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Good day, and thank you for standing by. Welcome to the Biomea Fusion BMF 650 GLP-131 Phase 1 Topline Results Conference Call. At this time, all participants are in a listen-only mode. Please be advised that today's conference is being recorded. After the speaker's presentation, there will be a question-and-answer session. To ask a question, please press star-1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 1-1 again. I would now like to hand the conference over to your speaker today, Ramjas Ertman, co-founder, Chief Operating Officer, and President of Biomea Fusion. Thank you, Operator, and welcome everyone to this conference call. Today, we will discuss top-line results from the Phase 1b, a multiple ascending dose study evaluating BMF650. our investigational oral small molecule GLP-1 receptor agonist, which we developed alongside our many inhibitor ICOVA-MENI. Before we begin, I'd like to remind everyone that today's discussion contains forward-looking statements. I direct your attention to slide two of our presentation and our SEC filings for a full review of the risks and uncertainties that could cause actual results to differ. The development of oral GLP-1 therapies has advanced substantially. Across the field, multiple programs have demonstrated that oral incretin therapies can deliver clinically meaningful weight loss and glycemic improvement. At the same time, the category continues to confront a practical challenge. As exposure rises to levels intended to produce meaningful efficacy, gastrointestinal tolerability frequently becomes the limiting factor. The challenge is straightforward to describe but has been difficult to solve. For example, in a real-world 2025 study of more than 125,000 overweight or obese adults who initiated a GLP-1-based therapy, 65% of them discontinued within the first year. To date, no oral program has conclusively demonstrated that potent clinical activity can be fully separated from a meaningful cumulative gastrointestinal burden. Across programs, the most consistent development response has been to primarily adjust and manage the exposure, which includes lower starting doses, slower escalation, additional intermediate steps, and a longer time before patients reach maintenance exposure. The MS650, however, was designed differently. It was designed with the intent to separate weight loss from GI tolerability and thereby allow patients to stay on treatment. With that, let me turn the call over to Torsten, our head of research and leader of the BMF650 development program. He has overseen this program since inception and will review the design rationale and our early non-clinical results, which provided us a first proof for the emerging 650 profile. Torsten? Thank you, Ramses. I will begin with Orfoglipron because it provided an important scientific reference point for our work. Or for glipron, established that a potent, orally available, non-peptide small molecule can activate the GLP-1 receptor and produce meaningful clinical activity. We admire the rigor and success of that program and the insights it delivered. That brings me to the central objective behind BMF650, which is captured in the title on slide 8. potential to separate GI side effects from weight loss in the oral GLP-1 receptor agonist space. A successful oral GLRP-1-receptor agonists should capture the convenience of oral dosing while addressing some of the limitations of the class. With BMF650, we specifically designed the molecule for less acute GLP-1 receptor organism in the GI tract, with the goal of improving GI tolerability. If successful, that could enable fewer titration steps, ideally just one, and ultimately support greater persistence with chronic therapy. Slide 9 takes you into the molecular design behind that hypothesis. BMF650 is a selective and biased GLP-1 receptor agonist with no off-target concerns identified in our counterscreening assays. Importantly, BMF 650 has approximately 26-fold lower agonists potency than Orfoglipron. This reduced potency is an intentional element of the design and part of our hypothesis for reducing acute GLP-1 receptor activation in the GI tract. Slide 10 shows another aspect of the design, bioavailability. In non-clinical PK studies in both monkeys and rats, the MF650 demonstrated high and prolonged exposure following oral dosing. Importantly, bio-availabilty was approximately two to three-fold higher than Orfoglipron in these experiments. So conceptually, the design is quite straightforward. Lower receptor potency coupled with high and sustained systemic exposure. The long clinical PK gave us confidence to take that hypothesis into humans, and you would see the human PK data in the clinical section that follows. But before entering the clinic, we wanted to know whether this profile could translate into meaningful weight loss. We therefore evaluated BMF650 in obese synomolbus monkeys using once daily oral dosing. As shown on slide 11, we observed significant dose-dependent weight loss of approximately 12 and 15 percent. The response was consistent across animals within the different treatment groups and showed no apparent attenuation towards the end of the study. Importantly, emesis events were relatively limited despite dosing without titration. On slide 12, I bring together these non-clinical observations to highlight three key elements of our design. First, BMF650 uses a relatively higher oral dose and was designed for broader intestinal absorption with the intent of reducing localized concentration peaks within the GI tract and supporting absorption across a broader intestinial surface and time window. Second, BMF650 demonstrated high oral bioavailability with low variability in our non-clinical studies. Our hypothesis was that this should translate into consistent and predictable exposure in humans. And third, BMF650 was designed to produce a gradual increase in systemic exposure with a relatively low peak to trough ratio, providing a more even exposure profile over the dosing interval. Taken together, this was the design hypothesis going into the clinic. Lower acute receptor activation combined with sustained systemic exposure could potentially achieve meaningful weight loss activity while improving GI tolerability. We sometimes describe the intended distinction as a blowtorch versus a radiator. concentrated intensity versus a more gradual and sustained delivery of the biological signal. Against this background, let's now turn to the Phase I clinical data and see how BMF650 behaved in humans. For that, I will turn the call to Dr. Juan Pablo Frias, who leads our scientific advisory board supporting the BMF 650 program. Juan Pablo is a recognized clinical investigator in diabetes, obesity, and metabolic disease, with extensive experience evaluating incretin-based therapies. Juan Pablo, over to you. Juan Pablo Sánchez- Thank you, Thorsten. Today I'll review the top-line results of the Phase 1 study of BMF650. I will focus on four areas, the study design, weight reduction, safety and tolerability, and pharmacokinetics. I will then briefly summarize what we believe these findings support as the program moves forward. Let's begin with study design on slide 14. This was a randomized, double-blind, placebo-controlled phase one study in overweight or obese participants. The first part evaluated single ascending doses of BMS650, primarily to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and the effect of food. The second part was a 28-day multiple ascending dose study. This part was primarily designed to evaluate co-primary tolerability measures, including adverse events, vital signs, EKG measures, like QT-CF interval, and safety labs. The secondary endpoints included percent change in body weight at study end, along with pharmacokinetic measures. We initially included four active dose cohorts and corresponding placebo participants. The dose regimens increased across the cohorts. The first four cohorts evaluated different weekly dose escalation schedules. Now let's turn to the baseline characteristics on slide 15. Overall, demographics and baseline characteristics were reasonably balanced between BMF650 and pooled placebo groups. Participants had a mean BMI of approximately 34 in the active group and approximately 36 in the pooled placebo group. Mean baseline body weight was approximately 100 kilograms in the active group and 110 kilograms in pooled placebo group. Each cohort included eight active and two placebo participants for a total of 32 active participants treated with BMF650 and eight pooled-placebo participants in the first four cohorts. Turning to the clinical activity findings on slide 16, this analysis examines the incremental weight change during each weekly dosing interval of cohorts one through four. Here we observed reductions across all four BMS650 treatment cohorts through day 29 compared with essentially no change in pooled placebo. MEAN REDUCTIONS RANGE FROM 1.5 TO 3.2%, WITH COHORT THREE ACHIEVING THE GREATEST MEAN REDUCTION OF 3.3% IN THIS KEY SECONDARY END POINT. WHILE THESE ARE SHORT DURATION PHASE ONE DATA FROM SMALL COHORTS, THE CONSISTENT DIRECTION OF WEIGHT REDUCTS ACROSS THE ACTIVE COHOTES PROVIDES ENCOURAGING EARLY EVIDENCE OF CLINICAL ACTIVITY FOR BMF650. On the next slide, you can see that across these first four cohorts, 14 of the 16 weekly dosing observations showed additional weekly weight reduction, and the magnitude of the weekly weight reductions generally increased at higher administered doses. Across these cohorts the mean weekly weight reduced at doses of 200 milligrams once daily or higher was approximately 1 kilogram per week. In cohort four, we observed an increase in weight during the first week, which was unexpected. Closer inspection of the pharmacokinetic data raised concerns that some participants may not have taken the study drug consistently. We therefore introduced cohort five under confinement to ensure dose and compliance. We also evaluated a simpler titration schedule in this additional cohort, starting at 200 once daily and increasing after one week to 400 milligrams once daily for the remaining three weeks. At that point, we had observed only limited safety findings and, importantly, no clear increase in gastrointestinal adverse events in the earlier cohorts. Turning now to the results of this additional cohort 5 on slide 20, we can see that the confinement allowed close assessment of safety and tolerability, but it also appears to have influenced eating behavior. All participants were provided 2,100 calories per day. The two placebo participants consumed approximately 33% of the presented food and may have been sensitive to the food choices. They experienced weight reduction similar to the active participants, which complicates the interpretation of weight loss under confinement. Cohort five participants receiving DMS 650 lost an average of approximately 1.55 kilograms per week for a total weight reduction of 6.2 kilograms or 6.1% after four weeks, with no observed attenuation over the treatment period. Because cohort five was small and the two placebo participants consume less food than active participants, the results of this cohort should be interpreted cautiously. We therefore view cohort five as an exploratory analysis and consider together with the dose response pattern across the complete dataset, the pharmacokinetic findings, and the observed tolerability profile. Taken together, these findings support potential meaningful pharmacologic activity. Coming to safety and tolerability on slide 21, overall, BMF650 was generally well tolerated across the five active dose cohorts. All treatment emergent adverse events were mild or moderate. No severe or serious treatment emergents adverse events was reported. There were no dose modifications and no study discontinuations related to treatment emerging adverse events. We also did not observe a clear association between treatment emergent adverse events and dose escalation, dose in cohort, or time at a given dose. On the next slide, we show selected gastrointestinal adverse events. Across the 40 participants treated with BMS 650 in the MAD cohorts, nausea was reported in seven participants, constipation in four, vomiting in three, and diarrhea in two. In the highest dose cohort, the selected gastrointestinal events were all observed to be grade one in severity. Only one of eight participants in cohort five reported nausea, and one reported a single vomiting event. There were no reports of diarrhea in this cohort, two participants reported constipation. DAT23 provides post-hoc descriptive context relative to selected Phase I disclosures of other oral GLP-1 receptor agonists that have progressed to late-stage development. At the highest BMF650 dose regimen, the observed incidences were 12.5% for nausea, 12.50% for vomiting, zero for diarrhea, and 25% for constipation. No head-to-head studies were conducted, and these cross-trial comparisons should be viewed cautiously. The studies differed in size, duration, dose escalation schedules, and adverse event collection and reporting. Nevertheless, we believe the observed gastrointestinal profile of BMF650 supports further evaluation at the 400 milligram dose. The 24 shows selected changes in liver enzymes, fasting glucose, and heart rate. Mean ALT and AST values decreased from baseline in both the active and placebo groups, and no adverse events involving ALT or AST elevations were reported. Fasting glucose decreased across all BMF650 dose cohorts with a mean reduction of 9.2 milligrams per deciliter in the pooled active group compared with 3.5 milligrams per decileter in pooled placebo. Mean heart rate increased by 6.4 beats per minute in pool active group, compared with 0.8 beats per minutes in pool placebo. No adverse events involving heart rate were reported. Turning to pharmacokinetics on slide 25, which were key secondary measures, BMS 650 achieved the target exposure predicted from the nonclinical studies. In cohort 5 on day 28, the mean exposure over 24 hours was approximately 79,000 hour nanograms per milliliter. The observed peak to trough ratio was approximately 1.7, indicating relatively limited fluctuation in exposure over the 24-hour dosing interval. The observed human exposure was also consistent with the efficacious exposure observed in the relevant nonclinical weight loss study. The pharmacokinetic analysis remains preliminary, but these results support one daily administration and confirmed the clinically relevant exposure was achieved. Turning to slide 26, in summary, BMF 650 was designed to separate weight reduction from GI safety risks. Across the five active cohorts, we observed that with increase in dose and exposure, participants achieved greater weight reduction while maintaining a very well tolerated profile with comparatively low GI effects. Bringing these findings together, the phase one results support the original BMF650 design hypothesis in three important respects. First, participants reached the target dose of 400 milligrams once daily through a single titration step after week one, supporting a potentially simple and practical dosing paradigm. Second, cohort 5 demonstrated sustained and meaningful weekly weight reduction at 400 milligrams across three consecutive weeks, reaching 6.1 percent mean weight reduction at day 29, with no evidence of attenuation over the observed treatment period. And third, the GI tolerability profile was very encouraging. the active multiple ascending dose cohorts, there were no serious treatment emergent adverse events, no treatment emergents adverse events leading to dose modification, and no treatment emergent, adverse events needing to study discontinuation. Biomea plans now to continue with longer term toxicology studies to support phase two clinical evaluation and advance the phase two planning including the assessment of whether participants can initiate treatment directly at the highest dose without titration at all with that i will turn the call over to mick the company's interim ceo thank you juan i am very pleased with the results bmf 650 demonstrated in this first clinical trial. In the highest-dose cohort presented today, we observed meaningful weight reduction together with an emerging safety and tolerability profile that we believe supports the design objectives we established for BMF650. Our goal was to create an oral GLP-1 receptor agonist while modifying its properties to improve tolerability and support sustained use over time. When we look at BMF650 in the context of the Phase I results reported for other advanced oral GLP-1 receptor agonists, we believe the combination of clinical activity and tolerability data we observed is encouraging. Importantly, we are not looking at the clinical activity or tolerability date in isolation. we believe the opportunity is to deliver both profiles and ultimately to provide a treatment experience that can support long-term use. Based on the results presented today, our intention is to continue advancing BMS650 towards phase two development. The next steps include completing the additional non-clinical work required to support longer duration dosing, manufacturing clinical supply, and preparing the program for the next stage of clinical development. At the same time, I want to be clear about how we think about capital allocation. We intend to invest in BMS 650 through the stages where we believe we can further establish its clinical profile and maximize the strategic value of the program. We do not currently envisage by OMERA independently funding a large global clinical obesity program. Our objective is to advance BMS650 and position the program for a strategic partnership which could include a licensing arrangement for late stage development and commercialization. We believe this strategy allows us to continue building the value of BMS 650 while remaining disciplined in how we we deploy Biomere's capital. At the same time, ICOVA-Meneb remains at the core of Biomare and represents a major potential value driver for the company. Our focus now is on validating the highly encouraging clinical signals we have observed to date and advancing the program through a series of important milestones over the next 18 months. Over the next two quarters, we plan to initiate two phase two studies in type 1 diabetes. Here we are expecting to get a first set of six months response data from 36 type 1 patients within the next 18 months. Then in the first half of next year, we expect two additional important phase two readouts. The 26-week primary endpoint for Icovomenib in insulin-deficient patients, as well as the primary endpoint from our study in patients with inadequate glycemic control on GLP-1 therapy. And toward the end of next year, we also expect results from our studies evaluating Icoven in combination with semaglutides, where we are investigating the potential for additional weight loss together with preservation of muscle, bone, and physical health. Taken together, these milestones are designed to help us organize end-of-phase two meetings with the FDA for type 2 as well as type 1 diabetes and move Icovimanib to late-stage development. We thank you for your continued support and appreciate your interest in the work we are doing at Biomea. Operator, we are now ready to take questions. Thank you. As a reminder, to ask a question, please press star 1 1 on your telephone and wait for your name to be announced. To withdraw your question, please press start 1 1 again. One moment for questions. And our first question comes from John Wallivan with Citizens, you may proceed. Hey, congrats on the data, thanks for taking the questions. Wondering if you could talk a little bit about the timing to complete a tox study, and then it sounded like you guys would be open to running a phase two program. Wondered how you could think about some initial thoughts given the freshness of this data. And then maybe a question for Dr. Frias. Wondering how you think about oral differentiation and how many oral drugs the field may need and what, you know, actually constitutes clear differentiation between these molecules. Thanks. DR. Hi, John. It's Mick. In terms of the Phase 2, I think given where we came out on the Phase 1, we want to do another dose in the phase one, possibly 400 directly, and figure out what was going on in the short term with that. That would lead us then to potentially a phase two design where we would have no up titration. We just started the dose that we were going to use and see how well that worked over time. I'll pass the other question over to Juan. Yeah, so I think, I mean, you know, the answer is quite similar to what you said. I think the differentiators would be, one, the tolerability of this pans out as we look further in the clinical development program, but then also, you Know, either having a very short escalation, you know, basically one dose step, or if the tolerability is there to be able to initiate and just have one dose. So I think that would be, you know, a fairly important differentiating feature. So, I think there certainly is room for a drug that has those characteristics. What's the minimal amount of weight loss you'd want to see for a drugs to be worthwhile to use? Um, you know, I think probably somewhere in the range of 10%, I think would be, you know, it could even be a little lower than that, but I think 10% is still, you know, on average, very good, good weight loss for a lot of patients. I would also say that the patients who would benefit from less weight gain, particularly if we're trying to prevent obesity-related complications and other cardiovascular risk factors. But I think somewhere in the range of 10% as a minimal. Thanks. I'll jump back in the queue. Thanks, guys. Maybe, John, I just want to add one more comment because I found it so profound when I looked at the data that in the highest dose, when we went into the, where we put the patients up in confinements and we added the highest dosage with one-step titration, the safety profile was upheld. And if you look at the safety profil and the tolerability that the drug has shown, it's so comparatively superior in my mind, and this is a personal view, but I was amazed that if you just do one-step titration going from 200 to 400, you're not incurring more safety issues. One, it stays fairly benign in comparison to all the other players in the field. So if you were to ask me, what is the key differentiator between us potentially as we validate our signals in further studies and others, it could be that the safety is the Key Point of differentiation. One, we can go faster there, and two, we're just unusually safe based on the design. And we spent quite a few slides on explaining the design, and Torsten's section goes into the reason for why we designed the drug we did, but I would argue that is, for me, the key differentiator. Trying to give somebody weight loss without all the GI of, you know, tolerability issues they have to go through. Anyway, next answer, next question, operator, would you mind? Yeah. And our next question comes from Joe Pankinis with H.E. Wainwright. You may proceed. Hey, guys. Good afternoon. Very nice start to the data. So, I have a couple of broader questions looking forward here. First, can you give sort of the profile you would be looking at with regard to a BD partner? And that also links to the profile of the drug you might want to see in the future. Obviously, you know, as Ramsey, you just said, a better safety profile, but would you look at, you Know, a maintenance therapy, frontline therapy, you Now, what kind of options would you potentially see for this drug? And so that's number one. And then number two, what would you consider to be, and you touched upon this a bit during your presentation, the open questions with regards to finalizing the dose and the quicker titration? Thanks. Yeah, thanks, Joe. So, if you look at the field, and that was sort of in my section, The persistence is the problem, meaning we have a great backbone here as in the GLP-1 strategy on how to address obesity, yes. So we understand that part, but we haven't fully figured out as a field on how to really do it in a way that we can get patients to stay on drug. And that's why we quoted that recent survey from 2025 in our slide deck. So if 125,000 users, 65% are not staying on drug within the first year, something's wrong. And the way we designed the drug, and that was evident already five years ago, the way we designed this compound was to achieve persistence. And that's where I think a partner would find a potential entry into the space. If you look at everybody was going for maximum weight loss, andthat's great. And now who's staying on drug and who can achieve persistence with patients potentially wins in the long run. Our goal was not to achieve maximum weight loss. Our goal is to achieve a good weight loss over time. You can step into this compound from another drug. You don't have to up titrate. You can easily just switch if you're unhappy with what you're currently on. Those kind of aspects, I think, could potentially add value. And so a BD partner would be somebody who has a failed program. It could be somebody who has program but hasn't gotten this aspect in his own drug. Or it could be someone who hasn't entered the space and wants to come in the space for something new. We're looking at all three of these categories. We're pursuing each one of them. And as a small biotech company that is surviving on good data and also non-diluted funding from pharma that's where we are seeing opportunities particularly 650. now you asked another question on finding the dose um and mick alluded to that we we think another cohort six in a non-confined setting so in an open setting where people have these choices for eating as much as they want to um would hopefully or not hopefully we think actually that would be a great setting for us to show the key difference between placebo versus us. We already know the safety because in confinement, for sure, the physician sits right next to the patient and picks up on every AE profile you may imagine. So safety-wise, we feel really certain that this is what it is. FPC-wise. Yeah, the placebo were a little bit behaving quite unnormal and that can happen if you have a small N and it did happen to us here. So what we're thinking of doing is initiating another cohort six, potentially with a partner, where we would go and add another, whatever, 10, 15, 20 patients with a larger placebo setting, not in a confinement situation, and run that cohort. That would more or less clarify the signals we have seen and allow somebody else very likely to take this drug into phase two. I appreciate that, Ramtiz. And if I could just fit a quick one in there, have any discussions started yet or are these data the impetus to go ahead so I can't really comment too much on it but you can imagine that we don't want to wait for pharma to approach us we are we're doing everything we can with what we have to engage conversations like every company should do in our situation so you can assume we've done the same. Thank you very much. Yeah, thank you. Our next question comes from Cha-Cha Yang with Jefferies. You may proceed. Hey, team. Thanks for taking my question. I just wonder if you can speak a little bit to the dose response that we see or specifically about cohort three performing better than cohort four do you think it's mostly a small n issue um or what other things are we thinking about here hi judge this is mick um i think the uh the thing that's important to see and i mean this is the reason we've broken it out is um you know the the dose response is pretty good if you get rid of to that first point in cohort four. So we think something went wrong there, which is basically, you know, changing the starting point for the rest of the line to go down. And I think, again, you Know, it is small numbers. There's only eight in each active cohort. And so that probably has something to do with it as well. But I really think it's the fact that it went up on the first dose, sorry, on the first week, and that sort of changed the starting point for the line to come down. Do you have anything else to add, Torsten? No. When you look at the cohort from compliance, yeah, so it is true that cohort four generated the most question marks towards compliance because the PK, as we've shown, is very reliant when you can measure it for participants. So essentially the T0 value on certain days is a good indicator of drug compliance on the day before. And so some of the analysis we did cohort four points towards there may have been a problem along those lines. That patients didn't take the drug because they didn't have sufficient exposure, right? Yeah. And you would have expected more exposure. And that kind of led us to the conclusion we're going to do cohort five because some patients haven't taken the drug. it would be false to conclude that cohort four is reality, right? And so that's why we said, okay, let's do cohort five. Cohort five, if you put them next to each other, is obviously under confinement. When everybody takes the drug is a beautiful response line. But we think a cohort six would, in a non-confined setting, would probably help clarify that. Our next question comes from with Citigroup. You may proceed. Hi. Thank you for taking the question. So, I had a few here. The first one is, when you look at the NHP data, which showed the 15 percent reduction at a month, can you just explain a little bit more how the exposure on the AUC and the TMAX compared in those animals versus cohort five in the confinement experiment. Were those similar or was the exposure higher in the monkeys? And then can you just explain a little bit more on the confinement? These patients were essentially in confinement 24-7 for the entire month, or was it just at certain points during the day when they were eating or taking the drug? Thanks. I start with, yes, so with respect to the exposure of the monkey stud in the 400-milligram titration target dose, these are cohort 4 or cohort 5. They align very well, actually. The exposure that you see at the area on the curve of 79,000 on day 28 on cohort 5 is essentially what the high-dose cohort of the monkeys had a daily exposure. And then it's approximately two to three-fourths less in the monkey for the low-dosed cohort, which aligns approximately between 200 and 300 milligrams titration target of cohort 2 and cohort 3. So everything kind of came out nicely. And personally, I'm actually a fan of cohort 3, the weight loss placebo-adjusted resembles almost all for glipron, actually. So that's that. And then addressing your question about the confinement, so cohort 5 was a complete confinement study for 30 days, actually, in the unit. So participants didn't leave the unit, everybody had their room, It was kind of staying there, sleeping there, taking their meals there under supervision, getting the protocol assessment and dosing under supervision for the whole time. Okay. So do you have a hypothesis as to why in the animals you saw mid-teens percent versus what looks like about 6%, I guess, 6% in the cohort and the cohort 5? is that how do you reconcile those? Yeah, so thank you for the question. So for me as a medicinal chemist, I always am faced with translating animal data to human data, and every animal almost has a conversion factor for PK parameters. I apply this for almost everything else. So for a monkey, generally that's three. So if you divide what you see in the monkey by three, you actually almost really get to the human number. So I would think a monkey with high metabolic rate and the smaller species altogether more heart rate everything that comes together to just adjusting it downward by approximately this factor so i am actually not surprised in fact that's what i would have expected i see okay thank you yeah thank you thank you our next question comes from michael king with rodman and renshaw you may proceed hey guys thanks for taking my questions. A couple of follow-ups. Just to focus on, like, if you look at cohort four, cohort five, I'm sorry, and compare the placebo-adjusted weight loss, you're in the almost identical ballpark as Karmic did some time back with CT996. So, you know, this does look like an active drug. I'm just wondering if there was any explanation from the site about why these individuals kind of starved themselves. And were food logs kept for patients in any of the other cohorts one through four to see if eating behavior was modified or how much it was modified? Yeah. So maybe the truly easy question first, so for cohort one to four, there's an outpatient thing, so there are no food logs available for those patients, but for cohort five, every meal has been traced against presented how much was consumed. So we have this for every patient for every meal in cohort five. Obviously, we looked at the placebo patients who behave this way. So one of them truly is 50% less than the next nearest consumer. So this was apparently a very committed person who had weight loss very much high on their personal agenda and did it from day one to the very end. So this person very much... What does the 50% mean? They've got much better willpower than I have. So they consumed 33% of the 2,100 calories that were presented, and they presented versus those that were on active drug, 60% of what they ate, meaning they ate less than the ones that were active. Yes, right. So that is very true. And Ramzes now went more for the average of the two versus I had peeled out the one. Okay. It was particularly noticeable. Yeah. So that's the tough part, Mike, if you have only two, right? If one is a dedicated and you asked for a response from the investigator, we interrogated them and they said, yeah, that's kind of what happened. and they may have been sensitive to the meal that we presented and said, I don't want to eat it, or they may just have wanted to lose weight. But they used this opportunity to achieve both. Yeah, but you think that the site would encourage them to, you know, everybody, you need to eat everything, right, eat up, because, you don't know if you're on placebo or not. They did it with all of them, and they didn't know who was on drug-complex. So they tried to encourage everybody to eat. But I think I would like to take an optimistic perspective and compare it to the pooled placebo. Of course, we would, too, but it's a little unfair. That's why we put the press release out the way we did. Yeah, I understand. The other question I have, well, a couple questions. Number one is, you know, we're talking about safety and dose response. It seems like another thought is instead of just titrating directly to 400, why not go to, say, 600 to see if you can get even greater weight loss, given the tolerability? It seems Like you've got a lot of room to play with on the tolerabilty side that you might even go higher than 400. What are your thoughts? so mike the um the the reality is obviously we could do that if we wanted to see more weight loss however you know the real objective here is to think about what we want to do for the longer term and having a greater weight loss in a short period of time isn't necessarily the goal of the program overall so i think you know we've already seen an amount which you wouldn't want to take forward into, for example, a six-month study because they'd be losing already 36% of their weight in six months. I think that would be pretty much over the top. So I don't really see the value in going forward with a weight loss program that sort of tries to force a higher amount of weight lost some we've already seen okay fair point um and then just finally i just would like to get your thoughts on well there's two things on the beats the cardiovascular uh effect on slide 24 um you know there is a fairly high you know if you're let's say baseline of 72 beats per minute normally, and cohort three goes up to 82. Is there any concern about that? And was that measured over time? Is that at the end of study? And was there any, I assume there was no tachycardia or shortness of breath that's associated with these increases in heart rate? So, the quick answer is none of the observations were called adverse events by the PI, so no. Everything was fine, just one release. I would add that this is in line with what's seen with the class, so I wouldn't be concerned. over the longer term, the heart rate will start coming down over several months. So, I mean, this is very short term. And again, no AEs from it. And actually, I don't think there was anyone even symptomatic from it, and you wouldn't expect it. So I think class effect, and I wouldn't be concerned about this at all. Okay. And then finally, just on slide 25, where you show the PK curves, I just want to tie this back to the discussion that the others have had with you guys about. Persistence, which I think is the right way to look at it, is there an ideal goal of the nanogram per ml levels that you'd like to maintain in a maintenance setting to, you know, to get that balance of continued efficacy as well as persistent weight loss? so based on everything that we've learned about the compounds of 4 to this 4 this would be at the moment the approximate exposure that we're shooting for I would give it a 2 forward arrow on maybe on the lower end but yeah this is approximately where we want to be even in the long run okay thanks appreciate it thank you Thank you. Our next question comes from Kumar Raja with Brookline Capital Markets. You may proceed. Thanks for taking my questions. With regard to the GI adverse events, at what time points are you seeing that? And what data do you have in terms of gas recamping delay? Thank you So, I didn't understand your first question, but again, we can— Time point. For time point when these two elements occurred. Oh, so there is no correlation to any event during the study. Meaning, it's not, you know, day one first dose or the up titration dose. They occur essentially spread out over the study for—among the groups. So, no pattern emerged from this. Also, interestingly, in cohort five, they were all mild, right? off the GI tract. Thank you. I should have started maybe with this, yeah. And we did not perform any gastric emptying studies, so we didn't do any, was it Tylenol that's sometimes used as a probe, so we did n't do anything of this. We anticipate that gastric emptying is also slowed by this compound very much with the class, but we have not investigated this in the course of this study. DR. Okay, great. Thanks. DR. Thank you. DR. Thank you, and as a reminder, to ask a question, please press star 1-1 on your telephone. And our next question comes from Manu Palmarama with J.P. Morgan. You may proceed. DR. Hey, guys. Thanks so much for taking the question. Just a quick clarification question. In the press release, it notes that there's long-term toxicology studies need to be done before the next study. Can you outline what exactly needs to be done from that perspective? Thanks so much. So we had the correct tox study to run this clinical study. The next tox program would generally be of 13 weeks duration. That would be the subchronic tox program, which is the one we would initiate to be able to run a 13-week weight loss study in the clinic. It's in two animals, right? In two animal species, yeah. So, one is a rat, and the other one will be a cinnamorgus monkey, as we have done for this enablement as well. That's all, Anupam. And then we would be able to go into a phase two, once we have that data in hand. Got it. Thanks so much for taking the question. Yeah. Thank you. Thank you, Anoopam. I would now like to turn the call back over to Mick Hitchcock for any closing remarks. I think what we've presented to you today gives you a clear picture of the information that we have generated from the GLP-131 trials. We're very pleased with the outcome. We're excited about the possibility of the drug moving further along. And as we said earlier, it's something we would like to do with a partner because we are very focused on our ICOVA-managed program for diabetes type 1 and type 2. So thank you very much for your attention today, and we'll close the call. Thank you. Thank you, this concludes the conference. Thank you for your participation. You may now disconnect.