Good morning, and welcome to the Skye Bioscience expert panel. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentations and fireside chat. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player. As a reminder, this call is being recorded, and a replay will be made available on the Skye Bioscience website following the conclusion of the event. I'd now like to turn the call over to Punit Dhillon, Chairman and CEO of Skye Bioscience. Please go ahead, Punit. Hey, good morning. Thank you, Tara. President and CEO. Paul Grayson is the Chairman. But good morning, everyone, and welcome to today's call. Today's about framing how to interpret the CBeyond Phase 2a topline, and what we're going to be talking today about what is meaningful, how we're translating the clinical readout into the next steps. But before we begin, I want to remind everyone that we're not previewing any clinical results today, but still we're going to be referencing some new preclinical data that we just announced today, and we're going to remind everyone of the cautionary note regarding forward-looking statements. Regarding the agenda, I'll start off with an introduction. I'll turn it over to Dr. Puneet Arora, our Chief Medical Officer, to cover the brief science and clinical update, and then I'll come back and talk about what success looks like at 26 weeks, and then we're going to follow it with a KOL discussion with our expert panel, and then followed by audience Q&A. So we're very thankful for the expert panelists today. Today we have Dr. Sean Wharton, who brings deep clinical experience across anti-obesity medications in the real world and clinical perspectives. Dr. Kenneth Cusi is also an endocrinologist and expert in obesity, as well as a CBeyond PI, and can speak to the trial conduct and interpretation as well. And then Dr. Marcus Goncalves is a physician, endocrinologist, and biomedical researcher at NYU Langone, and he bridges the intricate biology of the endocrine system, as well as human metabolism. And I'm going to be moderating. Dr. Puneet Arora, our Chief Medical Officer, will cover the science and study design. So over the past year, we've been on a warpath to prosecute and a really validated CB1 pathway with a novel peripherally acting allosteric antibody, which is nimacimab. And on the left of this screen is the evidence we've built, and on the right of the screen is the new data that we're sharing today. Just to orient the listeners here, on the left side is really about the foundation. So if you think about this across multiple species models, especially the DIO models, nimacimab reduces fat metabolism while preserving lean mass. It's... We're showing data now that modulates key hormones like GLP-1, leptin, resistin, and we've also shown weight loss durability after a dosing stops, as well as dose-dependent weight loss. So this is consistent with a mechanism that really resets the metabolic homeostasis. We also have shown data that highlights improved glycemic control, lowering fasting insulin, glucose, overall better tolerance, plus liver and lipid benefits with reduced steatosis and serum cholesterol. Importantly, the other data that has really been supportive of a unique mechanism here is the inflammation and fibrosis signals moving in the right direction. And then when we add nimacimab to the incretins, we see a greater additive weight loss preclinically. So mechanistically, it's really a distinguished molecule, being a negative allosteric modulator of CB1, and it's designed for this peripheral action, and that's also been helpful from a safety perspective, looking at multiple NHP biodistribution studies that highlight that it's unique in terms of being able to remain in the periphery. Today, we're adding two fresh new data sets. One is dose titration versus monlunabant, and there, the data is supporting nimacimab compares favorably on treatment, and again, shows limited post-treatment rebound across doses. For those that want to really dive into the details on the new data, we've posted four new videos today on the spotlight page with slides and a voiceover by Dr. Chris Twitty, our Chief Scientific Officer. So I'm not going to get into all of the key takeaways in my intro. But the additional data point, so there's the monlunabant data point, and then there's a repeat DIO study, where we're looking at nimacimab alongside tirzepatide, evaluating a combination with suboptimal and optimal doses of tirzepatide. And the headline there is that we've shown we're driving up to 47% vehicle-adjusted weight loss with minimal rebound profile, and that, again, supports this maintenance potential. On the... Just looking ahead, so on the clinical front, the Phase II proof of concept readout is expected late Q3, early Q4. And in parallel, what we've been working hard on is preparing for the Phase IIb, which we're going to refer to as CBeyond-2, and that's to evaluate multi-dose and dose frequency to ultimately set the dose or set the stage for the Phase III dose. We've also, as you know, highlighted this year, we've established a very robust R&D a preclinical program with this human CB1 knock-in model, and we have multiple data points coming out of that effort on a steady basis, so we're going to continue... I'll just mention that we've just recently completed the last patient visit in the 26-week treatment phase. So we're fully enrolled in the 26-week treatment phase, and that's done, and we also fully enrolled in the 26-week extension. So now that'll enable us to get to the 52-week data point for those patients that are participating in the extension study, and Dr. Arora will cover that in more detail. But in terms of data points, we're guiding for the extension readout in Q1 of 2026. So just to quickly orient the listeners on the molecule, nimacimab is engineered for peripheral restriction. It's significantly less in terms of brain penetration when we compare against small molecules, which really speaks directly to the safety concerns associated with historic CB1 approaches. Mechanistically, it's a negative allosteric modulator, so it's retaining the potency even when you have endogenous ligand competition like 2-AG and AEA. And this combination of having a peripheral CB1 engagement with really this allosteric control, I would say again, underpins our safety and tolerability for the TPP or our target product profile. And we're really able to then preserve efficacy with allowing for a potentially adequate therapeutic window, meaning that we have a very favorable PK/PD profile for dosing because of this unique difference from small molecules. Again, we've covered this in corporate updates, but just to orient the listener here, there's really four mechanistic pillars that we've been highlighting. Peripheral CB1 modulation affects appetite hormones, leptin and GLP-1. It improves glycemic control, so fasting insulin and glucose, enhances lipid metabolism, things like steatosis and cholesterol, and it reduces inflammation and fibrosis. And at the top-line readout, we're looking beyond weight loss. So many of these biomarkers will be evaluated and this would provide really strong mechanistic support for the antibody. Okay, so we've recently created this slide, and really the purpose of this slide is to just highlight that there's plenty of white space if we focus on the issue of tolerability. A few percentage points in terms of improving GI, and this slide is kinda highlighting one GI tolerability data point that's consistent across incretins, looking at nausea. And if we are able to have any improvement there, you can see that it really puts nimacimab in the spotlight in terms of being able to show a different, differentiated mechanism that can improve like improve the GI tolerability concern. So for us, there's kind of three ways of really looking at this. There's a value here from a monotherapy value perspective, looking at tolerability, as an improvement, where we can aim for semaglutide-like efficacy, with a much better day-to-day tolerability. There's also potential here for a combination, and, you know, we've covered this preclinically, but we're looking at this carefully in the clinical setting as well. Because CB1 is a differentiated mechanism to the incretins, we're targeting for a cleaner tolerability profile, and combination really becomes feasible, and that's something that we're gonna be watching for in the clinical readout. Then the other side of the market is this maintenance side. And what you're gonna hear today is better tolerability is what keeps people on therapy long term, and that's really the foundation for long-term use and maintenance of maintenance of weight loss after patients come on incretins or any other GLP-1 initiation or discontinuation. So it's really the biggest barrier, we think, is the drop-off rate because of GI burden. And a cleaner profile really highlights where nimacimab can really capture a big segment of the market. And that that's just a setup here in terms of highlighting the three kind of practical use cases that are emerging. This year, we spent a lot of time speaking to clinicians. We've done a survey of approximately 60 different endocrinologists and PCPs, and it's evident that there's a really distinguished market here for monotherapy, combination, and maintenance, where physicians have highlighted an unmet need around tolerability and chronic use, and what we're highlighting here is that there's an opportunity for a more tolerable regimen that supports the chronic therapy, and this includes the GLP-1 intolerant, or patients that have limited response, or those that are even looking for needing additional weight loss or maintenance after they initiate GLP-1, so our TPP is really built to address those realities, and we feel that our molecule does an excellent job on that. Now, I just wanted to kind of look at some of this overarching DIO evidence that's been built, and this is another visual here that really is emphasizing three important points. One is that when we look at DIO studies, they really inform the translation to human data directionally. So when you look across obesity mechanisms in any rank order, when in terms of different mechanisms or looking at combination in DIO, they've tended to translate directionally to human data. Number two is that CB1 is a very clearly validated biology. If you look at across multiple different CB1 mechanisms, including now with nimacimab, this peripheral antibody, all the different data speaks to robust, DIO weight loss and overall favorable metabolic signals. It's really supporting the mechanistic validity of the class. And the third point is specifically on nimacimab, where we've been able to show a consistent and very versatile molecule in repeat studies and showed now dose-dependent mono efficacy, combination additivity, additive weight loss, as well as the maintenance utility. And that's exactly how our TPP is designed, right? So we're looking at monotherapy, combination, and ultimately maintenance. And when we look at this, you know, from a high-level viewpoint of different data points, it really speaks to, you know, the robustness of what's been happening in the preclinical side. So today, we're obviously not gonna go through every single thing, but I've highlighted a few areas that we're covering. And the two points that we made in the press release today is favorable comparison to monlunabant, and then we also highlighted a combination with tirzepatide, evaluating rebound and maintenance after withdrawal of drug. And on that note, I'm gonna turn it over to Dr. Arora now to walk us through some of those highlights. Thank you, Punit. Now, you've all heard from Punit the important potential role an antibody to CB1, such as nimacimab, can play in the treatment of people with obesity and metabolic disorders. And this is true as a monotherapy, it's true as a combination, and equally important, it's true in maintenance of weight loss after initial weight loss has taken place, now that we know that there are effective agents out there that can cause the weight loss. I'm gonna take you through some really exciting data that underlines the strong science and the biological rationale for the potential of nimacimab. And we're going to look at these models that we've created. These are DIO mice. They're humanized mice, in that there's a human CB1 receptor that's been knocked into these, so we can use the antibody, nimacimab, itself. And in this first set of experiments that you're seeing in front of you now, we're looking at monotherapy. So we have a vehicle and then three different doses of nimacimab. So we're going to see a dose response for monotherapy with nimacimab. And equally important, we've added into this monlunabant. Now, you're all familiar with monlunabant. It's a small molecule CB1 antagonist being developed elsewhere, and it has clinical data, so it's part of this new generation of CB1 antagonists. These mice were all treated for twenty-four days, which, in mouse terms, is a pretty significant period to be able to see the effects of these agents in terms of weight loss, and then followed up for another twenty-four days to make a total of forty-eight days. In this second phase, there was no intervention, so we can see what happens when treatment is ended. These panels all show you absolute weight on the left side, and then vehicle or placebo-adjusted weight loss on the right side. I'm gonna focus on the right side, and you can see the flat line for the control. You can see a dose response in the three nimacimab doses, nimacimab seventy-five, two hundred and forty, and seven hundred and fifty, with a very significant weight loss all the way up to 24.2% in the twenty-four days, with the highest dose of nimacimab. In the green, you can also see monlunabant, and you can see that monlunabant, compared to nimacimab, tends to flatten out in terms of its response relatively early, and the final response of 13.9%, was just above what we saw with the two initial doses of nimacimab. So we saw some very favorable data in terms of total weight loss in 24 days with the nimacimab doses as compared to what we are seeing here with monlunabant. Now, let's look further and understand what happened when these cohorts of mice were withdrawn from therapy. So we can see up there in the black line, the control mice, and you can see that they end up gaining some weight back again. There was some initial weight loss in these mice. Monlunabant, we had already seen, had some flattening out, and then once the drug is withdrawn, there is a relatively quick uptake in terms of weight regain. Now, it's interesting, we've learned this from patients over the years, that weight regain after you've lost weight, and this is especially true when we put people on diets or suppress what they eat, ends up at a point not where you necessarily began your weight loss journey, but where you would have been if you had never undertaken that journey, and this becomes important as we go on, and I'll point it out again. But here you can see that monlunabant is back to approximately where the control is. On the other hand, with all three nimacimab doses, you'll see that nimacimab tends to have a more prolonged mitigation of this weight regain and a relatively flat period where there is no weight regain initially, till about day 33 or day 36, depending on the dose, and then some weight gain after that, as you see with any weight loss, to the extent of about 4%. So it appeared here that nimacimab drives a more durable weight loss and a relatively minimal rebound as compared to monlunabant treatment in this model, which bodes very well for maintenance of weight loss after treatment. So let's look further and, another experiment that is designed similarly in two phases, and this time we're using a vehicle and the middle dose of nimacimab that we saw, but we are comparing it to cohorts where two different doses of tirzepatide are now being administered. So there is a low dose, and there is a maximal dose of tirzepatide. And then, really exciting, we have a combination dose where we're giving the lower dose of tirzepatide in combination with nimacimab. After the twenty-four days of treatment, the nimacimab will be withdrawn, but the lower dose of tirzepatide will actually have a comparison between some mice that will be withdrawn from treatment and others that will then have maintenance therapy with nimacimab. Similarly, the high dose of tirzepatide, these mice will also move to nimacimab treatment to see how we can maintain the weight loss, and, the same will be true of the combination. So let's take a look at what we found here. So once again, here, the black line on top represents the adjusted control, and you can see below that the nimacimab, which looks similar to what we had seen before, about a 21% weight loss over twenty-four days. And then the two doses of tirzepatide, as you would, as you would expect, they have about a 30% and a 39% weight loss at the end of the twenty-four days. But the really exciting thing here is, so when we combine the lower dose of tirzepatide with nimacimab, then at the end of 24 days, that's where we see the maximal weight loss, more than what we are seeing with the maximal dose of tirzepatide, up to about 44%. And it's always equally interesting to me what the trajectory of the weight loss is, and the suggestion here is that this weight loss isn't done, especially in the combination treatment. And in this arm, it appears that if we continue to treat, there may be more weight loss yet. So going forward and looking at what happened after that, the control arm, as you would expect, just continues to gain weight, just in general through the study. With tirzepatide, now we're looking at the lower dose of tirzepatide, and we're looking at the mice that had withdrawal of treatment. We can see a very rapid weight gain, and as I had mentioned to you before, the weight tends to go back to where you would have been if you had never taken any of this treatment before. But in comparison to that, the nimacimab rebound looks very different. For one thing, up to about day 36, we had seen this previously, the weight tends to remain flat, and the trajectory of the rebound is slower after that as well, and we'll go on to see more with that. But let's look at what happened to the other cohorts here. So we can now see what happens, when the low dose of tirzepatide, instead of being withdrawn, was continued with nimacimab instead as a maintenance dose, and you can see here a significant mitigation in the weight regain that took place. The same is true in the circles with the red outline for the high dose of tirzepatide, followed by nimacimab. And finally, right at the bottom, you can see, and we've already seen that the combination does really well in terms of maximal weight loss. But if you follow that up with nimacimab instead of withdrawing treatment, there is a significant mitigation of that weight rebound, and weight can be maintained. You can see the flattening coming out of that with nimacimab. So switching to nimacimab treatment does limit rebound and shows significant... And nimacimab here shows significant potential as a maintenance therapy. So finally, this is a more complex experiment. We're adding more arms. You can see that we're now dividing up the higher dose again into maintenance with either vehicle or with nimacimab. And but what I'm going to focus right now with you today is on this particular arm in the light blue color, which is listed second, where we have a pair-fed set of mice to nimacimab. And what we are trying to show here, we're trying to answer the question of what the role of suppression of appetite with nimacimab is in terms of this weight loss. And this question comes up all the time because we talk about a peripheral action, but the mice who take nimacimab, based on this peripheral action, still have a decrease in their food intake. The question is: Is all the weight loss that you see with nimacimab only because of this decrease in food intake? We can answer that by feeding these pair-fed mice in the same way that the nimacimab-treated mice eat... Let's take a look here at what happened, and you can see pair-fed mice above and nimacimab right below that in the lighter blue and the darker blue. You can see that when you pair-feed mice with nimacimab, initially the trajectory seems to be similar, but very quickly with pair-fed mice, it flattens out, and there is even some regain of weight back again. Whereas in the nimacimab cohort, weight gain continues all through the time that we see treatment here for twenty-four days. It's clear that nimacimab enhances weight loss all along here, not just because of the decrease in appetite, but where the decrease in intake is seen even with these pair-fed mice, but because of other mechanisms as well. And this is what happens when we discontinue. The pair-fed mice just continue along and end up right where the control arm is, whereas at day thirty-five, when the nimacimab treated mice are seen, there is a flat trajectory, and in fact, we're not even seeing the beginning of weight regain here. So this highlights that nimacimab-driven weight loss is not a result of caloric deficit alone. So having gone through some of that really exciting new DIO data with you, I want to talk for a couple of minutes about what we're doing right now. You're all aware that we are in the midst of the Phase II CBeyond trial in patients with overweight and obesity. This trial has a twenty-six-week treatment period, and all patients have now completed the twenty-six weeks of treatment, and we're looking forward relatively soon to having top-line data from this trial. Just to revise the design of this trial with you, we have four arms in this trial. The randomization is two is to two is to one is to one, which means that the major part of this trial is nimacimab versus placebo, and the second smaller part of the trial is where all patients get Wegovy, and we're looking at a combination of Wegovy with nimacimab versus Wegovy with placebo. So we will also have data from this study on what happens when you combine treatments with Wegovy, in this case, which is semaglutide, with nimacimab. All of these cohorts are being treated for 26 weeks in the study, and as per the original design of the study, they will then get a 13-week follow-up from the last dose of nimacimab to week 39. Now, we have introduced another arm in this study, which is an extension to this study, to get further data out of this. Now, we did include the extension to the study somewhat belatedly, and by the time the study was set up and all the sites were activated for the extension, we had about 57 patients out of the original study that were eligible to go into the extension. We have now completed enrollment for this extension, and 43 out of the 57 patients have enrolled, 19 in the combination arm and 24 in the monotherapy arms. In order to maximize the number of patients who would be eligible, we allowed patients who were in the combination arm to roll over to the extension up to four weeks after the last dose of their treatment, and they would then get 26 weeks of treatment further. Since they're already on an active drug, we can keep the combination patients on blinded treatment. So these patients will continue either on semaglutide plus placebo or semaglutide plus nimacimab, and that's the data we'll be able to present to you 26 weeks from now, approximately sometime next year. The monotherapy arm, on the other hand,II has a placebo arm, as you all know. We are going to give all the monotherapy patients that go into the extension study open-label nimacimab to give everyone the opportunity to get active drug, and in the same way as the combination arm, they will get an additional 26 weeks of treatment, so we will have up to a 52-week data readout over here. Now, the monotherapy patients who started later in this study were allowed to roll over into the extension if they were still enrolled in the study and had completed 26 weeks of treatment, which means they could be as long as 13 weeks outside of their treatment and still be eligible for extension. Okay, I'm gonna hand it back to Punit to talk about what we should expect from this Phase II CBeyond trial. Thank you, Dr. Arora. Okay, so let's shift to this, top-line expectation side. So key point here is that the success span that we're looking for is approximately 5%-8% placebo-adjusted weight loss at 26 weeks. We've, you know, also indicated that if we're looking at 8% or placebo-adjusted, that's the upside scenario in terms of representing really the high end of the proof of concept study outcome. So the things we're watching for here is slope. Everything ultimately ties back to the TPP in terms of the efficacy signal that we're looking at. One of the key things that is an important consideration is the GI tolerability side as well. We wanna obviously you know highlight a very durable weight loss with a slope that's continuing to come down. It sets us up well for the 52-week view, and then in ensuring that we continue to see a really strong safety and tolerability side. When we look at combination, the expectation here is to have an additive weight loss to GLP-1. GLP-1s have shown about 9%- 11% at approximately the same time point. So we want to see anything additive on that. But importantly, again, a path to better tolerability. As we've highlighted before, the, you know, closely watching nausea, vomiting, diarrhea, or discontinuations related to any of those issues. So ultimately, having better adherence and better combination usability with better or a more favorable tolerability profile in combination is a huge win for nimacimab. So the idea here is to support a path to double-digit weight loss. This is unprecedented territory, so we are gonna be the first readout for showing in human CB1 and GLP-1 data. So we don't have a you know a true comparator, but the idea is to have additive weight loss with a better tolerability profile. The next kinda thing is obviously the issue of GI tolerability. We're looking at that closely in mono and combo. As I said, looking at all three common tolerability concerns, and the expectation there is a lower GI burden at the end of the day with our mechanism. We have really good evidence of this from Phase 1 and the Phase 1b, so we wanna be able to replicate that in a larger and longer trial. The idea you know is not only to have a best-in-class but potentially a best-in-field tolerability profile. Next, I'll just move to safety. So the, at the twenty-six-week time point, clearly, the biggest thing that is being watched in this mechanism is neuropsychiatric concerns. We have highlighted time and again our unique peripheral restriction and the fact that we don't see any of the same magnitude of brain exposure as other historical compounds in this class. So the gate for us in this expectation setting is really no neuropsychiatric concerns. We think that that's the cleanest and most best way to have adoption of this particular mechanism, and this is why we, you know, we bet on this from day one is because nimacimab had a very unique profile based on clinical data. So clean safety is really an important gate for us going into phase 2b for the antibody, and then finally, we are looking at body composition and biomarkers, so we'll look forward to highlighting that. The body composition trend that we're expecting is more of a preferential fat loss, and on a metabolic side, we're looking at a range of different metabolic biomarkers that really support the peripheral CB1 biology. I wanna just focus in on tolerability, so there's really kind of three important strategic looks here or things that we think are important for unlocking kind of that view on tolerability. One is that we're looking to see a real strong monotherapy differentiation here with a semaglutide-like profile in efficacy, with materially better tolerability, and that makes it a really compelling monotherapy, so we don't need to beat GLP-1 magnitude to win commercially. We just need to be able to really be able to show that differentiation, where you can rescue those patients and keep them on drug longer to have better sustainable weight loss. Number two is the combination potential, and that really makes for a more tolerable GLP-1 combination, and we feel with that, based on this preclinical evidence, that really can target higher weight loss and potentially better body composition without compounding any of the GI burden. So this is something that we think that the prior combinations with non-incretins really have struggled to achieve, and this is a differentiation in terms of the nimacimab mechanism, being able to really have this broader metabolic reset. And third is the persistence and maintenance component. We believe that better tolerability at the end of the day is really the underpinning for maintenance role. And that's why, you know, that's one of our top-line priorities. It's looking at safety, including neuropsychiatric concerns, the GI tolerability, and these other things that we've been talking about, including the trajectory and the combination side. So that's essentially kind of the three important, you know, points we wanna make in terms of a case for why we expect to have better tolerability and why that matters. Obviously, that's something that we're seeing how that translates directly into the top line readout priorities on the right side of the screen in terms of safety. Watching for GI, looking at some of the mechanistic quality side, and then, as I mentioned before, the efficacy signal and the trajectory. With that, we'll open it up now for a discussion with our panelists. So I'm gonna first ask kind of the burning question to Doctors Ken Cusi and Wharton. So the first question we wanted to ask was: for a first-in-class peripheral CB1 monoclonal antibody, like nimacimab, what's clinically meaningful weight loss range at 26 weeks, and how much does that slope matter? Great, so who wants to take that first? Kevin, did you wanna take it, or did you- Start, and then you can. Okay, yeah, go ahead with it. Thanks, Sean. Yeah. So, I think if we're looking at the 26-week mark, it's a little challenging to say exactly how whether the amount of weight loss at that point or even the slope is indicative of what's gonna happen at the 52-week mark. What we've been seeing recently is that it doesn't exactly tell us what happens at the end of the year. So it's been a little bit disappointing that we weren't always clear that this that getting to a 8% or 10% or even further was going to dictate a greater amount of weight change at the actual 52-week mark range. So I would say that you've gotta be in the ballpark. You've gotta be there, you've gotta be in the ballpark between that placebo-adjusted 5%-8% or just overall weight change about 8%-10% range, with a trajectory that the slope looks like it's continuing to come down. Whether that flattens out after those 26 weeks and starts to flatten out at 40, 46 weeks, 48 weeks, or keeps on going, is to be seen at the 52-week mark. But so I don't think that you can count your chickens exactly at that stage, 26-week, but you've gotta be a player. You've gotta be in within that ballpark, and it looks like nimacimab will be in that ballpark. I agree 100% as far as, being in the ballpark and the trajectory. The one thing that I'm very much focused on, I think, kind of more the population is really starting to take into focus, is that lean muscle mass preservation. And mechanistically, this is exciting, that nimacimab is gonna help preserve this lean muscle mass because the quality of, the... We're gonna start looking more and more about the quality of weight loss and not just the, the numbers. And so again, the nimacimab, with the, with the mechanism of action and the preclinical data, leads me to be pretty excited as far as what we're gonna see with those numbers. Great. You know, if we kind of drill into that further, so if we're starting to see in a higher band of those ranges that Dr. Wharton pointed out, you know, do you think that that's competitive to semaglutide? Like, what would really make it better in your opinion, if you're comparing it against current standard of care? From a lean muscle mass preservation? Yeah, like lean muscle mass, I think you highlighted. Is there any other things that you're kind of looking at? And I've mentioned kind of tolerability ad nauseam today in the opening remarks, but just wanted to kind of get your perspective. I mean, honestly, yeah, you've highlighted all of the highlights. You know, the butterfly effect from GI tolerability, it's not just maintaining on medicine, but as well as, as far as when you have that GI tolerability, you're able to allow the patients to really focus on the quality of calories intake, as opposed to just the quantity. You know, when you're not having good GI tolerability, they're gonna kind of reach to anything that's gonna get some calorie intake, and a lot of time, that what they're reaching for is not the quality that you're wanting on, so that you're wanting them to focus on. And so, again, GI tolerability is gonna allow you to really allow them to focus on protein intake and really the quality that you want. And so, again, the butterfly effect from, you know, just simply the statement of GI tolerability, that has a lot of positive butterfly effect that goes with that in a structured weight loss program. Yeah, and I think I would echo the fact that the competitive aspect, yes, is there a competitive aspect to semaglutide right now? And I would say that maybe there's not necessarily a need to be a competitive aspect against sema. The thing that we're really seeing is that even with medications that are having higher weight loss than semaglutide in that STEP 1 trial, it was a big deal trial, getting to 15%, but there's some medications that are gonna be at 20%, but they're not as good a molecule. If you're having greater side effect profile, if you're seeing a bunch of lean mass loss, if you're seeing an inability to tolerate it with the right type of dosing, the right way, you have to take it with certain medica- you can't take it with certain medications. There's a whole bunch of other things that sema seem to lock onto to have an okay tolerability, a pretty good weight change, and that is landing it in a decent spot. Competition against a molecule like that has to have all of those things, has to have the tolerability profile, has to have the weight change profile, and you may not just be competing against the weight change. You have to compete against just about everything to try to have that competition. But I don't even know if it'll be sema by the time this is out, whether you'll be competing against. It'll be amylin, it'll be other molecules. Right. Okay, so let's talk about the other burning question, and this is maybe directed towards you, Dr. Wharton, or anyone on the panel. But the you know, I'm just saying, from your experience on the small molecule side, that you might have a unique lens on this. Is there any amount of neuropsychiatric side effects that would be acceptable from the medical community for the CB1 class of drugs? Right, and the answer to that is probably no, so going back in history to try to understand where all this came from, so as a cannabinoid antagonist, you're antagonizing the endocannabinoid system. The endocannabinoid system is there in our body to help us to get hungry. We get the munchies whenever you smoke up. That's cannabinoids, right, and we have our own cannabinoid system that tells us it's time to actually eat, so you block it, and then you start to block hunger. That's the way this has worked, but also, at the same time, we saw a lot of great peripheral things happening, not just blocking the hunger, but we saw that a lot of fat loss was happening, a bunch of other things. But the older molecules got into the brain, blocked the cannabinoid system, and that seemingly should be okay, or maybe it's not okay. We just didn't know what was gonna happen, and what happened was not good, right? There was a lot of psychiatric components to that when it got into the brain. So the idea here is- Can you have a molecule that doesn't get into the brain, which is what the monlunabant is trying to do, not have that, that component of getting into the brain, but still maybe does, and maybe there will be some side effects, 'cause it's the same type of drug. It's called a bant just like the rimonabants were. So they're the same category. Whereas here, with nimacimab, we have an antibody that's big and doesn't get past the blood-brain barrier, stays in the peripheral system, activates leptin, GLP-1, and all the other things that do get into the brain. So leptin goes into the brain, the GLP-1 goes into the brain. All those things get into the brain to decrease the actual hunger, but the antibody doesn't go into the brain to cause those endocannabinoid problems. I think this is a unique molecule from that standpoint, and the hope is that because it doesn't penetrate, it doesn't cause the cannabinoid problem at that receptor. You really have to go back to the big ideas of why this is here, why we're talking about this. Otherwise, we don't have much to talk about. You really gotta go back to the history, and the history is that no psychiatric side effects will be really tolerated. I agree 100%. Yeah, thank you. Thank you for that. That's a really good explanation. Just to switch into the combination view, so we kind of, we made this remark in terms of expectation, setting around additive weight loss, is what we're expecting in the combo. What would you say, from a clinical perspective, qualifies as meaningful additive weight loss in the GLP-1 combo at top line, at the twenty-six view, twenty-six-week view? I mean, pretty much exactly what we said previously, as long as you're in the ballpark and that trajectory as long as it's an increase and that trajectory is continuing on that downward slope at twenty-six weeks, I think we can all be very encouraged. Yeah, so we did a study looking at the addition of naltrexone/bupropion to the GLP-1s, and this was in people with type 2 diabetes. We got an extra 4% weight change. Now, people do add this as a combination medication to the GLP-1. The big deal about the naltrexone/bupropion is it's not a GLP-1. The big deal about CB1 antagonists is they're not GLP-1s. That's a very important line 'cause it means you can combine them with the GLP-1s. It's not just about combining it to the highest dose of a GLP-1 and trying to push the weight down further, like 4% or 5%, but can you combine it with a low dose and get into those teens? Can you get into 17%, 18%, if you're combining it with a low dose of a medic- of, of the GLP-1 that would normally get you maybe about, about 8%? So you're seeing that you're adding another doubling of it. So we don't just want an extra 4 or 5 at the top dose, we want almost a doubling of, of a low dose, getting to the ranges where we're at, that 17%-20%. 20% is where we would like to see these newer medications land. So we've, we've, we've got a actual goal here. Right. Well, this is a lot. So, okay, there, there's one, another kind of important, if we dive a little bit deeper into the mechanism difference. But before we bring that back to you guys, actually, I'll let you guys stew on this maybe, and then we'll. I wanted to switch to Dr. Goncalves, and then we can come back to the clinical side. For Doctors Ken Cusi and Wharton, you know, I think one of the things that we were curious about is how CB1 and GLP-1 can really be positioned to work where other non-incretin add-ons, you know, have maybe not been so successful. Like tolerability has been one area, but more, you know, talking about from the differentiation as the orthogonal mechanism. So that's something that, you know, we wanna come back to you, but maybe to set up the clinical discussion, we can talk to Dr. Goncalves for a moment here on how investors might kind of translate all of this data that we're sharing today and have shared this year regarding the mono combo and maintenance signals. We're starting to see observed in the DIO models, and how that's kind of translatable. I think the second part of that question, Dr. Goncalves, is really maybe you can explain kind of the difference in the rebound curves between nimacimab, tirzepatide, and monlunabant, and we can flash up any slides you want. Yeah, thanks so much. Yeah, the data is very exciting, looks really promising. You know, a lot of people usually have concerns about using the mouse models to predict and or mimic human physiology, but in this setting, you know, it's been very valuable over the years to use the DIO model to mimic what we eventually will find in human subjects. You know, it's not perfect, but it definitely can give us a flavor and a taste for what we will expect, and that has certainly been the case for the incretins as a field. Many of the things we are seeing in human patients were first observed in the DIO models. The major clinical problems I see today in this space is really outside of access is that the majority of people, you know, two-thirds or greater, are off incretins at one year, and that about two-thirds of the weight come back once you're off the incretins. So those two specific issues are completely addressed by the data you presented today. It appears that the addition of this combination, you know, is not predicted to exacerbate any AEs, given the mechanism of action, which is important, and we also need effective drugs for that rebound state. As you can see from your data, the combination does look like it's giving you increased efficacy in terms of the weight loss, and you know, the rebound data is quite impressive. You can go back to those curves where you see just that rapid orange line from tirzepatide go all the way back up even above the starting weight, which is really dramatic. And that degree of rebound is cut pretty drastically, you know, 50% or more by switching to nimacimab, which is, you know, predicted to not have the GI toxicity. The other point about these rebound, you know, so why is the rebound being mitigated? You know, I see two major themes here. One, I guess the more obvious one is, you know, maybe the antibody is just still bound there. You know, it's cleared from the circulation, but it's still bound in the tissues and acting. That's one possibility. And the second, I think, more intriguing possibility is that there's been some sort of metabolic rewiring that's occurred. And, you know, some options are maybe there's improved leptin sensitivity, which has also been seen in this space in prior studies. The CB1 receptor could be modulated itself with persistent negative signaling. Maybe it's just down-regulated, you know, and all these things lead to this improved state where, you know, the drug is no longer needed to see this beneficial effect. Yeah. Thanks. That's really helpful. Sorry, we had a bit of technical snag on the slide. So you were saying on the tirzepatide combo, the curves of the rebound were kind of important to highlight. So looking at this, this- Yes. what you're referring to here. Yes, exactly. Look at that. I mean- Yeah 30% comes back over and above the zero point. You know, it's like they somehow remember what the placebo group is doing, and then go all the way back up, which is, you know, a bit odd to me, but that has been shown previously. It's not unique to this study. And then the nimacimab, you see, you know, if anything, only 25 days later do they come back to their initial baseline, but there is none of this over and above the weight regain that you see with the tirzepatide. I also just want to highlight, which I forgot to mention, is the pair-fed feeding data. You know, you know, it does highlight that there is something new happening with nimacimab that is not strictly based on food intake, and the most likely effects there are an increase in energy expenditure, and you know, we don't have great medicines that increase energy expenditure, so if this turns out to be a medicine that will increase energy expenditure, that would very nicely complement the incretins. That's a good point. Do you have any thoughts on this, on the dulaglutide kind of difference here? There's, you know, the steep drop initially and the rebound is really interesting, but just the difference here in terms of the persistence and consistency of nimacimab relative to the small molecule. Yeah, certainly seems like, you know, like I mentioned, it maybe the antibody is just, you know, stuck there for longer, and it takes a while to be removed from the receptor in the peripheral tissue, and for whatever reason, dulaglutide gets cleared from that. Or maybe there is a stronger negative signal that's imposed by the antibody that is leading to that metabolic rewiring. Okay. Well, I appreciate that, Dr. Goncalves. I think what we'll do is, within light of the time here, take questions from the audience, and then we can come back to anything else that we didn't cover. Great. Thanks, Punit. So please hold for a brief moment while we pull for analyst questions.