MBX Biosciences, Inc. ($MBX)

Welcome to everyone in the room and on webcast and 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 coagonist 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 [indiscernible] 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 Flight Health and Clinical Assistant Professor of Medicine at Wild 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 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 and obesity. Sam will then 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 [indiscernible] and it combines additional mechanisms, which are clinically validated all in a single molecule. I'll also present proof-of-concept data for [ emapextide ] in post-bariatric hypoglycemia, PBH and 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 eneboparatide in our growing obesity portfolio, where we believe we can have the greatest patient impact and long-term value creation. Multiple clinical stage programs, each designed to be best-in-class and multibillion-dollar markets are progressing well in development. Our PEP platform combines innovative peptide design, programmable prodrug and fatty installation 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 will present 1-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 Q2 -- 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. And preclinical data for MBX 5765 demonstrate a differentiated PK profile supportive of once monthly dosing as well as the expected PD effects. Our GGG GLP-1/GIP glucagon coagonist or multi agonist is on track for candidate selection next quarter, Q3. And we have a very focused discovery effort underway in obesity. The obese patient population is global, heterogeneous and vast, requiring [indiscernible] 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 [indiscernible] 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. So I'll now turn it over to Dr. Saunders for an overview of the obesity market landscape.

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 and 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's 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. So just to put this 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. So really 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. And this growth is really driven by many different factors, but you can think about it in terms of 3 different categories. So 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 help as many of our patients as we can. This is expected to allow more patients to consider this class of medications and really [indiscernible] them in meaningful ways. The Medicare expansion project, which is supposed to kick off in the next 2 months actually, well, hopefully, will be a big driver of improved access and affordability. And then finally, rising obesity prevalence and increased awareness of obesity medications to increase the addresable 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 the overweight category Class 1 obesity, which is BMI 30 to 35, and Class 2 and 3 combined is a BMI of 35 plus. The obesity prevalence is really most in the greater levels of obesity. So Class II and beyond. And 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. So let's take a look at the unmet needs. And it's really exciting to break it down in terms of exactly what we, as clinicians, need to be able to help as many people worldwide as possible. So one is just the response. The percentage of patients with obesity would benefit in terms of weight outcomes and health outcomes by losing more than 20% of their total body weight is substantial. And so looking for medications that provide greater efficacy is a big target. Number 2 is prevention of weight regain. We know that obese is a chronic disease that needs long-term treatment. We know that when people stop obesity medication, high risk of regaining very rapidly and regaining very significantly. So we really need more tools and more strategies for this important phase of weight maintenance and not just the phase of weight loss. Tolerability. The side effects that come along with many of the therapies affect adherence and persistence. So adherence, how patients take their medication compared to how it's prescribed, and persistence how long people stay on medication. Convenience, what patient does not want to take something that is way more convenient than regimens that we used to have, and it's improving very -- 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. On weight loss quality. So 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. And a huge part of that conversation is really taking a look at what kind of weight is lost. We know that a certain percentage of weight is lean body mass, which includes muscle. And so 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. And then finally, outcomes. Taking a look at different subpopulations is a big area of unmet need. Pediatrics, older adults, how medications really affect these different subpopulations. And the safety. 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. And so 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 type. What do we see clinically? So part of the mechanism of how these medications work is that they slow gastric emptying, their effects on GI motility. And so of course, see some nausea, some vomiting, some diarrhea. And the -- these side effects are really important in terms of patient's ability to stay on the medication. So the nausea voting and diarrhea are typically the most frequent. And what we do now is really a lengthy titration regimen to allow people to adapt to these medication be able to get to the optimal effective dose. These events often happen at initiation and also during dose escalation. And what does this matter? This matters because sometimes the side effects are mild, but when they're more than just mild, or when they're persisted, this is what really affects adherence and persistence. The key -- and they're a key driver of treatment discontinuation, which as I mentioned, because this is a chronic disease, is not the outcome we're looking for. So again, the lengthy and gradual titration to improve tolerability is the current kind of standard of care. And this, again, impacts our patient's ability to reach the dose they need to get to. So the goal really optimizing exposure may improve tolerability and decrease the amount of the required titration steps. And this is something that is a very exciting prospect. So finally, the goal really is to 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. And so when you take a look at the status quo right now, the numbers are pretty terrible in terms of people discontinuing. And 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 a year, and 64% stop within 2 years. And this is -- 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 at 65%, and within 2 years, it's 84%. And this is again, not what we're looking for. When patients stop medication, they regain weight and then it's a big waste of money to have treated patients for as long, reach these outcomes and then have them back to where they were in the beginning. So 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. So I'm going to hand it over to Dr. DiMarchi now. Thank you very much.

Indeed, a great pleasure to be here. I came from, from Bloomington, Indiana and to be here to discuss this subject, it only took me 50 years. Half a century. I trained with Bruce [ Merrifield ] then to be Noble 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 therapeutic spent little over 2 decades at Lilly and a little over 2 decades on my own, at the university starting companies with the likes of [ Kentarlic ]. So it really is indeed a pleasure to be here. These last 20 years, actually, 30 years, I have focused, as I said, on obesity. But the history of the GLP-1s reached back to 1983, right? It's a little over 40 years when Graham Bell cloned the gene, as he was coming out of [indiscernible] the University of Chicago and [indiscernible], who worked alongside me in the Merrifield laboratory up the Massachusetts General Hospital, did the characterization of the discovery of the active ingredient in those mid-80s as [ Jens Holtz ] and 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. But it was later in that year, again, still being at Lilly with [ Suade Fendik ], who was Chief of endocrinology at the Karolinska 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 have a patent that covered the whole field of GLP-1s for treatment of obesity. But it fell on deaf ears. That is -- 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. And so in that decade that followed, ascendatide, a [indiscernible], not an analog, a [ parallel of ] GLP-1 was registered by the [ Amylin ] Corporation, Joe Cook, who had been with us at Lilly was CEO of the company. And that was followed in 2009 when Matthias [indiscernible] he a professor at the University of Cincinnati, I and 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 [indiscernible] time, that distinguishes it from GLP-1s. [ Victoza ] was the first GLP-1 that was registered as a as is an analog, a fatty isolated analog once-a-day medication and notice 1983 to 2010, we're at about quarter of a century to get that far. And then in the decade of the 2010s, we get the emergence of what [indiscernible] I disclosed a couple of landmark publications integrating GLP-1 with GIP, which is the active mechanistic approach to [indiscernible] to Zepbound to [indiscernible] being the peptide and in '05 and in 2015, the triple agonist, right? The GGG as Lilly refers to a GLP-1/GIP glucagon was disclosed in the Nature Medicine publication, again, from my laboratory and collaboration with Matthias [indiscernible], who is now in Munich. [indiscernible] 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 and the breakthrough, right? The breaking of the sound barrier in 2018 was [indiscernible] disclosure in Phase III clinical studies that they could achieve 15% body weight lowering with semaglutide, the batty-diasolated peptide that has recruited folks interest commercially into this field. [indiscernible] gets approved in '21, [ Manzaro ], that co-agonist for diabetes in '22 and Zepbound in '23. And I think many of us are expecting that [indiscernible] be approved this year, or suits 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. It's incretin effect, right, on the pancreas to what is now obesity centric. And I will share with you that early in my training, I met with [indiscernible] many of you would know the name. He's the professed father of [indiscernible], right, contraception. And he shared with me they are rare times in the history of the pharmaceutical industry. where drugs have an impact that are bigger than the additional 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 proceed themselves. It's changing how they perceive life. Okay. So 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 had not tolerate this medication. And 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. And so 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 [indiscernible] molecules that is really the magic of why these substances are performing the way that they perform. Endocrine hormones have narrow therapeutic index. And we began to develop this chemistry for use in insulin something that I know a bit about because you know the consequences of an [indiscernible] of insulin are. [indiscernible] know in PTH, the calcium is every bit as important as glucoses. And so having precise control over drug concentrations so you can precisely, keyword right, precisely regulate the calcium levels was something that we put to work in [indiscernible] and then 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 dipeptide, 2 amino acids, and we just invert the confirmation. Europe peptides and proteins are in the trans configuration, right? They sit like this and that is why they're not falling apart to amino acids at a time. But strategically, inserting a [indiscernible] group, we can fix the CIS confirmation. And in the CIS confirmation, it's prone to [indiscernible]. The more [indiscernible] confirmation, the faster the cyclization, the [indiscernible] confirmation, the slower the cyclization so 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 a dose. You don't have to worry about the circulating concentration, you get the same cleavage rate. Very natural. Amino acid base. And so what you see here in building upon the advances with these [indiscernible] 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 [indiscernible] to kill the biological activity until you get that cyclization to release an active fatty isolated product very much like tezepatide or semaglutide and the extended duration of action. And that entity is capable of seeing either of the 2 receptors, GIP, GLP, bound to albumin, or in the free confirmation, which is only a small percent of that, which continues to circulate. That's how we extend the duration of action. That's also how we flattened the peak to trough, aiming for something that looks to have pump like action without having to wear a pump. And so we'll come back and talk a little bit about the clinical results, and I'll turn this over to Sam.

Thank you, Richard. And I'm very, very excited to be here to be before you and to present as a result, 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. And I'm going to start with what are the guiding principle at MBX that really is leading to our strategy? And we do believe that there is a big, really big opportunity in obesity with a once-monthly dosing with improved tolerability. So as Richard said, we are using our PEP platform, right, that 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 a monthly dosing. And this -- when you achieve this, you should get better tolerability. That's exactly what we get. So that's our strategy. We presented the graph, the figure. We started presenting this in January. But the story started way before that. It started with modeling with any 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've seen in green here, that's our profile. And we compare this with products that all of you know very well, [indiscernible] appetite, right? No need to present a GLP-1/GIP co-agonist marketed. And it's a weekly administration. But we compare also -- we are comparing also our product profile, PK with [indiscernible], which is in development for a monthly administration, right? So we said we want to get a gradual. What does it mean? That here smooth race to the [indiscernible], really smooth, look, and we compare with tirzepatide and [ MET-097i ], look how steep this curve is, right? How it goes to the Tmax very rapidly. And we know that it's related to the GI intolerability, right? And when you look again at tirzepatide, you see this variation, sorry, a variation around to Tmax, due to the weekly administration, it's not exactly what you want to get. You want to get something which is steady, stable with -- sorry, with no big something like this, right? That's what you want to obtain. And again, this is also related to GI intolerability. More variation you have around the Cmax, more tolerability issue you get. So now looking again at the [ MET-097i ], you see that then you have a slow decline in terms of concentration. And they refer to the time to have Cmax, which is a good proxy for the half life of 21 days. And when you want to get is a tea to [indiscernible] possible as close as possible to the Tmax. And why? Because again, [indiscernible] peak to trough variation is limited, is small. And so we improved the tolerability on one hand, but certainly, you improve this dosing schedule with a monthly administration. And that's exactly what you want here. So they refer to 21 days and we are aiming for and we're expecting to be beyond the 21 days, okay? So that's what we want. That's the story of how it started. Now I'm going to speak about MBX 4291, which is our GLP-1/GIP coagonist, right, with the goal of being administered on a monthly basis. We designed a Phase I clinical trial, which is ongoing. This study is ongoing. So 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? So it's still blinded. So this study, this Phase I study is divided in 3 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 a Part C, and you will see the differences. And each step informs the next. So the SAD will inform the MAD and the MAD will inform the last section of here. Sorry, here in form. We are on the target population of subjects with BMI at or above 30. So everything we see can be extrapolated to the larger population of patients on the way -- to the other way. So I'm going to spend some time on the SAD. The SAD will have -- we have 5 cohorts and evaluate -- we are evaluating 5 doses from 15 milligrams to 180 milligrams. We have -- each cohort has 8 subjects, 6 treated and to placebo. The [ NAD ] is a weekly administration potentially followed a week administration for 4 weeks potentially followed by a monthly administration. Again, the same target population, and we have 3 cohorts, each cohort has 8 subjects, 6 treated and 2 placebo, right? So the last and the most important one, the Part C is, again, in the target population. And we were talking about potentially doing a second cohort. We have -- we are confirming that we'll be doing a second cohort. And so each cohort will include this time, 30 subjects. So a much larger population of subjects with overweight of 20 treated, 10 placebo. One of the cohort, one of them will include weekly administration for 4 weeks, followed by monthly administration with a total exposure of 12 weeks. This study is -- has not started and is on track, however, to be delivered as promised by the fourth quarter of this year. So we're good on this. So 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 a focus on the GI tolerability, nausea, vomiting, diarrhea. And we want to find what will be the best streamlined dose titration. Secondary objective is the pharmacokinetic. We want to get a monthly administration. So the PK is extremely important to confirm the potential for monthly. The second one, which is the secondary objective is a pharmacodynamic effect, which is a weight loss, right? And this last one, which is to identify the dose and the titration regimen will be pushing for Phase II, right? So that's the objective of this study. I hope I'm good in keeping you waiting for the last slide. Next one. So now the SAD, I can show you in terms of PK, the results of the SAD. In this graph here, PK graph, you have 4 doses, 4 doses, which is -- we started with 15, 60, 90 and 180 milligrams as a single dose. And the 120-milligram is still ongoing. The cohort with 120 is still ongoing. So what can we see here? We see that we have dose proportional PK, right. Dose proportionalities achieved. But very importantly, gradual increasing and sustained concentration after single dose. You see gradual and steady and sustained concentration. It looks very similar to our TPP, right? So I can check the box almost and say, well, we have achieved our first objective to look at our TPP. So we like to compare and we look at tirzepatide and [indiscernible] again. And 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 milligram, 4 times for tirzepatide and [indiscernible] 1.6 milligram single dose. I mean know that this burst effect here. The burst effect here is linked to GI intolerability, okay? So how does it compare? I already gave you some insight, but how does it compare with our product? And here, you see in blue, the 60-milligram MBX 4291. And in green, the 90-milligram single dose, right? Here, that's 90 and that is 60. And here, again, tirzepatide and the [ MET-097i ]. And you see that we have a delayed Tmax, significantly delayed by up to 13 to 14 days as compared to 2 days. So -- and we have this sustained concentration. So we can already say that MBX 4291 as a cell titrating PK profile and which is anticipated to improve tolerability. It's not [indiscernible] since we already know that how we create, or we can improve tolerability and that through this [indiscernible] we can definitely improve tolerability. So what is the tolerability of the SAD? That a single ascending dose. And here, you have -- he has a 15, 16, 90,180 milligrams, 8 subjects. Again, the study is still blinded. So these 8 subjects, this adverse event profile really with a focus on nausea vomiting and the [indiscernible] include placebo in this report. If you look at the 15 milligram, you have only one subject with diarrhea, mild diarrhea. And in fact, 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 milligrams to 180 milligrams. And that's exactly what you want to show, right? That's what you want to go as high as possible. And you push those in order to get to this tolerability. So the 60-milligram, there's nothing. The 90-milligram are swift subject with one of each, one with nausea, one with vomiting and one with diarrhea for a total of 4 events. The 180-milligram is a maximum tolerated dose with 7 subjects, which is interesting, 7 out of 8, I'm not a wizard, but I know that one placebo is included, because [indiscernible] 6 and 2. And we have the maximum tolerated dose with 7 subjects, as I said, out 8 of showing episode of nausea vomiting or diarrhea. So in conclusion, we can say that [indiscernible] response, right, that the -- from 15 to 90-milligram single dose is well tolerated with adverse events, GI related, which are mild and we have reached MTD with 180. And again, as a reminder, the 120 is still ongoing, okay? So that's the SAD. And [indiscernible] going to pose because the next slide is the one you want to see. So here it is. The MAD. The MBX 4291 was given at the dose of 30-milligram every week followed by 4x a dose, 120-milligram single dose after following these 4 weeks, right? That's here, that the dose, very important. We went to 4x the dose. What you can see that you confirm that there is accumulation which time you give 30 milligram, there is -- the product accumulate that exactly, again, what you want to see. And here, you have a sustained concentration here of the active pap time. By the way, remember, MBX 4291 is a prodrug here and reporting the active concentration, the same things in the SAD. It was the active concentration of the pro drug. It's not the prodrug itself, but the active, the one really want the one you want to see. So in orange here, remember, that's my MBX 4291, 180-milligram Z1 that was the maximum tolerated dose, right? Remember? So we reach the same -- 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-milligram single dose, which was the MTD. But here, we have a completely different tolerability profile, completely different, and I'm going to have a specific slide showing you the tolerability profile. So we can say that MBX 4291 has a potential to sell titrate with repeated weekly starting dose, enabling better tolerability for 4x the higher dose, okay? 4x. So we compare again with [indiscernible] which is -- which has time to have the Cmax of 21 days, 20 to 21 days. It's a proxy, as I said, of half life. Okay, roughly. And what you want to get is the time to help 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 [ MET097i ] at 0.8 milligram 4x, followed by 1.6 milligram single dose, same treatment paradigms at 4291 30-milligram 4x followed by 120 milligrams. And we can observe that here [indiscernible] time to [indiscernible] is 26 days as compared to 21 days. 6 -- 5- to 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. So that's probably the most important slide. The one really -- now we are there. What's the weight loss? Again, the study is still blinded. So I'm reporting here 7%, 7, which is a very competitive weight loss, including both treatment and placebo in 8 subjects. And the range is 0% to 16%, the range of weight loss. In terms of tolerability, pretty remarkable. Only 1 out of 8 subjects showed GI-related adverse event, and it was diarrhea. Diarrhea following the first administration. There was no nausea, no vomiting. And there was no serious adverse event and the tolerability otherwise looks. We are very confident in the tolerability profile otherwise, and we haven't seen anything which was unexpected. So pretty good. And now I'm going to summarize this data. So MBX 4291 is designed for once monthly dosing with well-controlled sustained concentration with sustained concentration and improve tolerability. So data from the Phase I SAD show a PK profile supporting a self-rating weekly induction regimen and potential for a true 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 150 to 180 milligrams. The preliminary data from the MAD from -- it was the first MAD cohort, first one. MAD cohort following 4 weekly induction doses of 30 milligrams followed by 4x the dose of 120 milligrams indicate a gradual accumulation of the active peptide, a mean weight loss of 7%, ranging from 0% to 16% over 8 weeks in 8 subjects, again, still blinded. Only 1 event of diarrhea, only 1 throughout this 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, and I'm going to pass to Rich -- Richard.

Welcome back. And let's see where -- we are here. This is a discussion of [indiscernible], right? [indiscernible] as the folks in Denmark I refer to it as. And as I said, it's been a half century and get to this level of complexity. When I first designed [indiscernible] just inverting to 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 [indiscernible], dual amylin acetone receptor agonist which came after the introduction of the co-agonist for GIP and GLP, built on these that work that I referred to, that Matthias [indiscernible] and I had been about the Amylin Corporation formed in 1987 with first mover in this field of Amylin and they were formed by Ted Green and [ Garth ] Cooper to build antagonists of amylin. Because those amyloid like entities that you found in the pancreas, were believed to be pathological and had to be blocked. That quickly was redirected to what became [indiscernible], short-acting registered amylin agonist that borrowed 3 immuno acids from the rat sequence to give the human sequence a soluble biophysical property that would make it a drug. It ended up being not terribly successful drug. It was used for treating [indiscernible] in addition to insulin and had a prudent effect on the gut. And that's all preceded the use of BYETTA. Nordic Biosciences then advance this concept of dual agonism recruiting in calcitonin, which, as you would know, is an approved product for treating osteoporosis. But also with an ability to lower appetite and to suppress body weight to a small extent. And it was [ Thomas Cruiser ] 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 [indiscernible] Thomas is incredibly capable, chemist. He's also a co-inventor of semaglutide. And [ Novo ] has gone on to register, or in the process of registering [ cagrlinotide ] and the prospect of mixing it with semaglutide that you would know [ Cagrisema ] and then single molecules that bring in 3 activities. GLP-1 and the [indiscernible] and the amylin. So a lengthy history there. Our molecule was built off of [ a DAC ] that we had stabilized with novel chemistry. And it is very potent in vitro at GLP-1, at GIP, [indiscernible] at glucagon and quite potent and balanced at the amylenetonin receptors. We have profiled this molecule in rodents. The amylin activity is most notably seen in fact, [indiscernible] is most notably seen in fact, mice. And then you profile PK purposes in lean synologous monkeys and also note the pharmacology in those monkeys express appetite and any effect on the body weight in those lean animals. And so what I'm reporting here is the pro drug of [indiscernible]. So this is now more than the [indiscernible] that Novo has spoken about, which has GLP-1 monoagonist. This has co-agonist. It also brings GIP just as [indiscernible] has GIP. And 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. And you can see that we have observed greater efficacy and tolerability in these rodent studies, and it is something that we are 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 cynomolgous monkeys in green, I guess this Sam was showing you for the prodrug of the co-agonist. You can see this very flat pump-like exposure for the active [ amicratin ] that has activity against these -- notably, these 4 receptors and a taste of the glucagon. And you can compare in the blues, the [ SEMA ] exposure, the cagrolinotide exposures and [indiscernible], which were designed to be once-a-week drugs, right? And so it's the same story that you just heard about and 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. And for those of you who are not ceramicly 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 in molecularly is protecting your kidney, your pancreas, your liver and your brain from excessive highs and lows. And 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 nonhuman primates. And what you see here at a competitive dose to where we typically dose [ incretins ] and [indiscernible]. In fact, this is slightly higher than where you can dose a [ cagrolinotide ] molecule because [indiscernible] molecule has such adverse effects driven by the GI discomfort as I was sharing with you in [indiscernible] What we see over the course of 3 weeks after a single dose in a monkey. And remember, monkeys clear these drugs 3x faster than a human. It's because they're half life of [indiscernible] cleared 3x faster. A profound decrease in the body weight despite the fact that these are not obese monkeys, right? But this is industrial [ hematology ] aiming for toxicology, right? 50 [ nanomoles ] per kilogram, where in an obese rat, we're using 2 to 10 nanomoles per kilogram. But it gives us a sense of how we improve the therapeutic index. And the answer is, yes, we don't see the projectile vomiting. We do see the delays at these very high concentrations that are typical of these [indiscernible] activities, but much less profound than what we we see in the comparative single species. So 1 plus 1 equals more than 2 in terms of the efficacy and the safety. And we will publish and all of the story in a respectable peer-reviewed journal. And 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 the -- of Manhattan and 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, add efficiency, bio clearance, a fatty acid doesn't bring with it the toxicities that you see in a large molecular pen and also using this design to integrate in 2 and 3 activities and now 4 and a bit of the 5th. And so today, we just shared with you, we have selected that prodrug [indiscernible] a month could be used more frequently, for those who want even more precise exposure. And 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. So let me stop there and again, thank Kent and Pete for inviting me to join with you. Thank you.

Well, thank you, doctors, Saunders, DeMarchi and Azoulay for that master class. For those of you on the webcast, you can just feel the energy in the room here. So I want to bring it forward to another program. Steady Phase IIa proof-of-concept study in post-bariatric hypoglycemia, or PBH, consisted of 3 mixed meal tolerance tests administered to patients at 2 different dose levels of [ imapexatide ] and initially to establish baseline values. As a reminder, imapextide is a fatty isolated 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% to 35% increase in glucose [indiscernible]. And there on the right, 10% to 45% decrease in insulin peak. Additionally, [ glucose Nader ] increased in 90% of patients at 100 milligrams and 100% of patients at 200 milligrams dose of [indiscernible]. With normalization of insulin that is greater than or equal to 70 milligrams per deciliter, [indiscernible] 8 out of 10 patients with 100 milligrams and/or 200 milligrams of [indiscernible]. Based on these changes observed in these key biomarkers, [ imepexatide ] achieved proof-of-concept in PBH. I would like to thank the patients and the investigators who participated in study in 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 IIb study. We believe the preliminary data for MBX 4291 demonstrate that we can design differentiated PEP, novel PEP candidates with potential best-in-class profiles. Notably, we demonstrated true once-monthly exposure with [indiscernible] approximately 26 days compared to the [ MET-097i ], let's remember monoagonist, which has reported 20 to 21 days, [indiscernible]. 7% mean weight reduction at 8 weeks, and that's following a 4-week induction period in single once-monthly dose of 4291. And the self-titrating PK profile, about 2 weeks, which helps [indiscernible] the patients to the drug. Again, only one GI-related [indiscernible] during the 8 weeks. So we're on track to present top line results in Q4 for a 12-week MAD cohort. MBX 5765 applies our [indiscernible] technology and combines multiple validated anti-obesity mechanisms in a single molecule, which we call our [indiscernible]. So the preclinical data, as you saw, demonstrates a differentiated PK profile supportive, we believe, a once-monthly dosing, superior efficacy and improved tolerability. So in MBX, we are entirely focused on two areas. [ Canbuparatide ], which is on track to begin enrolling a confirmatory Phase III registrational study next quarter. and our growing obesity portfolio. In these two 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. And as I mentioned, we have cash of $440 million, which we believe will support our operations into 2029. And so it's a tremendous setup. I'm really proud of our team's effort and excited about our future. And with that, I will open it up for questions.

I'll start here in the front with Mike [indiscernible] at UBS.

Michael [indiscernible] from UBS. Thanks for the great presentation 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 [indiscernible] 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, there's more drug available, and so there's a possible better efficacy? Just maybe characterize the goal of what you could see between the first, second and third cohorts? And then one second question is just on disclosure of the [ amacretin or Omicrotin ] program. I noticed that it's GGG actually with [indiscernible], 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 [indiscernible] is particularly not hitting calcitonin very differentiated, and whether that's the way to go?

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.

Yes. Thanks, Mike. I think what we have already observed with the [indiscernible] is something as you've seen that which probably in the range of concentration of the 5-milligram [indiscernible]. But 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 not -- it's also a GLP-1/GIP coagonist that might have a more potent effect on the pharmacodynamic on the weight loss. So is that something we will be exploring later.

And Richard, regarding our [indiscernible] We're going to say [indiscernible]

Let me just add to what Sam is 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 [indiscernible] products that if you have a life-saving therapy, people will stand on their heads and inject in their eyes, okay? And maybe [ Regeneron ] actually went off and proved that people will inject in their eyes that they have a retinal disease. And so when I built this chemistry, it was all about performance. Greater efficacy, greater safety, greater tolerability. And we'll manage through the other elements that pertain to commercialization. I'm very encouraged by what I see in MDX and what they have done with PTH, and now what I see emerging with the products. Again, go back to 1996 when [indiscernible] and I patented the ability to lower body weight in obese human subjects, 4 subjects for 4 weeks. But it was predictive of where we have gone. So 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 [indiscernible], this is a less than clear story right now. [indiscernible], you remember, is [ Dacra ] that is maybe less than a [indiscernible] 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. And we've yet to detect that you can maintain the full efficacy we strive for when we are removing one of the subtype activities 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. Remember, we've been using calcitonin as a therapeutic. And so 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 going to get hit by lightning or something. And over the last 20 years, we've shown how you can use that in concert with other agonism. So the prodrug is something that extends the duration of action. [indiscernible] has a delayed clearance. It has a flatter peak to trough, nothing like what you get with a prodrug. And 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. And if that's true, then I think our prodrug should be doubly attractive.

Thank you, Richard, and 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 to a baseball player playing for both the Yankees and the [indiscernible]. It's a really unique perspective. So I'm sure you appreciate his participation today. I see one on the -- Tyler [indiscernible]. Can we have a microphone or just project maybe, Tyler?

Tyler Van Buren, TD Cowen. I appreciate the presentation. Just a follow-up on the MAD. When you see that last monthly dose, the exposure better than the [indiscernible] candidate. And clearly, you could potentially lead to greater weight loss. So I'm excited to see the future cohorts. But can you maybe compare the program, or position it against what you've seen with Amgen's [indiscernible] data? And what your view is of that candidate? And then also with respect to just in the maintenance peak to trough variability. Clearly, 4291 is going to have lower peak to trough variability in the maintenance based on what we're seeing. So is there a clinical benefit to that maybe?

Why don't we lead off with Sam again and Richard is welcome to add to it. We'll go back to the slide as a reference.

Yes, I think in terms of variability and just the fact that the time to help the Cmax is much longer that -- and reach 26 days is really aligned with a peak to variability, a small peak total [indiscernible]. That's the goal is really to minimize the peak to trough. And I think Richard was referring to infusion like that's the best example, in fact, in terms of being stable, not only -- but over time and as long as possible. So that's what we're, again, aiming for, and we're starting demonstrating already here. And when you can see -- and 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. And just what we observed with the really great results we already observed with show really a remarkable tolerability profile compared to Mercer or any other drug.

And recall, [ Mirati ] is fundamentally an as it relates to its PK profile. So you're really going to have this burst effect reflected here, getting to Tmax rapidly. Richard, any additional thoughts?

[indiscernible] is an interesting substance in many circles of controversial substance because as you would know, it is a GIP antagonist. It's an antibody that blocks GIP action to which they have semi-synthetically added a very high potency GLP-1 agonist. And it's used at pretty high doses, right? Hundreds of milligrams, I think, Phase II studies, they were up almost to 750 milligrams 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. And then that's where the controversion comes as to how can you have a GIP agonist and antagonist seemingly doing the same thing. I'm reminded of [ Fitch Gerald ] is saying that a form of higher intellect is the ability to hold two opposing forces in your mind and not lose your sanity, right? And so maybe this is one of those cases. [indiscernible] 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 a super agonist as opposed to blocking GIP action. But I'm not the most informed here. It's not just Amgen. There's a company in Copenhagen. [ Jens Holtz ] has been a part of it called [indiscernible] bring the data. Let's -- and then we'll sort this out.

Thank you. Jon [indiscernible] here at Citizens.

Jon Wolleben with Citizens. Just wondering if you can 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, Jon.

So the compound was designed to make as few changes as possible. I've been a part of drug development programs were in trying to reach -- for the ultimate, we changed several things simultaneously and you end up failing because you didn't understand the interactions that occur. So this molecule was designed to have tirzepatide like structurally unique, structurally proprietary, balance at those 2 receptors that look very much like tirzepatide in human subjects and then make prodrug of that substance. So what we're 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.

So a couple of quick questions for [indiscernible]. Can you just help us understand a little bit better the sort of full tolerability profile. We talked about GIAEs, but I think we also see other potential AEs in other charts. So it would be helpful to just have the context of things like injection site reactions dynamics like that, but I know these are the GI AE specifically. And then separately, 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? And 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 GI-related AEs that as Dr. Sanders mentioned, are just the most focused, or most commonly associated with these [indiscernible] and of interest and no serious adverse events. And as Sam said, nothing unexpected overall. And in the MAD, recall, this is just really remarkable with this very brief 1 month induction period and then a single monthly dose, only 1 event of diarrhea and nausea or vomiting. So Dr. Saunders, can you elaborate on just the dosing frequency and patient preference?

Yes, absolutely. Great questions. So 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 how patients are taking the medication compared to how it's prescribed. So if they're missing doses, if they're taking half the dose, whatever that is and persistence, how long people stay on? And since obesity, again, as 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. So having the ability to just do once a month would be very, very advantageous in terms of getting those outcomes. And then if you talk about what actually leads to these outcomes, is it more tolerability? Is it more ease of use, it's both. It's absolutely both. So the more we can do to improve tolerability, to improve ease of use the better were the outcomes we're going to see.

And 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, you'll get an even flatter profile than what you will get 1 once a month. Remember, oral semaglutide is a once-a-week drug. It's used every day, right? So 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.

Annabel from Stifel. So clearly, you've reached your target PK profile that you're looking for a smooth, slow release extended duration. And you're managing through the titration -- simplify titration just with the weekly dosing. I guess I'm wondering in a very heterogeneous population. Obviously, many people are going to need many different types of doses to reach their target profile. So how do you envision having those doses available for a broad population? And I noticed in the -- or A, Part B, Part C, the number of cohorts was actually declining. So 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 [indiscernible], and 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 4291. And just in terms of the treatment option it's a really interesting point Richard made, and maybe I'll ask Dr. Saunders to elaborate.

Yes. I think we -- as I said, we have these 3 parts, and each part informs the next, right? And we have not been so bad. Is that bad in terms of expecting this cohort with a really great result. And so a good testimony of learning from [indiscernible]. We may not have started as we did with 30 followed by 120, but we did because we learned from the SAB and we progressed as as we went. And the same thing that we'll be doing for the next cohort. That's why at this time, we cannot comment on the second cohort because we are learning as we go. I think I can say that very nicely. We are -- this study is still ongoing. So 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, but really a 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 [ MET-097i ] began with 12 once weekly doses in the to show monthly. And what we've shown here 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. So Dr. Saunders monthly, you mentioned you think your patients would be interested in that. Can you talk more about that, please?

Sure. Yes. No, I think 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. But again, the goal is improving tolerability, keeping people on medication. I think the more levers that we have as clinicians be able to really fine-tune and listen to our patients in terms of the timing of side effects, or the timing of when they're having hunger, cravings, food noise and really be able to choose to do weekly, or monthly, that is a huge benefit. And it's currently how we practice now when we're able to, given sort of limitations with different medications like some patients, we do every other week, and that works better for them. Or we do half a dose twice a week and that works better. So the more flexibility that we have to really listen to what's going on with our patients in terms of side effects and symptoms, the better that we can treat everyone. And again, the monthly is a big asset.

Okay. So just to follow up really quickly on that. So your, I guess, way of addressing a heterogeneous population is more frequency of administration as opposed to necessarily the dose? Like perhaps a patient reaching max, their Tmax, some may 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 [indiscernible].

Taking a step back. Really, the way we focused on addressing this is through our obesity portfolio, where we have 3 programs right, that we're advancing. Our most advanced one here, 4291 now [indiscernible]. And soon, next quarter, right, a GLP-1/GIP, [indiscernible] 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. And we think that we can make that with monthly be a really successful treatment option. And then we have these others that are coming as well.

And Kent, can you show the MAD results for a minute. I want to make sure that everybody has connected on those. You gave -- as I understand it, Sam, you gave 30 each week for 4 weeks. And then in the next 4 weeks, you did not increase the monthly dose. You gave the same amount of drug in the next 4 weeks, which means that the dose that they got in week 5, I think, was 4x larger than what they got in weeks 1, 2, 3 and 4 without causing adverse event. I find that pretty spectacular relative to how we so slowly titrate people 4 weeks, 4 weeks, 4 weeks, 4 weeks. It's that regimentation and the way we're doing this, that is a problem. So I'm optimistic about what this may foretell 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, 4, 4. And if you fall off that schedule, then what do I do? How do I get back on the wagon right? So I'm encouraged. But let's be clear. These 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 the renter 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.

Leland Gershell with Oppenheimer. Thank you for the presentation, really, really encouraging data. We look forward to seeing what you'll have for us later in the year with the extended results. Two 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 [indiscernible] weeks? But if you're not prepared to do that, then I'll just move on to my next question.

Yes, ongoing study [indiscernible]. So Q4, you'll get the top line results of...

It seems like you have a lot of room here given the AUC between 4291 and then what is a very much smaller AUC with the [indiscernible] compound? And also, I think that's only a GLP-1, whereas you guys have the dual mechanism. So looking forward to those data. And I'm wondering, given the tolerability comes down given the titration that patients kind of accustomed to this medication, how much room you may have to go up further? And again, based on this kind of PK profiling and clinical data we've seen, I think this dose, I'm not sure how much [indiscernible] shown, but at a much higher dose, I think they got to 12.3% weight loss in the [indiscernible] study. Just curious if you have any take there and the 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. But Sam, maybe you lead off?

No, I think it's -- 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? And we have been conservative in our evaluation at 7% because we mix everybody. So that's what I can say in addition to...

12-week data in Q4, very exciting.

Okay. Stay patient we continue to explore. This is one is ongoing. And again, in terms of AUC, et cetera, we will have more data as we go.

Great. And 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 [indiscernible]. Just wondering what you may be able to share with us in terms of the outlook on mitigating the muscle mass loss with dosing ribbons that are less frequent and/or maybe 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 [indiscernible] 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 the drug a long time without going on and off?

Let's start with Richard on 4291 design and then Dr. Saunders on clinical experience. Our and [indiscernible].

The [indiscernible], the 5,000 series?

Yes, 5765.

Again, this is -- it's different from the co-agonist tri-agonist incretins, where we make a molecule that is the same size as of the native hormone, and we just make a [indiscernible] sequence. But at the end of the day, it's like a master key that can see all 3 receptors, but it looks physically like a glucagon, a GLP or GIP. In this instance, the 2 hormones are sufficiently different, and the receptors are sufficiently different that you have to use both peptides and tie them together. And you would know that [ Novo ] has spoken about the fact that they make a linear fusion of these two molecules. And I might remind you that the first in this series was [ davolinotide ], which was an amylin molecule where they had taken pramlintide and tied it in with [ Ascend ] in [indiscernible], right, BYETTA and quickly divorce themselves from the area because they saw such severe GI effect in that compound, the projectile vomiting that they said this we can't go both of these mechanisms have a GI adverse effect. And so there was this real question as to why anybody would want to make [indiscernible] But to the credit of the folks at Nordic Biosciences, and I said the folks at Novo, they really did a terrific job in advancing the [indiscernible] 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 review [indiscernible].

And maybe both can comment. My understanding is that preclinically, we've seen some signs that [indiscernible] can preserve lean mass, but we're still looking for that signal in the clinic.

But -- so again, when we're in monkeys. We don't go above 30 nanomole per kilogram when we're studying these molecules, right, when you're doing aggressive dosing. With this prodrug, we get to 150 nanomoles per kilogram without seeing those side effects that we had seen at 30 in a lean monkey. And it's, again, a nature of the fact that it is a fully potent [indiscernible], but as a [indiscernible]

So the story is unfolding. Dr. Saunders, please share some clinical insights.

Sure. So just briefly in terms of -- there's so much hype right now about muscle loss. And I think in many ways, there's almost too much hype and [indiscernible] mongering. And what we actually see is no matter how people lose weight regardless of the mechanism, literally from [indiscernible] to a range of medications to surgery, about 25% to 33% of what people lose is lean body mass, which includes muscle. And so it has nothing to do with the mechanism. It's more to do with how much people lose and what that looks like. We're learning much more with so many trials underway about different mechanisms that can affect this. But 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 protein requirements and physical activity, including strength training. So that's what we do right now and the ability to sort of use precision to make sure that people aren't losing weight too quickly, or too slowly is a huge asset. And also the ability to have everything be just much more streamlined because as you said, if people 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. So having the characteristics that we're talking about here, we'll have to see if the data are promising in terms of the effect on lean body mass.

I share that perspective. Very much. And what goes around comes around and takes us back to the late '90s when we were all focused on [indiscernible] And I think what we're seeing is we reduce body weight that elderly subjects suffer from [indiscernible] certain degrees. And unquestionably, if you can find a substance that is safe and the emphasis on safe, right. Testosterone builds muscle 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 and elderly subjects safe, safely it'd be great just as a stand-alone and additive, or integrated as part of an [ incretin ] wouldn't that be lovely.

I love the reference to precision. It reminds me of our PEP platform, right, precision endocrine peptide. Well, Pete has given me the sign.

It's not quite the sign. Just 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 SAD MAD data for 4291.

Yes, I can definitely confirm this. I would say it's no concern with regard to the ISR. I mean, it's a peptide. So we observed some reaction, but nothing that will be worrisome off of concern.

Okay. I see a question in the back. Second to last row. Arm raised.

Jess Fye, JPMorgan. First one to ask about the MAD. So based on cohort be, I guess, the B portion of the MAD, is 30 milligrams weekly followed by 120 monthly, the favorite regimen at this point? And can you confirm if that's one of the regions in Part C? And 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? And then second one is 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?

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 B [indiscernible] And we'll see what we end up deciding for the Part C. But I want to be clear, that has not started yet or the final decision on dosing regimen been decided either. But Dr. Saunders, you're popular with the questions today, please on the oral 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. And then just given the efficacy of the available orals versus the efficacy of injectables, if people are on an oral and they 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? But when we explain kind of the differences and especially if someone is a higher dose of an injectable, an oral may not cut it for them. And so most of them choose to stay on an injectable. I think that people don't -- it's not such a crazy idea anymore to be on an injectable for obesity. When we were convincing people to take daily injectable, that was a little bit harder. But if something is working and tolerable, then people will take it. So I think short answer, there's a role for both. I think oral more for initiation and injectable just right now is they're the more effective medications. And to be able to do a month, a weekly or a monthly instead of taking something every day is absolutely very attractive for many people.

See a question, also second row from the back. Can you -- so I can't see too well from here, but please, can you pass the mic down. Is that Srikripa, please announce yourself.

This is Srikripa from Truist. So for -- between tirzepatide and 4291 you reached Tmax obviously, at a different time frame. Could there be a difference in appetite suppression for the first 2 weeks of -- for patients who are on 4291 -- and how does that -- how will that evolve? And also for Dr. DiMarchi, going back to the PEP platform, how tunable is the cyclization rate? And maybe from a life cycle management perspective, would there be a potential quarterly in the future?

We'll start with Sam and go to Richard again.

I don't think it will have any impact on the appetite separation. And we saw it even from our first B1 cohort that we get this 7% weight loss average after 8 weeks. So I don't think that we'll have a significant impact or any impact?

The pet platform is is incredibly versatile. As I said, you can go from 1 hour to 1,000 hours, no enzymes, no cofactors, 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 going to be? Because now you've got to give 365 days of drug as opposed to 1 day of drug. And what are you going to use is the protractor? Because -- what we have here is built on albumin or plasma proteins, predominantly albumin as the reservoir slating reservoir, it's turning over with a half-life of 21 days, right? So whether you convert into an active entity or not, the albumin that it's bound to is going to disappear, right? So you have nonproductive clearance. So 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, but 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 the last question. Pete, you can direct it. Please ask the question with -- the microphone is coming.

Great. [indiscernible] Barclays. Congratulations on the data. Just a quick follow-up for me. So 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? And just I think it was asked already, but I just want to confirm, will we get that second cohort from Part C at the data update later this year?

I'll lead off. Thank you, [ Eli ]. 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 commit to. But in terms of how we're thinking about it, I'll let Sam give some more thoughts.

Yes. We are clear about first cohort will be a weekly administration for 4 weeks, followed by a monthly administration for over the 12-week period. And that's what we are thinking right now. So the things that we'll have to determine it will be what dose, we will be exploring in this cohort C.

And 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 of success. Thank you for participating in it, and we wish you a great rest of the day.