All right. 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. Alexander Abitbol. We're gonna cover a number of topics in the diabetes space concerning both type one and type two, and with a particular emphasis on icovamenib from Biomea Fusion. We also find our call to be particularly timely as we are exactly one month today from the start of the ADA conference, which takes place this year in New Orleans. Before I ask Dr. Alexander Abitbol to introduce himself, we want to point out that we have a research coverage of Biomea Fusion. 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 three months. Finally, if you have questions for Dr. Abitbol that you would like me to anonymously ask on your behalf, please shoot me an email at mking@rodm.com, and I would be happy to put that in front of our guest. With that out of the way, Dr. Alexander, we'd 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 Alexander 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, 85% have type two diabetes, and then about 10%-15% are affected with type one diabetes. I'm also an investigator for Centricity Research. My relationship with Biomea Fusion 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. We were also selected for some of their early phase type two diabetes and type one diabetes trials, after they had initially started in the States and we got started in Canada. My interests certainly have anything to do with wide-ranging clinical implications for patients. I have received investigator fees as part of the clinical trials that we supported Biomea Fusion. I'm also an advisor and consultant for Biomea Fusion, 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 two 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 does your typical patient flow look like on a day-to-day basis between, type one, type two, and then those that are participating in clinical studies? It depends on which day of the week, but if I'm booked for clinic, usually my patients are booked at intervals that anywhere between 10 and 15 minutes. I work with a physician's assistant, I'll probably see between 30 and 35 patients per day, mostly follow-ups, but between five and eight 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. In that diabetes cohort, it's 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 dietician 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. What proportion of patients are new, you know, new to treatment versus follow-up? I'd say about 10%-15% are newly diagnosed with diabetes. 50%-60% are probably on more complex insulin managements or either on or recently started on GLP-1s. 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. Has that flow changed at all in the era of GLP-1s at all, or does it, is it, has it really not bent the curve at all? Yeah, I would say it has. When I started practice, you know, we would say that when specialists start prescribing a new agent, it takes on average between five and seven years before family doctors, you know, 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. 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 Winfrey taking. Fundamentally, you know they're asking, the GPs are having to be a bit more receptive to newer agents and newer technology a bit faster than before. 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 wanna start. Yeah Mechanism of action of icovamenib, I also want to explore this, you know, 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 one would be eligible for treatment with icova, clearly there's a large population of the type two diabetics that could also benefit. My question's two parts. First is, you know, I didn't ask you specifically, but what proportion of your type two diabetic patients are already on a GLP-1 and failing to get benefit, and what proportion of type twos are on insulin, and even further to that, what proportion are of this brittle form or this SIDD form? Yeah, good question. I would say that for the proportion that are on GLP-1s in specialty practice, you're always gonna see higher proportions. We sit around 35%-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 two diabetes, we're somewhere between 15%-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%-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 is on basal insulin only. In primary care, it's always gonna be less. They see a diabetes patient every 40th or 50th patient. I see every second, or two out of three patients with diabetes. In my practice, I'm always gonna see more insulin. In primary care, they're seeing those patients, but they're either not really managing the diabetes cause they're followed by a specialist, or they're seeing a much lower proportion, usually 10%-20%, that are treated with insulin. Right. Are they coming to you, are type twos coming to you, on GLP-1s and not getting an adequate response, or do you not see that patient? They, they- Typically, SITID in your clinic? It varies extensively, but I would say that, when semaglutide launched, and maybe in the five years that followed, the majority was being started in my office. People were being referred for GLP-1, the same as before GLP-1, they were being referred for insulin. Now we're still getting the same if not more patients referred for insulin, 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. Right. 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? They have to manage the diabetes for longer. They're comfortable starting metformin, then an SGLT2- then another agent. I see. When they're out of option, I'm gonna refer. Got it. If I'm seeing an executive health physician and I'm newly diagnosed with diabetes, I wanna see a specialist right away, and I have access to one because I'm in. Toronto, so- Yeah It's a little bit different. What type of failure, not necessarily failure rate, but relapse rate or inadequate response rate are you seeing in that, in that population? Do you have any sense of that? It depends what you mean. If you mean. I mean the patients that are type two diabetic that have been on a GLP-1 for six months, 12 months. Yeah. You know, their, the slope of their, you know, their weight loss is either, you know, plateauing or coming back, or because of tolerability challenges, they've gone off. Yeah You know, have to have some other alternative. We'll talk about this when we get into the mechanism of icovamenib. Okay Fundamentally, diabetes is a progressive condition. If you manage a patient for long enough, whether they are being treated with one agent or two agent or three 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, you know, 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 it in detail several weeks ago with a call I did with the company in late April. I think it bears repeating that icovamenib operates by a mechanism that is unique in the diabetes space and derived from human biology. That's right. Dr. Alexander, I like the way you described it during our prep call yesterday in the Expert in the Space, and we, you know, we'd like to understand how you view the science and what you found captivating or compelling about it. Yeah. I think that for me, what captivated me is that whenever you get at a 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, you know more advanced disease and is looking to lessen their burden of medicines. 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. Why it's progressive is because you're not at your maximal insulin production forever. Eventually, you come down. When you go onto 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 heterogeneous 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. 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 two space. As we get to it in the type one space, well, that's where I'm even more excited as a clinician. We've had nothing new in type one 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 one, 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. Yeah. It definitely is fascinating stuff. I wanna just talk about the, you know, sort of the initial observation by Satyajit K. Karnik in 2007 in his paper at Stanford. It's rooted in the observation that menin is naturally expressed in pregnancy and lactation and 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 some, you know, simply managing glucose, you know, on a day-to-day basis? 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. By inhibiting it, as we see through a prolactin-mediated process in pregnancy, you see obviously that the cellular expansion and growth can allow, you know, 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. 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 oncologist had it for longer than we did because it was a unique target to consider an acute myeloid leukemia for ultimately, you know, inhibiting the cellular growth process that leads to cancer formation. If you were to let's say, icovamenib is approved and it's, you know, whatever, 2029, 2030, when you explain it to a patient, you know, they've progressed to either type one or type two, you know, that you find them to be a suitable candidate, do you think this is a, you know, the narrative of what icovamenib does is easily understood by the patient and would be embraced by the patient? The narrative today, based on the trials they've done so far, could look like, and you mentioned the SIDD patient cause I'm sorry. Yeah I didn't cover that before, but amongst the ADA framework, they define different patient subtypes. Right. 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. The narrative today could look like you're on two or three agents, you're needing a fourth agent. If you don't do well on that, you know, you might even need insulin to protect yourself against kidney disease or eye disease or heart disease. Instead of me giving you a medication that you're gonna have to take for the rest of your life, I'm gonna give it to you for between 12 and 24 weeks. We're gonna 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. At least reduce the dose, correct? Yeah, reduce the dose. Yeah The fast-acting doses and maintain them with just basal. The basal. You're right. right. Right. There are a lot of people who go on semaglutide. Or someone with prediabetes who's, you know, being told about lifestyle factors and weight management and all of that, very, very important, but instead of inevitably, you know, 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. The other study that they haven't done is the before metformin study. When you've reached, you know, a threshold, I've tried my hardest for three to six months. Yeah I've done everything I can, I've told my family doctor to just give me another chance 3x or 4x and I'm still in a range where he's recommending therapy, then okay, I'm not on lifelong therapy. I'm on a three-month or six-month course of therapy, and then I stop. Then I don't need to worry about taking long-term medicine and have similar control to those who take regular medicines. Right. Right. Well, yeah, it'll be very interesting to see how long that effect does last and we'll come back to that in a minute. That's important. I'm just, you know, for sure. I'm just curious, were you familiar with this work by Karnik before? It seems like such a fundamental and intuitive for me anyway who loves, you know, 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, you know, to more work on it. I don't know if you can comment on that. I was a bit surprised that there weren't, you know, a whole host of papers following on that. I'll say two 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. Mm-hmm. Mm-hmm. I think it's one of a few different protective mechanisms. I was shared this mechanism by Biomea Fusion in full disclosure. I sit on a few of the advisory panels where, you know, some of these experts did speak to the mechanism. It was not only palatable to me, but, you know, through global experts in the field. 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. I am not familiar with any protection that has ever been demonstrated in people. Affected with insulin resistance, pre-diabetes or diabetes, where they naturally see improvement like pregnant women do through an only prolactin mediated process. I think it's one of the explanations and maybe, you know, the uncoupling of menin as the partial response for why beta cells, but I think there's other things going on as well that are also preventing hyperglycemia in pregnancy. Okay. Well, it's good to know. There may be further work to be done there. What, you know, the one thing I do think is interesting, and again, as a clinician, what that means to you is that this is, you know, the menin regulation is context dependent. It's glucose dependent. 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 MEN1. Right Which is a gene that's coded in humans that when it's mutated can actually lead to tumorigenesis that affects pituitary, pancreatic, and other neuroendocrine tissues in the body. My worry was that by inhibiting it the way that they're doing it, that you may see neuroendocrine tumor growth. Fortunately, they did a robust job of tracking every possible subcellular signal, and we didn't see anything remote to that. 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 it in leukemia, they also didn't see any new tumors forming. Right As they were inhibiting the cancer. Yeah. That also provided me with a lot of reassurance. Okay. Then, the glucose dependency, is that, you know, protective against hypoglycemia or TDD? Yeah, that's the distinct advantage of when you're using endogenous factors. Yeah You're not gonna 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. We weren't gonna 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 cause 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. Yeah. I often get asked about, you know, what, to what do we attribute the, you know, the durability of the effect? You know, if you take a GLP-1 and take it away you'll regain your weight. You take most medications, your heart medic, your blood pressure, you know, your cholesterol, you take the medicine away and, you know, you return to your, you know, your baseline. We don't see that yet with icovamenib. You would think that, you know, the beta cells could proliferate, get healthier, but you would think once the medication's taken away, they would probably regress. Any thoughts on what changes is it creating some kind of effect, you know internally or what do you think may be responsible for the durability? It's the mechanism of action and the fact that all of the other agents you mentioned, DPP4s, MET, SGLT2, 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. Cause, you know, about a day and a half after not taking an SGLT2 inhibitor, glucose will stop being urinated out. You don't take your metformin for about 18 hours or so, you're gonna see more production of glucose from the liver in a disordered process that it's not happening. None of that is in essence intended on allowing the pancreas to regrow or expand the beta cell mass. By withdrawing the therapy, you accept that, okay, this is now my regenerated and regrown beta cells. Yeah, this is my new set point. Which is functioning at a higher level than before. Right. Yeah. I'll withdraw the therapy. I know I will probably lose these beta cells again in the future, as, you know, 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. Fundamentally, diabetes is a high glucose factored over time. The higher your glucose and for longer, the more you'll damage eye, blood vessels. Right Kidney blood vessels, heart blood vessels. 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'm gonna kinda work in reverse order here because the most recent data was in type one. In terms of your type one patients, what remains the hardest problem to solve, even those that are on the best-in-class glucose monitoring, automatic to insulin delivery, what other challenges do you face with them? 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, you know, 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. Even the best closed loop systems, you still have to announce meals, you still have to count carbs, you still have to warm the pumps before you're exercising. 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, obviously the older injections and the animal injections from 50 years ago, way worse than before. Type ones today, you know, are surrounded by technology, but they still fundamentally only have insulin to utilize, and many of them now are, you know, plagued with similar weight issues that are, of course, affecting the general population. Insulin is a growth factor. Yeah insulin they use for their condition, the more resistance they may ultimately develop from it, and then there's weight issues. Absolutely, you know, 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 two, then, you know, you may fundamentally move beyond the technology that we're providing them. Right. Now, are you seeing, you know, speaking of that, the weight gain, the growth factor aspect of insulin, are you starting to see these type one and a half patients? Yeah. Yeah. A lot. Yeah. Yeah. It's always been the case. People are becoming resistant to the exogenous insulin, and there are great papers by Shaw, by, you know, others in the field that have demonstrated that even in people on closed loop systems that have type one and high BMI, they do better when you also add in GLP-1s. Yeah Weight-wise and glucose control-wise. There's certainly something to be said about weight management, even in those that need it for type one, and the insulin requirements they have often exceed the pump reservoirs that we have today. It's even more complicated in managing some of these, you know, type ones with insulin resistance. Yeah, yeah. Interesting. All right, as I said, we're gonna run in reverse chronology here. Just interpreting the COVALENT-112 type one 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. The patients that are on 200 milligrams, you saw a 7% decline from the peak, try to week 52 following that 12-week course. What's your clinical reaction? We had, you know, sort of two arms, two 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 ones who've been inside of 15 years since their diagnosis. Obviously, you know, you're super excited. You try to put it next to, you know, the early teplizumab data and some of the other ones that we're not looking at stage three type one, but stage two and before type one, 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, you know, some of the non-responders here, I'm curious, you know, why we didn't see always a response. Yes, type 1 diabetes also a very, very heterogeneous condition, but still, you know, fundamentally did it match with the exposure that they got to the dose? Was it something else that might explain it? 52 weeks, you know, I think is a long timeframe to obviously have given the dose for as long as they did and then see a decline thereafter. 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, you know, look at insulin doses and certainly complications long term is the most important thing to be looked at for a type one. Yeah 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, as been demonstrated by all of the big type one registries. Yeah, I know. How do you know, not to interject, but how do you. No How do you look at that, at C-peptide and, you know, an improvement in the AUC over that period of time versus the, you know, 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 the C-peptide or would you choose the A1C reduction? I would choose the C-peptide. Yeah. Because in the long term, the A1C with a type one has so much to do with how they titrate insulin and how good they are at obviously adjusting. The C-peptide is the biggest predictor of complications. It means that even if you manage somebody with type one perfectly, if their C-peptide is zero, 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 is 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. If you're making a bit of C-peptide, like we see in our honeymooning type ones who are newly diagnosed and new to insulin and they still have a lot of endogenous pancreatic production before. Right They really run out of it completely. Yeah They're a lot easier to manage. Their insulin doses are a lot more liberal. Right. That's what we hope to see with this as well. Right. Now that you mention the honeymoon period. Yeah I would ask you to comment about you said, you know, you made a mention that the patients had been less than 15 years with their from diagnosis. Also, these were all stage three. That's right. Type ones. How does that impact your perspective on the data versus the patients that might be earlier or still in the honeymoon period? The honeymoon period is still stage three, 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, it's clearly not type two diabetes, it's a juvenile form. The idea is that in this phase, you are clearly antibody positive, clearly having hyperglycemia, may have presented in DKA, but your doses are not quite at 0.3- 0.5 unit per kilos yet. You're usually well below that because there's still some endogenous production. Within one year, two years, five years in the best case, that person usually becomes C-peptide negative or near undetectable, you see their doses move up to the conventional. When we talk about earlier stages of type one, 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. Right. In stage two, 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 pre-diabetes or at-risk zone, where they're not quite meeting the definition for type two diabetes, but we have antibody positivity and they are close to it. It's very difficult to find those people. I'm very excited about something for stage three type one because that's what I see. Yeah. That's what we detect. That's when the patient usually becomes aware of the disease. The type one 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 three type one diabetes, we're really nowhere near there clinically. Outside of research registries, even there it's rather slow in my opinion. Right. When you say infused, you mean with teplizumab? With teplizumab. Yeah. That's right. Yeah. Okay. You did touch upon this, but I wanna come back to it and ask you know, again, we're very close to ADA. Yeah. Biomea Fusion's data will be presented on the 5th. Yeah. The things, the things that you'll be looking for or asking about are what? From the 12th. I mean, I'm an early yeah, 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 endpoint's kind of outline. Early phase trial, I need to see the Treatment-Emergent Adverse Events. I wanna look at liver, I wanna look at kidney, I wanna make sure there are no surprises with any of these neuroendocrine hormones that I mentioned. Not 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 gonna run into skepticism. Right. You really need clean 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. We do it. Let us know how the audience reacted. Going forward, a company outlined a very interesting trial in the T1D population where they're gonna give, you know, an upfront placebo-controlled regimen for six months with icovamenib monotherapy versus placebo, and then re-randomize either off therapy, continue with icova, immune suppressant baricitinib. Sorry, yes, the JAK inhibitor alone. Sure. Comment about the study design. Does it make sense? Do you worry about combining with a, with a JAK, which tends to have their own idiosyncratic side effects? I'm not an expert with immunosuppressants. 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. I find it interesting. It's a four-arm comparison, they're gonna need a lot of patients to get enough statistical power to show differences in those groups. 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 wanna see. We wanna see if the drug beats out placebo, and then thereafter, how long it persists for with or without immunosuppression. Kudos if they can pull that off, cause that's the trial everybody will wanna read. Right. I mean, obviously you could do a study like this with teplizumab, you could do it with, well, SAB-142 was investigative, but, you know, one could think about other, you know, the IL-2 agonist from Nektar. I mean, there are lots of different, you know, immune suppressants, immune modulators that you can think of. Would you wanna start to see further development there as well? I reviewed 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 two type one diabetes. Two, okay. This is to prevent the development of type one diabetes as a one-time treatment that I can never do again, allegedly, and then that will buy me between four and six years before I'll go on to develop the disease. When I'm treating stage three type one diabetes, 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. 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. That's the worry of endos. You can show me that I can make C-peptide in type one, if my immune system is just gonna come back and wipe it out really quickly. Yeah That is unfortunately not as advantageous as it will be in a type two patient. Yeah, yeah, for sure. Okay, great. Well, let's transition to the type two population. One in three 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 two. Okay Diabetes lifetime risk, although they're a bit outdated in an emerging world of these potent GLP-1s. Right where you're not going to insulin next, you're going to GLP-1s. 2018 data would've said about 45%-50% eventually need insulin for type two diabetes. Okay. That can be for different reasons, right? We always think of the person who's maxed out on four 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. Right Trying to get pregnant, they go to insulin first because none of these other agents are approved. 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. 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, you know, not getting any further benefit or, you know, still on the drug, coming back. How much of that are you seeing now? To that population, what do you have to offer them? It's a great question. We see a lot of that now. 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 a GLP-1. In my own practice, we know that a lot of the people that would've 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, cause these are our patients for many years, but, you know, the two to three -year rates are very different than when you were looking at the one to three -year rates that were looked at in the clinical trials, and treatment failure, if you follow somebody for long enough, is inevitable. Yeah. What do we do? Well, the GLP-1s now have higher doses, we consider them. For many of them, there is poorer access to things like Mounjaro or tirzepatide, we would love to transition even though there isn't a lot of data for switching. 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 two, three years after a GLP-1, whereas it was maybe six months to a year after a DPP4 'cause the durability is way better, it's not permanent. It's when you look at a patient statically in a clinical trial and you say, "Wow, you know, 79% of people on Mounjaro reached a target of A1C," that's robust data, it should not be discounted. Two, three years later, that percentage will have whittled down and you're gonna need to be doing something with that patient after. Right. All right. Do you, I mean, do you routinely look at, has anybody looked at in any systematic way about, you know, C-peptide in the type two patient populations that are, you know, that require insulin, what does that look like? No. I don't know. Okay. No, it wouldn't work well either because the different calculators like HOMA-B, HOMA-IR, you know, are fraught with discrepancy based on the glycemic control and body weight. tends to make it very discrepant. You can't look at a C-peptide as a static measure in type two. It's really just to answer a clinical question. It's, "Okay, wait a second. This person is referred to me for type two 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 two diabetes and not type one diabetes. That's how we diagnose autoimmune forms or type one forms in the adult population, where they're often mistakenly think, thought of as people with type two diabetes. If I were to track somebody's C-peptide, well, it might look at first in type two diabetes like they're actually making more C-peptide, or their glucose control might improve, 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. 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, it's a clearly a leading question, but, you know, it's been shown that menin inhibition increases the number of GLP-1 receptors in the pancreatic beta cell. It makes for a very intriguing experiment, I guess, or hypothesis generation about, you know, wouldn't it be great to, in a type two diabetic who's on a GLP-1, to put them on a menin inhibitor in order to get more out of the GLP-1, as well as, you know, 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. Okay. 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. Okay the people on this call. We're about to enter a world of generic semaglutide. 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. Of course, I never wanna go on insulin. If my only option. Right Now were to pay a lot for a branded product or to go onto basal insulin, 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, seeing obviously the effect that you might see with GLP-1s. 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, you know, in Canada start this summer, and you'll be seeing in the United States probably in the early part of next year. That's a very, very important message, because it doesn't augment too much today if you're paying, you know, the same for different products, but it does if, you know, there is a price advantage for augmenting your generic medicine. Right. Right. Yeah, you know, I would, I think we've seen sort of the prototypical type two patient who is going on insulin is probably. is usually, you know, overweight, obese, and you're giving them the insulin so they don't get the complications, but at the same time, you know, you're pushing the rock up the hill the wrong way. True You're trying to, you know, you're losing control of their weight, so. That's right. Um, you know, it might be- 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. Yeah weight regain is seen in a high percentage of people that ultimately even are very successful at approaching 20% and 25% body weight. That's because of biology. That's, you know, leptin-mediated and appetite regulation centers that have no idea that you're trying to lose weight. It thinks you're starving in the forest. It's trying to keep you alive. Right. 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 one in every eight person, I think, in the latest survey in the U.S. mention that they are either on or considering being on a GLP-1 for weight management. If you can enhance what, 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 the study of type two patients. We saw A1C reductions between 1.2 and 1.5 percentage points. Yeah. C-peptide 24%-35% at the end of 52 weeks. Is that a meaningful, you know, is that a meaningful outcome? If, obviously smaller studies, but we'd have to replicate. Right that in phase III. Is that a meaningful, you know, outcome? Same story. Yeah It's early phase, TEAEs looked clean to me. There were no grade threes. I really loved seeing that data. I was happy to be a part of that clinical trial. 1.5%- 1% - 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%. This would be a little bit more with the early GLP-1s that we see. Meaningful. We approve agents that have a 0.4% A1C reduction. Hugely clinically meaningful. Yeah differentiator is short-term versus continuous treatment. 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. Well, you know, one of the things that I found a bit curious on COVALENT-111 was that the, I can actually even share my screen on this. 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. You know, bouncing, these A1C numbers bounce around a lot. There's relatively small, but not so small numbers. A1C is measured over 90 days. Any thoughts about. Yeah, it's the same thing. What's going on here? Yeah, it's an early phase study where you're seeing the improvement not matched to the exposure. 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 the arm C that had a lower dose but took it with food and therefore saw a greater response? 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 know, you see negligible A1C reduction. If they have high exposure, then I'm a skeptic. If they see no exposure, then it's formulation. You gotta go back to figuring out how to get that drug into the bloodstream so it can augment the effect. Yeah. Yeah, I'm not sure that's a concern at this point. No It's a good point. Okay. Just real quick, you know, I guess looking forward, that, you know, 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 one versus type two, the drug is clearly, you know, exerting a strong clinical effect in both type one and type two, although the etiology of the underlying condition is different. I mean, they're losing pancreatic beta cells in type two, but it's not an autoimmune reaction. Right. Um, so, um, you know, does that, uh- Yeah I guess, does it surprise you that it works in both patient populations? Yeah, it does, but it's because of how it works. Yeah. The same way SGLT2 inhibitors, we studied them in type one 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 euglycemic DKA, which we didn't really consider at the time in type ones, and why the FDA and only a handful of European countries ended up actually approving it outside of North America. If the mechanism makes sense, then the only thing that's common between type one and type two diabetes is that they both share high glucose. 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. Right, right. especially with type one diabetes. Yeah How long it lasts is the most important question. In type two, the effect is less important. As long as you can do something, it's of a reasonable clinically meaningful improvement in A1C. Or allows you to buy time until your next agent. Yeah 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. It's not really being about on those medicines, it's about preventing heart disease, preventing stroke, preventing blood clots, preventing microvascular complications. You accept that if I have this disease, I'm gonna manage it by staying on this medicine to improve my numbers on my lab, but also to prevent the diseases that follow. People don't wanna 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 to the pharmacy. To try to fill it, right. 50% get stopped within the first year. 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 eight different ways we have high glucose and tries to give therapy to match those different processes. 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 one space and that is- Right There has been some recent concern about teplizumab Tzield safety, and if I don't know if you could comment on that in the stage three population? Specifically, like just the concerns, like with the. Uh- or with some emerging- No, no, with the side effects. It was just, there was a, you know, they got a CRL at from the FDA before they got their approval for, you know, for prophylaxis, but I don't remember. Seema, do you want to comment? I remember seeing things related to immune side effects. Yeah. I remember that the initial paper, which was New England Journal. Right 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, cause I think we're at, like, five or six people infused in all of Canada, is that a lot of that has been very well-tolerated. Oh, yeah, okay. Medications that weren't given, and now better protocols of pre-medications have been created. I see. I know there's concern about serum sickness and- Yeah And the like of that, but, uh- For sure. You're saying if you. Immune-mediated disease. Right. Like other- You're saying if you pre-medicate and. Yeah 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, you know, within the University of Toronto system, couple have done very well, and there was no immune-mediated reactions. Okay. That's the prevailing thing, that you're getting a daily infusion for, I think it's like a week or a week and a- Yeah, for 8 hours a day, something like that. Yeah. You're vigilant for that five days for the same thing you would get with a blood transfusion or a platelet transfusion, like any serum sickness. Yeah immune 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? Firstly, if they can show in that trial that they enhance the effect of GLP-1, their entry is for those failing GLP-1s. I think the key is gonna be when you're managing a patient that has. We didn't touch on this. Their most robust effect in type two was in a SIDD patient. Right. If you can demonstrate in either an insulin-using type two that you can still replicate that improvement in beta cells, or in a lean type two that we wouldn't really consider for GLP-1s, then you'll have certainly differentiated yourself as a new molecule with consideration. Right. 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 gonna start to get referred people with type two diabetes that have probably been on GLP-1s for weight management and are now dealing with high glucose and need something else. 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, I would think that the population large enough to. Absolutely All come out in the wash. Okay. Well, we're just at time, so I'm gonna wrap it up here and thank everybody for participating, and obviously, we wanna thank Dr. Alexander for his participation and his candor. We look forward to seeing you down at ADA. Yeah. Maybe we can catch up again after. Looking forward to it. I hope it's been helpful, and appreciate, you know, 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.