Biomea Fusion, Inc. (BMEA) Earnings Call Transcript & Summary

We're going to go ahead and get started. I'm Juan Frias, I'm the Chief Medical Officer and Head of Diabetes at Biomea Fusion. And I want to start by thanking you for making it to this educational program bright and early. And also want to thank Yehuda Handelsman and his staff at World Congress for making this possible and congratulate Yehuda and his staff on the 21st Annual Meeting of the World Congress of insulin resistance, really appreciate that. And also my esteemed colleagues that will be joining me for this program. So we have an action packed 45 minutes, where we'll be covering the breadth of information on the covalent menin inhibitor, BMF-219 that's in clinical development for the management of diabetes, both Type 2 and Type 1 diabetes. We have Tom Butler, who is the CEO and co-founder of Biomea, and Tom is going to be giving a brief overview of the company as well as the molecules of BMF-219 and also some pre-clinical data. Tom will be followed by Priyanka Somanath who is the Associate Director of Translational drug development. She'll be speaking to us about some of the animal models, the murine models where we've looked at BMF-219. And very pleased to have Professor Rohit Kulkarni from Harvard Medical School and the Joslin Diabetes Center in Boston who will be speaking to us or giving an overview of our friend, the beta-cell in diabetes and also some very interesting data on donor islet micro-tissues and work we've done with BMF-219 in these micro-tissues. And then I'll wrap up with some of our clinical data in patients with type-2 diabetes. We'll have time for Q&A, hopefully, 5, 10 minutes towards the end, but we are all going to be around throughout this congress. So look forward to this being a jumping-off point to having many more discussions during this meeting and beyond. So with that, I'll turn it over to Tom Butler.

Okay. Thank you, Juan. Good morning, everybody, and thank you very much for having us. We're excited to be here and to share with you how we plan to address the root cause of diabetes with BMF-219. I'll talk a little bit about the company background. Our development principles at the company, the benefit of covalency, and some of the key translational work we did leading into the clinical development of 219 in diabetes. And then we'll follow up with why we think 219 is uniquely positioned for targeting diabetes. We formed the company, Biomea Fusion in 2017 to develop a reversible menin inhibitor program. We quickly learned that focusing on Menin, rather it's many binding partners was the key to drive menin-specific pathway to control. We were lucky enough to become members of the JLAB community in 2018 to build out our proprietary covalent binding technology. And a year later, we discovered BMF-219. Following two years in 2020 and 2021 of important investments, we were able to get into the clinic in 2022, dose our first patient and announced our first clinical data for the company and the first for 219 this year. We have a long history of developing successful drugs together and really a broad range of therapeutic areas stemming from antiviral to oncology and, of course, metabolic disorders. Our development principles are simple, taking covalent chemistry with validated targets and proprietary combinations, we feel sets the path to long-term patient benefit. And it starts with chemistry, covalent chemistry is the key, and that's why when we started with the company early on, we brought on Jim Palmer, who I worked with at Pharmacyclics, he invented ibrutinib while at Celera. And Thorsten Kirschberg I worked with while at Gilead Sciences, he helped invent Harvoni, the 8-week cure for Hepatitis C. And here's really highlighting the power of covalency, and just as a quick refresher, covalency is when you take a small molecule and you form a permanent bond with the target of interest. And what we're highlighting here on the left-hand side is a commercial covalent inhibitor, ibrutinib or commercially called IMBRUVICA and what is highlighting here is the green line shows you the pathway disruption or the pathway control the small molecule exhibits when it's dosed in a patient. So within the first 4 hours, you get maximal impact or maximum pathway control while only needing about 4 to 6 hours of relevant exposure. So the patient spends the majority of the day without really any drug on board because the drug has done its work by binding to the target and controlling the pathway of interest. And that green line -- the space between the green line and the blue line is that patient benefit that really allows the patient to have maximum efficacy to be able to be dosed at the right exposure, but also have the best tolerability profile possible with your small molecule. And that certainly encourages persistency and compliance with the medication, which we find is very important. And with the combination of high selectivity, deep target and activation, you really get a strong therapeutic window. Our Fusion system, our platform that we use to discover and develop novel covalent inhibitors against many diseases, goes through a target selection process. We use PDB Crystal Structure-based Drug Design and Proprietary Scaffold Construction. And it's really a very different method than the typical compound library screening technique where you will first take your target of interest, screen existing scaffolds and try to optimize. Here at Biomea, what we do is with the understanding of the crystal structure, we build a scaffold from scratch. And so the scaffold ends up being quite novel and unique. We definitely go through a matching process. And when we do our covalent target/ligand identification, it starts with the crystal structure, of course. And then through a matching process, we look to aim to build the right proprietary scaffold within the pocket, but also screening the warhead for efficient bond formation. And it starts with human genome wide covalent pocket analysis. You really have to interrogate and understand the depth and the spacing of your pocket -- of your target. You have to also make sure that you're targeting to the correct cystein. Targets can have many approachable cysteines. And I'll talk about menin's approachable cysteins in a few slides here. And really the importance is trying to find the right angle and also the right distance to the cystine, which is the key amino acid you need to form a covalent bond to get efficient bond formation. Menin is a very interesting target, and it really has no function on its own. It's function is really dictated through the formation of complexes. And we like to describe Menin as a joystick, sitting at the epigenetic level inside the nucleus and allowing either the suppression or the promotion of transcription. In the case of cancer and oncology, this complex is forced into the on position, resulting in uncontrolled cellular growth in the off position or in the suppression position is preventing your beta-cell pool from repopulating in a depleted state. Some of the work we did to understand 219's ability to target menin started with some target engagement work that we did, and we used Octet BLI and really it allows you to understand the binding kinetics of your small molecule. So you can get a good understanding of how quickly does it bind to the target? And then what is its off rate? What's the binding affinity of the removal of your molecule? And as you see, we screened a variety of reversible and covalent inhibitors here, and you can see BMF-219 displaying quite potent KD activity in the [indiscernible] range. And then on the bottom right-hand side, you can see the dissociation constant here is extremely low, which suggests the formation of Covalent engagement. We also did some Covalent Adduct Formations and peptide mapping, where we look at the binding specificity of 219 to Menin looking at the attachment sites with human Menin. And what we do is look at the overall sequence coverage of our cystine fragments identified that 85% -- and what we looked at is which cystine -- there are 6 cysteines on menin that you can actually bind to, how many cystines did 219 bind to? And fortunate for us that 2019 bound only to the single cystine, the target cystine of interest for us and what we think leads to the dramatic pathway control. Some of the human islet work was also very informative for us to understand how is this molecule working? How is it generating proliferation? What does the core gene signatures look like? That's when we started to do some human islet work looking at CCNA2, which we know expression has been shown to support the proliferation of beta-cells, resulting in an increase in beta-cell mass. And what's nice to see is 219 showing a nice dose response that's similar to what you saw in published literature with menin knockdown experiments. We also looked at PBK and PBK also showed nice dose response increases and expression with increases of exposure or a dose of 219. And again, matching what you see in the literature when you start to knockdown menin protein and PBK expression has also been shown to help drive beta-cell proliferation and really result in an increase in beta-cell mass and function. PBK expression is regulated by Menin's binding partner JunD. And we like to use that proliferation to drive the increase in beta cell mass in our patients. And we know that through the course of the progression of disease with diabetes, and Rohit will certainly go into this in more in depth. We want to try to restore the beta cell mass that was lost in the patient through the course of the disease. And hopefully, that results in proper insulin secretion and glycemic control. And by focusing on beta cell health with investigational BMF-219, we think with an oral small molecule and a short-treatment duration leading to durable glycemic control will have broad application to diabetic patients. Okay. I'd like to turn it over to Priyanka.

Thank you so much, Tom. Good morning, everyone. I will be sharing some of the key animal data we generated with BMF-219 in animal models of diabetes. Zucker Diabetic Fatty rat is a model of pancreatic exhaustion that displays islet atrophy, insulin resistance and glucose intolerance. ZDF rats mimic many aspects of human diabetes with rats losing up to 50% of their beta cell mass as their diabetes progresses. We measured the ability of BMF-219 in restoring glycemic control in the ZDF rat over a 4-week dosing study. 10 rats per group were treated orally once daily with BMF-219 at two doses. BMF-219 was included at 170 mg per kg for 4 weeks and also at 40 mg per kg for two weeks, which was then increased to 200 mg per kg for the following two weeks. Liraglutide was also included at a clinically efficacious dose. The animals were monitored for an additional 28-day drug washout period during which they continue to feed on a high chloric diet for us to be able to assess the durability of response. BMF-219 was well tolerated in all animals. In terms of efficacy, all treatment groups, including both BMF-219 dose group as well as Liraglutide displayed significant reductions in fasting blood glucose levels at day 21. However, only the BMF-219 higher dose group displayed significant reduced blood glucose at day 29 outperforming Liraglutide. Fasting insulin and c-peptide levels also gradually increased as treatment progressed. Notably, on day 29, there was no change to the insulin levels by the BMF-219 higher dose group, what was concomitant with reduced fasting blood glucose, indicating less beta cell exhaustion in this group. By an oral glucose tolerance test, BMF-219 higher dose group as depicted by the blue line graft also outperformed Liraglutide, displaying significant glycemic control and higher insulin sensitivity. We next assess beta cell function through the HOMA-beta Index in BMF-219-treated ZDF rat. The HOMA-beta scoring is a system in which a score greater than 200 indicates adequate beta cell function while value is less than this suggests beta cell deficiency. On day 21, both liraglutide and the BMF-219 170 mg per kg group, and I'd like to note here that we use this dose group to assess the HOMA-beta function as this dose was administered throughout the entire duration of treatment. So BMF-219 and liraglutide displayed elevated HOMA-beta scores bigger than 200 at day 21, indicating restoration of normal beta cells function. If you look at day 29, however, only the BMF-219 dose group sustained this effect on beta cells function by maintaining a HOMA-beta score of 200. In comparison, while liraglutide did elevate HOMA-beta scores to normal function at day 21, this effect was not maintained at day 29. We measured the HbA1c reduction in the ZDF treated animals in both the BMF-219 treatment groups as well as liraglutide. On day 21, both BMF-219 dose groups displayed a 1.8% reduction of A1c relative to vehicle control. On day 29, the HbA1c reduction reached 3.5% compared to the vehicle control. And importantly, this effect was sustained during the drug washout period on day 43, 15 days after treatment stopped. In comparison, liraglutide lowered HbA1c 1.8% relative to vehicle control on the last day of treatment at day 29. And after drug washout, this effect was not statistically significant. So in summary, BMF-219 was well tolerated in all animals. BMF-219 displayed significant glycemic control in ZDF rats outperforming liraglutide and reduction of fasting blood glucose by day 29 and by an oral glucose tolerance test conducted on day 25. BMF-219 significantly reduced HbA1c 3.5% relative to vehicle control during treatment and during drug washout. We had also conducted additional studies in an STZ model of diabetes in which the model is created through targeted beta cell destruction. Due to time limits, we're not sharing that data today, but we saw some very similar significant control glycemic control in this model with BMF-219. So collectively, these data suggest a durable effect of BMF-219 on glycemic control as well as beta cell function and has enabled further clinical studies. Thank you very much. And I'll turn it over to Rohit.

Thanks very much, Priyanka. And I also want to start by thanking Yehuda on this excellent meeting here. We've been here a couple of times before. And again, also thanks to Tom Butler at Biomea to allow me to be part of this exciting journey. So I'll preface my talk by focusing a little bit on beta cells and beta cell mass in the context of both type 1 and type 2 diabetes. Having worked at the Joslin now for 26 years, I'm really excited that therapeutics for addressing beta cell mass is coming to fruition in some ways. So let's see what we can learn about. So as we all know, beta cells try to compensate. And when you define diabetes, these are always defined as individuals who have poor insulin sensitivity and a failure of compensation of the beta cells. Right? failure of the compensation is important. So -- but you can see that in physiological states in mammals as shown by this cartoon, you have a number of approaches for maintaining beta cells. So beta-cell mass can be maintained over a period of time from neonatal period to adulthood and beta cell replication goes down over a period of time and then goes up for a specific physiological mechanisms. And one classical mechanism is pregnancy. And we know that pregnancy shows an increase in beta-cell mass. This has been shown in both rodent models and in humans, and this remarkably goes back down. So there is an ability of the beta cells to replicate even in the human scenario. So there's two examples I wanted to emphasize, which is usually overlooked by the medical community. One is the data that's shown here of beta cell mass and two sets of individuals. So shown on the left is individuals who have BMI less than 25, and the right BMI between 26 to 40 and you can see that the beta cell mass plotted on the Y axis shows the differences when the individual does not have diabetes or has type-2 diabetes. So clearly, you can appreciate that in type-2 diabetes, there is a decrease in the mass. But what we also can notice is that the beta cell mass can increase. So the two individuals who are BMI less than 25 and BMI 26 to 40, there's an increase in the mass in those individuals who are non-diabetic but who have a higher BMI. So that is an important observation. Look at it another way, you can look at beta cell mass in lean and obese individuals. And I want to emphasize that these are non-diabetic individuals. So we know that obese individuals are insulin resistant. But the ability for the beta cell mass to go up in these individuals is likely enough to overcome this lack of insulin sensitivity and they so remain non-diabetic. So this is an important observation because this argues for why beta cells are important for targeting in the context of both type-1 and type-2. And I'll make the case for type-1 as well. So shown here is data from the Medalist Group study The Joslin Diabetes Center by my colleague, Sir George King and Susie Bonner-Weir, and you can see that these individuals who have been followed up for over 50 or 60 years with type 1 diabetes unfortunately pass on and provide their pancreas for analysis. Shown here are examples, 4 examples of 4 different groups of sections of pancreas where you can see there are single beta cells outside the islet. There are beta cells within the islet and far right, you can see as many as 80% the islet is composed of the beta cells. And I want to emphasize that these are individuals with type-1 diabetes for more than 50 or 60 years. The second study in this in Joslin Medalist Group as well as [indiscernible] group in England and another group in Australia, have shown that these individuals when they're given a mixed meal tolerance test show an increase in c-peptide. So there are two points here. One is their ability to replicate in type-1 diabetes. Number two, they are functional in response to a mixed meal tolerance test. So this argues, again, that the beta cell should be an equal therapeutic target in addition to immune suppression in type-1 diabetes. So I hope that these data will convince you that both type-1 and type-2 could be potential targets for enhancing beta cell mass. So we put together this review article a few years ago arguing that there are many therapeutic agents which can enhance human beta cell proliferation. So I won't go into great detail here, but just to make the point that there are a number of candidates now ever since I finished medical school, the number of agents that can enhance replication has really gone up. And this suggests to us that there are agents which can be now used to target the beta cell in disease states. But what about Menin? We should add Menin to this cartoon for several reasons. One is this article landmark study, which is reported in 2007, much before Biomea was formed arguing why Menin is important in the context of diabetes. So the Stanford Group by Sun Kim's Group, whom I know them well, argued and showed data that menin controls the growth of pancreatic beta cells and use the pregnancy as one more. And they show that if you block the effect of menin, it promotes alleviation of glycemia which leads to an improvement in the diabetes. In fact, when you knock out the menin molecule, it leads to improved glycemia and the cure of the diabetes state in these animals. So clearly, these data argue that if you block Menin, you interfere with glucose stimulated progression of the cell cycle in the beta cell, which then leads to an improved beta-cell mass. So fast forward to what we're doing right now in the context of Biomea Fusion, studies now done in animals, shown by Priyanka show clearly that there is an effect in the animal model. But I'm sure we have to look at what maybe happening in the human islet tissue. So shown here a couple of examples of preliminary data, looking at the BMF-219 compound on human islet micro-tissues. So the design of the study is shown here. So you take these human islets and obviously, the cadaver-derived islets. The donor data is shown at the bottom. You have donors of two different ages. You can see their BMI and HbA1c. So these islets, the micro-tissues are treated either for one week, two weeks or three weeks or they're treated with two weeks along with a 1-week of washout period to look at how sustained the effect is and also do a dose response effect on these micro-tissues. And the readouts are proliferation of beta cells and insulin content to look at one of the important parameters for beta cell biology. And this has been done in two different glycemic control -- glycemic levels, 5.5 millimolar which is physiological and a slightly higher level, which resembles what would be happening in patients with type-2 diabetes at 8 millimolar glucose. So shown here are the data in donor #1. On the left hand, you have -- this is a bit heavy slide, but I'll run you through this. On the Y-axis is a marker of proliferation, which is EdU, many of you know EdU is used as a proliferation marker and we use NKX6.1 as one of the transcription factors and the fraction of the beta cell, which is proliferating. So the left part of the left curve is the standard glucose and high glucose. And you can see that in basal state, without any compound addition, there is a slight increase in proliferation, and this is expected. Glucose enhances proliferation of beta cells. Let's see what happens when you add BMF-219 or Harmine which is used as a positive control. And you can see that there is an increase in the proliferation, which is much more dramatic at high glucose in response to BMF-219. So this is very interesting. The second point to make is at day 21, the proliferation is still seen is much lower after day 14. And more importantly, when you wash out the compound, there are no more additional beta cells proliferating suggesting that there is no -- there is nothing like a sustained high elevated proliferation. It goes up, you take away the compound, it goes back to norm. So this is an important observation that there is an effect which is sustained and also that is -- when you wash it out, the effect goes down. And shown on the right are examples of the proliferation data. Same thing with donor two. And you would expect, I'm sure you'll agree, there is inter-individual variability when you're looking at proliferation responses. So again shown here is the effect of glucose, high glucose having an effect, and the effect of the compound, again, you can see that this is a slightly different experiment where you did a dose response curve, ensure that BMF-219 does have a dose-dependent effect of proliferation. Again, similar to donor 1, you wash it out, there's no response and shown on the right is an effect of proliferation. What happens to insulin content? I'm sure you're thinking about what could be happening there. So donor 1 at the top and donor 2 at the bottom, standard glucose on the left and high glucose on the right. And you can see that when you add Harmine, the insulin content goes down or is sustained at a lower level. When we look at the effect of BMF-219, you can see that the basal levels, the insulin content is maintained and the high glucose as you would expect when you have more beta cells, insulin content goes up. And the insulin secretion data is consistent with what we see with insulin content. Same effect with donor #2. So I think these data argue, first of all, that BMF has an effect, dose-dependent effect, there's a sustained effect but can be washed out. This effect does not last for a long period of time, and many of us are worried about proliferation for a long period of time. And you take away BMF-219, proliferation goes back to basal levels and it has a dose-dependent effect. So in summary, I just want to argue that BMF-219 promotes controlled proliferation, enhances insulin content in beta cells, ex vivo in a glucose dose-dependent manner. These data suggest that induction of beta cell proliferation is one mechanism for the improved glycemic control in BMF-219 treated patients with diabetes. An ongoing studies aim to explore changes in gene expression, protein signatures, looking at single cell RNA sequencing, proteomics to begin to look at the signaling pathways, which are important for safe activation and reactivation of human beta cell proliferation. And thank you for your attention. And I want to introduce Juan back again.

Okay. Thank you, Rohit, we have a very great talk, and I appreciate everyone's talks up to this point. I would tell I'm a clinician and it strikes me when I look at the animal data and these variants in micro-tissue data that the glucose dependency of the proliferation, which is so important, and I can tell you that in our oncology program in our healthy volunteers we've studied, and to date, in the patients with type-2 diabetes that we've studied, we've not seen any clinically significant hypoglycemia. So this is very important that you don't get overproduction of beta cells, and these are glucose responsive. So I'm going to take what we've heard up to now and really translate it into humans. I'll talk about some of the work that we've completed in our multiple ascending dose study in patients with type-2 diabetes and this is, as we've heard about the covalency of BMF-219. It's important to note as I go through these slides that I'm going to show 12-week data, but patients are treated for 4 weeks with once daily BMF-219 for 4 weeks, and then we have follow-up data at week 8. I'll be presenting -- actually, we have a poster here. I'll be presenting tomorrow evening as well, looking at 26-week data, so 22 weeks after the final dose of 219. So this is the multiple ascending dose study, primary objective with the safety and tolerability of 219 in patients with type 2 diabetes. We looked at pharmacokinetics as well, glycemic parameters, including hemoglobin A1C change as well as continuous glucose monitoring metrics and markers of beta cell function as well. The eligibility criteria on the top left, these were all patients, adult with type-2 diabetes with less than 15 years duration of diabetes, poorly controlled with an A1C at baseline from 7% to 10%, and they were treated with either diet and exercise up to three antidiabetic agents, excluding insulin secretagogues, so meglitinides, sulfonylureas, and no insulin as well. And what I'm going to focus on is in the box there, which are two of the cohorts. These are 100 milligrams once daily. There were 10 patients who were treated with the active drug 219 with food and 10 patients without food and each of these cohorts had two controls. And again, if you see on the bottom, treated for 4 weeks once daily and then a 22-week follow-up and what I'll show is the 12-week follow-up here. These are the baseline characteristics. You see mean age around 50, duration of diabetes vary from an average of 4 to close to 9 years. A1c at baseline, the average was around 8%. And you see the therapies, the majority of the patients were metformin monotherapy, there was one patient treated with lifestyle alone and a handful of patients that were treated either with two or failing, three agents at the time of randomization. If we look at the pharmacokinetics, and this is important as I go through the clinical data, the patients and what's shown on the left there is a day 28, this is the area under the curve of the exposure to BMF-219. And you can see in the 100-milligram without food, there was higher exposure. It was about 2.7-fold higher without food than with food, which is shown in orange. And if we look at the summary of glycemic results, you can see in the first column, that is without food, that's where we had higher exposure. What you see here is a dose response if you will, those patients who were treated without food at the end of 12 weeks. So this again, is 4 weeks of treatment, 8 weeks off of treatment, remaining on their background medication at an average 1% reduction in hemoglobin A1c. Placebo corrected, it was 1.1%. 90% of the patients at week 12 had at least some reduction in A1c, 80% had greater than or equal to up 0.5% and 40% of these patients had remained with a greater than 1% reduction in A1c and achieved an A1c level of less than 7% at week 12. What the final row shows is -- and this is a post talk sort of exploratory analysis, but we looked at those the median or the 50% of patients that had the best response at week 4. So at the end of the active treatment and looked at how these patients responded through the additional 8 weeks or week 12, and you can see in the 100-milligram group without food, there was a mean reduction in A1c of 1.5% in those patients. And this illustrates this with line graphs. You see all of the participants on the left. So with placebo, a small increase in hemoglobin A1c, without food, you see the reduction in A1C at week 12 of approximately 1%. And again, treatment period of 4 weeks and this 8-week follow-up period. And if we look again at that median with the highest where the biggest response at week 4, you see a continued decline in A1c and those 50% of the patients treated without food, the mean A1C at week 12 being 1.5%, the mean reduction, I should say. I'm going to go through one of the cases, and this is one of the responders here. This was a 51-year-old man with a 4-year history of type-2 diabetes. He was treated with metformin 500 milligrams twice daily. You can see very poor glycemia controlled baseline with an A1c of approximately 9%. Patient was obese with the BMI of 32. And again, he was treated with 219 at 100 milligrams daily without food for 4 weeks. Metformin was continued yet no tolerability issues or adverse events that were reported. And on the left, you see the change in hemoglobin A1c in this patient. He had about a 1.6% reduction. At the end of the treatment period, it was about 0.8% you can see there and what I show on the right is the CGM metric. So in green, is it the time and range. It went up from somewhere around 35% to around 75% time and range at the 12-week time point without any time in the lower range, so below 70 milligrams per deciliter. So very consistent results, and we've seen this with other patients, consistent results with the continuous glucose monitoring with what we're seeing with respect to A1c reduction. With respect to safety and tolerability, well tolerated and safe. Based on these studies, no severe or serious adverse events were reported. There were no dose discontinuations in these cohorts or any dose modifications, and there was no symptomatic or clinically significant hypoglycemia that we're seeing, again, pointing to this glucose dependency in the beta cell proliferation. So in summary, in patients with type-2 diabetes, 4 weeks of BMF-219, 100 milligrams once daily, resulting in clinically meaningful improvements in glycemic control at week 12. So this is 8 weeks after discontinuation of therapy, higher BMF exposures were seen in the 100-milligram without food resulted in greater improvement in glycemic control. 219 was generally well tolerated, and we are now completing the multiple ascending dose studies. These have been fully enrolled at this point. But we've also initiated -- we want to see higher doses and longer duration if we can capture more patients to get to these types of targets. So we've initiated a Phase II study looking at 8 or 12 weeks of dosing with 100 and 200 milligrams once daily. That study has a follow-up at week 52, and we're very excited to be starting a study in patients with type 1 diabetes as well where we'll look at 12 weeks of dosing with those same 2 doses, 100 and 200 milligrams once daily with follow-up again out to week 52. So with that, I am going to ask the panel to come up and we have some time for Q&A, and I think there's going to be a roving microphone. I'm going to check the time because we've been told we have to get next door, have to wrap up here at 7:45 and we have about 10 minutes, if anyone has any questions.

I'm going to start actually with a question that I got this morning and yesterday evening, I was speaking to some folks, and this I think is for Rohit but Tom as well, please. In the study in type-1 diabetes, we are not using any immunomodulation or any therapy to dampen the immune response. And the questions that I've been getting is, do we think that these new beta cells that we proliferate in this study might be attacked by the immune system and what's the thinking around that?

Yes. Great question, Juan. And there's two components here. So from an immunomodulation perspective, we've seen in literature that actually the continued destruction of beta cells actually keeps the autoimmune component going. And further, the contents of the cells activating the immune system over time. So if we can stop the destruction and start to rebuild the pool, we think that, that would dampen some of the immune response. The second component is as we were studying in our oncology studies, we studied patient samples and then we studied their B cells when we are conducting a CLL investigation and when we do gene expression analysis of these B cells, we learned that through the GEO database at the top pathway disrupted by 219 was the B-cell T-cell cross-talk. So we think there will be actually a direct benefit from 219 on reducing T cell activation.

Yes. Thanks, Juan, and thanks, Tom. So yes, I think one of the physiological features in type-1, if one looks closely at what may be happening in patients with type-1, these data are emerging now because we have access to pancreas sections from these individuals. We can look at large volumes of data. So one feature is that the insulitis is lobular in pattern, right, so individuals with type-1 diabetes, there are some lobules with insulitis. Other lobules are free of insulitis. So there are other lobules which have these beta cells, which don't have insulitis. So the question is whether we can harness those beta cells in the context of pushing them to proliferate just a little bit, for example, reduce inflammation in those beta cells and make them functional. The second point is the Medalist study argues for the presence of replicating beta cells even when you are 80 years with type-1 diabetes. So a comprehensive study, both from the Joslin group, the Exeter Group in England and Australia have showed that the Medalist, we call the Medalist because they get a medal because they've had more than 50 years of type 1 diabetes, these individuals have replicating beta cells. And if you do a mixed meal tolerance test, they are showing an increase in C-peptide. So this, again, argues that there are certain beta cells in these individuals, which could be harnessed to push for replication and proliferation in a very sustained control manner. So these two important observations in type-1 suggest that in addition to immune therapy, we also need to think about pushing the beta cell proliferation to go up.

Yes. That's a good point, Rohit. And I would just add, the animal data that Priyanka shared with us, the ZDF animal model, and we did staining of the islets compared that to the liraglutide in vehicle arm, we did see that 2019 resulted in a reduction of inflammation and reduction in necrosis of the islets.

That's great. So I appreciate the response. And I would say the type 1 study also has two open-label arms. So we'll be able to see this, and we'll know relatively soon. We have two open label arms and then a randomized controlled portion of this with 150 patients. So it's a pretty robust study but we'll be able to look at some of these data in real time, which I think would be very interesting. I don't know if there are any questions from the audience, but yes, Tim?

Yes, Perhaps a bigger problem in type 2 diabetes is not so much a decrease in beta-cell mass, but impaired glucose sensing by the beta cell and reduced insulin secretion on that basis. So I'm wondering if menin or this compound enhances glucose sensing by existing beta cells, number one. And two, do you think the recruited or -- beta cells as a result of drug action will be sensitive to glucose toxicity and lipotoxicity as the disease progresses like endogenous beta cells or original beta cells. I don't know what's the right term there is. So 2-part question.

I can take the first part. It's a great question. I think as we've learned with our animal studies with the human islets and now in the clinic, we think it's very important to drive down or drive out the glucotoxicity as we're generating the new beta cells so that these beta cells can then differentiate mature and become insulin-producing cells. Once we've cleared that out, we think we would prevent the additional glucose toxicity and lipotoxicity that happens over time because we're driving down the glycemic burden and getting the patient near normal range from a CGM perspective.

Yes. So and to the first part, I think that's something that will be very important to look at. Is there improvement in glucose sensing in these new cells? I would say theoretically, yes. But to Tom's point, I think these cells would still be prone to the same type of insults of the previous cells were we just have to improve glucose, improve lipid, certainly, there's no reason this can't be used in combination. And in fact, some of our patients have been an SGLT2 inhibitor, GLP-1 receptor agonists, and we really see this as complementary therapy particularly when these other agents are being used for extra glycemic effects as well.

So maybe I just want to also add to Tim's point here, it's that we observe at least in the limited number of islet studies that we have done in vitro and islet micro-tissues, the basal insulin secretion goes down. We know that basal insulin secretion being up is a problem in diabetes as well. So the -- when you treat them with BMF-219, the basal secretion goes down and the glucose stimulator response is maintained or even improved. So I think the new beta cells that are coming up reflect what would be happening in the normal scenario, low basal insulin secretion, improved glucose secretion.

Okay. And unfortunately, we're going to have to wrap up. I just wanted to remind everyone that we do have a poster here. That poster will be an oral presentation tomorrow, as you can see, and we have a table in the exhibit area. Many of us will be around, and we look forward to discussing this further with you. We're in the conference. So thank you very much, and have a great conference.