Welcome to everyone in the room and on webcast, thank you for joining us for Obesity Day. Today, we are excited and honored to present our novel and transformative approach to treating this global chronic disease. We've experienced increasing interest in learning about our obesity portfolio. We thought this was a timely opportunity to highlight our remarkable progress which we are making toward our 2026 milestones. Standing tallest is 12-week MAD data in Q4 for MBX 4291, our GLP-1 GIP co-agonist prodrug. We said that it would be important to show true once-monthly dosing and improve tolerability as a monthly drug. We also said we should expect to see competitive weight loss, given these are the gold standard mechanisms. Sam Azoulay, CMO, will present preliminary data from our ongoing blinded phase I study which demonstrate this target product profile. We're very encouraged by what we're seeing with MBX 4291, which reads through to our entire expanding obesity portfolio, all built on our proprietary PEP technology. We're joined today by two leaders in the obesity field, Katherine Saunders, co-founder of FlyteHealth and clinical assistant professor of medicine at Weill Cornell Medicine, and Richard DiMarchi, distinguished professor of chemistry at Indiana University, scientific co-founder of MBX Biosciences, and my partner for more than 20 years in multiple successful companies in obesity, including Marcadia Biotech, where Richard pioneered multi-agonists in obesity, which have helped revolutionize the field. Dr. Saunders will provide an overview of the evolving treatment landscape and the remaining treatment gaps in obesity. Dr. DiMarchi will follow with the progression of pharmaceutical treatment and, as the architect of the PEP platform, discuss its application to the development of long-acting therapeutics in obesity. Sam will present the preliminary blinded clinical data for MBX 4291 summarized in this morning's press release. Richard will introduce our newest development candidate, MBX 5765. We call it an amycretin, it combines additional mechanisms which are clinically validated all in a single molecule. I'll also present proof-of-concept data for imapextide in post-bariatric hypoglycemia, PBH, provide an update on our priorities and milestones for 2026 before we open it up for questions. Note I will be making forward-looking statements. Please review our risk factors and other disclosures in our SEC filings, which are available on our website. At MBX, we are completely focused on once-weekly canvuparatide in our growing obesity portfolio, where we believe we can have the greatest patient impact in long-term value creation. Multiple clinical stage programs, each designed to be best in class in multi-billion dollar markets, are progressing well in development. Our PEP platform combines innovative peptide design, programmable prodrug, and fatty acylation to achieve unique pharmacokinetic and PD profiles. We achieved proof of concept with our PEP approach in our lead program, once-weekly canvuparatide. We presented very positive phase II results last September, which were supportive of best in class, and we'll present one-year OLE data at ENDO in June. We hope to see you in Chicago. We're on track to start enrolling our confirmatory registrational phase III study in Q3 next quarter. Mark Hope was recently appointed CCO, Chief Commercial Officer, to lead our commercial launch planning. Turning to our obesity portfolio, our ongoing blinded study is on track to report top-line results for a 12-week MAD cohort in Q4. We believe the preliminary data demonstrate that we can design differentiated PEP therapeutics with once-monthly dosing, improved tolerability, and competitive weight loss through gradually rising and steady drug exposures. MBX 5765 applies our PEP technology in multiple mechanisms in a single molecule. In preclinical data for MBX 5765 demonstrate a differentiated PK profile supportive of once-monthly dosing as well as the expected PD effects. Our triple G, GLP-1 GIP glucagon co-agonist or multi-agonist, is on track for candidate selection next quarter, Q3. We have a very focused discovery effort underway in obesity. The obese patient population is global, heterogeneous, and vast, requiring varied treatments to address it, particularly the individual needs of patients. The clinical data in new obesity candidate presented today reinforce our aspiration to become a global leader in endocrine and metabolic disease. We're well-capitalized with $440 million in cash, which is expected to provide runway into 2029. It's an incredible setup and compelling program today. I'll now turn it over to Dr. Saunders for an overview of the obesity market landscape. Great. Thank you so much, Kent, and thank you for having me here today. It's really a pleasure to be talking about this exciting field and the progress that we're making. Let's take a look first at the worldwide obesity prevalence. When you look at the numbers according to the World Health Organization and the World Obesity Federation, we know that 1 in 8 people worldwide are living with obesity. Breaking that down in adults, that's almost 900 million adults with obesity, and then more broadly, the overweight category is 2.5 billion adults throughout the world. In kids, the numbers are also staggering. 160 million children are living with obesity, and when it comes to overweight, there are 390 million children and adolescents with overweight. When you look at kids as young as age 5 and below, that number is even $35 million. Just to put things in perspective in terms of the growth, obesity rates have doubled since 1990, and it's projected that by 2035, 25% of the world population is projected to have obesity. Really huge, huge, huge numbers here, which make it so that the obesity market, which is now $60 billion today, is projected to rise to over $90 billion through 2031. This growth is really driven by many different factors, but you can think about it in terms of 3 different categories. The first is investment in exactly what we're talking about today, GLP-1 and next gen treatments for obesity. We're looking at treatments with improved efficacy and safety profiles. We're looking at more oral options and more varied oral options and different routes of administration that will drive uptake and really improve adherence and persistence of medication. Two is improved access and affordability, which we're really hoping for as clinicians to, you know, help as many of our patients as we can. This is expected to allow more patients to consider this class of medications and really, you know, be on them in meaningful ways. The Medicare expansion project, which is supposed to kick off in the next two months, actually, hopefully will be a big driver of improved access and affordability. Finally, rising obesity prevalence and increased awareness of obesity medications to increase the addressable population. Taking a look at compound annual growth rate, it's interesting to break it down in terms of BMI. When you take a look at, you know, the overweight category, Class 1 obesity, which is BMI 30-35, and Class 2 and 3 combined, which is a BMI of 35 plus, the obesity prevalence is really most stunning in the greater levels of obesity, so Class 2 and beyond. Estimates indicate that actually 40% of U.S. adult population will have obesity without Type 2 diabetes in 2030, and nearly half of this population is in exactly that population, the patients with obesity that is at least Class 2 or Class 3. Let's take a look at the unmet needs. It's really exciting to, you know, break it down in terms of exactly what, you know, we as clinicians need to be able to help as many people worldwide as possible. One is just the response. You know, the percentage of patients with obesity who would benefit in terms of weight outcomes and health outcomes by losing more than 20% of their total body weight is substantial. Looking for medications that provide greater efficacy is a big target. Number 2 is prevention of weight regain. We know that obesity is a chronic disease that needs long-term treatment. We know that when people stop obesity medication, they're at high risk of regaining very rapidly and regaining very significantly. We really need, you know, more tools and more strategies for this important phase of weight maintenance and not just the phase of weight loss. Tolerability. You know, the side effects that come along with many of the therapies really affect adherence and persistence. Adherence, you know, how patients take their medication compared to how it's prescribed, and persistence, how long people stay on medication. Convenience. You know, what patient does not wanna take something that is, you know, way more convenient than the regimens that we used to have, and it's improving in a very exciting way to help people to be able to not have it be a huge burden in their life to take a medication for a chronic disease. Just to make it as easy as possible would be ideal. Weight loss quality. We're not just talking about how much weight somebody can lose. We're talking about health outcomes, and we're talking about quality of life. A huge part of that conversation is really taking a look at, you know, what kind of weight is lost. We know that a certain percentage of weight is lean body mass, which includes muscle. There's a big focus on what we can do to preserve not just muscle mass, but muscle function, and other factors related to that. Finally, outcomes. Taking a look at different subpopulations is a big area of unmet need. Pediatrics, older adults, you know, how medications really affect these different subpopulations, and the safety. You know, how can we make these treatments as safe as possible, not just for kids and older adults, but also for people with a wide variety of different comorbidities? Let's zone in a little bit on the GI side effects, which is a huge topic of conversation both in this room and just more broadly. We see all the side effect hype. What do we see clinically? Part of the mechanism of how these medications work, you know, is that they slow gastric emptying, their effect on GI motility. Of course we see, you know, some nausea, some vomiting, some diarrhea. These side effects are really important in terms of patient's ability to stay on the medication. The nausea, vomiting, and diarrhea are typically the most frequent. What we do now is really a lengthy titration regimen to allow people to adapt to these medication to be able to get to the optimal effective dose. These events often happen at initiation and also during dose escalation. Why does this matter? This matters because sometimes the side effects are mild, but when they're more than just mild or when they're persistent, this is what really affects adherence and persistence. They're a key driver of treatment discontinuation, which, you know, as I mentioned, because this is a chronic disease, is not the outcome we're looking for. Again, the lengthy and gradual titration to improve tolerability is the current kind of standard of care. This again impacts a patient's ability to reach the dose they need to get to. The goal really, you know, optimizing exposure may improve tolerability and decrease the amount of the required titration steps, and this is something that is a very, you know, exciting prospect. Finally, you know, the goal really is to, you know, be able to provide obesity care with new tools in a way that helps people to achieve their weight and health goals and to keep them on medication. When you take a look at the status quo right now, the numbers are pretty terrible in terms of people discontinuing. Again, there are many reasons for this that we just reviewed, but looking at the actual numbers, patients with type 2 diabetes, the numbers are a little bit lower, but 45% of people stop within 1 year, and 64% stop within 2 years. This is, you know, we're talking about a chronic disease that needs long-term treatment. When you look at obesity, those numbers are even higher. Within 1 year, it's 65%, and within 2 years, it's 84%. This is, again, not what we're looking for. When patients stop medication, they regain weight and, you know, it's a big waste of money to have treated patients for this long, reach these outcomes, and then have them back to where they were in the beginning. There's a huge, huge, huge need for more tolerable treatments and everything that we can be doing to get people on the medications they need and more importantly, keep them on long term. I'm gonna hand it over to Richard DiMarchi now. Thank you very much. Indeed, a great pleasure to be here. It, I came from Bloomington, Indiana, and to be here to discuss this subject, it only took me 50 years, half-century. I trained with Bruce Merrifield, the then to be Nobel laureate over at the Rockefeller University, and have gone on to be at the forefront of advancing this field of macromolecular medicinal chemistry, building these optimized peptides and proteins as therapeutics. Spent little over two decades at Lilly and a little over two decades on my own at the university, starting companies with the likes of Kent Hawryluk. It really is an indeed a pleasure to be here. These last 20 years, actually, 30 years, have focused, as I said, on obesity, but the history of the GLP-1s reach back to 1983, right? It's a little over 40 years when Graeme Bell cloned the gene as he was coming out of Chiron, going to the University of Chicago, and Svetlana Mojsov, who worked alongside me in the Merrifield Laboratory up at the Massachusetts General Hospital, did the characterization, the discovery of the active ingredient in those mid-1980s as Jens Holst in Copenhagen was doing similar work. In the 2000s, we saw this shift from a focus on diabetes, right? Glycemic control to body weight, as Steve Bloom published in January of that year in Nature, the acute administration into the brain of a rat could minimize their appetite. It was later in that year, again, still being at Lilly with Suad Efendic, who was chief of endocrinology at the Karolinska University Hospital in Sweden, that we submitted a patent that disclosed the treatment of obese type 2 diabetics for 4 weeks could lower body weight. That led to Lilly having a patent that covered the whole field of GLP-1s for treatment of obesity. It fell on deaf ears. It was 20 years before the American Medical Association declared obesity as a disease. What's the route to treat it? Would people ever take an injection? Could you ever get a meaningful decrease in body weight? Could you get beyond the 4%, 5%, 6% to something close to what we're experiencing right now? In that decade that followed, exenatide, a paralog, not an analog, a paralog of GLP-1 was registered by Amylin Pharmaceuticals, Joe Cook, who had been with us at Lilly, was CEO of the company. That was followed in 2009 when Matthias Tschöp and I, he a professor at the University of Cincinnati, I in Bloomington, discovered that you could use glucagon, not as an antagonist, but as an agonist integrated in with GLP-1 to get superior outcomes. It was the beginning of what we now see being advanced as the active ingredient in retatrutide that distinguishes it from GLP-1s. Victoza was the first GLP-1 that was registered as an analog, a fatty acylated analog once-a-day medication. Notice 1983 to 2010, we're at about, you know, quarter of a century to get that far. Then in the decade of the 2010s, we get the emergence of what Matthias Tschöp and I disclosed in a couple of landmark publications integrating GLP-1 with GIP, which is the active mechanistic approach to Mounjaro, to Zepbound, tirzepatide being the peptide in 2005 and in 2015, the triple agonist, right? The Triple G as Lilly refers to it, GLP-1, GIP, glucagon, was disclosed in a Nature Medicine publication, again from my laboratory in collaboration with Matthias Tschöp, who is now in Munich. Saxenda becomes that first GLP that is registered for the treatment of obesity. Wasn't a terrific product, right? It was looking like the oral compounds that were giving us the 5%, 6%, 7% body weight lowering. The breakthrough, right, the breaking of the sound barrier in 2018 was Novo's disclosure in phase III clinical studies that they could achieve 15% body weight lowering with semaglutide, the fatty acylated peptide that has recruited folks' interest commercially into this field. Wegovy gets approved in 2021, Mounjaro, that co-agonist for diabetes in 2022, and Zepbound in 2023. I think many of us are expecting that retatrutide will be approved this year or soon thereafter as the triple agonist. It's quite a journey as we move from diabetes-centric, a drug that was focused on for its glycemic effect, its incretin effect, right, on the pancreas, to what is now obesity-centric. I will share with you that early in my training, I met with Carl Djerassi. Many of you would know the name. He's the professed father of the pill, right? Contraception. He shared with me there are rare times in the history of the pharmaceutical industry where drugs have an impact that are bigger than the medicinal purpose for which they were registered. This is one of those cases. This is more than lowering people's glucose. This is more than lowering people's body weight. It's changing how they perceive themselves. It's changing how they perceive life. Okay, the whole focus now is getting from drug-centric to patient-centric. As Dr. Saunders has shared with you, we have tolerability issues, right? Compliance is not what it needs to be, and there are many patients who just cannot tolerate this medication. We have this crazy algorithm for getting to steady state that takes as much as 6 months. That's not the typical way in which we prescribe medicines. Tolerability, improved compliance led me over 2 decades ago to anticipate this to be the case as we put together this chemistry, prodrug chemistry for macromolecules that is really the magic of why these substances are performing the way that they perform. Endocrine hormones have narrow therapeutic index. We began to develop this chemistry for use in insulin, something that I know a bit about, because you know what the consequences of an overdose of insulin are. You also know in PTH that calcium is every bit as important as glucose is. Having precise control over drug concentration so you can precisely, keyword, right, precisely regulate the calcium levels was something that we put to work in Canvu. Recognizing that we could use this to address the tolerability issues that we have with the GI effects that the incretins, notably GLP-1, has. The magic of this is that we take a dipeptide, two amino acids, and we just invert the conformation. Your peptides and proteins are in the trans configuration, right? They sit like this, and that is why they're not falling apart two amino acids at a time. By strategically inserting a methyl group, we can fix the cis conformation. In the cis conformation, it's prone to cyclize. The more the cis conformation, the faster the cyclization. The less the cis conformation, the slower the cyclization. We can control that cleavage anywhere from 1 hour to 1,000 hours, which gives us precise control because it's an intramolecular reaction, which means that it's concentration independent. You don't have to worry about the dose. You don't have to worry about the circulating concentration. You'll get the same cleavage rate. Very natural. Amino acid based. What you see here in building upon the advances with these fatty acylated compounds that have the once-a-week time action, could we introduce another fatty acid on a dipeptide in a strategic position, as we did in Canvu, to kill the biological activity until you get that cyclization to release an active fatty acylated product, very much like tirzepatide or semaglutide in the extended duration of action. That entity is capable of seeing either of the two receptors, GIP, GLP, bound to albumin or in the free confirmation, which is only a small% of that which continues to circulate. That's how we extend the duration of action. That's also how we flatten the peak to trough, aiming for something that looks to have pump-like action without having to wear a pump. We'll come back and talk a little bit about the clinical results, and I'll turn this over to Sam now. Thank you. Thank you, Richard. I'm very, very excited to be here, to be before you and to present the results, the MBX 4291 preliminary results. Like, with a nice story, I'm not going to go directly to the results, right? I'm going to keep you a little bit waiting. I'm going to start with what are the guiding principle at MBX that really is leading to our strategy. We do believe that there is a big, really big opportunity in obesity with a once monthly dosing with improved tolerability. As Richard said, we are using our PEP platform, right? What we are going to optimize the pharmacokinetic of our molecules, our peptide, in order to have something like a unique profile, very differentiated profile with the goal of a gradual, flattened, and sustained exposure for monthly dosing. This, when you achieve this, you should get better tolerability. Is that exactly what we want to get. That our strategy, we presented the graphs, the figure, we started presenting this in January, but the story started way before that. It started with modeling, with animal preclinical data, and we came up with this profile, with this product profile in terms of PK here, which I can show you here in green. What you see in green here, that our profile. We compare this with products that all of you know very well, tirzepatide, right? No need to present a GLP-1, GIP co-agonist marketed, and it's a weekly administration. We are comparing also our product profile or PK with MET-097i, which is in development for a monthly administration, right? We said we want to get gradual. What does it mean? That here, smooth raise to the Tmax. Really smooth, look. We compare with tirzepatide and MET-097i. Look how steep this curve is, right? How it goes to the Tmax very rapidly. We know that it's related to the GI intolerability, right? When you look again at tirzepatide, you see this variation, sorry, a variation around the Tmax due to the weekly administration. That's not exactly what you want to get. You want to get something which is steady, stable with no peak, something like this, right? That's what you want to obtain. Again, this is also related to GI intolerability. More variation you have around the C-max, more tolerability issue you get. Looking again at the MET-097i, you see that then you have a slow decline in terms of concentration, they refer to the time to half C-max, which is a good proxy for the half-life of 21 days. What you want to get is a T to half C-max as long as possible, as close as possible to the T-max. Why? Because again, the peak to trough variation is limited, is small, and so you improve the tolerability on one hand, but certainly you improve this dosing schedule with a monthly administration. That exactly what you want here, so they refer to 21 days, we are aiming for, and we're expecting to be beyond the 21 days. Okay. That what we want. That's a story of how it started. Now, I'm going to speak about MBX 4291, which is our GLP-1 GIP co-agonist, right? With the goal of being administered on a monthly basis. We design a phase I clinical trial, which is ongoing. This study is ongoing. The data I'm going to present you are still blinded. All the clinical data are blinded. We are mixing the data on the treatment and on placebo are together, right? It's still blinded. This study, this phase I study, sorry, is divided in three parts: the SAD, the MAD, and again, another multi-dose administration, which is part A for the SAD, part B for the MAD, and the last one, which is the part C, and you will see the differences. And each step informs the next. The SAD will inform the MAD, and the MAD will inform the last section of here. Sorry, here. Inform. We are on the target population of subject with BMI at or above 30. Everything we see can be extrapolated to the larger population of patients overweight, who is overweight. I'm going to spend some time on the SAD. The SAD we have 5 cohort, we're evaluating 5 doses from 15 mg to 180 mg. We have each cohort has 8 subject, 6 treated, and 2 placebo. The MAD is a weekly administration for 4 weeks, potentially followed by a monthly administration. Again, the same target population. We have 3 cohort. Each cohort has 8 subject, 6 treated, and 2 placebo, right? The last and the most important one, the part C, is a target population. We were talking about potentially doing a second cohort. We are confirming that we'd be doing a second cohort. Each cohort will include this time 30 subjects, a much larger population of subject with overweight, of 20 treated, 10 placebo. One of the cohort, one of them will include a weekly administration for 4 weeks, followed by monthly administration, with a total exposure of 12 weeks. This study has not started and is on track, however, to be delivered as promised by the fourth quarter of this year. We're good on this. What are the study objective? As any phase I study, the first objective is to assess the safety, to assess the tolerability, but also to find the maximum tolerated dose, and especially with the focus on the GI tolerability, nausea, vomiting, diarrhea. We want to find what would be the best streamlined dose titration. Secondary objective, the pharmacokinetic. We want to get a monthly administration. The PK is extremely important to confirm the potential for monthly. The second one, which is the secondary objective, is the pharmacodynamic effect, which is the weight loss, right? The last one, which is to identify the dose and the titration regimen we'll be pushing for phase II, right? That's the objective of this study. I hope I'm good in keeping you waiting for the last slide. Next one. Now the SAD. I can show you in terms of PK, the result of the SAD. In this graph here, PK graph, you have four doses, which is we started with 15, 60, 90, and 180 mg as a single dose. The 120 mg is still ongoing. The cohort with 120 is still ongoing. What can we see here? We see that we have dose proportional PK, right? Dose proportionality is achieved, but very importantly, gradual increasing and sustained concentration after single dose. You see? Gradual and steady and the sustained concentration. Looks very similar to our TPP, right? It can check the box almost and say, "Well, we have achieved our first objective to look like our TPP." We like to compare, and we look at tirzepatide and MET-097i again. When you look at the Tmax, which is extremely important, it's a very important parameter. For both products, the Tmax is achieved after a maximum of 2 days, right? Here, maximum of 2 days for 2.5 mg, 4 x for tirzepatide and MET-097i, 1.6 mg, single dose. We know that this burst effect here, the burst effect here is linked to GI intolerability. How does it compare? I already gave you some insight, how does it compare with our product? Here you see in blue the 60 mg MBX-2109, and in green the 90 mg single dose. That's 90 and that's 60. Here again, tirzepatide and the MET-097i. You see that we have a delayed Tmax, significantly delayed by up to 13 to 14 days as compared to 2 days. We have this sustained concentration. We can already say that MBX 4291 has a self-titrating PK profile and which is anticipated to improve tolerability. It's not us telling, we already know that how we create or we can improve tolerability, and that through this PK, we can definitely improve tolerability. What is the tolerability of the SAD? That's a Single Ascending Dose. Here you have, here's a 15, 60, 90, 180 mg. 8 subject. Again, the study is still blinded. These 8 subjects, this adverse event profile, really with a focus on nausea, vomiting, and diarrhea include placebo in this report. If you look at the 15 mg, you have only 1 subject with diarrhea, mild diarrhea. In fact, there is a dose response in terms of the GI effect, GI-related effect. Dose response, we have an increase in terms of adverse event, from 15 mg to 180 mg. That's exactly what you want to show, right? That's what you want to go as high as possible, and you push the dose in order to get to this tolerability. The 60 mg, there's nothing. The 90 mg, 3 subjects with one of each: one with nausea, one with vomiting, and one with diarrhea for a total of 4 events. The 180 mg is the maximum tolerated dose with 7 subjects, which is interesting, 7 out of 8. I'm not a wizard, but I know that when placebo is included because with 6 and 2, and we have the maximum tolerated dose with 7 subject, as I said, out of 8, showing episode of nausea, vomiting, or diarrhea. In conclusion, we can say that there is dose response, right? That the from 15 to 90 mg single dose, it's well-tolerated with adverse event, GI related, which are mild. We have reached MTD with 180. Again, as a reminder, the 120 is still ongoing. Okay? That's the SAD. I'm going to pause because the next slide is the one you want to see. Here it is, the MAD. The MAD say MBX 4291 was given at the dose of 30 mg every week, followed by 4 x the dose, 120 mg single dose following these 4 weeks. Right. That's here, that's the dose. Very important. We went to 4 times the dose. What you can see that, you confirm that there is accumulation. Each time you give 30 mg, there is the product accumulate. That's exactly again, what you want to see. Here you have a sustained concentration here of the active peptide. By the way, remember, MBX 4291 is a prodrug. Here, I'm reporting the active concentration, the same things than the SAD. It was the active concentration of the prodrug. It's not the prodrug itself, but the active, the one you want to see. In orange here, remember, that's my MBX 4291, 180 mg, the one that was the maximum tolerated dose, right? Remember? We reach almost the same concentration, but a very different treatment paradigm. Very, very different. Relatively fast titration, 4 weeks, right? You get to 180 and you get the same concentration that the 180 mg single dose, which was the MTD. Here we have a completely different tolerability profile, completely different. I'm going to have a specific slide showing you the tolerability profile. We can say that MBX 4291 has a potential to self-titrate with repeated, weekly, starting dose, enabling better tolerability for 4 times the higher dose. Okay. 4 times. We compare again with MET-097i, which has a time to halve the Cmax of 21 days, 20-21 days. It's a proxy, as I said, of half-life. Okay. Roughly. What you want to get is a time to halve the Cmax to stay as high or as minimum as possible, as long as possible in order to improve tolerability and also to improve your chance for potential monthly administration. The treatment paradigm was the same here. 4 weekly administration of MET-097i at 0.8 mg 4 x, followed by 1.6 mg single dose. Same treatment paradigms at MBX 4291, 30 mg 4 x followed by 120 mg. We can observe that here our time to halve the Cmax is 26 days as compared to 21 days. 5-6 day difference is highly important. It's very, very important in terms of reducing the peak to trough and increasing the chance for monthly administration. That's probably the most important slides. The one really now we are there. What's the weight loss? Again, the study is still blinded, so I'm reporting here 7%, which is a very competitive weight loss, including both treatment and placebo in 8 subjects. The range is 0%-16%, the range of weight loss. In terms of tolerability, pretty remarkable. Only 1 out of 8 subjects showed a GI related adverse event, and it was diarrhea. Diarrhea following the first administration. There was no nausea, no vomiting, there was no serious adverse event, this tolerability otherwise looks, we are very confident in the tolerability profile otherwise, we haven't seen anything which was unexpected. Pretty good. Now I'm going to summarize this data. MBX 4291 is designed for once monthly dosing with well-controlled sustained concentration, with sustained concentration and improved tolerability. The data from the phase I SAD show a PK profile supporting a self-titrating weekly induction regimen and potential for a true once monthly regimen, including dose proportionality, sustained concentration of the active peptide for 28 days, and dose-dependent GI-related adverse events across the 4 dose cohorts ranging from 15-180 mg. The preliminary data from the MAD, from the first MAD cohort following 4 weekly induction doses of 30 mg followed by 4 times the dose of 120 mg indicate gradual accumulation of the active peptide, a mean weight loss of 7%, ranging from 0-16% over 8 weeks in 8 subjects, again, still blinded. Only 1 event of diarrhea, only 1 throughout these 8 weeks. We are also on track for the large cohort, larger cohort over the 12-week period, and we should be delivering these results by the fourth quarter 2026. So this year. Thank you. I'm going to pass to Richard DiMarchi. Well, I'm back. Let's see where we are here. This is a discussion of an amycretin, right? Amycretin, the folks in Denmark refer to it as. As I said, it's been a half century in getting to this level of complexity. When I first designed Humalog, just inverting 2 amino acids, people asked me, "How do you know that's going to be safe?" People had waited 60 years to get the native sequence, and here we are doing things that are so much more sophisticated to drive much better pharmacological performance. The roots of this are in DACRA, dual amylin calcitonin receptor agonist, which came after the introduction of the co-agonist for GIP and GLP, built on that work that I referred to, that Matthias Tschöp and I had been about. The Amylin Pharmaceuticals, formed in 1987, was a first mover in this field of amylin, and they were formed by Ted Greene and Garth Cooper to build antagonists of amylin because those amyloid-like pro entities that you found in the pancreas were believed to be pathological and had to be blocked. That quickly was redirected to what became pramlintide, a short-acting registered amylin agonist that borrowed 3 amino acids from the rat sequence to give the human sequence a soluble biophysical property that would make it a drug. It ended up being a not terribly successful drug. It was used for treating prandial excursions in addition to insulin and had a potent effect on the gut. This all preceded the use of Byetta. Nordic Bioscience then advanced this concept of dual agonism, recruiting in calcitonin, which as you would know, is an approved product for treating osteoporosis, but also with a potent ability to lower appetite and to suppress body weight to a small extent. It was Thomas Kruse at Novo that took this to another level in stabilizing the confirmation of the peptide, putting a fatty acid on it to make it a once a week entity that you would know as cagrilintide. Thomas is incredibly capable chemist. He's also a co-inventor of semaglutide. Novo has gone on to register or in the process of registering cagrilintide and the prospect of mixing it with semaglutide that you would know as CagriSema, then single molecules that bring in 3 activities, GLP-1 and the calcitonin and the amylin. A lengthy history there. Our molecule was built off of a DACRA that we had stabilized with novel chemistry. It is very potent in vitro at GLP-1, at GIP, less so at glucagon, and quite potent and balanced at the amylin calcitonin receptors. We have profiled this molecule in rodents. The amylin activity is most notably seen in fat rats. The incretin activity is most notably seen in fat mice. You profile for PK purposes in lean cynomolgus monkeys, and also note the pharmacology in those monkeys suppress appetite and any effect on the body weight in those lean animals. What I'm reporting here is the prodrug of this amycretin. This is now more than the first amycretin that Novo has spoken about, which has GLP-1 monoagonist. This has coagonist. It also brings GIP just as Zepbound has GIP. It's integrated in with the DACRA and formed chemically as a prodrug to extend its duration of action, improve its peak to trough, minimize the adverse GI effects that Sam was just referring to in the coagonist incretin alone. You can see that we have observed greater efficacy and tolerability in these rodent studies. It is something that we're advancing as a single molecule as opposed to a mixture which should facilitate the ability to develop it as a marketable product. Here is a profile from lean cynomolgus monkeys. In green, just as Sam was showing you for the prodrug of the co-agonist, you can see this very flat pump-like exposure for the active amycretin that has activity against these, notably these four receptors and a taste of the glucagon. You can compare in the blues, the SEMA exposure, the cagrilintide exposures and the Novo amycretin, which were designed to be once a week drugs, right. It's the same story that you just heard about in the ability to treat this in a chronic mode in a way that sustains a precise level of drug, but never getting to these excessively high levels. For those of you who are not chemically oriented, I would suspect you have a surge suppressor on your computer and your TV and your precious electronic devices to protect it from highs and lows. What we're doing here molecularly is protecting your kidney, your pancreas, your liver, and your brain from excessive highs and lows. What's more precious than those organs relative to your personal computer? In the course of developing this, doing the toxicology assessments of this compound, we make measurements in these non-human primates, and what you see here at a competitive dose to where we typically dose incretins and amycretins. In fact, this is slightly higher than where you could dose a cagrilintide molecule because cagrilintide molecule has such adverse effects driven by the GI discomfort as I was sharing with you in pramlintide. What we see over the course of 3 weeks after a single dose in a monkey, and remember, monkeys clear these drugs 3 x faster than a human. It's because their half-life of albumin is cleared 3x faster. A profound decrease in the body weight, despite the fact that these are not obese monkeys, right? This is industrial strength pharmacology aiming for toxicology, right, 50 nanomoles per kilogram, where in an obese rat, we're using 2-10 nanomoles per kilogram. It gives us a sense of have we improved the therapeutic index, and the answer is yes. We don't see the projectile vomiting. We do see the malaise at these very high concentrations that are typical of these incretin DACRA activities, but much less profound than what we see in the comparative single species. One plus one equals more than two in terms of the efficacy and the safety, and we will publish all of the story in a respectable peer-reviewed journal. I'd be glad to answer questions as we come to close here, just to reflect the fact that MBX has built this very nice portfolio of compounds that have built upon the ability to use synthetic chemistry in a way we were still building 50 years ago, across on the east side of Manhattan in the Merrifield Laboratory to generate molecules that are focused on pharmacology, not just physiological replacement, that have used these fatty acids to extend the duration of action, atom efficiency, bioclearance. A fatty acid doesn't bring with it the toxicities that you see in a large molecular PEG. Also using this design to integrate in two and three activities, and now four and a bit of the fifth. Today we just share with you, we have selected that a prodrug amycretin as a once a month could be used more frequently for those who want even more precise exposure. Later this year, we hope to bring back to you a triple agonist that builds upon the work that we have done with the co-agonist. Let me stop there and again thank Kent and Pete for inviting me to join with you. Thank you. Thank you. Well, thank you Doctors Saunders, DiMarchi, and Azoulay for that master class. For those of you on webcast, you can just feel the energy in the room here. I want to bring it forward to another program. STEADY phase II-A proof of concept study in post-bariatric hypoglycemia, or PBH, consisted of three mixed meal tolerance tests administered to patients at two different dose levels of imapextide, initially to establish baseline values. As a reminder, imapextide is a fatty acylated GLP-1 antagonist with a 90-hour half-life. As we observe on this slide, looking at the left, imapextide led to changes from baseline of approximately 20%-35% increase in glucose nadir, there on the right, 10%-45% decrease in insulin peak. Additionally, glucose nadir increased in 90% of patients at 100 mgs and 100% of patients at 200 mgs dose of imapextide. With normalization of insulin, that is greater than or equal to 70 mgs per deciliter, achieved in 8 out of 10 patients with 100 mgs and/or 200 mgs of imapextide. Based on these changes observed in these key biomarkers, imapextide achieved proof of concept in PBH. I would like to thank the patients and the investigators who participated in study and our dedicated MBX team. Given our growing number of peptide-based therapeutics candidates and our strategic focus, we are not committing additional resources to conducting a phase II-B study. We believe the preliminary data for MBX 4291 demonstrate that we can design differentiated novel candidates with potential best-in-class profiles. Notably, we demonstrated true once-monthly exposure with t half Cmax of approximately 26 days compared to the MET-097i, let's remember, monoagonist, which has reported 20-21 days t half Cmax. 7% mean weight reduction at 8 weeks, and that's following a 4-week induction period and single once-monthly dose of MBX 4291. The self-titrating PK profile, Tmax about 2 weeks, which helps tolerize the patients to the drug. Again, only 1 GI-related AE during the 8 weeks. We're on track to present top-line results in Q4 for a 12-week MAD cohort. MBX 5765 applies our PEP technology and combines multiple validated anti-obesity mechanisms in a single molecule, which we call our amycretin. The preclinical data, as you saw, demonstrates a differentiated PK profile supportive, we believe, a once-monthly dosing, superior efficacy, and improved tolerability. At MBX, we are entirely focused on 2 areas: canvuparatide, which is on track to begin enrolling a confirmatory phase III registrational study next quarter, and our growing obesity portfolio. In these 2 areas, we see the greatest opportunity to help transform the lives of people living with endocrine and metabolic diseases and to deliver long-term value. Recapping some of our key 2026 milestones, we have initiation of our registrational and confirmatory phase III study in Q3. We have top-line results coming in Q4. As I mentioned, we have cash of $440 million, which we believe will support our operations into 2029. It's a tremendous setup. I'm really proud of our team's effort and excited about our future. With that, I will open it up for questions. I'll start here in the front with Mike Yee at UBS. Just the 3 of us? Yeah. Kent is sitting there. Hi. Good afternoon, Michael Yee from UBS. Thanks for the great presentations, and it's great to see Richard here as well. Maybe just two questions. First on the MAD dosing, great initial blinded data. Can you talk about what your design of the study and design of the PK was expected to deliver? Is it expected to deliver more drug than tirzepatide, such that you could get great tolerability, but as you keep going up, either in this dose or the following cohorts, which are still coming, that there's more drug available, so there's possibly better efficacy? Just maybe characterize the goal of what you could see between the first, second, and third cohorts. One second question is just on the disclosure of the amycretin program. I noticed that it's a triple G actually with Amylin, but maybe do you have a view on whether or not balanced calcitonin amylin receptor delivery is a good thing or a bad thing, given that a loriglaptide is particularly not hitting calcitonin and is very differentiated, and whether that's the right way to go? Thank you. Thank you, Mike. I'll start with Sam for the first part of the question regarding the MAD dosing regimen, and then Richard will take the second part. Thanks, Mike. I think what we have already observed with the 4291/30/120 is something, as you've seen, that which probably in the range of concentration of the 5-mg tirzepatide, it's not something that we will be, how can I say, only looking at, because the pharmacodynamic effect might be different. Remember that it's also a GLP-1 GIP co-agonist, might have a more potent effect on the pharmacodynamic on the weight loss. That's something we'll be exploring later. Richard, regarding our, amycretin. Tomato, tomato. We're gonna say amycretin, okay? Let me just add to what Sam was saying. I'm a great believer that performance is the most important criteria, right? I had often said at a time when Lilly was struggling with parenteral products that if you have a life-saving therapy, people will stand on their heads and inject in their eyes, okay? Maybe Regeneron actually went off and proved that people will inject in their eyes if they have a retinal disease. When I built this chemistry, it was all about performance. Greater efficacy, greater safety, greater tolerability. We'll manage through the other elements that pertain to commercialization. I'm very encouraged, but by what I see in MBX and what they have done with PTH, and now what I see emerging with the prodrugs. Again, I go back to 1996 when Suad Efendic and I patented the ability to lower body weight in obese human subjects, 4 subjects for 4 weeks, okay? It was predictive of where we have gone. In vitro, in vivo, in veritas. Put it into patients, let me see what's occurring, then we can decide how to further optimize this. As to the amycretins, this is a less than clear story right now. Y ou remember, is a DACRA that is maybe less than a DACRA because it has been diminished in one of the subtypes of the amylin receptor. I'm not as certain about calcitonin. Lilly would have to speak to that. We can only be guided by our own data, okay? We've yet to detect that you can maintain the full efficacy we strive for when we are removing one of the subtype activities, when we are removing calcitonin or amylin activities. The best performing molecules have the full cascade of R1, R2, R3 amylin receptors and have calcitonin receptors. Now remember, we've been using calcitonin as a therapeutic. For people who have fears, there's reason to think about it, but I haven't seen any safety aspects that hold me back. Again, I've been a big proponent of glucagon. People were trying to tell me that I was gonna get hit by lightning or something, over the last 20 years, we've shown how you can use that in concert with other agonism. The prodrug is something that extends the duration of action. a lore has a delayed clearance. It has a flatter peak to trough, nothing like what you get with a prodrug. Until I'm shown otherwise, one person's opinion, I think that a good deal of the improvement that they're reporting, if it continues to hold up in subsequent studies, comparing appropriate compounds, may be contributed or partially contributed by the improved PK. If that's true, then I think our prodrug should be doubly attractive. Thank you, Richard. Giving you some insight into Richard's mastery of translation to marketed drugs is part of his resume he didn't mention earlier that he was group vice president at both Lilly and Novo Nordisk, which I'm told is similar to a baseball player playing for both the Yankees and the Red Sox. It's a really unique perspective, so I'm sure you appreciate his participation today. I see Tyler Van Buren. Can we have a microphone or just project maybe, Tyler? There you go. Thanks very much, Tyler Van Buren, TD Cowen. Appreciate the presentations. Just a follow-up on the MAD. When you see that last monthly dose, the exposure looks better than the Metsera candidate, and clearly you could potentially lead to greater weight loss. I'm excited to see the future cohorts. Can you maybe compare the program or position it against what you've seen with Amgen's MariTide data and what your view is of that candidate? With respect to just in the maintenance peak to trough variability, clearly MBX 4291 is gonna have lower peak to trough variability in the maintenance based upon what we're seeing. Is there a clinical benefit to that maybe? Why don't we lead off with Sam again, and Richard, you're welcome to. Add to it. We'll go back to this slide as a reference. Yeah, I think in terms of variability and just the fact that the time to reach the Cmax is much longer that and reach 26 days is really aligned with the peak to trough variability, a small peak to trough variability. That's the goal is really to minimize the peak to trough. I think Richard was referring to infusion-like. That's the best example, in fact, in terms of being stable, not but over time and as long as possible. That's what we are again aiming for, and we're starting demonstrating already here. When you can see. Again, here we're comparing concentration, not necessarily the pharmacodynamic effect, right? Because it might be a different PD effect on the weight loss and also on the tolerability. Just what we observed with the really great result we already observed with the 30/120, show really a remarkable tolerability profile compared to Metsera or any other drug. Recall, MariTide is fundamentally an antibody as it relates to its PK profile. You're really gonna have this burst effect reflected here getting to Tmax rapidly. Richard, any additional thoughts on the field? Well, MariTide is an interesting substance in many circles, a controversial substance, because as you would know, it is a GIP antagonist. It's an antibody that blocks GIP action, to which they have semisynthetically added a very high potency GLP-1 agonist, and it's used at pretty high doses, right? Hundreds of mgs. I think in phase II studies, they were up almost to 750 mgs or more. I think so much of the success of that compound should be rooted in whether GIP antagonism can add something above and beyond what you can do with GLP alone, and is there a unique contribution relative to GIP agonism. That's where the controversy comes as to how can you have a GIP agonist, an antagonist seemingly doing the same thing. I'm reminded of Fitzgerald saying that a form of higher intellect is the ability to hold two opposing forces in your mind and not lose your sanity, right? Maybe this is one of those cases, let the data talk. I'm a great proponent of do the experiment, let's see the data, and try and sort this out. The published results of a year ago just suggested that it was mechanistically different, that the GIP antagonism was actually promoting GLP agonism. It was making the GLP a superagonist as opposed to blocking GIP action. I'm not the most informed here. It's not just Amgen. There's a company in Copenhagen, Jens Holst has been a part of it, called Antag. Bring the data. Let's. We'll sort this out. Thank you. Jon Wolleben here at Citizens. Can you get a microphone, please? Thanks for hosting, Jon Wolleben with Citizens. Just wondering if you talk about the relative potencies for the GLP and GIP receptor in 4291, and then seeing 16% weight loss from a patient here at 8 weeks. Can you talk a little bit how the different PK profile might change time to peak weight loss in these patients? Richard. Thank you, John. The compound was designed to make as few changes as possible. I've been a part of drug development programs where in trying to reach for the ultimate, we change several things simultaneously, and you end up failing because you didn't understand the interactions that occur. This molecule was designed to have tirzepatide-like performance, structurally unique, structurally proprietary, balance at those two receptors that look very much like tirzepatide in human subjects, and then make a prodrug of that substance. What we were aiming to do was to change the pharmacokinetics, right? As opposed to changing the molecular mechanism of action. I see a question from Seamus Fernandez at Guggenheim. Thanks for the question, Kent. A couple of quick questions. First off, can you just help us understand a little bit better the sort of full tolerability profile? We talked about GI AEs, I think we also see other potential AEs in other charts. It'd be helpful to just have the context of things like injection site reactions, dynamics like that. I know these are the GI AEs specifically. Maybe for the doctor, if you could just give us your sense of the impact of injection frequency, on patient drop-off in particular. How much would a monthly potentially impact your practice? Is it more important to have a better tolerability profile more so than a less frequent injection profile? For the first part of the question, very simply, this is an ongoing blinded phase I trial. What we're sharing here in this table is the tolerability for the single ascending dose, and we've just highlighted the three GI-related AEs that, as Dr. Saunders mentioned, are just the most focused or most commonly associated with these incretins and of interest, and no serious adverse events, and as Sam said, nothing unexpected overall. In the MAD recall, this is just really remarkable with this very brief one-month induction period, and then a single monthly dose. Only one event of diarrhea, nausea, or vomiting. Dr. Saunders, can you elaborate on just the dosing frequency and patient preference? Yeah, absolutely. Great questions. When you take a look at what actually leads to better weight outcomes and better health outcomes, the two metrics that we talk about regularly are adherence, which means, you know, how patients are taking the medication compared to how it's prescribed. If they're missing doses, if they're, you know, taking half the dose, whatever that is, and persistence, how long people stay on. Since obesity, again, is a chronic disease, people need to stay on it, on the medication long term to achieve the optimal results and then to sustain those results long term. Any of my patients on weekly would love to be on a monthly injection instead of having to do it every week. People often miss doses if they're traveling, if they forget, you know. Having the ability to just do once a month would be very, very advantageous in terms of getting those outcomes. If you talk about, you know, what actually leads to these outcomes, is it more tolerability? Is it more ease of use? It's both. You know, it's absolutely both. The more we can do to improve tolerability, to improve ease of use, the better the outcomes we're gonna see. Yeah. I guess I would also say it provides optionality. It's not just a once-a-month drug. If you want to use this every week, you can do that, and you'll get an even flatter profile than what you will get once a month. Remember, oral semaglutide is a once-a-week drug. It's used every day, right? In a marketplace where there may be as many as 1 billion subjects, we shall see. There's going to be preferences for many different presentations, and the more optionality that we can provide, the better. I see a question from Annabel Samimy. Hi. Thanks for taking my question. Annabel from Stifel. Clearly you've reached your target PK profile that you're looking for, smooth, slow release, extended duration. You're managing through the titration, simplified titration just with the weekly dosing. I guess I'm wondering, in a very heterogeneous population, obviously many people are gonna need many different types of doses to reach their target profile. How do you envision having those doses available for a broad population? I noticed in the part A, part B, part C, the number of cohorts was actually declining. What kind of optionality will physicians have in the real world to find that right dose for that right patient? I guess that's the first question. Let me kind of break that in two. Thank you, Annabel. Let's go back to Sam just talking about this progression from SAD to MAD to the 12-week MAD, and what we're going to learn from that in terms of informing our phase II trial, which we are already conducting the phase II-enabling studies and planning our phase II for MBX 4291. Just in terms of the treatment optionality, that was a really interesting point Richard made, and maybe I'll ask Dr. Saunders to elaborate. Yeah, I think we, as I said, we have these three parts, and each part informs the next, right? We have not been so bad, that bad in terms of expecting this cohort with really great results, and so good testimony of learning from the other. We may not have started how we as we did here with 30 followed by 120, but we did because we learned from the SAD, and we progressed as we went. The same things that we'll be doing for the next cohort. That's why at this time we cannot commit on the second cohort because we are learning as we go. I think Kent said it very nicely. This study is still ongoing. We are learning from this phase I, and I think from my side at least, it's a little bit premature on how we are going to perform our phase II study and our phase III program. Really the good learning here is we get exactly the PK we wanted with a really great tolerability profile with quite good weight loss. Let's recall that MBX-2109 began with 12 once-weekly doses and then extrapolated to show monthly. What we've shown here today on this ongoing blinded phase I study is true monthly dosing, right? After a single once-monthly dose, we were able to show this impressive weight loss in this time to half Cmax of 26 days. Dr. Saunders, monthly, you mentioned you think your patients would be interested in that. Can you talk more about that, please? Sure, yeah. No, I think, you know, going back to the idea that obesity is such a heterogeneous disease, and everybody responds differently to different doses, people have different side effect profiles. Again, the goal is, you know, improving tolerability, keeping people on medication. I think the more, you know, levers that we have as clinicians to be able to really, you know, fine-tune and listen to our patients in terms of the timing of side effects or, you know, the timing of when they're having hunger, cravings, food noise, and really be able to choose to do, you know, weekly or monthly, that is a huge benefit. It's currently how we practice now when we're able to, given sort of limitations with different medications. Like some patients, you know, we do every other week, and that works better for them. We do a half a dose twice a week, and that works better. The more flexibility that we have to really listen to what's going on with our patients in terms of, you know, side effects and symptoms, the better that we can treat everyone. Again, the monthly is a big asset. Okay, just to follow up really quickly on that. Your, I guess, way of addressing a heterogeneous population is more in the frequency of administration as opposed to the, necessarily the dose. Like perhaps a patient reaching max, you know, their Tmax, some might reach a Tmax maybe at 5 weeks, and then you start monthly or I mean, I guess I'm trying to figure out how you deal with that heterogeneous population? Taking a step back. Really, the way we've focused on addressing this is through our obesity portfolio, where we have three programs. Right, that we're advancing. Our most advanced one here, 4291, now in amycretin. Soon, a next quarter, right, a GLP-1 GIP glucagon triple agonist. All of them are built with this PEP approach for the gradually increasing and steady drug exposures. We talk about self-titrating. These drug candidates self-titrate to help the tolerization for the patients. We think that we can make that with monthly be a really successful treatment option. You know, we have these others that are coming as well. Kent, can you show the MAD results for a minute? I wanna make sure that everybody has connected on those. You know, you gave, as I understand it, Sam, you gave 30 each week for 4 weeks. Yep. In the next four weeks, you did not increase the monthly dose. You gave the same amount of drug in- Exactly that next four weeks, which means that the dose that they got in week 5. Is the same. was 4x Times larger than what they got in weeks. Exactly 2, 3 Yep four without causing- Exactly right. An adverse event. I find that pretty spectacular relative to how we so slowly titrate people 4 weeks, 4 weeks, 4 weeks, 4 weeks, 4 weeks. It's that regimentation in the way we're doing this that is a problem. I'm optimistic about what this may foretell and how quickly can we get to that therapeutic dose that will be meaningful for most. Can we get back to conventional medicine where you go to see your doc, they give you a dose. If it's safe, we can increase the dose if you need to increase the dose. We don't have to live on this regimented schedule of 4, 4. If you fall off that schedule, then what do I do? How do I get back on the wagon, right? I'm encouraged, but look, let's be clear. These are limited numbers. We're talking about 2 months of data here. The amount of weight loss that's being cited is about 1% per week, which is about 2 pounds per week. No need to go any faster than that through the first 8 weeks. Where do we go from here, right? I talk about a patient being able to take a dose of MBX 4291 once a month when they pay their rent or mortgage and not have to think about their disease for the rest of the time. That is really quite a transformation in the lifestyle of patients living with obesity. Great. Thank you. Leland Gershell with Oppenheimer. Thank you for the presentation. Really encouraging data. We look forward to seeing what you'll have for us later in the year with the extended results. 2 questions. First on sort of the data itself and kind of what they could mean. I mean, obviously, if you go to the previous slide from this one, you have the comparison with the Metsera compound, which is now part of the Pfizer portfolio. It seems like First of all, I'm wondering if you're able to characterize what the weight loss may be in that second month, versus just the 7% over the 8 weeks. If you're not prepared to do that, I'll just move on to my next question. Yeah, ongoing study. Yeah. Blinded, Q4 you'll get the top-line results. It seems like you have a lot of room here, given the AUC between, you know, 4291 and then what is a very much smaller AUC with the Metsera compound. Also, I think that's only a GLP-1, whereas you guys have the dual mechanism. Looking forward to those data. I'm wondering, given the tolerability comes down, given the titration, the patient's kind of accustomed to this medication, how much room you may have to go up further. Again, based on this kind of PK profiling and clinical data we've seen, I think this dose, I'm not sure how much Metsera has shown, but at a much higher dose, I think they got to 12.3% weight loss in the VESPER-3 study. Just curious if you have any take there, and then I have a second question for the physician. I think you're referring to a longer time point, and again, this is a phase I ongoing study, and we'll have data in Q4. Sam, maybe you lead off. No, I think you, first of all, we don't have the individual data. I mean, I cannot see who is placebo or treated. Even we have some ideas, but it's not sure, right? We have been conservative in our evaluation at 7% because we mixed everybody. That's what I can say in addition to. 12-week data in Q4. Very exciting. Okay, we'll stay patient. We continue to explore, this phase I is ongoing. Again, in terms of AUC, et cetera, we will have more data as we go. Great. You brought up the topic of muscle loss with weight loss, which is a, I think more and more of a problem that people are aware of here societally. Just wondering what you may be able to share with us in terms of the outlook on mitigating the muscle mass loss with dosing regimens that are less frequent, you know, and/or, you know, may be operating on multiple receptors. I mean, I think I'm not sure if tirzepatide is any better than semaglutide in that regard, but it's a once weekly. Wondering if once monthly would be better, and perhaps it just comes down to compliance. If you know, patients who cycle on and off therapy, how much of a problem is that when it comes to muscle preservation versus being able to stay on a drug long time without going on and off? Let's start with Richard on 4291 design and then Dr. Saunders on clinical experience. 4291 in what respect? Our 4291 and the amycretin. The amycretin, the 5,000 series. Yeah, 5765. Again, this is different from the co-agonist and triagonist incretins where we make a molecule that is the same size as the native hormone, and we just make a chimera, chimerized sequence. At the end of the day, it's like a master key that can see all three receptors. It looks physically like a glucagon, a GLP or a GIP. In this instance, the two hormones are sufficiently different, and the receptors are sufficiently different that you have to use both peptides and tie them together. You would know that Novo has spoken about the fact that they make a linear fusion of these two molecules. I might remind you that the first in this series was davalintide, which was an amylin molecule, where they had taken pramlintide and tied it in with exendin-4, right. By etta. Quickly divorced themselves from the area because they saw such severe GI effect in that compound, and the projectile vomiting that they said, "We can't go here. Both of these mechanisms have a GI adverse effect." There was this real question as to why anybody would want to make a DACRA. To the credit of the folks at Nordic Bioscience, and I said, the folks at Novo, they really did a terrific job in advancing the DACRAs and now Novo leading in putting this into a single molecule. Ours is also a single molecule. I'm not prepared to tell you exactly the chemistry that we use, but as I promised, it will be in a peer-reviewed report. Maybe you both can comment. My understanding is that preclinically, we've seen some signs that amylin DACRA can preserve lean mass, but we're still looking for that signal in the clinic. Well, again, when we're in monkeys, we don't go above 30 nanomoles per kilogram when we're studying these molecules, right? When you're doing aggressive dosing, with this prodrug, we get to 15 nanomoles per kilogram without seeing those side effects that we had seen at 30 in a lean monkey. It's again, a nature of the fact that it is a fully potent DACRA, but as a prodrug. The story's unfolding. Dr. Saunders, please share some clinical insights. Sure. Just briefly in terms of, you know, there's so much hype right now about muscle loss, and I think in many ways, there's almost too much hype and, you know, fear-mongering. What we actually see is no matter how people lose weight, regardless of the mechanism, literally from diet to a range of medications to surgery, about 25%-33% of what people lose is lean body mass, which includes muscle. It has nothing to do with the mechanism. It's more to do with, you know, how much people lose and what that looks like. We're learning much more with, you know, so many trials underway about different mechanisms that can affect this. Basically, what we do right now is make sure that people don't lose weight so quickly that they're not able to keep up with, you know, protein requirements and physical activity, including strength training. That's what we do right now, and the ability to, you know, use precision to make sure that people aren't losing weight too quickly or too slowly is a huge asset. Also the ability to, you know, have everything be just much more streamlined, 'cause as you, as you said, if people stop medication, then they gain weight, and then it's the cycling that's also a problem because you don't necessarily rebuild all of that lean mass each time, and it can get worse. You know, having the, you know, the characteristics that we're talking about here, you know, we'll have to see with the data, but, you know, are promising in terms of, you know, the effect on lean body mass. I share that perspective very much. What goes around comes around and takes us back to the late 1990s when we were all focused on sarcopenia. I think what we're seeing as we reduce body weight, that elderly subjects suffer from sarcopenia to certain degrees. Unquestionably, if you can find a substance that is safe, and the emphasis on safe, right? Testosterone builds muscles like no other substance, but again, it's not something that is viewed as being suitable for long-term treatment. If we can find something that is capable of building muscle in elderly subjects safely, it'd be great just as a standalone, an additive, or integrated as part of an anchor tenant. Wouldn't that be lovely? I love the reference to precision. It reminds me of our PEP platform, right? Precision Endocrine Peptide. Pete's giving me the sign. It's not quite the sign. Just one, getting questions online maybe you or Sam can address, just confirm that we're not seeing anything notable or concerning with regard to injection site reactions in the SAD/MAD data for 4291. Sam. Yeah, I can definitely confirm this. I would say there's no concern with regard to the ISR. I mean, it's a peptide, so we observe some reaction, but nothing that will be worrisome and or for concern. Okay, I see a question in the back, second to last row. Arm raised. Yes, there. Thank you. Hey, great. Good morning. Thanks for taking my question. Jess Fye, JPMorgan. First wanted to ask about the MAD. Based on cohort B, the B portion of the MAD, is 30 mgs weekly followed by 120 monthly the favorite regimen at this point? Can you confirm if that's one of the regimens in Part C? What's the other dose combination or regimen for Part C? Will the disclosure in the fourth quarter be for one of those Part C MAD cohorts or for both? Second one's just commercially for Dr. Saunders, just a bit kind of high level. Can you talk about where you see the injectables living in this large market, and where you think the orals are going to live in the market? Thank you. I'll take the first part. This is an ongoing phase I trial where Sam said the SAD, 4-week MAD informs the part C. I think Sam was a bit understated. We really did well choosing this first MAD cohort, right? Cohort B1, we'll see what we end up deciding for the part C. I wanna be clear, that has not started yet, or the final decision on dosing regimen been decided either. Dr. Saunders, you're popular with the questions today. Please, on the oral- Sure Alternative question. Honestly, I think the more options we have, the better, because different people want different things. Different people respond to different things. Where orals have a big role right now is initiation of treatment. Just given the efficacy of the available orals versus the efficacy of injectables, if, you know, people are on an oral and they, you know, max out and need to step up, then we would switch them over to injectable. Most of our patients, when they know their oral options, come in saying, "Oh my gosh, can I switch over from an injectable to an oral?" When we explain kind of the differences and especially, you know, if someone is on a higher dose of an injectable, an oral may not cut it for them. Most of them choose to stay on an injectable. I think that, you know, it's not such a crazy idea anymore to be on an injectable for obesity. You know, when we were convincing people to, you know, take a daily injectable, that was a little bit harder. If something is working and tolerable, then people will take it. I think, you know, short answer, there's a role for both. I think oral more for initiation and injectable just right now is, you know, they're the more effective medications. To be able to do a weekly or a monthly instead of taking something every day is absolutely, you know, very attractive for many people. I see a question also second row from the back. I can't see too well from here, but please, can you pass the mic down? Is that Kripa? Please announce yourself. Yeah, this is Kripa from Truist. Thank you so much for taking my question. Between tirzepatide and MBX 4291, you reach Tmax obviously at a different timeframe. Could there be a difference in appetite suppression for the first two weeks for patients who are on MBX 4291, and how will that evolve? Also for Dr. DiMarchi, going back to the PEP platform, how tunable is the cyclization rate? Maybe from a life cycle management perspective, would there be a potential quarterly in the future? Thank you. We'll start with Sam and go to Richard again. I don't think it will have any impact on the appetite suppression. We saw it even from our first B 1 cohort, that we still get the 7% w eight loss, average after eight weeks. I don't think that will have a significant impact or any impact. The PEP platform, this chemistry is incredibly versatile. As I said, you can go from 1 hour to 1,000 hours, no enzymes, no co-factors, intramolecular, all dependent upon time, temperature. That's not the challenge. We just dial in what do we want the speed to be. The bigger challenge in doing what you just asked, can you make a once a year or once every 6 months, is how big is the dose gonna be? 'Cause now you gotta give 365 days of drug as opposed to 1 day of drug, and what are you going to use as the protractor? Because what we have here is built on albumin or plasma proteins, predominantly albumin, as the reservoir, circulating reservoir. It's turning over with a half-life of 21 days, right? Whether you convert into an active entity or not, the albumin that it's bound to is gonna disappear, right? You have non-productive clearance. You have to introduce a second mechanism for extending the duration of action, and we have published on some of that, and this is not the forum to discuss it. It is something that is possible, and something that I would be interested in continuing to work on. Yes, we are. We're down to our last question. Pete, you can direct it. Please ask the question. The microphone is coming. Great. Thank you so much. Ellie Merle, Barclays. Appreciate you squeezing me in. Congratulations on the data. Just a quick follow-up from me. On the second dose or dosing regimen that you're adding to the phase, or the Part C portion, can you elaborate on sort of how you're thinking about that, particularly the phrasing that you had on another potential dosing regimen, sort of what you might be thinking about there in terms of exploration? Just, I think it was asked already, but just want to confirm, will we get that second cohort from Part C at the data update later this year? Thanks. I'll lead off. Thank you, Ellie. We are committing to the first 12-week MAD cohort in Q4, as previously guided. We have also today announced that we intend to have a second cohort. The timing of that we've not yet committed to. In terms of how we're thinking about it, I'll let Sam give some more thoughts. Yeah. We are clear about first cohort will be a weekly administration for four weeks, followed by a monthly administration for over the 12-week period. That what we are thinking right now. The things that we'll have to determine, it will be what dose we will be exploring in this cohort C. Based on the MAD-B1 cohort data, which Sam shared, I think you can understand why we're pretty excited about advancing potentially that dosing regimen in cohort C1. With that, I think we can declare Obesity Day a success. Thank you for participating in it, and we wish you a great rest of the day.