Biomea Fusion, Inc. ($BMEA)

All right. Good afternoon, everybody. Thank you for joining us this afternoon for what I believe will be an informative and lively discussion with our guest KOL, Dr. Alex Abitbol. We're going to cover a number of topics in the diabetes space concerning both type 1 and type 2 and with a particular emphasis on icovamenib from Biomea Fusion. We also find our call to be particularly timely as we are exactly 1 month today from the start of the ADA conference, which takes place this year in New Orleans. Before I ask Dr. Abitbol to introduce himself, we want to point out that we have a research coverage of Biomea. We rate the shares a buy, and I hold an $8 price target. Neither I, nor members of my household own shares in the stock. The firm does not own greater than 1% of the stock. The firm has not received investment banking compensation in the past 12 months, but it may seek compensation in the next 3 months. Finally, if you have questions for Dr. Abitbol that you would like me to anonymously ask on your behalf, please shoot me an e-mail at [email protected], and I would be happy to put that in front of our guests. So with that out of the way, Dr. Abitbol, can you would like you to introduce yourself and tell us a little bit about yourself, where do you practice, what kind of patients you see? And then tell us about any conflicts or disclosures that you want to mention.

Certainly. Thank you for having me, everybody. I'm Alex Abitbol. I'm an endocrinologist and Assistant Medical Director at LMC Healthcare, which is the largest single specialty group of endocrinologists that practice together across 11 sites, mostly in Ontario, Canada, centered mostly around the Greater Toronto area as well as a site in Calgary, Alberta that we have as well. As part of my role, I see patients with general endocrine disorders, of which about 50%, 60% are affected with diabetes. And within that breakdown, about 80% or so, 80%, 85% have type 2 diabetes, and then about 10% to 15% are affected with type 1 diabetes. I'm also an investigator for centricity research. And so my relationship with Biomea is that I met them initially as we were being considered as an early phase site for their Phase I single ascending and multiple ascending dose trials. And then we were also selected for some of their early phase type 2 diabetes and type 1 diabetes trials after they had initially started in the States and then we got started in Canada. My interest certainly have anything to do with wide-ranging clinical implications for patients. And I have received investigator fees as part of the clinical trials that we supported Biomea. I'm also an adviser and consultant for Biomea as well as all of the major pharmaceutical companies that have anything to do with GLP-1s, SGLT2 inhibitors, DPP4s and lipid-lowering medications that we use in type 2 diabetes and cardiovascular disease.

Great. Well, thank you for that thorough overview. To set the stage, LMC -- you gave us a bit of a tease there, but your role at Centricity Research, what is your typical patient flow look like on a day-to-day basis between type 1, type 2 and then those that are participating in clinical studies?

Yes. So it depends on which day of the week. But if I'm booked for clinic, then usually my patients are booked at intervals that anywhere between 10 and 15 minutes. I work with the physician's assistant. So I'll probably see between about 30 and 35 patients per day, mostly follow-ups, but between 5 and 8 new patients that are referred to me. The breakdown, as mentioned, is the majority, I would say, 50%, 60% are affected with diabetes. The other remaining have general endocrine disorders, like thyroid and lipid and pituitary adrenal disease. And then in that diabetes cohort, it's about 80%, 85%. The flow-through is most of them are referred by their family physician. In general endocrine care, it's pretty rare to see people who are only on metformin or on no therapy because they're often managed by their family physician. And when they're referred, it's either because we're in an urban region where there are good access to specialists and they want access to dietitian support. They want access to injectable medicines like GLP-1s earlier on in the disease course. And so fundamentally, they refer them earlier, or in some of our more remote locations or suburban communities like Oakville and Brampton, the family doctor is traditionally managing them until they're out of options and referring them either for an insulin start or when the management becomes too complex because of comorbidities like kidney disease, and they don't know how to adjust the medicines anymore.

And what proportion of patients are new to treatment versus follow-up?

I'd say about 10% to 15% are newly diagnosed with diabetes. 50%, 60% are probably on more complex insulin management or either on or recently started on GLP-1s. And then the remaining might come from referrals outside of GPs, like internists, cardiologists or nephrologists, with either a specific question or a diabetes patient who's also managing for something else, like a lipid disorder or a kidney disorder or happens to have a general endocrine disorder that also needs to be managed.

Does that flow changed at all in the era of GLP-1s at all? Or is it -- has it really not bent the curve at all?

Yes, I would say it has. When I started practice, we would say that when specialists start prescribing a new agent, it takes on average between 5 and 7 years before family doctors will jump on board, and you'll see them start referring to this to specialists, and they'll actually start prescribing it for themselves and feeling more comfortable. And then you see sort of the uptick in primary care matching the initial uptake that you see in early adopting specialty care. But I would say now it's faster. And people are asking their doctors for the therapy that they see advertised on the Internet or that their friends are on or that they see Oprah taking. And so fundamentally, they're asking. And so the GPs are having to be a bit more receptive to newer agents and newer technology a bit faster than before. But it's still messaging to specialists and then messaging to primary care, depending on obviously how it's doing in specialty care.

Got it. Okay. I do want to start diving into the mechanism of action of icovamenib, but I also want to explore this discussion about the patient population because they're obviously not all monolithic, and I'd like our listeners to better understand the potential commercial opportunity for icovamenib. I think it's a given that a large preponderance of type 1s would be eligible for treatment with icova. But clearly, there's a large population of the type 2 diabetics that could also benefit. So my question is 2 parts. First is, what is -- I think we -- I didn't ask you specifically, but what proportion of your type 2 diabetic patients are already on a GLP-1 and failing to get benefit? And what proportion of type 2s are on insulin? And even further to that, what proportion are of this brittle form or this SIDD form?

Yes. Good question. So I would say that for the proportion that are on GLP-1s in specialty practice, you're always going to see higher proportions. So we sit around 35% to 40%. And it's a lot higher where we reside in Ontario because of better public access to GLP-1s for those over the age of 65. When you look at primary care rates or sort of the overarching rates just amongst all people affected with type 2 diabetes, we're somewhere between 15% and 20% for those affected with diabetes. Across the lifespan, somebody with diabetes will need insulin 50% of the time. In specialty practice, we see about 50% to 60% that are treated with insulin currently. And of that, about 20% are treated -- or sorry, of that 60%, 20% is treated with multiple daily injections. The other 40-or-so percent is on basal insulin only. In primary care, it's always going to be less. They see a diabetes patient every 40th or 50th patient. I see every second, every -- or 2 out of 3 patients with diabetes. So in my practice, I'm always going to see more insulin. In primary care, they're seeing those patients, but they're either not really managing the diabetes because they're followed by a specialist or they're seeing a much lower proportion, usually 10% to 20% that are treated with insulin.

Right. And are they coming to you -- or type 2s coming to you on GLP-1s and not getting an adequate response? Or do you not see that patient in your clinic?

It varies extensively, but I would say that when I -- when semaglutide launched and maybe in the 5 years that followed, the majority was being started in my office. And people were being referred for GLP-1s. The same as before GLP-1s, they were being referred for insulin. Now we're still getting the same, if not more patients, referred for insulin, but more are coming to us already on GLP-1s, looking for the next GLP-1, looking for what to do when they failed GLP-1 therapy and either need more weight loss or more glycemic control to a much greater degree. I'd say it's probably about 50-50 only because in my Toronto office, we get referred them earlier on. So there, I'm probably seeing about 30% referred to me on GLP-1s. In Oakville, where I practice, they have a very savvy GP population. They're about 60%, maybe 65% are coming to me on GLP-1s.

Why would it be higher if the GPs are savvier?

Because they have to manage the diabetes for longer. They're coming metformin than an SGLT2 than another agent and they're out of option, I'm going to refer. I'm an executive health physician and I'm newly diagnosed with diabetes, I want to see a specialist right away. And I have access to one because I'm in Toronto. So different.

And what type of failure -- not necessarily failure rate, but relapse rate or inadequate response rate are you seeing in that population? Do you have any sense of that?

It depends what you mean.

Well, I mean the patients that are type 2 diabetic, that have been on a GLP-1 for 6 months, 12 months. Now the slope of their weight loss is either plateauing or coming back or because of tolerability challenges, they are -- they've gone off and now have to have some other alternative.

And we'll talk about this when we get into the mechanism of icovamenib. Fundamentally, diabetes is a progressive condition. So if you manage a patient for long enough, whether they are being treated with 1 agent or 2 agent or 3 agents, they will eventually need another agent because none of the agents we utilize right now outside of those that cause profound weight loss and can mitigate to a certain extent the course of the disease, there is the unfortunate consequence that eventually, you're going to need another agent, or you're going to want more weight loss after achieving good glycemic control.

Got it. Okay. All right. Since you brought it up, let's switch to the mechanism of action of icovamenib. I did cover this in detail, and this is for our listeners. I covered in detail several weeks ago with a call I did with the company in late April, but I think it bears repeating that icovamenib operates by a mechanism that is unique in the diabetes space and derived from human biology. Dr. A, I like the way you described it during our prep call yesterday in the expert in the space. And we'd like to understand how you view the science and what may -- what you found captivating or compelling about it?

Yes. So I think that for me, what captivated me is that whenever you get an underlying disease process that leads you to have something that intervenes with the pathway of the disease, then you're able to consider it at any point in the spectrum of diabetes. And that means not just when someone is diagnosed, but somebody who might have prediabetes, somebody who might have risk factors for diabetes, somebody who might have more advanced disease and is looking to lessen their burden of medicines. But the real fundamental key with this is that most people who are diagnosed with diabetes are under the impression that their disease just started at that very moment. The way it works is your pancreas is usually making a lot more insulin for many years without you being aware, and you only become aware when you've reached that maximal capacity. And why it's progressive is because you're not at your maximal insulin production forever. Eventually, you come down. And when you go on to metformin or other agents, all you're doing is lessening the glucose, either by telling the liver to make less, to let the kidneys pee more out, to make more insulin in response to meals with older and newer agents. But the beta cells and the loss that happens over time in both function and number is what eventually leads people to say, "I'm doing the same thing. I'm taking the same medicine. Why does my sugar get higher and higher? And why is it that I need another agent?" What's heterogenous here is that everybody may respond to medicines differently, may have different durability of these medicines, and they may be heavier, leaner. They might have more family members affected. And so when we get at something that can actually prevent the next medicine, something that may lead to essentially what protected you from high glucose for many years before you're getting at the disease is what excited me in the type 2 space. And as we get to it in the type 1 space, well, that's where I'm even more excited as a clinician. We've had nothing new in type 1 in over 100 years. It's just been insulin. But to make insulin in someone who no longer makes insulin for someone who's type 1 begets millions of questions as a clinician because there's an immune-mediated process by which they destroy it. But we're talking about groundbreaking research there if you can give somebody who has not made insulin for many years and all of a sudden allow their beta cells to not only come back, but to be regenerative and allow hopeful an insulin reduction or a reduced rate of complications.

Yes. It definitely is fascinating stuff. So I want to just talk about the sort of the initial observation by Karnik in 2007 in his paper at Stanford. It's rooted in the observation that menin is naturally suppressed during pregnancy and lactation -- expressed in pregnancy and lactation and it enables the beta cell to expand and increase insulin output. As a clinician, how intuitive is that biologic rationale? And do you think the field is ready to embrace a short course of therapy that aims to restore the underlying cellular machinery rather than simply managing glucose on a day-to-day basis?

So the way I understand it is that menin is essentially one of those ubiquitous processes that's involved in essentially putting the brakes on cell growth and proliferation. And so by inhibiting it, as we see through a prolactin-mediated process in pregnancy, you see obviously that the cellular expansion and growth can allow it to restore or even enhance what you're seeing in the case of a pregnant female pre-pregnancy levels and hopefully in somebody with diabetes to the state by which they had before they ran into the problems of high blood sugar and needing more medicines. And that's why ultimately, when you were looking at a ubiquitously present process that was involved in cell growth, that's why I think the oncologists had it for longer than we did because it was a unique target to consider an acute myeloid leukemia for ultimately inhibiting the cellular growth process that leads to cancer formation.

So if you were to -- let's say, a icovamenib is approved and it's whatever, 2029, 2030, when you explain it to a patient, they progress to either type 1 or type 2, you find them to be a suitable candidate. Do you think this is a -- the narrative of what icovamenib does is easily understood by the patient and would be embraced by the patient?

So the narrative today, based on the trials they've done so far, could look like -- and you mentioned the SIDD patients because I'm sorry, I didn't cover that before. But amongst the ADA framework, they define different patient subtypes. But I can't say that when I'm sitting in my office, I'm actually thinking of these patient subtypes, especially not if I'm not thinking in the paradigm of this is somebody who might have insulin deficiency, I should start them on insulin. I'm not really thinking of other subtypes. But the narrative today could look like you're on three or three agents, you're needing a fourth agent or if you don't do well on that, you might even need insulin to protect yourself against kidney disease or eye disease or heart disease. But instead of me giving you a medication that you're going to have to take for the rest of your life, I'm going to give it to you for between 12 and 24 weeks. We're going to allow the subcellular process by allowing your pancreas to regenerate and make more beta cells. And then you'll be able to stop that therapy and have durable improvement in glucose where maybe we prevent the need for more agents, reduce your risk of complications and in the best case, can even reduce your background medicines. In the case of the studies they haven't done, then someone on insulin could be put on this therapy and then ultimately remove the need for their background insulin.

Or at least reduce the dose, correct?

Yes, or reduce the dose or reduce the fast-acting doses and maintain them with just a lot of people who go on semaglutide or someone with prediabetes who's being told about lifestyle factors and weight management and all of that very, very important. But instead of inevitably staring down the problem of eventually developing diabetes, taking a short course of treatment and thus preventing many more years before they develop the disease. And the other study that they haven't done is the before metformin study. So when you reached a threshold, I've tried my hardest for 3 to 6 months, I've done everything I can. I've told my family doctor to just give me another chance 3 or 4 times, and I'm still in a range where he's recommending therapy, then okay, I'm not on lifelong therapy. I'm on a 3-month or 6-month course of therapy and then I stop and then I don't need to worry about taking long-term medicine and have similar control to those who take regular medicine.

Right, right. Well, yes, it will be very interesting to see how long that effect does last, and we'll come back to that in a minute. I'm just -- yes, for sure. So I was just -- I'm just curious, were you familiar with this work by Karnik before? Because it seems like such a fundamental, and for me anyway, who loves drug targets that arise out of human, either human genetics or human physiology, it seems so physiologic. I'm surprised that it didn't sort of open the floodgates to more work on it, but I don't know if you can comment on that. I was a bit surprised that there weren't a whole host of papers following that.

It was -- so I'll say 2 things. It was a new mechanism for me. And if I'm giving my opinion, as I mentioned yesterday, I don't think it's the only mechanism that protects against the insulin resistance that happens through placental-mediated processes when you're pregnant. I think it's one of the few different protective mechanisms. And I was shared this mechanism by Biomea in full disclosure, and I sit on a few of the advisory panels where some of these experts did speak to the mechanism, and it was not only palatable to me, but through global experts in the field. But I will say that general endocrinologists also treat high prolactin in a pathologic process. They're usually from pituitary tumors or background medicines that have the side effect of raising prolactin. And I am not familiar with any protection that, that has ever been demonstrated in people affected with insulin resistance prediabetes or diabetes where they naturally see improvements like pregnant women do through an only prolactin-mediated process. So I think it's one of the explanations and maybe the uncoupling of menin as the partial response for Y beta cells. But I think there's other things going on as well that are also preventing hyperglycemia pregnancy.

Okay. Well, it's good to know. There may be further work to be done there. What -- one thing I do think is interesting, and again, as a clinician, what that means to you is that this is -- the menin regulation is context dependent, it's glucose dependent. So how does that give you comfort as far as treating your patients with a menin inhibitor?

Well, I think my main concern is menin is also known as ME1, which is a gene that's coded in humans that when it's mutated, can actually lead to tumor genesis that affects pituitary, pancreatic and other neuroendocrine tissues in the body. And so my worry was that by inhibiting it the way that they're doing it, that you may see neuroendocrine tumor growth. Now fortunately, they did a robust job of tracking every possible subcellular signal, and we didn't see anything remote to that. But it was also explained to me better thereafter that it's very different when you're inhibiting it thereafter in the context of hyperglycemia in a pathologic state than when you're born with this genetic mutation and, of course, never had the ability to encode any of the protecting factors that prevent that from happening, which is why when they did in leukemia, they also didn't see any new tumors forming or inhibiting the cancer. That also provided me with a lot of reassurance.

Okay. And then the glucose dependency, is that protective against hypoglycemia or...

So that's the distinct advantage of when you're using endogenous factors, you're not going to have a high risk of hypoglycemia. We didn't see much hypoglycemia, although the full disclosure is that they excluded people who were on background agents that could cause that or insulin. So we weren't going to see a lot of hypoglycemia. But certainly, we didn't expect that a beta cell response that heightens the amount of insulin led to low blood sugar. That only happens with sulfonylureas and background insulin because there's no way to turn that off endogenously when it's happening.

Right, right. Okay. One more mechanistic question, and then we'll move on. I often get asked about what -- to what do we attribute the durability of the effect. So if you take a GLP-1 and take it away, you'll regain your weight. You take most medications, your heart, your blood pressure, your cholesterol, you take the medicine away, and you return to your baseline. We don't see that yet with icovamenib. You would think that the beta cells could proliferate, get healthier, but do you think once the medication is taken away, they would probably regress. Any thoughts on what changes? Is it creating some kind of effect internally? Or what do you think may be responsible for the durability?

The mechanism of action and the fact that all of the other agents you mentioned, CPP4s, MET, SGLT, they're all reliant on their half-life. Once the medicine is gone, the effect on whatever tissue it's operating on to reduce glucose, nothing to do with beta cells or insulin resistance, but just to reduce glucose, is lost because about 1.5 days after not taking an SGLT2 inhibitor, glucose will stop being urinated out. You don't take your metformin for about 18 hours or so, and you're going to see more production of glucose from the liver in a disordered process that it's not happening. But none of that is, in essence, intended on allowing the pancreas to regrow or expand the beta cell mass. And then by withdrawing the therapy, you accept that, okay, this is now my regenerated and regrown...

This is my new...

Which is functioning at a higher level than before. I'll withdraw the therapy. I know I will probably lose these beta cells again in the future as I don't know how long that will be, but the same process is still going on in the background. It's just giving me more time and more beta cells to thus prevent the need for more medicines. And fundamentally, diabetes is a high glucose factored over time. So the higher your glucose and for longer, the more you'll damage eye, blood vessels, kidney blood vessels, heart blood vessels. So any means that reduces that and ideally by preventing the need for more medicines and insulin and thus reducing the rate of hypoglycemia is going to put that patient in a better situation.

Okay. Wonderful. I want to -- I'm going to kind of work in reverse order here because the most recent data was in type 1. But in terms of your type 1 patients, what remains the hardest problem to solve? Even those that are on the best-in-class glucose monitoring, automated insulin delivery, what other challenges do you face with them?

Yes. So that's a good question. I mean I live in a very spoiled closed-loop system world with a lot of technology, but these are all just insulin delivery mechanisms that are algorithmically adjusted. And still, there are obviously operator dependence, wear dependence, skin issues, hypoglycemia that even in the most savvy of closed-loop system remains an important complication. And even the best closed-loop systems, you still have to announce meals, you still have to count carbs, you still have to warn the pumps before you're exercising. So we're certainly not in a perfect setting of managing type 1 diabetes. We're just in a much better setting than when people were using injections and obviously, the older injections and the animal injections from 50 years ago way worse than before. But type 1s today are surrounded by technology, but they still fundamentally only have insulin to utilize. And many of them now are plagued with similar weight issues that are, of course, affecting the general population. Insulin is a growth factor. So the more they use for their condition, the more resistance they may ultimately develop from it, and then there's weight issues. So absolutely, if we can get at a process here as well that reduces or limits the amount of insulin they'll need, which, of course, doesn't change as much as in the lifespan of somebody with type 2, then you may fundamentally move beyond the technology that we're providing them.

Right. Now are you seeing -- speaking of that the weight gain and the growth factor aspect of insulin, are you starting to see these type 1.5 patients?

Yes, yes. Yes, it's always been the case. People are becoming resistant to the exogenous insulin. And there are great papers by Shaw, by others in the field that have demonstrated that. Even in people on closed-loop systems that have type 1 and high BMI, they do better when you also add in GLP-1s, weight-wise and glucose-control wise. So there's certainly something to be said about weight management, even in those that need it for type 1, and the insulin requirements they have often exceed the pump reservoirs that we have today. So it's even more complicated in managing some of these type 1s with insulin resistance.

Yes, yes. Interesting. Very interesting. All right. So let's -- as I said, we're going to run in reverse chronology here. Just interpreting the COVALENT-112 type 1 data that the company put out, it's a 52-week data from COVALENT-112 that came out last week, showing a 52% increase in mean C-peptide at week 12. In the patients that are on 200 milligrams, you saw a 7% decline from the peak to week 52 following that 12-week course. So what's your clinical reaction? We had sort of 2 arms, groups of patients in that study? What were your reactions to the data that you saw there?

My reaction was generally positive. I'm missing a little bit of data to really kind of uniform it in my brain, that we're seeing endogenous C-peptide production in type 1s who've been inside of 15 years since their diagnosis. So obviously, you're super excited. You try to put it next to the early [ teplizumab ] data and some of the other ones that we're not looking at Stage 3 type 1 but Stage 2 and before type 1 and really trying to wrap your head around a lot of what this means. I would have liked to have seen sort of the PK/PD with the response to C-peptide since as we discussed yesterday, some of the nonresponders here, I'm curious why we didn't see always a response. And yes, type 1 diabetes is also a very heterogeneous condition, but still fundamentally did it match with the exposure that they got to the dose? Was it something else that might explain it? And 52 weeks, I think, is a long time frame to obviously have given the dose for as long as they did and then see a decline thereafter. But we're dealing with an autoimmune form of diabetes. So great that we've demonstrated that it works and that we can make more C-peptide. What this means clinically is still an important piece because we didn't look at insulin doses and certainly complications long term is the most important thing to be looked at for a type 1 because even if they don't come off of insulin, more C-peptide is also tied to less complications for that person for many, many years to come has been demonstrated by all of the big type 1 registries.

Yes. Now how do you -- not to interject, but how do you look at that C-peptide and an improvement in the AUC over that period of time versus the relative or absolute reductions in A1c? Are they equally as important? Or if you had to choose one versus the other, would you choose a C-peptide or would you choose the A1c reduction?

I would choose the C-peptide. Yes. Because in the long term, the A1c with a type 1 has so much to do with how they titrate insulin and how good they are and obviously adjusting, but the C-peptide is the biggest predictor of complications. It means that even if you manage somebody with type 1 perfectly, if their C-peptide is 0, that person is still, at some point, maybe 40 years, 50 years, going to see complications at a higher rate than someone who might have similar control and it's still making some C-peptide. I analogize it for my patients like a parachute. If you don't have anything left in the pancreas, then when you're not calculating perfectly when you're seeing hyperglycemia, there will be no response whatsoever from your pancreas. But if you're making a bit of C-peptide like we see in our honeymooning type 1s who are newly diagnosed and new to insulin and they still have a lot of endogenous pancreatic production before they really run out of it completely, they're a lot easier to manage. Their insulin doses are a lot more liberal, and that's what we hope to see with this as well.

Right. And now that you mentioned the honeymoon period, I would ask you to comment about -- you said -- you may have mentioned that the patients had been less than 15 years with -- from diagnosis. But also, these were all Stage 3 type 1. So how does that impact your perspective on the data versus the patients that might be earlier or still in the honeymoon period?

So the honeymoon period is still Stage 3 because you're usually honeymooning when you have high glucose, but you still have detectable C-peptide. We usually find other antibodies or they're very young, and so it's clearly not type 2 diabetes. It's a juvenile form. But the idea is that in this stage, you are clearly antibody positive, clearly having hyperglycemia may have presented in DKA, but your doses are not quite at 0.3 to 0.5 unit per kilos yet. You're usually well below that because there's still some endogenous production. But within a year, 2 years, 5 years in the best case, that person usually becomes C-peptide negative or near undetectable, and then you see their doses move up to the conventional. When we talk about earlier stages of type 1, this is when they have antibodies and have no discernible hyperglycemia. And even if we challenge them with the juices that we give in pregnancy, they still are normal, but they have positive antibodies, which means we have to watch out that they might develop it. And in Stage 2, they have positive antibodies and they are beginning to have hyperglycemia, they either only have it on challenge like the juice we give in pregnancy or they're in like the prediabetes or at-risk zone, where they're not quite meeting the definition for type 2 diabetes, but we have antibody positivity and they are close to it. It's very difficult to find those people. So I'm very excited about something for Stage 3 type 1 because that's what I see. That's what we detect. That's when the patient usually becomes aware of the disease. The type 1 detection programs that are going on are fantastic, and they're a little further along in the U.S. than we have in Canada. But success is not a lot of patients. The number of people that have been infused is a few hundred. And that's because to find somebody with earlier stage than Stage 3 type 1 diabetes, we're really nowhere near there clinically. And outside of research registries, even there, it's rather slow in my opinion.

Right. And when you say infused, you mean with teplizumab or...

Teplizumab, that's right.

Yes. Okay. You did touch upon this, but I want to come back to it and ask you, again, we're very close to ADA. Biomea's data will be presented on the 5th. The things that you'll be looking for or asking about are what...

Yes. So this is an early phase trial. So like I get excited by glimpses of data that show me C-peptide and hopefully improvements in A1c and robustness of rates of hypoglycemia and insulin doses as all of their endpoints kind of outline. But early phase trial, I need to see the treatment-emergent adverse events. I want to look at liver, I want to look at kidney. I want to make sure there are no surprises with any of these neuroendocrine hormones that I mentioned. And that's because I'm actually worried about the mechanism actually leading to it, but with a novel molecule in a new space amongst endocrinologists that have never heard about it before, you're going to run into skepticism. And so you really have seen data early on to get anywhere outside of the effect that largely we're excited for in later Phase II and early Phase III data.

Right, right. Okay. Well, maybe we'll book an appointment with you to come back after ADA and let us know how the audience reacted. Going forward, company outlined a very interesting trial in the T1D population where they're going to give an upfront placebo-controlled regimen for 6 months with icovamenib monotherapy versus placebo and then rerandomized either off therapy, continue with icova, immunosuppressant baricitinib or -- sorry, yes, and then the JAK inhibitor alone. Comments about the study design, does it make sense? Do you worry about combining with a JAK, which tends to have their own idiosyncratic side effects?

I'm not an expert with immunosuppressant. I've been involved in a handful of the interferon-based ones with GLP-1s in my early days as a sub-investigator with older mentors, but I find it interesting. It's a 4-arm comparison. So they're going to need a lot of patients to get enough statistical power to show differences in those groups. So the methodology of the trial is very challenging and a huge undertaking because I worry they'll see small differences after they cross over the groups, but it's what we want to see. We want to see if the drug beats out placebo and then thereafter, how long it persists for with or without immunosuppressant. So kudos, if they can pull that off because that's the trial everybody will want to read.

Right. Are they -- I mean, obviously, you could do lots of different -- you could do a study like this with teplizumab. You could do it with -- well, SAB-142 is investigative. But one could think about other -- and the insulin -- sorry, insulin, the IL-2 agonist from Nektar. I mean there are lots of different immune suppressants immune modulators that you can think of. Would you want to start to see further development there as well?

I review that data, and I really thank you for sharing it with me. But I really think the distinct difference here is that they are different populations of patients. If I'm thinking about infusing somebody with teplizumab, if I'm thinking about using Nektar's molecule, this is in Stage 2 type 1 diabetes. So this is to prevent the development of type 1 diabetes as a onetime treatment that I can never do again allegedly. And then that will buy me between 4 and 6 years before I'll go on to develop the disease. When I'm treating Stage 3 type 1 diabetes, and I am either using a short-term treatment to lessen the burden of insulin, hopefully reduce doses and come off, but that's very presumptive at that point. But also, I know that if I use this medicine for long enough, continuously, I have no idea yet that by making sure that I have more C-peptide than I started with, I can bank on having less complications long term. And all the better if it's a short course or a continuous course that's paired with an immunosuppressant that works because that's the worry of endose. You can make -- you can show me that I can make C-peptide in type 1. But if my immune system is just going to come back and wipe it out really, then that is unfortunately not as advantageous as it will be in a type 2 patient.

Yes, yes, for sure. Okay. Great. Well, let's transition then to the type 2 population. 1 in 3 patients in the U.S. will eventually progress to insulin use. Is that consistent with what you're seeing in your clinic?

The rates are higher as far as I know, the type 2 diabetes lifetime risk, although they're a bit outdated in an emerging world of these potent GLP-1s, where you're not going to insulin next, you're going to GLP-1s. But 2018 data would have said about 45% to 50% eventually need insulin for type 2 diabetes. And that can be for different reasons, right? We always think of the person who's maxed out, on 4 agents with a GLP-1 and needs insulin. There's also very lean people who don't go to a GLP-1, they go to insulin first. There's a lot of younger people, like those pregnant, they go to insulin first because none of these other agents are approved. And then your comorbid patients with more advanced kidney or liver issues, some of these agents weren't studied there. So there they often get more insulin too.

Right. Okay. And I think we touched upon this a little bit earlier, but I want to come back to the population that's been on a GLP-1, not getting any further benefit or still on the drug coming back? How much of that are you seeing now? And to that population, what do you have to offer them?

It's a great question. So yes, we see a lot of that now. I mean, even in my own practice, like when we look at the registry of GLP-1 users, there are still about 30%, 40% that are either treated with insulin or got started on insulin after they were treated with the GLP-1. In my own practice, we know that a lot of the people that would have been either treated with GLP-1 early on still will be started on an SGLT2 inhibitor, see problems of glucose control. It's not always as quick as it used to be. But when we have a registry that follows these people because these are our patients for many years, but the 2- to 3-year rates are very different than when you were looking at the 1- to 2-year rates that were looked at in the clinical trials and treatment failure, if you follow somebody for long enough, is inevitable. So what do we do? Well, the GLP-1s now have higher doses, so we consider them. For many of them, there is poor access to things like Mounjaro or Tirzepatide. So we would love to transition even though there isn't a lot of data for switching. But many of them eventually get started on basal insulin and progress from there in order to manage their glucose control. It's just that it depends on your frame of reference. It's that we're starting them maybe 2, 3 years after a GLP-1, whereas it was maybe 6 months to a year after DPP-4 because the durability is way better, but it's not permanent. It's when you look at a patient statically in a clinical trial and you say, wow, 79% of people on Mounjaro reached a target of A1c, that's robust data. It should not be discounted. But 2, 3 years later, that percentage will have whittled down, and you're going to need to be doing something with that patient after.

Right. All right. And do you -- I mean, do you routinely look at -- does anybody look at in any systematic way about C-peptide in the type 2 patient populations that require insulin? And what does that look like?

It won't work well either because the different calculators like HOMA-V, HOMA-IR are fraught with discrepancy based on the glycemic control and body weight tends to make it very discrepant. But you can't look at a C-peptide as a static measure in type 2. It's really just to answer a clinical question. It's, okay, wait a second. This person is referred to me for type 2 diabetes, but they're lean, and they're telling me they've lost a lot of weight, and they're being managed with therapy that doesn't look like it's actually made an improvement. Let me take a second here and make sure this person is actually type 2 diabetes and not type 1 diabetes. And so that's how we diagnose autoimmune forms or type 1 forms in the adult population where they're often mistakenly think -- thought of as people with type 2 diabetes. But if I were to track somebody's C-peptide, well, it might look at first in type 2 diabetes like they're actually making more C-peptide, or their glucose control might improve. And so it might look like they're making less C-peptide. But really, it's just that they don't need to make as much because their glycemic control is better. So that's why we can't look at it as a measure over time.

Got it. Got it. One of the things that intrigues me, and it's clearly a leading question, but it's been shown that menin inhibition increases the number of GLP-1 receptors in pancreatic beta cell that makes for a very intriguing experiment, I guess or hypothesis generation about wouldn't it be great to -- in a type 2 diabetic who was on GLP-1, to put them on a menin inhibitor in order to get more out of the GLP-1 as well as to stave off them going to insulin for as long as possible. I mean is that a reasonable future scenario?

You hit the nail right on the head there, Michael. To be honest, that is I mean, I'm a clinician, so I can't put on my marketing hat or my financial forecasting hat like probably the people on this call, but we're about to enter a world of generic semaglutide. And so that looks very different than a world where you're paying a lot more for Ozempic or Wegovy because you're right, not only if I'm failing therapy, would I be more reluctant to go to the more expensive branded product? And of course, I never want to go on insulin. So if my only option to pay a lot for a branded product or to go on to basal insulin, then to enhance the effect of my background medicine or to augment it if I was initiating that over the more potent branded products, is a very strong message for clinicians because it's not changing therapy. It's enhancing therapy in the short term and then seeing obviously the effect that you might see with GLP-1s. And so in a generic semaglutide world, it's truly what a lot of the competitors would fear, to essentially even augment the penetration of generic semaglutide, which we're seeing in Canada start this summer, and you'll be seeing in the United States probably in the early part of next year. So that's a very, very important message because it doesn't augment too much today if you're paying the same for different products, but it does if there is a price advantage for augmenting your generic medicine.

Right, right. Yes. And I would -- I think we've seen sort of the prototypical type 2 patient who is going on insulin is probably -- is usually overweight, obese and you're giving them the insulin so they don't get the complications, but at the same time, you're pushing the rock up the hill in the wrong way because you're trying to -- you're losing control of their weight. So it might be...

And ultimately, the same thing that happens with the progressive disease of diabetes, well, weight management often follows the same course. You even see it in a lot of the weight loss trials that go to 78 weeks, because inevitably, even on the most potent therapy, people plateau, and weight regain is seen in a high percentage of people that ultimately even are very successful at approaching 20% and 25% body weight. And that's because of biology. That's left-mediated and appetite regulation centers that have no idea that you're trying to lose weight, and it thinks you're starving in the forest, and it's trying to keep you alive. So you touched on diabetes, but as I always say, diabetes and GLP-1s, that's old news it's obesity and GLP-1s that now 1 in every 8 person, I think, in the latest survey in the U.S. mentioned that they are either on or considering being on a GLP-1 for weight management. So if you can enhance even though that's not really what they're putting forth in clinical trials yet. But if you can show that you enhance GLP-1s in diabetes, why couldn't you do that same thing for weight management shortly thereafter?

Right, right. Okay. COVALENT-111, this was a study of type 2 patients. We saw A1c reductions between 1.2 and 1.5 percentage points, C-peptide 24% to 35% at the end of 52 weeks. Is that a meaningful outcome? Obviously, smaller studies, but we have to replicate that in Phase III. Is that a meaningful outcome?

Same story for that one. It's early phase, TAEs looked clean to me. There were no grade 3s. I really love seeing that data. I was happy to be a part of that clinical trial. 1% to 1.5% A1c, if replicated in a Phase II or Phase III trial would be on par with some of the GLP-1-based medicines. Now we're seeing obviously dual and triple agonists now pushed to a mean reduction of 2%. So this would be a little bit more with the early GLP-1s that we see but clinically meaningful. We approve agents that have a 0.4% A1c reduction, hugely clinically meaningful. And again, differentiator is short term versus continuous treatment. That you really can't put these agents together when one is being given continuously and one is being given spurts in treatment, and then we're monitoring for this A1c reduction off treatment.

Right, right. One of the things that I found a bit curious on COVALENT-111 was that the -- I could actually even share my screen on this. But I found that there was a lot of noise in the system, as you can see here. I mean, obviously, major reductions in A1c and with the Arm B is the continuous for 26 weeks. But bouncing -- these A1c numbers bounce around a lot. And I know they're relatively small, but not so small numbers, and A1c is measured over 90 days. So any thoughts about what's going on here?

Same thing. Yes. It's an early phase study where you're seeing the improvements not matched to the exposure. So did Arm A, Arm B, Arm C, did they see the same exposure to the medicine as tracked by their PK and PD or because Arm C had a higher dose, but they took it on an empty stomach, they actually didn't see as much exposure as Arm C that had a lower dose, but took it with food and therefore, saw a greater response. So I don't know. I don't love noise, and I agree with you. That would be an eyebrow raise for me, too. But I need to see that next to the area under the curve for the PK/PD. Otherwise, you see negligible A1c reduction that have high exposure, then I'm a skeptic. If they see no exposure, then it's formulation. You got to go back to figuring out how to get that drug into the bloodstream so it can augment the effect.

Yes. I'm not sure that's a concern at this point, but it's a good point. Okay. Just real quick, I guess, looking forward that the readouts, I think we've covered this pretty thoroughly. Let me ask a different question because I think we've touched upon this already. When you think about type 1 versus type 2, the drug is clearly exerting a strong clinical effect in both type 1 and type 2, although the etiology of the underlying condition is different. I mean they're losing pancreatic beta cells in type 2, but it's not an autoimmune reaction. So does that -- I guess it doesn't surprise you that it works in both patient populations.

Yes, it does, but it's because of how it works. So the same way SGLT2 inhibitors, we studied them in type 1 because you can pee out sugar and still see improvements in how high your sugar goes after meals even if you're not making any insulin from your pancreas, the problem was ultimately the risks of you glycemic DKA, which we didn't really consider at the time in type 1 and why the FDA and only a handful of European countries ended up actually approving it outside of North America. So if the mechanism makes sense, then the only thing that's common between type 1 and type 2 diabetes is that they both share high glucose. But when you have no beta cells and an autoimmune component, then regenerating beta cells is likely to be favorable, but how much you can regenerate and at what point you can still regenerate it with type 1 diabetes and how long it is the most important question. In type 2, the effect is less important. As long as you can do something and it's of a reasonable clinically meaningful improvement in A1c or allows you to buy time until your next agent, then a short-term treatment is welcome in the field of any chronic disease because it's unlike anything that you see in diabetes, cholesterol and hypertension management. You're on those medicines, you're on them forever because it's not really being about on those medicines, it's about preventing heart disease, preventing stroke, preventing blood clots, preventing microvascular complications. So you accept that if I have this disease, I'm going to manage it by staying on this medicine to improve my numbers on my lab, but also to prevent the diseases that follow. But people don't want to be on medicine forever. That's why they don't go see their doctor. That's why we give them prescriptions, and 40% of them don't make it [indiscernible]. And then 50% get stopped within the first year. So that's the huge potential of a short-term treatment that affects the underlying disease process and not Dr. DeFronzo's ominous octet that tells you the 8 different ways we have high glucose and tries to give therapy to match those different processes, but none of them regenerate beta cells.

Very good point. All right. I did have a question. It does not concern menin, but it is in the type 1 space, and that is, there has been some recent concern about teplizumab T Shield safety. And I don't know if you could comment on that in the Stage 2 population.

Specifically, like just the concerns like [indiscernible] with some emergency?

No, no, with the side effects. It was just -- there was -- they got a CRL from the FDA before they got their approval for prophylaxis. But I don't remember. [ Sima ], do you...

I remember seeing things related to immune side effects. I remember that the initial paper, which was New England Journal had an appendix that was not immediately available for some of the lymphopenia, cytokine syndromes and some of the infections that everybody was wondering. Now I don't remember hearing much of that after like 2021, 2022 and having spoken to physicians in the states that have much more experience with teplizumab than I do, because I think we're at like 5 or 6 people infused in all of Canada, is that a lot of that has been very well tolerated and had to do [indiscernible] that weren't given and now better of premedication...

I see. And I know there's concern about serum sickness and the like of that. But sure. You're saying it is...

it's mediated disease.

Right.

Like others.

Like if you premedicate and do what you're supposed to do, it should be well tolerated?

From what I hear, having never prescribed it myself, yes. And for my colleagues in Toronto who prescribe it within the University of Toronto system, the couple have done very well, and there was no immune-mediated reactions. But that's the prevailing thing that you're getting a daily infusion for, I think it's like a week or a week.

Yes, for 8 hours a day, something like that.

So you're vigilant for that 5 days for the same thing you would get with a blood transfusion or a platelet transfusion, like any serum reaction you might see.

Exactly. I did get a question through the chat. It says, in your opinion, what would it take for icovamenib to stand out in a space crowded by GLP-1s?

Well, firstly, if they can show in that trial that they enhance the effect of GLP-1, then their entry is for those failing GLP-1s. I think the key is going to be when you're managing a patient that has -- okay, so we didn't touch on this, but their most robust effect in type 2 was in a SIDD patient. So if you can demonstrate in either an insulin using type 2 that you can still replicate that improvement in beta cells or in a lean type 2 that we wouldn't really consider for GLP-1s, then you'll have certainly differentiated yourself as a new molecule with consideration. But being short term before GLP-1, long term or short term after a GLP-1 or ultimately, when they're either failing a GLP-1 or considering insulin, I'm okay with the entry at any point there because I don't necessarily have to consider it before my GLP-1. In fact, the way the landscape is moving is we're going to start to get referred people with type 2 diabetes that have probably been on GLP-1s for weight management and are now dealing with high glucose and need something else. So I think that the order of entry is an important question, especially for market penetration, but clinically before or after is very suitable for this agent.

Right. And I would think that the population large enough to...

Absolutely.

It'll come out in the wash. Okay. Well, we're just at time. So I'm going to wrap it up here and thank everybody for participating. And obviously, we want to thank Dr. A for his participation and his candor. We look forward to seeing you down at ADA, and we can catch up again after.

Looking forward to it. I hope it's been helpful, and I appreciate you mentioning the candor. I speak from the heart here as an investigator and obviously, as a clinician, excited about new molecules and patient care.

Sounds great. All right. Thanks again. All right. Bye-bye, everybody. Enjoy the rest of your day. Take care.