Good morning and welcome to the Corbus Pharmaceuticals Investor Webinar. At this time, all attendees are in a listen-only mode. A live question-and-answer session will follow the formal presentations. As a reminder, this call is being recorded, and a replay will be available on the Corbus website following the conclusion of the event. I will now turn the call over to Yuval Cohen, Chief Executive Officer and Director of Corbus Pharmaceuticals. Please go ahead, Yuval. Thank you, Wilson. Good morning, everyone, and thank you for joining us on this call, this webinar to discuss our results published this morning on our single ascending and multiple ascending dose. Very quickly, the forward-looking statement can be found on this slide, the second slide of our deck, and I'll remind you that we'll be making, and as will some of the panelists, making forward-looking statements. So I'm joined today by two distinguished guests that will help our discussions for the data that we announced this morning. First and foremost, Dr. Sarah Barenbaum. Dr. Barenbaum is Assistant Professor of Clinical Medicine at the Weill Cornell Medical College and an Assistant Attending Physician at the New York-Presbyterian Hospital. Dr. Barenbaum specializes in care of patients with obesity and weight-related medical complications. She sees patients at the Comprehensive Weight Control Center and also with the GI Metabolic and Bariatric Surgery Program, where she serves as the Obesity Medicine Director. Dr. Barenbaum received her BA from Yale University. She received her MD from Drexel University College of Medicine. Dr. Barenbaum completed both her residency and obesity medicine fellowship at the Weill Cornell Medicine New York-Presbyterian Hospital. Our second distinguished panelist is Dr. Daniel Lee. Dr. Lee is a board-certified psychiatrist with over 14 years of experience spanning clinical psychiatry, clinical pharmacology, medical monitoring, regulatory affairs, and CNS drug development. He has extensive background in both clinical and industry setting, including direct patient care, psychiatric, and medical oversight in academic, military, FDA, and pharmaceutical environments. Dr. Lee has supported phase I to IV clinical studies, suicidality assessment, psychiatric drug safety monitoring, and clinical pharmacological studies. He has deep expertise in trial design, medical monitoring, FDA regulatory reviews, and industry-sponsored research, having been a psychiatrist in the U.S. Army and a regulator at FDA. Dr. Lee received an MD from the Uniformed Services University of the Health Sciences, completed his residency in psychiatry at Walter Reed National Military Medical Center, and is board-certified with the American Board of Psychiatry and Neurology. Moderating today's discussion is my colleague, Dr. Dominic Smethurst, our Chief Medical Officer. So what we thought we would do is I'm going to go through the slides very, very quickly. You can find them on our website. You can find a link to them also in the press release. And I really want to spend most of this morning session with Dom and myself, really having a dialogue, a discussion with Dr. Barenbaum and Dr. Lee around the data. So let me go quickly through the slides for those of you who have not seen them yet. And Wilson, if you can just cycle to the next slide, please. Everyone on this call has heard us talk about the role that CB1 plays in metabolism, so we can skip to the next slide. Next slide, a reminder that both monlunabant and CRB-913 are offspring. They share a common ancestor in Ibipinabant, one of the first-generation CB1 inverse agonists, and also a reminder that there were quite a few first-generation CB1 inverse agonists. Next. A big distinguishing feature between our drug, CRB-913, and monlunabant is the degree of exclusion from the brain or peripheral restriction compared, for example, to rimonabant, the classic first-generation CB1 inverse agonist. Our brain-to-plasma ratio is 1/50 than Rimonabant, so we are highly, highly excluded from the brain compared to Rimonabant. And also compared to monlunabant, if we look at levels, and of course, these can only be done in mice, if we look at levels within the brain, we are 1/15 of the brain levels at the same dose compared to monlunabant. So we really do have a heightened best-in-class peripheral restriction. Next slide, please. This is very quickly the schema of the SAD-MAD study. Very, very typical. It's effectively patients or volunteers, in this case, participants climbing a ladder where they receive higher and higher and higher doses, often doses that are much higher than will be given in normal clinical study. And so we have on the left-hand side the SAD with 64 participants. It went all the way up to 600 mg. So just to put that in perspective, that is 60 times more drug than the effective dose of monlunabant. On the right-hand side, we have the MAD or the MAD, in this case, seven days of dosing in clinic, followed by an additional seven days in the clinic for observation, so for a total of 14 days in the clinic. All the blue cohorts are healthy volunteers. They were not pre-selected for BMI. There are two green cohorts, one in SAD, one in MAD, and those were selected specifically for people with obesity, so for high BMI. The primary reason we do a SAD-MAD study is to look at things like safety and PK. The primary reason we have people with obesity in these cohorts is because PK may not necessarily be the same in someone who is suffering from obesity. Their metabolism may not necessarily be the same. Next. Starting with safety, and again, juxtaposing with monlunabant. And here, again, kudos to the Novo team for their publication this past November. It was very informative, and kudos to them for a very heightened degree of transparency. We know a lot about not only the adverse events that were experienced on monlunabant, but the cadence when they showed up and to what extent they showed up. There are two highlights that we want to mention here. The first one is very surprising to us, and that is gastrointestinal adverse events. We have seen so many of them, obviously, with other mechanisms of action, but they tend to not be associated that much with CB1 inverse agonists. monlunabant is an outlier. There were very meaningful levels of GI adverse events. They happened very, very early. They typically happened in the first week. 90% of them were done in the first two weeks, and there are a lot more than we would expect. If we juxtapose that with CRB-913, CRB-913 is much more in line with first-generation CB1 inverse agonists, maybe even more so. It has an unusually benign GI adverse event profile. We had the sum total of a single case of potentially or possibly related mild diarrhea, again, compared to monlunabant with markedly higher events. It also tells us that when we do look at the weight loss in a few slides' time, the weight loss is not being driven by GI adverse events. They are simply effectively absent from this cohort. Next, please. This is a slide we were all waiting for in terms of the data, and that obviously is a neuropsychiatric adverse event, sort of the problem associated with the first-generation CB1 inverse agonist. Surprisingly, also found with monlunabant. Again, very helpful to have provided us with the cadence and the degree of neuropsychiatric adverse events in that Lancet Diabetes paper from September. What we see is very typically they happen early. That's pretty typical of neuropsychiatric adverse events. Most of them are gone by the time you get to 60 days. Again, that was seen with other first-generation CB1 inverse agonists. There is a surprisingly high number of them. In 180 patients that received monlunabant, there were 111 events. That is surprising. That is markedly more than one would expect. There were cases of depression, both in their phase I and their phase II. It was, frustratingly, the most common cause of dropout in the study. If we juxtapose that on the right-hand side with CRB-913, and again, with its very differentiated brain exclusion, it's really a very, very different picture. As Dr. Lee will discuss in a second, C-SSRS, PHQ-9, and GAD-7, the standard questionnaires, the validated questionnaires for suicidality, anxiety, and depression and anxiety, were negative. They were negative for all participants at all cohorts at all time points. There wasn't a single exception to that. No cases of suicidality or depression or even dysphoria. No cases of insomnia, which was really wonderful to see. We had three events of mild anxiety. They were associated with, again, negative GAD-7, PHQ-9, and C-SSRS, and one event of mild irritability, again, associated with negative outcomes on the validated screens or questionnaires. And to sort of give you a tiny bit of a preview, we saw weight loss even in cohorts or circumstances where there were no neuropsychiatric events reported whatsoever. So a very differentiated profile, not only compared to that first generation, but really markedly differentiated compared to monlunabant. Next. This is the slide. When we saw this slide, we were delighted and honestly wonderfully surprised. So a reminder, this is the cohort that dedicated to people with obesity. Their BMI on average was high, BMI of 36. They spent seven days, like all the other MAD cohorts, seven days in the clinic being dosed on a daily basis and another seven days being observed. The half-life of CRB-913 is very similar to the half-life of the other CB1 inverse agonist small molecules. It is long. It is measured in days, and that's very typical. CB1 inverse agonists tend to be very, very stable molecules, and so what we saw, first, as an individual sort of waterfall plot, was reassuringly placebo did not lose weight, but every single participant on CRB-917 lost weight, and sometimes quite a marked amount of weight loss in a period of just two weeks. If you want to convert for percentages to actual weight unit, the back of the envelope, typically these patients are about 100 kg each, so that's the individual participants' weight loss at day 14 compared to where they started, and if you do the placebo adjustment, you end up with just under 3% in 14 days, again, not being driven by GI adverse events, and we can look at it differently in the next slide, Wilson, where what we're seeing is the cohorts themselves on a daily basis. So every day they get tested for everything, whether it's safety, including neuropsych, but also for their weight. And what we can see, which was really very reassuring, was weight loss started early, very early, in fact, and then deepened as we were dosing them for more and more. And then you can see that momentum staying there again as a result, presumably, of the long half-life. And we have the PK to correspond to that, whereas placebo do not. Placebo behaved very nicely. So that, again, was very reassuring. Next slide. While we didn't have a dose response for cohorts that specifically enrolled people with obesity, we do have three cohorts that simply did not discriminate based on BMI. And they do have ever-increasing doses from 25 mg to 75 mg to 150 mg a day, which corresponds to the cohort that had selected for people with obesity. And what we see, albeit, remember, with participants that have a lower BMI and average just 28, what we see is reassuring. We see weight loss in both the 75 mg and the 150 mg, and in fact, it's very similar weight loss. And we see the indications of some sort of effect also starting to come up with the lowest dose, although, again, it's much more subtle and neutralized by the placebo in that case. It does tell us or give us an indication that the 150 may be beyond the linear range. And that's the case with not just CB1 inverse agonists. That's the case with we see that, for example, with incretin analogs as well. It's reassuring for us because if we want to dose lower, that means that we can dose within the linear range. We have an indication for that in the next slide, please, which is a format that all of you are familiar, certainly from the incretin world, which is this cross-trial comparison, and it has all the usual caveats. Nevertheless, it can be wonderfully informative. What we have here is Rimonabant, both at one month and 16 weeks. A reminder, Rimonabant was back in the day a promising drug, but the annual weight loss seen with Rimonabant placebo-adjusted was still only about 6.5%. In today's world, that's less exciting. We have the three doses of monlunabant. What I want to draw your attention to are two things, which I think were lost a little bit in the initial press release from Novo, but really shined through in that Lancet Diabetes paper. monlunabant is a surprisingly potent CB1 inverse agonist. It is markedly more potent than Rimonabant. And in fact, just to contextualize it, you can see where Orforglipron, an oral GLP-1 agonist, would effectively fall on this graph. Monlunabant is within the same ballpark in terms of efficacy. It has the safety issues, of course, but its efficacy is pretty surprising for a CB1 inverse agonist. And then what you can see also with monlunabant is as they dose higher from 10 mg to 20 mg to 50 mg a day, the weight loss is not linear. In other words, they're probably already beyond the linear range because the 50 mg a day is not that much more weight loss than their 10 mg a day. It's a relatively modest addition. Again, very reassuring for us in terms of finding that zone of linearity. Lastly, on the very left-hand side, that tiny little green line, that's CRB-913. And again, early days, of course, and different doses, et cetera, et cetera, but it does seem to fall within the ballpark of monlunabant. It seems to be markedly different than what we would have seen with the first-generation CB1 agonists. Next slide, please. And where does that leave us in terms of next steps? And here we look not only at our data, but also at monlunabant's data, again, very closely. Monlunabant had some very potentially painful lessons that we would very much like to learn from and avoid repeating, but also looking beyond CB1 inverse agonism to what are best practices these days in the world of other mechanisms of action of anti-obesity medication. And so we've launched or initiated CANYON-1. It is a phase I-B study. Its primary purpose is still safety and tolerability. That's very important. It shares many similarities to the study that Novo conducted with monlunabant. It's exactly the same number of patients. It's pretty much a similar dosing duration. Ours are three months. Theirs were four months. We are in U.S.-only sites. The Novo study took place in Canada. Our doses are very similar. We're doing 20 mg, 40 mg, and 60 mg. They did 10 mg, 20 mg, and 50 mg, and we are titrating. We are, I believe, the first-ever CB1 inverse agonist to titrate, and we're titrating because, again, we looked at the monlunabant data, and it's clear that when they started with higher doses, they were less tolerable, but we're also looking at things like the GLP-1s and the success that titration has had in terms of building tolerability for higher and higher doses. The last thing is very important. We will be much more vigilant and strict about screening criteria, much more in line, for example, with what others have done, and we will be excluding patients, for example, or participants that score high on the PHQ-9 at baseline, so with that, just the final slide in conclusion, and then we'll open it up to our panel, and there really are four lessons that we can think of that we learned from this study of 112 participants. The one is that this very high, very unusually high best-in-class peripheral restriction really did seem to be associated with a favorable safety and tolerability. That hypothesis translated nicely from the preclinical to the clinic. We elicited weight loss early, and it deepened. So that's encouraging as well. The weight loss was not driven by GIAEs, and that's very unusual. And we really want to highlight that fact. These participants were not losing weight because they're experiencing nausea or vomiting or diarrhea or constipation. The last thing about it is maybe the most intriguing one, which is the weight loss is associated with restriction to the periphery. And this has been a very lively debate in academia for 20 years now. Which organ system drives the weight loss with CB1 inverse agonism? Is it a centrally acting effect or peripheral effect? Until now, what we've lacked as a community is a CB1 inverse agonist small molecule that just had this high degree of peripheral restriction. And now we have one. And what we see is that the weight loss is there. In fact, it's strikingly there. And so for the first time, we're able to start to really narrow down the hypothesis and point out to the fact that it does seem to be the effect on those peripheral organs of metabolism and their CB1. So with that, maybe first turning over to my colleague, Dr. Smethurst, to Dom and say, Dom, or ask, any color, anything you want to add? You were so hands-on and involved in this study. What would you like to share with our audience that perhaps doesn't come across in these slides? Yeah, thanks, Yuval. I mean, it's a phase I environment. It's very unusual. We've not seen this data shared in such an intimate way. The FDA asked us to do two things. They asked us to look at these three questionnaires every day that the patients were on the unit. So it was a magnifying glass of hypervigilance. They also asked us to bring in an independent psychiatrist to whom these patients could be referred. We'd have a discussion with the PI just as if any of these instruments triggered a warning sign. It's fantastic they didn't. I'd like to turn to Dr. Lee. Specifically, given that you were our specialist psychiatrist on this study, and I know you have a wealth of relevant experience specifically implementing these instruments, clearly top of mind is the neuropsych profile. We're seeing that in this study. Despite daily testing, no suicidality or depression, negative outcomes with those questionnaires. We did have three mild cases of anxiety. One of those cases had mild irritability as well. Could you help contextualize this for our audience, please? Sure. First off, good morning, everyone. I spoke intensively with the investigator and kind of reviewed everything. The big take home is that it's not outside the realm of normal human experience. Based on the way everything went down, it essentially translates to, "I am mildly uncomfortable right now." These were self-contained cases that resolved without need for alteration of dosing, usually resolved within one to three days at the very most, and they did not trigger on any of these scales, the GAD-7, the C-SSRS, or the PHQ-9, which is those scales are intended to quantify how much of a condition is present, be it depression, anxiety, or what have you, and so the fact that we never even got even remotely close to the mild cutoff on any of those scales tells you something. Honestly, if I was in a strange environment where I couldn't leave and had to sit around all day and focus on myself, I'd probably feel a little bit uncomfortable too. And that seems to be all saying. So brilliant. I think that's really helpful. I did a PHQ-9 on myself a few weeks ago, three below normal threshold. But yeah, it turns out jet lag can do that to you. Can you specifically just say, do these things all measure the same thing? Or does C-SSRS, PHQ-9, GAD-7, do they measure something different or overlapping? There's a little bit of overlap between the PHQ-9 and the GAD-7, mostly because anxiety and depression are two very linked conditions. They're usually very, very high degree of comorbidity, and the symptoms sometimes crossover. The C-SSRS is completely different. It measures suicidality specifically. That's really helpful. It sort of did occur to me reviewing the study that we test for suicidality twice. So they have 28 questions. It's almost enough to make one feel down, like you say, the introspection, the closed four walls being stir crazy, et cetera. That's not to diminish the fact that they're looking for a signal, et cetera, and we have placebos, but it's incredibly helpful. If I may, I'd just like to take a quick case study, one patient, a male who started the study. He was in the patients with obesity cohort or healthy volunteers with obesity cohort. He was in the multiple dose, 150 mg fed, and had a BMI of 32.3, weighed 106 kg on the day of dosing. He hit his nadir 3.3 kg down, so 2.9% on day 12. Then so he'd stopped dosing on day seven, dosing every day, building up, building up, building up, and then sort of gradually washing out, hit the nadir then, and then started building back up, was discharged on day fourteen after a week of observation, and then came to the follow-up and had already regained half of his losses. I just want to take you through the GAD-7, the anxiety tests here, which were all zero at baseline. I mean, not even ones and twos, which you'd expect in the normal population, but they were all zero, very well-screened patients. The patient's score was zero every day for the first 14 days, discharged to the community, come back on day three, and a follow-up. I tell you, the investigator spent the weekend trying to debate whether she felt it was restlessness or anxiety. And in the end, she spoke to the patient again on Monday, and she came down on the side of anxiety. And so the patient scored one for anxiety and another one score because they'd had it for more than half a day since discharge. And they also expressed concerns about being easily annoyed or irritable once they'd gone back out into the community. Now, clearly, the drugs have been involved, and it is what it is. But I just thought it would be helpful to show how these things occur. And yeah, I think the patients were really, I don't want to say happy, but they all wanted to know when this drug is going to be available. And I think that's a real testament. It's obviously still a long way away. It's seven days of dosing. We're amazed with sure anything. But yeah, no, that's really helpful. I'll just hand it back to Yuval now. Sure. Thank you, Dom. Maybe turning to Dr. Barenbaum, sort of a high-level question and being slightly provocative, is do we actually need alternative to incretin-based therapeutics, and one thing that occurred to me is we think about, at the moment, we think about these drugs being given as monotherapy. Do you find yourself actually combining drugs? And is there room for combinations with incretin therapies? Absolutely, and hi, everybody. Good morning. I think this is a really great and really important question that is often overlooked. We definitely need so many more mechanisms than just the GLP-1 family. I think the media has really made it seem like these are miracle drugs. Everyone responds. They lose so much of their weight, but we know from the clinical trials, we know from clinical practice that they're not. At least 15% of people don't respond to GLP-1s. They lose less than 5% of their body weight on these drugs. A lot of people don't tolerate them, and obesity is a complex multifactorial disease that is driven by so many different pathways. We need drugs that treat different pathways. I'll say there are more smaller, mostly retrospective studies that are coming out now too, and that were just presented at obesity week recently showing that if people start on one GLP-1 and they don't respond to it and they switch to another, they often also don't respond to it, so creating more and more drugs in the same family don't necessarily lead to more help for people, and at least 40% of American adults have obesity. We just need more options. And absolutely, thinking about monotherapy versus combinations of medications, I think this is also often overlooked and not fully understood. We often have patients on several different medications. This is not new to us. For years and years, we've been combining different drugs because, again, obesity is a multifactorial disease. We need to target different pathways, not just one. And combinations of different drugs target different pathways and can lead to an incredibly synergistic effect. Sometimes it allows us to use lower doses of any given drug, which can help improve efficacy and reduce side effects too if somebody's having tolerability issues. So I do think it is important. And I will say, lastly, we think about people who might need more combination therapy. And right now, we do have a lot of people with higher BMIs. And in that population, if you're starting with a high BMI, 60, 70, 80, for example, say you do achieve optimal response with the GLP-1, you're probably still not going to lose enough weight to see resolution in all of the related conditions. Obesity is associated with over 200 conditions. It is the root of all metabolic disease. And this is why we treat obesity. It's not just to lose weight. It's to treat these diseases that are associated with it and improve cardiovascular mortality. And so I think that's another reason why having combinations of drugs that can be additive and lead to more weight loss can especially help that population. Thank you for that. I think one of the things that I just find so scientifically fascinating is both we in 2023, and for that matter, Novo actually in a year earlier than that, published, of course, in mice because you can do everything in mice, studies in DIO mice where we combine these two orthogonal mechanisms. So in our paper from Obesity 2023, we looked at combining CRB-913 in DIO mice co-administered with either liraglutide, semaglutide, and tirzepatide. And it was scientifically very, very satisfying to see how these two completely orthogonal mechanisms played nicely together and actually increased weight loss and the other outcomes that are easy in mice. It's always been something that I've found really, really intriguing about this approach, especially today where we are no longer like 2006 with very few options. We have these wonderful options now. And maybe it really is shifting to, as you said, the non-responders and/or the combinatory approach. Dr. Barenbaum, if we can stay on this topic in a sense, sort of from the macro to more specifically on our data, it's early days, it goes without saying. Again, these are a relatively small number of patients. They're being observed for just 14 days. But I'm curious what you think of that weight loss, sort of the speed of it, the degree we've seen, and especially your thoughts around what strikes me at least as a really differentiated GI adverse event sort of profile, again, because of the orthogonal mechanism of action. Sure. In terms of the degree of weight loss, I think it's fantastic and really exciting. I think, of course, as you mentioned, it's early days. We need to see longer-term data. We need to see what happens. But when we think about weight loss, as I mentioned before, we think about improvements in health. It's not just numbers on a scale, or we're not aiming for a "normal BMI." And our benchmarks, we start to see improvements with 2%-5% weight loss. But we use these benchmarks to help determine whether or not a patient is responding and we're seeing improvements in health. And so that first benchmark, even at 14 days, it's there, and it's almost at that 5% benchmark. That 5% benchmark is what the FDA uses as criteria for approval for drugs. And it's also driven by our guidelines. Our obesity guidelines recommend only continuing a drug at 5% if it leads to 5% weight loss. And that's at three months. And so technically, if something is at least 5% weight loss at three months, and it's safe and tolerated, we continue it. The fact that you're seeing 4% at 14 days is pretty remarkable. I'm excited to see what comes in the longer-term study. I think in terms of the GI side effects, I thought that was really interesting too. I mean, clinically, so I should mention I'm a full-time attending. I have a full panel of patients. I'm dealing with side effects of medications all the time. Looking at this versus monlunabant, which had so much GI toxicity, and our GLP-1 family, which has so much GI toxicity, it is a common reason why we might have to take people off medications or make changes. I think the overall profile, again, early days, but as you showed in the other studies, a lot of those GI issues happened early and quickly. I'm excited about the tolerability of this drug. Maybe turning to actually both of you. I'll start with Dr. Lee, but I do want to also hear from Dr. Barenbaum. One of the interesting things, and Dom was mentioning this because it just came across in the reports, in that cohort with the people with obesity, was a very positively described by the participants' reduction in food cravings or what's colloquially known as food noise. Would love to hear from, again, Dr. Lee and then Dr. Barenbaum, first of all, how important is that in general in obesity? And I think that I wonder if sometimes we underestimate the importance of that. And secondly, your thoughts around just the usefulness of seeing that with a CB1 inverse agonist. We know we've seen that with the incretin analogs, but just how important is it? How useful is it? How reassuring is it that we're seeing it? So Dr. Lee, maybe starting with you. It's huge. The thing about kind of how our dopaminergic reward system works, it's not the joy of actually having the thing. It's the anticipation. Think about it with a kid, the Christmas present, the birthday present. It's not receiving the gift that is the most pleasurable part. It is the looking forward to it and kind of the build-up to it. And in many ways, it's similar to that with kind of food drive and obesity. The noise of the food and the anticipation of how pleasurable it'll be when you consume it is driving a lot of this kind of increased consumption. So the ability to short-circuit that in some ways will make things so much easier for them to do all the other things that they need to do to lose weight. Dr. Barenbaum? Yeah, I'd be happy to add to that. I think obesity, as we've been talking about, is really complex. And people don't just eat because they're hungry. People eat for a lot of other reasons, whether it's celebration or any other reason, boredom, habit. I will say something that people do talk about a lot is this kind of pervasive thinking about food that is very intrusive. And that is kind of how I define food noise and how patients have defined it for me. This nonstop thinking about food. What am I going to eat in an hour? What am I going to eat for lunch? I know I have something in my fridge that I really want to eat. I'm working from home. I can't stop thinking about it. I'm going to go eat it. And it can be so disruptive to people's lives on an hourly basis even. And I've had so many patients come in over the last couple of years and say, "Starting X medication has changed my life. I am no longer thinking about food all the time. I feel normal," is what people say. This must be what it feels to be normal to not be thinking about food all the time. And it has such an impact on people's lives, and I think their psychological health. But it also allows them to then focus on weight loss too. And removing that mechanism that drives people to eat can really, really help people achieve their weight loss goals. Super helpful. Tara, I wonder if we can open it up to our audience and maybe take some questions from them. Absolutely. Thank you to our speakers. At this time, we'll be conducting a live question-and-answer session. As a reminder to our webcast audience, please use the Q&A text box at the bottom of the webcast player to submit a question. To our covering analysts, please raise your hand to join the queue and kindly hold for a brief moment while we pull for questions. Our first question comes from Brian Abrahams at RBC Capital Markets. Please go ahead, Brian. Hey, guys. Good morning. Congrats on the data. Thanks for hosting this and thanks for taking my questions. Just a few from me, I guess. First, I was wondering if you could maybe talk a little bit more about the persistence of the weight loss out the additional week, whether this is all kind of related to that multi-day half-life or if there's something else in the mechanism that leads to this persistence. Maybe if you can talk about maybe any of the PK or exposure curve relationships to weight loss. I'm also curious on the safety side if you saw any sort of lab changes, any changes to vitals such as changes in body temperature or patterns there. Maybe just lastly, curious maybe if the panelists can talk about their views on how titration with this mechanism could potentially impact the safety profile therapeutic window. Thanks. Thank you, Brian. I'll take the first one. Dom, maybe you'll take the safety, and then we'll open it for titration to the panel. Brian, yes, the half-life is several days, very, very typical. We see the PK curves, so they correspond with still a very meaningful amount of drug even in that second week. We've not presented the PK curves. As you can imagine, they're highly confidential because they offer such an important competitive advantage, so at some stage, we will, but not yet. That's fairly typical. That was also seen, by the way, even back in the day with Rimonabant studies. There's a really nice momentum that's built into this mechanism. Like I said, these are highly, highly stable compounds. They also tend to be hydrophobic, so they like to hide in fat. And so they slowly release out of it. And that's seen both preclinically and clinically, and again, just across the class. Dom, maybe the question around any other AEs? Well, I mean, we had very early on, we had one patient who had a little bit of arthralgia. We had a patient who got COVID with a sort of cluster of symptoms around there, but nothing too bad. There's no manifest or extreme changes in any of the vitals and nothing really. There's great pleasure looking through all the labs. You look to sort of ALT, AST, etc., and there's nothing there. The obese, the patients with obesity, their cohort did yield a couple of patients who on some days had a blood pressure that would be diagnosed as hypertensive, but that was probably just subclinical hypertension in obese patients, and they probably hadn't seen the doctor for a while, but there was nothing worrying at all, and then triglycerides were migrating down more rapidly in the obese patients in the Fed cohort, but it was nowhere near as striking, just reassuring. It's nowhere near as striking as our weight loss was, but it was a very clean study subject to lots and lots of vigilance. Brian, just to add to that before I turn it to the titration question, again, that will be the advantage of having several hundred patients over 90 days of dosing. We'll be able to get much more granularity around those. Maybe on the titration, I'd love to start with Dr. Barenbaum because you have so much experience with titration. But I also want to hear from Dr. Lee's thoughts around titration and just psychiatry. But Dr. Barenbaum, please, if you can start. Sure. Yeah. I think with pretty much all of our medications that we use for obesity, not just the incretin agonist, we start at a low dose and we slowly increase. And what I always one of the main reasons we do that is that we slowly increase the dose. It really can improve tolerability. And also, some people are very sensitive to medications. You might be able to use a lower dose and see weight loss without having to go up. So you might avoid having side effects by just using a lower dose that's effective. And so I think it's a brilliant idea to see what happens with titration. If people aren't losing weight, you can go up. And this is why you do these studies to see the safety and efficacy of it. And I think it's a great approach to try. And I'm excited about the titration aspect. Dr. Lee? I mean, the nice thing that we observed is that the AEs appear to be dose-dependent, but the efficacy, the weight loss does not. So even though we have an incredibly clean profile to begin with, we can mitigate against this even further by not taking the 150 mg further in development. So we're going to already be improving the already fantastic profile by going with this lower dose. And then the titration is definitely something else that we will implement that should hopefully make this more tolerable as well. So we're hitting this from multiple angles. And I've definitely noticed that there are people that are very sensitive to lower doses that for some reason have an easier time tolerating a drug when we get past that initial starting dose. Now, granted, all of my experience here is with antidepressants and antipsychotics, but I can't say if this pertains to this particular mechanism, but it seems like it would be reasonable to assume it would. That is true of obesity medications too. Thank you. Thank you, Brian. Thanks, Brian. Our next question comes from Felicia Berben at Piper Sandler. Please go ahead, Felicia. Hi. Thank you for taking our questions. I was just hoping you could frame today's 2.9% placebo-adjusted weight loss at day 14 in the obesity cohorts against expectations for the upcoming phase I-B doses, particularly given the titration plan and the lower daily doses being selected, and also just a question for Dr. Barenbaum. I was hoping you could just elaborate a bit more on where you see this fitting into your treatment practice if CRB-913 makes it to market in several years, if there are certain patient subgroups where this might be most ideal to use. Thanks. Thank you. If we can go, Tara, can you go to the slide where we show the different drugs and the weight loss across study, across trial comparison? Thank you, so there we go. A couple of thoughts, Felicia. We see from monlunabant, as I've mentioned, if you look at their different doses, it's clear that their higher doses are beyond linearity. In other words, you're really not getting that much more, even though you're dosing five times more than your lowest dose. Our strong suspicion is that the 150 mg is in that zone. We'll find out. But it makes sense. Something similar was seen even with Rimonabant in their earlier studies. The other thing to think about is we have reason to believe that our efficacy is similar to monlunabant. We are, after all, sort of distant relatives and preclinically as well. And so we think that we can really dial it down and still get very similar efficacy. As Dr. Lee mentioned a second ago. It's really wonderfully reassuring that in the cohorts that did not select specifically for people with obesity or high BMI, but had patients or participants with a BMI of average of 28, but some of them were higher than that, when we cut the dose from 150 mg to 75 mg, when we compared the 150 mg to 75 mg, we take no penalty in terms of efficacy whatsoever. Another thing to add, and it goes back a little bit to Brian's question around the PK, we are not yet at steady state after seven days of dosing. We're not nearly at steady state after seven days of dosing. So as we dose longer in those studies, and that's why that 90 days will be so informative, as we dose longer, our expectations are that we will see the levels rise. And that, of course, again, is very encouraging in terms of the potential to elicit efficacy. They're not going to rise as high as 150 mg, not even for our 60 mg dose. But for example, our lowest dose at 20 mg is going to rise meaningfully, and we've got the modeling for that. We know where that should end up. So we're really optimistic about it. Will we ever be able to reach those doses? Maybe. The titration will tell us. And as Dr. Barenbaum mentioned and Dr. Lee mentioned, even with, for example, the incretin analogs, we recently saw data with semaglutide, both injected and oral, at doses that were higher than had previously been tried. And that's the wonderful thing about titration. It allows a process of adaptability. And then there was a question for Dr. Barenbaum about where do you see this in your practice, any subsets? How might you contextualize it in years to come? I think, Felicia, that's a great question and one that is so hard to answer right now because I think it's a little too early to know. I mean, it's only 14 days of data. And this data is different from some of the data we've seen before. The weight loss is really remarkable. It's better tolerated. So it's hard to judge that based on just 14 days. I will say, I'll just kind of reiterate. I think just the need for so many different mechanisms of medications is so important. But I need to see the phase I, II, III trials, have some clinical experience before I can really answer that. But I think it would serve a very important role to have a different mechanism. I think the other really important part is it's not just my decision. I talk about it with my patients. It's a shared decision-making model about what they're comfortable with, what they're interested in. There isn't just a set flow chart of how we think about medications, and we don't have like, "This is first line. This is second line." It's not how our field works because it's so complex and everybody has such different struggles. So if it turns out that this medication ultimately has remarkable outcomes with food noise, then I would think about this as something to help treat food noise for patients. So I think, unfortunately, I can't answer it because it's just too early, but I'm excited to see the next trials and where the data goes that I can better answer that in a couple of years. I think that's such a great point, Dr. Barenbaum. And again, going back to the wonderful world of mice, for what it's worth, and the data we've published recently, again, in obesity, and we have another manuscript in, what we know from mice is there are three things we can do to mice with this mechanism. And the same would apply for that matter with monlunabant. We can show monotherapy, and that, of course, is what the first generation showed as well. We can show additivity, at least with the injectable incretin analogs. We haven't done it yet with the agonists, but it stands to reason that you could do that. And then we have a paper that's been submitted recently where what we do in a mouse in a DIO model is induction maintenance. In other words, we induce the weight loss with semaglutide in the mouse and then take them off semaglutide and then switch them immediately to CRB-913. And unsurprisingly, it maintains that weight loss. But those are mice. And so we'll see what happens in people. We just need more patients, longer exposure. And we, of course, will start with monotherapy. The first thing we want to see, Felicia and everyone, is we first want to see what this looks like on its own to really understand and get a feel for the dynamics of this compound. Wilson. Thank you, Felicia. Our next question comes from Graig Suvannavejh at Mizuho. Please go ahead, Graig. Graig, you're on mute. Oh, go ahead. Thanks so much. Can you hear me okay now? Perfect. Yes. Okay. Thanks so much. Thanks so much for doing this presentation. Congrats on the data. I'm just wondering, we saw some differences in anxiety between obese and non-obese patients. I was wondering if there was an explanation. Is that just random chance? Any thoughts there? A couple of thoughts on that. One is in the 150 mg, and Wilson, I wonder if we can go back to the neuropsychiatric adverse events line. What's interesting is in the 150 mg so-called non-obese cohorts that did not select for just high BMI, maybe a couple more slides up. So in the non-obese 150 mg cohort, there were some, there we go. There were some participants who actually had high BMI and actually lost weight. And we saw we didn't see anything reported from them. So that's sort of one piece of data. I think, though, on the whole, it's just too early. We need to really understand what this looks like in higher numbers. Some of these events happen post-dosing. So that's important to think about. What does that mean? Is that just the background noise? Is that patients perhaps regaining weight or not? The good news about having is that we have very, very few of them. The difficulty is we also have very, very few of them. So we just don't have enough to really call it out. And did Dr. Barenbaum or Dr. Lee want to come in with an opinion? I mean, I would basically echo everything that was just said. At this point, we don't know if this is having any specific impact on neurotransmitters or anything. So it's really hard to tell at this point. We do know that folks with obesity are at increased risk of depression and anxiety at baseline. So they may be more sensitive to some of the effects of the drug, or they may just have a higher rated baseline. And it's impossible to tell at this point. This would just be purely speculative on my part because I wasn't a part of the study, of course, and I'm not a psychiatrist. But in clinical practice, I see a lot of patients who are struggling with anxiety and depression who have been trying to lose weight their entire life. And here in this study, you've given people a drug. They're losing weight on it, and they know this drug is about to end. They're about to go back into their regular life. And I would imagine that that alone could cause some anxiety in people. Yeah. Dr. Barenbaum, that's really interesting. Again, the case study that Dom was referring to, for example, earlier on, the events occurred as the participants started to regain weight. Again, speculating, but that can be. I can imagine that emotionally can be a difficult thing. Then I'm thinking. Yeah, Greg, go ahead. If I could just ask. Yeah, if I could ask a follow-up maybe for Dr. Barenbaum. We're seeing across the industry so many different new products, new mechanisms. I hear you on looking for additional mechanisms that go beyond perhaps GLP-1-based mechanisms, but if you look into the future, if you look into your crystal ball, is your current view that GLP-1s will be the go-to induction way of getting patients to start losing weight, and then perhaps other mechanisms coming in as a more maintenance type of treatment, or just overall thoughts on where novel mechanisms like a CB1 will fit? I know it's early days, you mentioned, but is it still going to be GLP-1-based to start off and then maybe looking to switch or add something later on? It's a great question. And our guidelines are old, and there are some new guidelines coming out this year and next year where we might see that there is a recommendation of first line, second line. But I will say one of the biggest barriers we currently face is access. Even if it's recommended to start first line with a GLP-1, so many patients can't afford them. A lot of insurance companies don't cover them or don't cover them well enough. And out of pocket, as we all know, these are very expensive drugs, and they're lifelong drugs. And so even if they were to become recommended as first line in the incretin family as an induction medication, I don't know how many people would actually have access to them. Hopefully, that will change. This is dynamic. It's changing all the time. We'll see. But based on what I know right now, and there's always going to be a need for different mechanisms too. So I do think it's exciting thinking about perhaps having some medications as induction and then other medications going on to help with maintenance. We are seeing more trials like that going on right now. So I don't really, again, it's a hard question to answer because I don't have a crystal ball, but I would say that even if it does become the case, who's going to have access to them? Thank you for that. And just it's something I'm immensely passionate about. A reminder to everyone, this is a small molecule. It's synthetic, like all the CB1 inverse agonists. Rimonabant, at its height, I think, had 500,000 prescriptions. They were making literally metric tons of it. And it's doable. This is not the same as a peptide or other mechanisms. We have actually run out of time, believe it or not. I'm delighted. This went much faster than I thought. So I just want to thank everybody. A reminder, CANYON-1 has been initiated. We should complete CANYON-1 by the middle of next year, summer of next year. And then looking forward to releasing that data. Again, that should be a really informative data set, both in terms of patient numbers and exposure and time. So I just want to thank our panelists for joining us this morning. I want to thank Dom and his team for the incredibly hard work doing all this and LifeSci Advisors organizing it and just thank our audience. I believe there are over 100 people listening in and more now, I think so thank you, everyone, for taking the time in a very busy time of year and we really look forward to talking about this further and for CANYON-1 to be down. Thank you, everyone.