Hi, good morning, and welcome to H.C. Wainwright's 20th Annual Global Investment Conference. I'm Ananda Ghosh, Senior Biotech Analyst at Wainwright. Today, we are very pleased to host Ramses Erdtmann, Co-Founder, President, and COO of Biomea Fusion for our company presentation series. Welcome. Thank you. Thank you for hosting. This is actually, you typically do fireside chats, and now you make me present. You had me work this presentation, and I hope I can make it in 20 minutes. There's a lot to cover. The company was founded in 2017. Today, we have two assets that we're pursuing. We're no longer having our research department. We basically are 35 people strong, and we're focused on two assets. One, a first-in-class beta cell restorative therapy. We are the first menin inhibitor that targets diabetes, and this pathway was detected in 2005. 2007, 2010, early academic papers came out, and when we started the company in 2017, we read those papers and thought, if ever menin, which was originally identified for cancer, if ever that target can be addressed safely with a menin inhibitor, we should go after diabetes. The market is so huge and nothing in diabetes restores. Everything is trying to sort of bring down the sugar. We thought it was a phenomenal opportunity, so we spent a lot of time working through pre-clinical animal models, and now we have a first-in-class, and potentially best-in-class, Type 1 and Type 2 diabetes agent. We're in phase II, and I will show you where we are exactly. Then we have, with the team, about four or five years ago, we started, and we said, "This GLP-1 space is just heating up. Is there a way to make it better? Can we, as drug developers, come up with a scaffold or improve a scaffold that threads the needle just a little better?" Right now you're fighting between the persistence of patients. Patients are not staying on drug. Why? Because they have GI side effects. Okay. You're fighting that on the one hand with, "I need to get this weight down, but not only through vomiting." That would not be a good outcome. Seven out of 10 patients, in the worst of all studies I have read, drop within the first year, even though you pay for them. So what kind of drug is that? That's not a good drug. The class is great, the effects are great, but can we improve this profile to keep patients on drug? I will talk about that as well. So that's our next generation all GLP-1. We have multiple phase II readouts. We have a fairly experienced leadership team with a clear vision and execution plan. Probably every biopharma says that. Then we have a cash runway through key upcoming inflection points. That's a very important graph, and I'll show you that as well. Okay. Here is the milestone slide. It is very busy. I will walk you through each one of those important findings. One, we saw our pathway has phenomenal impact. Literally unusual impact in Type 1 patients. That blew me away when I saw this data. We are showing C-peptide increases in a patient where the immune system is attacking those cells, and we see that the C-peptide, meaning the output of those cells that are being attacked, is going up, which means the mass is growing. That is our targeted approach. We want this mass to grow, and C-peptide is the marker for that. We saw that. We were really excited about this opportunity. We have two studies planned in Type 1. We have a study where we show the benefits of the use of our menin inhibitor in combination with the GLP-1 agonist in obesity because we saw muscle preservation, additional weight loss, and general health benefits when combining menin inhibition with GLP-1 agonism. That study will read out by the end of next year. The Type 1 study will engage at the beginning of next year. We will have a first patient in, and we will read out by the end of next year as well. We have our core, which are the two studies here. The ones in Type 2 diabetes, where the subsets are identified here. One finished enrollment, and they are on track to read out next year as well. The primary goal for a company like ours is what? The primary goal is finish your phase II, show to the FDA that we have the data sets necessary to go into a commercial study, which is a phase III, and that is the primary goal. That is why we are here. We are here. After that, anybody can do this work because to translate a II to a III is difficult, but is not overly complex. You just take the protocol. If the protocol is acceptable to FDA, which we hope it is, and replicate it in your phase III studies. We already talked about how many patients are needed for these phase III studies. So we feel comfortable if we produce the data, we will be in end of phase II meetings with FDA by the end of next year. Here down there, you can see the GLP-1 is the BMF-650, is the next generation GLP-1 that we created, which will read out by the end of this quarter. Lots going on. Okay, let us go into it. Most people do not know that diabetes is actually a disease that is not approached at its root cause level with the medicines we have. What does that mean? That means you go to the doctor, you say, "Oh," the doctor indicates to you you have diabetes. What is he going to give you? He is going to give you a drug or one of a drug class of drugs, and they typically have a lifespan of two to five years, whatever the literature you can find. He is going to give you another drug and another drug, but all these drugs are doing is they are addressing the sugar that is circulating in your blood. Diabetes is an indicator that your pancreas that has beta cells are fitted to you at birth, but they do not fit your current lifestyle. Your current lifestyle is maybe sedative, maybe you eat the wrong things, maybe too much sugar intake, which is very likely your lifestyle, and thereby you are depleting these cells. When you hit about 50%, your body signals side effects, and these side effects are indicators that you have too much sugar circulating and the pancreas is incapable of managing that sugar. The insulin production is insufficient. So you typically have lost 50% of that capacity. Losing means losing, they do not come back. You do not make new cells, generally speaking. Only under two circumstances, and I will get to those. If you get this indication, the doctor addresses this disease by addressing the symptom, which is sugar, and he addresses it with different drug classes. As you cycle through these classes, you will end up on insulin. One out of three patients ends up on insulin. Did you know that you lose 12 years of your life by being a diabetic? This is a really severe disease. I worked in oncology for over 10 years. I have never had a statistic as clear as this, the premature mortality. It is brutal. You have diabetes, you lose 10 years of life. So what can we do to change these dynamics as you see them here? The only thing we can try to do is not get a better agent to address the sugar. Could be one way, but there are so many ways people have tried to get the sugar out of your blood. The better way is your pancreas. Why do not we restore the cells in your pancreas so they can address the sugar? So what the body does is, and I am going to show you some This is just basically high level. It is a big disease, we know, diabetes and obesity. What was found is, and this is the paper of 2005 I mentioned earlier, is in your pancreas, there is a control switch called menin. When you go through obesity as a male or you go through pregnancy as a female, your body upregulates a hormone called prolactin. This hormone, when upregulated, downregulates menin, which is a protein. When menin is downregulated, the body can now address the need for more insulin by increasing the cells of your pancreas. A pregnant woman who died during pregnancy has an enlarged pancreas. Women who have gone through more than one pregnancy have less probability of diabetes. Women who have gone through breastfeeding have less probability of diabetes. If you put these facts together, and this pathway has now been found in animals as well, menin regulates pancreatic islet growth. Can I address this menin protein and allow the body to respond in a diabetic circumstance and bring these beta cells and restore the pool of beta cells? That is the question we asked. What we found is that icovamenib has been shown to directly inhibit menin, and I will show you this example here. There were so many stories about us early on because what we are doing here is actually too good to be true. I can restore your health with a medication. How is that possible? Well, what you can see here on the left is the protein menin gets reduced in donor islet cells. That is where you typically show, are you having an effect on the target, left side. On the right side, you can see here, under high glucose condition, the proliferation rate of more menin inhibition, higher green bar, is higher in a high glucose environment. If you have standard glucose conditions, even though we inhibit menin, the body does not proliferate these beta islet cells. Very interesting finding. We know we are on target left, and we know while we are on target, the effect is improved the more we inhibit the target, if you are in a high glucose environment. Meaning, if your HbA1c is above seven, you are not controlled, the physician will give you a drug to address your diabetes. That is this high glucose environment. When we saw this is a cell experiment, we also did animal experiments. In 2022, we showed you the animal experiments. They show that in the animal we can address, and not only we showed that, others have shown it as well. It is a wonderful experiment. You take a diabetic animal group here and another group here, and one physician, he CRISPRed out menin. He took menin out all the way of these animals. They infused them with sugar. Here, sugar is controlled. Here, sugar goes up. Phenomenal experiment. We saw this when we started our work in menin, and we said, "Can I replicate this with a menin inhibitor where I do not CRISPR out menin, I just inhibit the protein menin?" And we saw the exact same results. That was published in 2022. Then we did the islet experiments where you take human islets, so you know the translation from animal to human is working. Now when we had this, we understood the pathway. On the one hand, we are creating beta cells. On the other hand, we have done a lot more work since then. We know that on the surface of these beta cells that are proliferating, there are receptors. These receptors are more expressed. Oh, okay. What could that help us with? Let us find out. We also know the GLP-1 hormone in the body is more expressed. When you know these two things, you potentially have an impact on these two subsets. And those are the categories of patients we then found. One, if a patient is highly deficient in insulin, he should be responding really well to this menin inhibition. Also, if you are obese on a GLP-1, there could be synergies because you have more beta cell expression and more receptor expression. And you are up-regulating GLP-1. What we then did is we tested, there is more information on the pathway, we tested these two subsets in an all-comers study. In this group, you can see here, we dose for 12 weeks, the green shaded area, and then you can see the A1c curve, which is the purple line, had already responded, meaning while you are on drug, you are coming down in your sugar levels. Then post-treatment, we stop, and you can see how this A1c curve goes further down. And the reason for that is those cells that are proliferated have to come online, and they take time to be fully functional. So you can see this benefit continuing. The study was stopped at 52 weeks. I would have loved to know what happens at 104 weeks. The next study we are doing and the studies we are enrolling today are actually longer. We will have a 52-week readout, and then we have a follow-up study just to know what do I have to do with this patient, if anything, within a year, two years, or three years down the line. We also looked at the production of their insulin. Insulin is measured as C-peptide. It is a surrogate. If you go for the insulin production, you can see insulin coming up. Great. That is our mechanism. But the effect that is going up post-treatment is the miracle here, and it is basically happening in humans, and we can measure this. This was extremely convincing for us when we read out our study, and we also saw in patients who were on a GLP-1 where the sugar was rising, so the GLP-1 does not have any more effect. We are improving that effect of the GLP-1 by synergizing this effect with a menin inhibition, and you can see here the A1c is coming down, and then it comes down off drug even further because GLP-1 receptors are more expressed and the GLP-1 is up-regulated after the menin inhibition. Okay, these are the two subsets here as well, C-peptide increase. If you compare our results, and we are the first drug that has targeted menin in diabetes. We are the first to show in a bonafide all comers phase II study these results, and we are the first, and potentially best-in-class, that will take this into now these two subsets I characterized earlier, and we will hopefully be the first to be in phase III. But what you can see on the far right, it is 1.5-1.8 A1c reduction. That is comparable to the best drugs in this field. Ozempic, Mounjaro, those are heavy drugs that are being used for diabetes as well as for weight loss. We are extremely satisfied with the outcome. We have improved on understanding the patient profile. We understand the amount of drug is needed, and we understand the amount of dosing that is needed. These are things our competition still has to find out. We have over 500 patients dosed so far to- date with all our studies. We know the safety profile, and I can show you that as well here. Do not look at this up here and tell me which one is placebo, which one is drug. You are going to have a hard time seeing a difference between the two. In the brackets, you see the percentages. The percentages are very much the same. Treatment Emergent AEs are the same between placebo and drug. There is a slight increase in ALT and AST, that is Grade 1 mostly, and it is transient. So it is very favorable from my perspective as a safety profile. Safety is clear, efficacy is clear, target patients are clear. Let us do phase IIs, and that is kind of what we are doing now. The way we identify ourselves is when current standard of care is failing, we are going to fit right there in before you need to go on insulin. We are pushing out for the healthcare system, for FDA, for patients, the need to be on insulin. One in three patients ends on insulin. That's not a good thing. We're trying to help a patient not to become insulin dependent. These are the two study designs. As you can see in the enrollment criteria, they're very standard. HbA1c at a certain level, BMI at a certain level. You're failing your background agent. You're good for our study. That's 211. Now let's go into and ask the question, or re-ask the question. My best insulin deficient patient is a Type 1. He's completely insulin deficient. Can I have an effect in the Type 1 population? Current therapy, just remember, on the left-hand side, all current therapies, they're trying to do is preserve the cells. Keep the immune system from attacking the cells and try to make these cells survive that attack longer. Shut down immune system, protect the cells. That's what all therapies and developments are trying to do. Name one that is trying to restore the cells. We're completely new in this field, but we tested and we did an all-comer study there as well, trying to see, can I restore, expand these cells that are there? We didn't really care much for the type of Type 1. We actually asked the question. Basically, we said zero to three years since diagnosis, 3- 15 years. Other drugs are taking patients between zero and 90 days. Why? Because they try to preserve what's there. We didn't really care for that. We just asked zero to three years, and you see here in a patient populace of zero to three years, we are increasing their C-peptide, meaning their insulin production, by 50% +. That's very unusual. The N is small, I know, and obviously, that's what research does. We start with a signal like this. But you can see the signal translate between the 100 mg, which is the lower graph, and the upper graph, 200 mg. The signal is there. We're now starting two phase II studies in Type 1 to explore this signal and make use of what our understanding is today. I talked a little bit in the beginning about 650, and I gave you the examples. Here is the readout of what we had seen in animals. And monkeys have similar receptors. We think efficacy is on par. The key differentiator between our GLP-1 next generation and the ones in the market, hopefully will be on the safety aspect of the drug. What's the question? No. Okay, good. You can see here the milestones that I've covered early on. Type 1, end of phase II. That's the goal for next year. Icovamenib in obesity. We're trying to get that readout done next year as well. Icovamenib in Type 2 diabetes. We have a six-month readout in Q1. We have a six-month readout in Q2 for the two studies we're pursuing there in Type 2. So there as well, we go for an end of phase II meeting. 650, by the end of this quarter, will have its 28-day weight reduction. There we can see we tried a one-step titration for orforglipron. One, two, three, and they needed four steps to get to their target dose. In phase II, they tried various ways to get to target dose. They expanded the target dose. They lowered the entry dose. In phase III, they said, "Oh, wait a second. Let's go monthly titration because it's too risky, and let's bring down that target dose further, and let's bring down the entry dose even further." Because they're battling tolerability. What we're saying with this readout, let's just show the difference, us and them, one step. If I can reach a similar efficacy with just a one-step titration and I have tolerability on my side, I think we have a very exciting scaffold. That readout comes at the end of this quarter. Very likely we will continue tox work, but we'll focus on finding a licensing partner for this compound. That ends my presentation. Thank you for listening.