping, identifying the patients most or least likely to benefit from a particular drug or to have safety issues.

Guo called for academia, the pharmaceutical industry, and government agencies to work together to build integrated datasets with data on mechanisms, omics, biomarkers, imaging, socioeconomic determinants, and clinical measurements and outcomes. The ultimate goal would be to enable precision medicine using the GLP-1R agonists.

A Lived Experience Perspective on GLP-1R Progress

Patricia Nece said that she was impressed and excited to hear about all the work going on with GLP-1R agonists. “Most of this is new to me, and it’s exciting,” she said. “I know people with all these different conditions, and it’s so important to come up with adequate and successful treatments for them so that they can just live their lives. Just live their lives—that’s all they want to do. . . . And the work you’re doing is certainly going to move the needle, I am confident on that score, for these patients.”

She did caution, however, that the GLP-1 medicines should not be thought of as miracle drugs. For one thing, not everyone can tolerate them, and results vary from person to person. Furthermore, she added, “it certainly isn’t a snap-your-fingers-and-your-obesity-is-gone drug. You have to work at this. Every day I work at it. I wouldn’t overpromise as you’re developing these new drugs and other therapies.”

Nece also said that she was struck by the discussions about teasing apart the different ways in which GLP-1R agonists enact their different effects and the relation between their effects on weight and on other factors, such as cholesterol levels or inflammation. “I think it’s fascinating, and I think parsing that out could lead to other discoveries.”

Finally, she said, it is vital that researchers and clinicians understand and keep in mind the real-world experiences that patients have, such as how a drug’s side effects may influence their lives. “I hope you’ll just keep patients in mind with everything you’re doing,” she said. “It’s so easy to get caught up in the minor details. I hope you’ll lift your head and look at the bigger picture.”

DISCUSSION

The High Prevalence and Cost of Disease in the United States

Mahin Khatami asked why there is a high prevalence of illness in the United States despite the large amount of spending in health care, including for the treatment of cancer, neurodegenerative diseases, and autoimmune diseases.

“It’s a great question,” Hayes said. Many of these diseases, especially metabolic diseases, have multiple underlying causes and a complex etiology. “And for some of the other CNS diseases we’ve covered today,” he continued, “the complexity just deepens. But it’s an important topic to look and consider—not only how we treat the disease, but what perpetuates and causes the disease.”

Alexandra Sinclair said that in the United Kingdom decisions about which drugs patients can access take into account considerations from health economics, a topic that had not come up in the workshop. “I wanted just to urge us to think a little bit about building in health economic assessments into our clinical trial design,” she said. Then decisions about the drug will consider not only the cost of the drug but also the cost savings resulting from its use.

GLP-1R Agonists in the Pediatric Population and Long-Term Use

Linda Rinaman noted that the FDA has approved some GLP-1R agonists for the treatment of obesity in children as young as 12 years old. She said, “I continue to be amazed that there is so little basic science research, let alone clinical research, about what the effect of that is on the developing brain.” How might these drugs change the brains of adolescents and teenagers, and might the changes be permanent? She urged anyone funding or conducting basic science to recognize the importance of these questions. “’I think that we have the tools with the animal models to get at a lot of these questions,” she said.

Guo responded that her group is doing a meta-analysis of 17 clinical trials to look at the effects of GLP-1R agonists in the pediatric population, but they do not yet have the results. They are also looking at data from electronic health records from the OneFlorida+ network, which has a large proportion of pediatric patients. And Montoya added that NIDA would be very interested in funding studies exploring how the GLP-1 system develops and how GLP-1R agonists can affect the developing brain.

Chris Brandl from Pennsylvania State University asked about long-term use of GLP-1R agonists. Guo said that there is an ongoing debate about

whether patients with obesity will need to take the drugs for the rest of their lives. “We saw some data that when you stopped the medication, you have some regain of weight,” she said, “but it seems the weight management is still better than before you took the drug.” For semaglutide specifically, which was approved in 2021, there are only 2 to 3 years of clinical data available, “but with time going on we will have more data to answer the questions,” she noted.

Considerations for Use of GLP-1R in CNS Disorders

Sinclair said it will be important to consider how GLP-1R agonists will be delivered for use against brain-related disorders, such as Alzheimer’s disease or substance use disorders. While the agonists used to treat type 2 diabetes and obesity are typically delivered orally or through intramuscular injections, this may not be the best approach for drugs that need to get into the brain. “Should we be thinking about reformulating the drugs for CNS delivery?” she asked.

Ellen Mowry said that although it had not been discussed at the workshop, multiple sclerosis is another neurodegenerative disease that may be helped by treatment with GLP-1R agonists. Although the younger-age peripheral immune problem of multiple sclerosis has been solved, the neurodegenerative phase of the disease still requires treatments, and her group is planning a trial of a GLP-1R agonist for that purpose, she said.

CLOSING REMARKS

Many workshop participants discussed how both preclinical and clinical data point to the potential for GLP-1R agonists to be effective in treating not only obesity and type 2 diabetes but also various CNS disorders, including ingestive behavior disorders, neurodegenerative diseases, and substance use disorders. However, workshop participants highlighted that questions remain regarding how GLP-1R agonists enter the brain, their mechanisms of action, ensuring fair access to different populations, and evidence-based public education. Throughout the process, researchers, clinicians, policy makers, and drug developers may benefit from considering the perspectives and needs of individuals who could potentially receive GLP-1R agonist.