Okay, welcome everyone to a really interesting hour with a distinguished thought leader in diabetes. I have with me Dr. Ralph DeFronzo, who is a Professor of Medicine and the Chief of the Diabetes Division, University of Texas Health Science Center in San Antonio. Dr. DeFronzo has an incredibly distinguished career in endocrinology and in diabetes. Too many accolades and honors to list here, but he's certainly very, very knowledgeable, and we're looking forward to having a conversation. As a reminder, Yigal Nochomovitz, one of the Biotech Analysts at Citi. For those of you listening, feel free to shoot me over questions for our expert on email. I'll do my best to field those in real time over the course of the next 60 minutes. With that, Dr. DeFronzo, thank you so much for taking time. I'm sure you have a very busy schedule.
Maybe if we could just start a little bit with a very quick level on your background and sort of the type of research and clinical focus that you have in diabetes.
Yeah, so as you said, I'm Professor of Medicine and Chief of the Diabetes Division here at University of Texas Health Science Center in San Antonio. I also am the Deputy Director of the Texas Diabetes Institute. We see about 10,000 unduplicated diabetic patients annually, so we have a huge clinical experience, largely underserved Hispanic population. I am the longest consecutively funded NIH NIDDK investigator from 1975 till the present. I've won a number of awards, Outstanding Lifetime Achievement Award from the American Diabetes Association, also from the European Diabetes Association. I have about 9,900 publications. My major interest is on the pathophysiology of type 2 diabetes, what causes it. I single-handedly brought metformin to the United States in 1995. I also invented, but unfortunately not very smart, did not patent the SGLT2 class of drugs. I'm a big proponent of combination therapy in type 2 diabetes.
I think probably that's enough of my background. I feel very comfortable handling really anything about pathophysiology and treatment in the type 2 diabetes field. We'll just let you take it where you want to take it.
Okay, I'm sure we could spend more than an hour talking to you for no question. Maybe just as a high-level starting point, give us your sense of the landscape. What are some of the big themes that you're seeing in the treatment of type 2? I guess you could talk about type 1 as well if you feel so inclined. What are some of the big themes you're seeing? Obviously, the GLP-1s are a major focus, but what else? We're going to talk more in detail, of course, about the menin inhibitors too.
Yeah. I've always been a big proponent that if you understand what is underlying the pathophysiology of type 2 diabetes, you'll better be fit to treat it. Unfortunately, if you look at the American Diabetes Association Standards of Care, they say very little about pathophysiology. To me, that's essential. If you don't understand what causes disease, you're not going to understand what treats it. If we could sort of distill type 2 diabetes into two general categories, one hand we have insulin resistance, and the other hand we have beta cell failure. This epidemic of diabetes that we're experiencing today is being driven by the epidemic of obesity, and that's basically lipotoxicity, lipotoxicity causing insulin resistance.
The other big aspect of the disease is this large number of people who actually have primary beta cell failure and who progress rather quickly to severe hyperglycemia because we really don't have the kind of medications that we need to stop this progressive beta cell failure. Now, of course, with regards to the obesity epidemic, everybody is focused on the GLP-1 receptor agonist, and they've lost, I think, perspective a little bit here. The GLP-1 receptor agonist, I was intimately involved with Byetta, the very first drug. I actually did all the mechanism of action work. The reason why Byetta worked and the GLP-1 receptor agonist worked so well is because they have a big effect on the beta cell. Now the newer ones, in addition to having this big effect on the beta cell, which people have forgotten, have a huge effect to promote weight loss.
The GLP-1s are sort of like the talk of the town and what can we combine GLP-1s with to promote even more weight loss. We've kind of lost perspective, however, that there is severe beta cell failure and we need to have ways of slowing or reversing stopping it. The other big problem, of course, is we have insulin resistance that goes well beyond just obesity, and we really don't have good drugs for treating insulin resistance. I'm a big proponent of pioglitazone, but lots of great clouds and misconceptions about pioglitazone have prevented it from catching on.
You raise a very interesting point in terms of the insulin resistance and the primary beta cell failure. Would you categorize those as entirely mutually exclusive, or is there some belief there's an overlap there?
Yeah, it's clearly an overlap. If you start with beta cell failure, and I can go into this pathophysiologically in more detail if you want, you will end up with insulin resistance. If you start with insulin resistance, this puts an enormous stress on the beta cell. Part of the genetic background for type 2 diabetes is progressive beta cell failure. You are not going to develop overt hypoglycemia unless your beta cells fail. If you start with insulin resistance, and we could say this is a genetic cause of insulin resistance, which clearly is there, but we do not understand the genes that are involved, or it could be an acquired form of insulin resistance such as obesity. This is going to put an enormous stress on your beta cells to secrete more insulin.
When the beta cells are stressed like that, this leads to progressive beta cell failure. On the other hand, when I was a youngster back in the 1950s and 1960s, when we did not have obesity, the predominant cause of diabetes were these lean people who had predominant beta cell failure. We have kind of forgotten that that is 20% of the population because what is really driving the current epidemic of diabetes is obesity. There is a large population, 20%-25% of the population, in whom I believe that beta cell failure is the primary defect. Those people still are suboptimally treated. That group is at very high risk for cardiovascular complications. They are very high risk for the microvascular complications, and they are very difficult to treat, by the way.
We need to understand that we need drugs that are both going to work on the beta cell and drugs that are going to improve insulin sensitivity.
That's a good point for me to kind of get into a little bit more detail here, which I think is important as we talk about some of the menin inhibitors in a little bit. Within the insulin deficient segment, as far as I understand, there's the severe insulin deficient, the SIDDs, and then there's the mild age-related diabetics, the MARDs. On the other side of the coin, you have the insulin resistant patients, the mild obese-related diabetes, or so-called MOD, and then the severe insulin resistant diabetics, the SIRD. There are these four buckets, not exactly equally distributed in terms of numbers of patients, but roughly so. You mentioned the ones that are sort of the skinnier folks that have the severe insulin deficiencies.
How easy is it as a clinician to identify these different segments, not only for you as a super expert, but for the sort of ordinary internist that's treating the diabetic population? Are these terms and these classifications fairly well understood, or is there work to do to help people get this classification right?
Yeah, so this classification came from a study. Actually, Leif Groop was a fellow with me many, many years ago, and he went back to Sweden. He started the Botnia study. This classification that you just took you through is this famous Ahlqvist paper. I have to say, the classification is correct. We've published extensively showing, in fact, in more sophisticated ways than the original Swedish paper, and using more sophisticated techniques that the classification is correct. The problem is that I would say by the sort of primary care physician, the classification per se, the SIDD, et cetera, is not very well understood. The simplest way to understand it is there are people who have severe insulin deficiency. I don't think we need to attach some sophisticated name to this, although it is in the classification. There are people who have severe insulin resistance.
In between, we have kind of a continuum of people who have both insulin deficiency and insulin resistance. If you want to do this in a very simplistic way, the people who are lean or leaner and who are the worst control, those tend to be the people who are severely insulin deficient. The sort of very obese people with BMIs 35-40, I mean, you just look at them. Those are the people who are the insulin resistant people who initially have reasonable beta cell function. I think what people do not totally understand is you are not going to develop type 2 diabetes, whatever category you are in, unless your beta cells fail.
These people who start off with severe insulin resistance, five to 10 years down the line, as their A1C starts to go up to eight, 8.5, nine, 10, the reason why that's happening is because their beta cells are failing. Eventually, once you get these poorly controlled people, they're all going to have some significant degree of beta cell failure. The lean ones are the ones who have the more severe insulin deficiency. They progress much, much more rapidly. Those are the people who are the most difficult to treat. Those are the ones who end up going on to insulin therapy. Insulin therapy for type 2 diabetics is very, very, very difficult. The reason why these people fail is because we don't have good treatments to preserve their beta cell function.
Let's talk about that. We have some new options or potential new options in the class of menin inhibitors, but there have been some other attempts. I think you referenced one earlier. What else has been attempted in the way of beta cell, not only preservation, but regeneration and regrowth? Why is that such a critical approach?
Yeah. As the diabetes progresses, and I think I outlined this very nicely in my advancing lecture in 2008, you initially start to lose beta cell function, and then eventually you start to lose beta cell mass. When you lose a critical beta cell mass, say 70%-80% of your beta cells, then these people become insulin dependent. Okay? How can we attack the beta cell failure part of the story? As I said, people have forgotten that GLP-1 receptor agonists are actually very good at improving beta cell function. These drugs do not increase beta cell mass. They take a sick beta cell and they can make it healthier. If you have lost 70% or 80% of your beta cells, GLP-1 receptor agonists are not going to regenerate beta cells.
We would like to have a therapy that both can increase beta cell mass, particularly in this severe insulin deficient group, and improves beta cell function. I think the menin inhibitors are a class which actually have the potential to do this. The other potentially exciting, interesting aspect of this, which is becoming more apparent, is that this class of drugs increases GLP-1 receptor expression on beta cells. When you increase GLP-1 receptor expression, this now is going to allow the GLP-1 that's coming endogenously from the body to better interact with the receptor. That's going to contribute to an improvement in function. The menin inhibitors, I think, have a lot of potential, particularly in this severe beta cell group.
I also think that they have a role to play in the insulin resistant group because with time, those people, and it may take five years or ten years, they eventually are going to develop beta cell failure and a loss of beta cell mass. They are also going to need treatment with drugs that are going to improve function and increase beta cell mass.
Okay. Obviously, one of the key biomarkers in monitoring the function of the pancreas and the ability to produce insulin is the cleavage product, otherwise known as the C-peptide, which is why people use that because, as I understand, it has a much longer plasma half-life. When you're looking at C-peptide, how do we know, or what is the way you think about increases in C-peptide as being tied to not just an improvement of the existing beta cells, but in fact, a signal that you're increasing the mass? How do we tell those apart, or can you tell those apart?
You know, you really can't tell them apart. Of course, animal studies, it's very easy to tell them apart because you can measure beta cell mass. Unfortunately, I have a major interest in this area, by the way. We have some ways in which we can get an index on beta cell mass. I'll come back and tell you about an approach that we're taking. Ultimately, we would like to have a technique, PET technology, with an isotope that we can give the isotope, and then using positron emission tomography, we can measure the beta cell mass. Unfortunately, we don't have a technique, a PET technique that will allow us to quantitate beta cell mass. As I said, I have a major interest in this topic, and I'm working with someone in Scandinavia, Oluf Pedersen , who may have an innovative way to look at this.
I can come back and tell you how you can get an indirect handle on this. When you measure the C-peptide, the C-peptide, if we have an intervention that increases the C-peptide, that could reflect an increase in beta cell mass or an increase in beta cell function. In humans, we do not have a way of differentiating between those two. The fact is, if C-peptide goes up, whether we are improving function or mass, that is very, very good because that tells me I am restoring insulin secretion. Now, with the menin inhibitors, in animal studies, you can be very invasive. You can measure beta cell mass. We know from in vitro and in vivo studies using human islets that the menin inhibitors markedly increase beta cell mass. They cause proliferation of beta cell mass. I also believe they probably also improve function.
Because they increase GLP-1 expression on beta cells, the fact that now your GLP-1 can more effectively work, you are for sure indirectly improving function as well.
I've seen some of the early work that's done by one of the companies that's pursuing this approach, Biomea, and they have a menin inhibitor, icovamenib, as you likely know. They showed some really good early data in sort of the spheroid cell model showing increase in beta cell, basically mass. I'm just wondering, what else can you share as far as your understanding of the mechanism of icovamenib, and there are others as well? What are they doing? Is it known how they actually work to increase the mass of this class of cells that's on a steady decline and basically as a result of the autoimmune process?
Yeah. The experiments are pretty straightforward. You can take isolated human beta cells or from various animal models, and you can culture them with or without the icovamenib. You can show marked increase in mass. Okay? You can take a variety of animal models, ZDF, and there are a number of animal models that looked at. You can treat the animal models in vivo. At the end, you can take out the pancreas, and you can measure the beta cell mass, and you can see that it's increased.
I think at the molecular level, the genes that are turned on and off, I think there's still a lot of work that needs to be done in this particular area to define why at the sort of molecular level, what are the genes that are turned on and off that are contributing to the hypertrophy and the replication of the beta cells? The fact that the beta cells are replicating, that's unequivocal. I mean, that's pretty clear. You can show this with human beta cells in culture. We will see some C-peptide data that's coming up at a recent meeting, a meeting that's coming up, I think, soon in Europe. I think that these data with the icovamenib, I think it's March 22nd, they're about to be released.
I think what you're going to see is an enormous amount now of molecular work that define the mechanisms at the sort of intracellular level, the gene level by which the menin inhibitors are working.
Okay. Speaking of some of the detailed data, I think this company we're referencing, Biomea Fusion, they had actually produced some data for HbA1c at week, I believe it was week 26. That was after the patients had been off the therapy for quite some time. I think it was 14 weeks. They had shown what looked to be very, very encouraging reductions in HbA1c. What did you have a view as to the strength of that data? How might it compare with the available therapies we have today?
Yeah. In this study, they had three arms in the study. They call it A, B, and C. There were three arms. The important part of the study is that prior to analyzing any of the data, they had a pre-specified analysis that would use this classification of diabetes that we talked about earlier to see if there were specific groups that benefited more than other groups. Again, for simplicity's sake, in the severe insulin deficient group, which was pre-specified in advance, the A1C decline in this group, whether they were in arms A, B, or C, really did not make any difference. The treatment was a little bit different, but basically involved icovamenib. Treatment up to 12 weeks, as you said, and then no treatment, and then analysis at 26 weeks.
There was a progressive decline in the A1C, sure, at 12 weeks, but even more impressive is 12 to 26 weeks when there was no treatment that was going on. That suggests, since these are severely insulin deficient people, that there was, in effect, on either increasing beta cell mass or function or some combination thereof. They had some C-peptide data, and a small number of people in the C-peptide went up. I would say it was a small number of people. We'll see on March 22, when they present the C-peptide data, what really happened. Again, I would be very, very surprised based on that progressive drop in A1C if we don't see a significant and really quite robust increase in C-peptide, meaning a big increase in insulin secretion.
As I said, there is no way where you can tell whether this is an increase in number of beta cells or in beta cell function. One of the things that we're contemplating here, doing as an investigator-initiated study, is trying to get at the beta cell mass by taking people with type 2 diabetes. We're going to look at both severely insulin deficient as well as insulin resistant people. We can do what we call a stepped hyperglycemic clamp. I can raise your glucose by 100mg per deciliter, then by 200, and then by 400. Now I've raised your glucose to the maximum amount. That's the maximum stimulus to your beta cells to release insulin in response to glucose.
At your glucose level increased by 400 mg per deciliter, which is a huge stimulus, maximum stimulus for beta cell, we are going to give a GLP-1 receptor agonist. Okay? We know there will be another huge increase in insulin secretion. After that, we are going to give an amino acid load. What I am sort of getting at here is this is going to give me the maximum beta cell response, which will be indicative of beta cell mass. This is sort of indirectly.
It's like a calibration, sort of.
Yeah. Yeah. This, because until we have a PET mechanism, we can actually measure beta cell mass, we can say, yes, we're 100% convinced what's going on in the animals. Also, they have primate data. We actually have a big primate colony here in San Antonio. Anything you see in primates, I guarantee you're going to see in humans. The non-human primate, and we've looked at all of the major genes in the beta cell and the muscle. Primates are just like humans. They've shown, again, very similar data in primates in terms of increase in C-peptide. I believe that we will see when we see these new data coming out, we'll see March 26, pretty close, what happens to C-peptide. Now we're speculating right now. I would be very, very surprised if the C-peptide doesn't go up.
Okay. Okay. All right. Let's start with the, what are your, I mean, what would be, everyone always asks the question, what would good look like? C-peptide, I mean, I recall there was sort of a mini debate last year because they had shown some C-peptide results, and the % increases looked very good, but they were off a very, very low base, meaning I think it was, and these may not be exactly right, but for example, 0.1 nanogram per mil going to, say, 0.2 or 0.3. It sounds like it's great on a percent basis, but on an absolute basis, it may not necessarily be that much, and it may be reflective of some assay noise. I don't know. What is needed sort of on an absolute basis on C-peptide to be interesting? If there is a percent increase, that would also be interesting.
What would that need to be, both that percent and the absolute? Because they kind of go together.
This is a very important point that you bring up. The point that I'll make, the point first, then I'll come back and answer your question more directly. Whatever the percent increase was, and you can argue that it's small, the A1C dropped by 1.5%. That's a huge drop in A1C. You cannot interpret the increase in C-peptide or percent or absolute in a vacuum. If you are normally insulin sensitive, and I have a small increase in C-peptide, that can have a huge effect to drop the A1C. If you're very insulin resistant, I may need a much larger rise in A1C and C-peptide to drop the A1C. People who have raised these objections, in my opinion, clearly don't understand the pathophysiology of type 2 diabetes.
If you are a very, very insulin deficient person, but you have really quite reasonable insulin sensitivity, modest changes in C-peptide can have huge effects in terms of glucose tolerance. Moreover, you can't just look at C-peptide in isolation. You need to know, look, what was the rise in glucose? Okay? And that's the stimulus for C-peptide. If you, and again, we have been one of the foreleaders in understanding beta cell function. There are other people, Steven Kahn, there are other people at the same level that we're at. The fact is, if you truly want to interpret the C-peptide response, you have to express the C-peptide per increment in glucose. In addition, insulin resistance has its direct effect, complicated, but the beta cell can tell how insulin resistant you are.
The sort of gold standard for beta cell function is the increment in C-peptide divided by the increment in glucose, all affected by how insulin resistant you are. When you say, look, you have to have a certain increase in C-peptide or a certain percentage increase, in a certain way, that's true, but you also have to understand what was the stimulus for this C-peptide and how insulin resistant or sensitive is the person. I would say, look, if your A1C drops by 1.5%, whatever that C-peptide increment was in absolute terms or percent-wise, that's a huge drop in A1C. The other thing that's very, very important to remember is that these insulin deficient people are the most difficult people in the world to treat. The drugs that we have don't treat them.
Now we have a study with the icovamenib that showed in this incredibly difficult-to-treat population, amongst the most difficult people in the world to treat, I just dropped the A1C by 1.5. That's very impressive. They failed on all these other drugs. A lot of these people, remember, had failed on GLP-1 receptor agonist as well. Now we're treating these people with the best drugs that we can have. Their A1C is 8.5, and they're failing. Now I give them this new approach, and now all of a sudden, the A1C drops by 1.5. That's an enormous drop.
That's one detail I need to check, but the data that we're getting, the C-peptide data, is this based on a glucose tolerance test as you referenced and calibrated that way? Or is this just the basic C-peptide measurement outside of a glucose tolerance test?
Yeah, it's outside of a glucose tolerance test. It's what's happening to the fasting insulin secretion, but then what's happening to insulin secretion in response to a glucose tolerance test or a meal tolerance test. You have to look at both. The increase in the fasting C-peptide, that's going to have its major effect on the liver. When we go to sleep at night, our liver produces glucose. It keeps our glucose about 80 mg per deciliter. That's critically important because our brain only can utilize glucose. In diabetics, the liver is very resistant to insulin. We were the first people to show this, I don't know, 40 or 50 years ago using isotopes. The cause of fasting hyperglycemia is excess glucose production by the liver.
The increase in C-peptide in the basal state, which is reflecting the increase in insulin in the portal vein, is what's controlling hepatic glucose production. That's controlling the fasting glucose. It's very important that the diabetic starts their day with a normal fasting glucose. Now they have a meal. They may start with a high fasting glucose, and the glucose shoots up very, very high. That's because of muscle insulin resistance. Okay? In response to the meal, it's critical that the C-peptide and the insulin level go up to stimulate the muscle glucose uptake. We have to look at both. If you want to know what the composite effect of the change in beta cell function is, you have to know what's happened to C-peptide in the basal state and what's happened in the insulin stimulate state.
I think we will get some insight into that when we see these new C-peptide data presented in the next day or two.
Just to simplify for everyone listening, this data we're going to get, though, is not going to be, you're not going to be able to do that analysis of change delta C-peptide over delta glucose in that specific way. Is that correct?
Probably not. I don't know what they're going to present, but I'm for sure they're not going to be able to, because they haven't done measures of insulin sensitivity using sophisticated techniques. From the oral glucose tolerance test, many, many years ago, we developed an index of insulin resistance. It's called the Matsuda Index. From the oral glucose tolerance test, if they have these data, they actually could express the increase in C-peptide and factor it by the change in insulin sensitivity or insulin resistance.
Okay. To sort of boil it down, when you see the data in a few days, in addition to the HbA1c, which you've already commented on, what would your incremental takeaway be on the C-peptide? What would you like to see there or observe there that would make you supportive of the continued disorder of the mechanism of action? Is there a number? I mean, I know it's a complex question here because of all the variables associated with the disease state, insulin situation, and where they are with their fasting glucose. How could you summarize it?
I would like to see, as I said, it's almost impossible to sort of put quantitation for all of the reasons that I said. I would like to see the fasting C-peptide go up. I'd like to see the C-peptide in response to a meal go up. As I said, in order to interpret those data, you need to see, look, I could have a 50% increase in the C-peptide in one person, and I could have the A1C drop by 1.5%. I could have a 100% increase and have the A1C drop by 1.5%. Unless you know what the impact is in terms of.
You could have someone who's very insulin resistant, then if you double the C-peptide, you may not see a change on the HbA1c, right?
Yes, exactly. I mentioned this earlier because I think these very insulin resistant people, eventually, their beta cells are going to fail. You simply are not going to develop significant hyperglycemia unless your beta cells fail. Initially, when you study these insulin resistant people, you may see a doubling of the C-peptide or even more, but not much of a change in the A1C because they're so insulin resistant. Now, as their beta cells start to fail, their A1C starts shooting up. At that point, something that improves beta cell function or mass actually could have a big impact in that group. I know they're focusing because it makes sense. Let's focus on the people with severe insulin deficiency. That's the way my drug works. That's where I'm going to see the biggest response. It's 20% of people in the U.S.
If you go to China, you have lean people, it's going to be bigger. We don't have a treatment for these people. We know.
Let me ask you this. Is there a minimum percentage increase in C-peptide that's interesting, or we can't even frame the question that way?
I think that's really, as I said, it's inappropriate. I know you would like a number, but the fact is.
Okay. That's fine. No, I'm just trying to get a feeling for it. All right, I think that's helpful. Let's talk about, let's just say we move forward and this therapy were at one point in the future to be introduced into clinical practice, not necessarily just the Biomea one, but this class of menin inhibitors. At least the premise now is that the goal is a pharmacodynamic effect in building the beta cell mass in addition to maybe improving the function of the existing ones, with the thinking being that you do this, you give people an epoch of drug, and then you stop because you've kind of achieved what you want to achieve.
They kind of get, assuming you haven't fixed the underlying autoimmune disease, there will be another decay again, and then there'll come a point where they'll need a booster, essentially, right? Then like another course of the menin inhibitor. That's, as I understand it, how the company is thinking about it currently. How do you think about it? Do you agree with that? Or do you think it should be more of just a chronic therapy or is this episodic approach consistent with how you think about it?
Yeah. I think the company's approach is quite reasonable. I mean, obviously, as the drug develops and it's being used, the company's going to learn more and more about the long-term effects. It is very clear that the initial treatment for 12 weeks, and then I think the A1C drop at week 12 is like 0.7 or 0.8. At 26 weeks, the drop was 1.5% in that severe insulin deficient group. Clearly, they treated them only for 12 weeks, and we see a nice effect is still persisting. We'll see what happens at 52 weeks. If I had to guess forward, the A1C actually will drop maybe a little bit more, but will be at least plateaued at 1.4%-1.5%.
The benefit of this is now I just treated you for 12 weeks, and now for the rest of the year, your A1C is going to stay under control. Will it stay under control for two years, three years? I mean, that all needs to be defined. It is pretty straightforward. I'm sure they'll do a study and they'll see, look, they're following these patients. Now at 52 weeks, if the A1C is still down, do I need to retreat these people again? Probably not. Now let's say at 52 weeks, I decided the A1C has dropped, it's in the normal range, and it's there. I'm just going to follow these people. Then over the next six months, the A1C stays down. Okay?
Then maybe at year two, they see the A1C starting to go up, then they may have to come in with another course of therapy. I think it remains to be defined how long this benefit and increase in beta cell mass and function is going to persist. Now, in type 2 diabetes, I think this is, I think, pretty straightforward. They'll do the appropriate clinical studies that define, look, when do I have to retreat? What's optimal? Okay? Now, type 1s, we didn't talk much about type 1.
I'm sorry to ask. Yeah.
We can if you want.
Yeah, briefly, sure.
In type 1s, this is an autoimmune disease. If I destroy all my beta cells and now I come in because we know these activated T-lymphocytes, they may not be circulating in the body after six months after you destroy all your beta cells. I know if I come and try to give you new islets, those activated T-lymphocytes say, "Oh, I can see you're trying to trick me. I'm going to go destroy those islets." The immune response is a big problem. What is interesting here is if there's a way you can temper the immune response, and we're learning that there are ways in which we can shut down, move up this new drug has promise, and I think we'll have even newer drugs that show that we can temper the immune response.
The other thing I find that's very interesting is we have these type 1 diabetics who live to be 100, and they don't develop complications. Almost all of them have significant C-peptide secretion, which means there is a population, now this is a pretty simplistic interpretation from a non-type 1 expert, okay? For some reason, not all of their beta cells were killed in the immune response. What's different? Why are these people still having C-peptide secretion? That suggests to me that their beta cells, whatever the antigen is on the beta cell that the immune response is directed against, it hasn't been directed against these beta cells. Maybe this is a population who has residual C-peptide that I can increase that sort of clone of beta cells, and they won't be rejected.
It may be, look, just like islet cell transplantation, I need to have some immunosuppressive therapy that goes with it. I think these are all things that really are to be discovered. To me, it's a very, very exciting area because what are we doing now? We don't have enough beta cells. What we're doing is now we found out, oh, we can get stem cells. We know if we give stem cells and induce them into beta cells, they get rejected. Now we've got to coat them and now give coated islets to protect. Maybe we'll have better immunosuppressive therapy. Now when we increase the beta cell mass endogenously with newer therapeutic interventions, we can also have a treatment for type 1 diabetics. To me, this is a very exciting area.
I'm not a type 1 person, but there are some really good people, Dr. Melton, Dr. Stewart, these who really are experts that I'm sure are very excited by this area.
Are you doing work, I mean, not directly here, but are you following any of the work in some of these programs, these facilities you kind of referenced, these hypoimmune cell therapies that are delivering insulin-producing beta cells? There are a bunch of companies that are doing this sort of thing.
Yeah. I mean, I think it's a very exciting area. I think this could be a huge advantage. Of course, the Bionic Pancreas was just approved for type 1 diabetics. I guess they're on the stock market now, the company that makes it. This is a huge advance. Still, it's cumbersome. Yes, it's better than having to stick your finger three or four times or using CGM and adjusting the insulin infusion rate. It would be very nice if we had a way that your own pancreas made its own beta cells that responded to glucose and wouldn't have to worry about a pump malfunctioning.
By the way, that experiment you referenced earlier, the one where you were going to sort of give a very high dose of glucose to kind of figure out the maximal output of the C, so you could kind of do a calibration on what the mass is and then work it out. Are we going to, I'm curious, is that something we're going to get to see soon? Where is that in the clinic? How's that going?
I'm talking about it with one of the companies about funding the study. I'm working with Professor Rohit Kulkarni at the Joslin Clinic. We'll see where this goes. Again, we hope that in the near future, and I'm talking about months, there'll be interest in funding the study. We have thought about submitting to the NIH, but at the current time, as I think everybody knows, the funding levels have been cut down dramatically at the NIH. I think it's more likely that we will hopefully get funded through one of the pharmaceutical companies that are in this menin inhibitory field.
Okay. Now, you talked a little bit also about the combo idea with the menin inhibitors increasing the GLP-1 receptors. Assuming we see these menin inhibitors such as the Biomea one hit the market, is it going to be your approach that you would just be doing combo, or is there a role for the menin inhibitors as a monotherapy? Seems like a pretty good argument. They have some animal data, some early human islet data as well, where the combo is doing a pretty good job with the GLP-1.
I'm a big advocate of combination therapy in general because there are multiple defects. When I gave the Banting Lecture in 2008 at the American Diabetes Association, I called it the Ominous Octet. From the , the Triumvirate was insulin resistance in liver, insulin resistance muscle, beta cell failure. It was the Young Investigator Award at the ADA in 1987. I called from the Triumvirate to the Ominous Octet, a new paradigm for the treatment of type 2 diabetes. I went from three problems to eight problems. Okay? In a subsequent follow-up lecture, just at the level of insulin resistance, I called it the Ominous Octet for insulin resistance. Eight distinct causes of insulin resistance. We're going to have multiple reasons why your beta cells fail. I also have an Ominous Octet, as you can imagine, for beta cell failure.
One of the very important ones we know is there's a decrease in mass. That's a huge problem. We also know there's severe resistance to GLP-1. Okay? What I found was quite striking in the early data that was presented with the icovamenib is that a lot of these people were on GLP-1 receptor agonists. These are incredibly powerful drugs. They were failing. They had A1Cs of 8.5, 9. To me, that's resistance to the effect of GLP-1. That's very clearly shown by Jens Holst and people in Scandinavia. If I can improve the sensitivity to GLP-1, that's going to be fantastic. Okay? That's going to markedly improve insulin secretion. If I can give you more beta cells, and I can make those beta cells more sensitive to GLP-1, that's going to give me a huge effect on the beta cell.
Now, to me, they'll do the study at some point where they look at the menin inhibitor alone and the menin inhibitor with the GLP-1 receptor agonist. They'll be able to define, is there a benefit by putting the two together? Quite frankly, I would almost predict right now with 100% assurity. I never predict things wrong, quite frankly, in the diabetes field. I joke all the time. I said, "If you go against my idea, the likelihood of you being successful is 0%." I have never called anything.
You got to come work on Wall Street.
Oh, yeah.
We need you. We need you.
Look, I was so stupid. I didn't patent the SGLT2 inhibitors. My goal is to make science for things that are going to help people. If you want to pay for the research, of course, that is good. I'm more than happy to talk to the people on Wall Street. My prediction is that the GLP-1 plus the menin is going to be a really quite powerful combination to increase insulin secretion.
Now, let's just, okay, so in that world, how would it work? This is just completely thinking off the cuff here, but I mean, if it's episodic for the menin inhibitor, then you kind of do the menin plus the GLP-1 for a period of time, then you stop both, or do you stop one or the other? Or how do you do this?
Yeah. That needs to be defined, of course. For sure, you put the two together. It looks to me like the, I mean, we'll see. 12 weeks of treatment give you a good effect that persists, with the A1C still dropping at 26 weeks. We'll see what is going to be critical is what happens at 52 weeks in these initial studies. Okay? Let's say at 52 weeks, the effect is still there. Okay? I would say here, you would treat the combination therapy at the beginning, and you'd be using an oral GLP-1 so that you can combine it with the menin inhibitor. After 12 weeks, you would then just go with the oral GLP-1. This, of course, needs to be defined, but with time, and we will define it. At 52 weeks, maybe you have to give another course.
You have to give the menin inhibitor alone. I mean, we really need to see what happens at 52 weeks. You may not have to repeat. If you now regenerate the beta cell mass, and now you have the GLP-1 receptor on board to improve the function and the mass stays there, maybe you do not have to repeat the menin inhibitor therapy at 52 weeks. I mean, the fact is we are very early in sort of looking at the natural history of what this class of drugs is doing. I think the C-peptide data coming out in a couple of days will be important. What happens at 52 weeks is going to be important as well.
The one area we'd be remiss not to touch on is obviously on the other side of the clinical equation, that's safety. As you know, in the menin inhibitor space, these drugs have also been developed in a totally different world in acute myeloid leukemia. There, one of the double-edged swords is that while they do what they're supposed to do, sometimes they can almost work too well in terms of what you see as what's called this differentiation syndrome. Some think or wonder whether is there a way or world in which, because you're getting this proliferation of the beta cells, if you do that too much or too long, that it could become oncogenic or produce some sort of aberration that would be problematic. What are your thoughts on that whole side of the equation?
Yeah. I mean, this is a significant concern, and it will be addressed on a long-term basis. Now, the initial studies, there was an increase in the LFTs. There was a temporary hold in the icovamenib studies. That was with a higher dose of 200-400 mg. As they've decreased the dose to 100 mg, they really are not seeing any significant liver signal. The data that they published in the three arm study, A, B, and C, there was a little increase in nausea, maybe a little increase in diarrhea. These were very mild grade one type side effects. I would say right now, the early side effect profile looks okay. Now, the menin inhibitor syndrome, there's a genetic defect that has been described, and you can get adenomas in the pancreas and other endocrine organs.
Here now, this is a genetic defect. You're born with this defect all of your life, and you see these adenomas develop later in life. The idea is I treat you for 12 weeks. It's a very short period of time. The anticipation is that you're not going to get into this problem with endocrine organ adenomas. I think this is very likely to be true. You won't get a problem. Again, this is going to have to be monitored very carefully with long-term follow-up studies.
Okay. And then sort of last question to wrap up. You know, as you've been doing diabetes for many decades and have seen many, many successes and failures, obviously, since the 1980s, I mean, how would you position or rank this approach, this menin inhibitor approach in terms of overall novelness and potential as a new class? I mean, of course, the idea is not new, but the potential for it to actually work maybe is new.
Yeah. Personally, I'm very excited. This to me is a major advance that if we can increase beta cell mass and function, this is huge, huge. For sure, in this severe insulin deficient group, these are the most difficult people in the world to treat. They progress very rapidly. They don't respond to anything. Okay? You can see a lot of these people not even responding to GLP-1 receptor agonists. This is a huge unmet need. There are very, very good published data. These people are very, very high risk for microvascular complications as well as macrovascular complications. They're very difficult to treat. If we have an approach that can actually regenerate beta cells and make them function better, and we can normalize the A1C for this 20% of people, this would be a huge, huge advance.
As I said, even in the other group of people who are more insulin resistant, at some point, their beta cells are going to fail. When their beta cells fail, now they're becoming an insulin deficient group. Even at that point, I think this approach with the menin inhibitor plus minus the GLP-1 receptor agonist actually can be beneficial in that group as well. I am excited about this. I think it's novel. I think it has a lot of potential. For this severe insulin deficient group, I think it really can be a major advance.
All right. Thank you so much. Really appreciate it. Maybe we'll circle up again after some of this data has been released, and we can debrief on your updated views.
Yeah. I think I'm actually, I don't know what the results are going to be. I'm excited to see. Of course, when we see what they present, we'll have better insights. Like I know you'd like to know more about the C-peptide. When I see the results, I'll be able to give you a better idea of what I think about the C-peptide data too.
Okay. We look forward to that. Thank you. Enjoy the rest of the afternoon down in Texas. Thanks so much. You're very, very interesting.
Okay. It was a good chat. You're a good buzzer.
Thank you. All right. Thank you, Dr. DeFronzo.
Yep. Bye-bye.
Bye.