Q&A: Banting Medal recipient’s work on dual agonists transforms diabetes, obesity care
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Key takeaways:
- Matthias Tschöp, MD, is the 2023 recipient of the Banting Medal for Scientific Achievement from the ADA.
- Tschöp’s research led to the discovery of dual agonist therapies for diabetes and obesity treatment.
SAN DIEGO — Matthias Tschöp, MD, has played a major role in the recent influx of novel therapies for the treatment of diabetes and obesity.
The approval of tirzepatide (Mounjaro, Eli Lilly) to improve glycemic control for adults with type 2 diabetes and the development of other dual and triagonist drugs for diabetes and obesity stem in part from research conducted by Tschöp alongside his long-time colleague, Richard DiMarchi, PhD, the chair of the Gill Center for Biomolecular Science at Indiana University. The two worked together in the early 2000s at Eli Lilly & Co. and connected again after DiMarchi went to Indiana University and Tschöp joined University of Cincinnati as a professor of endocrinology and diabetes.
“We were convinced that gut hormones would be the very likely path to success,” Tschöp, CEO and scientific director for Helmholtz Zentrum München research center in Germany, told Healio. “If you directly mess with synapse receptors in the brain, you always cause side effects. We don’t have the pharmacological tools to address certain neurons and not others. Neurons are such complicated networks; you would always affect mood or cardiovascular [health]. If you use an indirect way and you use endogenous gut hormones for metabolism, they know where to go in the brain to affect metabolism.”
Tschöp and DiMarchi went on to discover multiple dual agonist agents that are currently being developed. Data from trials on some of these agents were presented at the American Diabetes Association Scientific Sessions, where Tschöp was the 2023 recipient of the Banting Medal for Scientific Achievement.
Healio spoke with Tschöp about some of his career milestones, the dual and triagonists he helped discover and what research he is looking forward to in the future.
Healio: Can you discuss your research on the ghrelin hormone and what led up to this discovery in 2000?
Tschöp: When I decided I was going to be devoting my career to finding new drugs for the treatment of obesity, and from that, then potentially preventing diabetes, the next step was to look at where I would learn to do that kind of research. It was an exciting time because leptin was recently discovered. My friend Jeffrey Friedman, MD, PhD — back then he was just a professor at Rockefeller University — reported that there’s this leptin hormone from adipose tissue that turns fat into an endocrine organ and is the first molecular regulator. It did a lot of things: It started the field, took away the stigma from obese individuals and made me enthusiastic about how this is possible.
The first place in the world where they were able to make synthetic leptins soluble and active was at Eli Lilly in Indianapolis. So, I said I would go to Indianapolis and study at Lilly because they seem to know how it’s done. After 3 years, it turns out that leptin wasn’t the cure for obesity because there is leptin resistance and obese individuals already have high leptin levels.
[After researching this] for years with my mentor, Mark Heiman, PhD, we discovered there’s another hormone that’s important for body weight that’s called ghrelin. That peptide was already [described]. Japanese colleagues Masayasu Kojima, MD, PhD, and Kenji Kangawa, PhD, had described it, and they thought it was maybe relevant for hormone secretion. But we discovered that it does something else, it increases hunger. And until today, it’s the only hunger hormone we have in the body. It increases body weight; it makes you store your calories very efficiently in fat. You gain some weight when you inject it as well, and this works in preclinical mouse models. But locking the ghrelin pathway, which is very tricky, didn’t do the job.
We learned a lot of things. Like leptin, ghrelin works in the brain to do what it does. So, the picture became clearer. Obesity seems to be a brain disease. Certainly, the genetic studies we know about human genetic sequencing all point to that fact. And second is that it’s not going to be just one factor. There are so many factors, you have to identify a pattern of two or three that’s then powerful enough to change the set point in the brain.
Healio: Your work on dual and triagonist drugs really transformed medicine. Can you describe your research in that area?
Tschöp: The first dual agonist that we discovered was a glucagon/GLP-1 receptor dual agonist. The thinking was it was going against everything that was back then believed in the field. Glucagon receptor activation helps us with burning calories. It helps us with satiety. It will increase blood glucose, but if you add the GLP-1 and you lose weight, you will be overriding that. There are several of these clinical trials. There are prototypes of this from AstraZeneca, MedImmune, Boehringer Ingelheim and many others. They seem to also be doing better than normal agonist treatment. None of them have been FDA approved yet, but it’s coming.
Then, we said let’s do something without glucagon. And we looked at glucose-dependent insulinotropic polypeptide (GIP), another one in that preferred glucagon peptide family. GIP is very interesting. It also has receptors in the brain and also drives satiety powerfully to be turned into a longer-acting soluble, more powerful agonist. It needs to be combined with something. We tried with GLP. And this is what we then described in 2013 as a new drug class, the GIP/GLP-1 dual agonist — single molecules that activate both receptors. There are several representatives of that, the most popular and well known is tirzepatide.
It’s fantastic, after 30 years, seeing tirzepatide come to clinical success. What Lilly did differently was not only did they take advantage of the advanced pharmacology of the recent years, but they also chose to have a five-to-one ratio of GIP to GLP. When we first described it, it was more balanced. It turns out the more GIP you have in this, the better. In my mind, GIP might even be the more important hormone than GLP. The reason is, I believe, that GIP doesn’t cause the nausea side effects, GLP does. And when you put them together, GIP suppresses the side effects of GLP. So, you can then dose those higher with fewer side effects. And this is part of that success.
It took us 5 years of tweaking the solution until we had our first triagonist: GIP/glucagon/GLP. That worked twice as good as the dual agonist, GIP/GLP, in decreasing your body weight. It took a while for these to become mature for the clinic. But now there are three of them going into clinical trials. One of them again, is Eli Lilly with retatrutide. I speculate based on all the available preclinical data and the phase 1 clinical data that Lilly already disclosed, it seems to be like we saw in our preclinical data when we first reported the discovery of triagonists, this is significantly better than dual agonists.
Healio: Is there a specific person or mentor that has had the biggest influence on your career and why?
Tschöp: I was lucky and benefited from a lot of very good mentors. But without a question, the most important influence was my friend and collaborator Richard DiMarchi. Richard DiMarchi is the chemist who, for the last 20 years, basically ran a joint lab with me, even though he is working in Indianapolis, and I’ve been working in Cincinnati and now I’m working in Munich. We go back and forth almost daily, then weekly until today. “What do you think works?” “How does this work?” “What do you know about your physiology, endocrinology?” “How is that translated to the chemistry?” “Do we need to tweak this?”
It’s the best version of an interdisciplinary, complementary relationship. He’s older than I am and has more experience — that has helped me a lot. He had spent many years at Eli Lilly as a senior vice president, so he knows how the pharmaceutical world works. But we’re both in academia now and I am a physician, so I know a little bit more about the disease. We had a joint vision and literally neither of us would have been successful alone.
Healio: What are you currently working on and is there any research you’re planning to do or looking forward to in the near future?
Tschöp: I’m leading a major research organization, the Helmholtz Association of German Research Centers, that’s about 10,000 staff and scientists working in health research. There’s exciting stuff happening there that I’m blessed to be able to co-lead. Artificial intelligence is changing the way we do research. The postdocs of tomorrow won’t be working like I did with an iPad — it will be robotics and a lot of machine learning.
We’re working hard on figuring out the mechanisms of how dual agonists and triagonists work because there are a lot of open questions. What really does GIP do and how can it be that some folks see some benefits with GIP receptor antagonists or agonists? We have some of the answers. The agonists work mostly with the brain and antagonists probably in the periphery. One of my colleagues has probably found the neuron subset that’s relevant for tirzepatide action, we’ll publish that soon.
Finally, together with DiMarchi, we’re establishing the next generation of molecules. We are thinking that metabolic precision medicine in the future will be focusing on targeting specific cells and organs, subpopulations will benefit more from one drug than the other. Which ones are those? Are there other diseases where we can use the same dual/triple-receptor strategy, something in neuroscience, neurodegeneration or other diseases? We believe that there’s a lot to be done.
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