Good morning, and welcome to the Corbus Pharmaceuticals conference call to discuss the phase I-B top-line results for CRB-913 in obesity. At this time, all attendees are in a listen-only mode, and a question and answer session will follow the formal presentation. As a reminder, this call is being recorded, and a replay will be made available on the Corbus website following the conclusion of the event. I'd now like to turn the call over to Yuval Cohen, Chief Executive Officer at Corbus Pharmaceuticals. Please go ahead, Yuval. Good morning, Tara. Good morning to those of you who are listening in this morning. We appreciate you being here. I'd like to welcome Dr. Harold Bays. Professor Bays is board certified in endocrinology and internal medicine. He's a member of numerous scientific and medical associations and fellowships. He's also the Medical Director of the Louisville Metabolic and Atherosclerosis Research Center, known as the Monroe Biomedical Research, and a clinical associate professor at the University of Louisville School of Medicine. He has served as an investigator in over 700 phase I all the way to phase IV clinical trials. He is the Chief Science Officer of the Obesity Medicine Association and the Editor-in-Chief of Obesity Pillars®, the Journal of the Obesity Medicine Association. He has written and/or served as contributing author for approximately 400 peer-reviewed scientific manuscripts and book chapters, hundreds of abstracts in major scientific meetings. He is also the recipient of multiple scientific awards. Dr. Bays, thank you for being here. Thank you for being part of our study. We really appreciate that. With that, let's look at some data together. I think the overall arching question around this project from its inception was, can we design a safe and tolerable CB1 inverse agonist with competitive weight loss to incretin therapies? Obviously, there's a lot built in there. Fundamentally, the question was a question of essentially engineering. This is not a novel target. Those of you who have heard us talk about this over the last three years or so, or are familiar with the literature, will recognize that this GPCR, the cannabinoid type 1 receptor, has been extensively characterized for the last nearly 30 years. We know an enormous amount about where it's found, what it does, and its role in metabolism. The question has always been, rather, can we engineer out the issues that were associated with that first generation of CB1 inverse agonists? 20 years ago, and Dr. Bays and I will touch upon this a bit later, 20 years ago, this was a very high-profile mechanism of action for obesity and associated morbidities. Multiple big pharma were focused on this mechanism, but the focus was to target the CB1 inverse agonism, the action of it, in the brain. These were highly brain-penetrant CB1 inverse agonists. With the rise and subsequent fall of that class, a new effort came about, and the idea was to try and exclude the action from the brain and rather focus it on those peripheral organs, where CB1 is involved in metabolism. What is unique about our compound, CRB-913, is that it is an exceptionally peripherally restricted CB1 inverse agonist. Just to put that a little bit in proportion, we are at about 2% of the brain levels, or the brain penetration of, for example, rimonabant, a member of that older generation of CB1. Or compared to monlunabant, a recently discontinued CB1 inverse agonist from Novo Nordisk, we are 15 times less brain penetrant than that drug. What has been lacking to date in this field was a tool, was a compound that could truly be thought of as being peripherally restricted. A summary of what you are about to see here today. CANYON-1 is our phase I-B study that explored the efficacy and safety, or I should say safety and efficacy, of CRB-913. It enrolled 254 patients across 15 sites in the U.S. The trial represented a well-balanced representation of the population of obese patients or patients with obesity in the United States, with an average BMI of 37, and of whom 71% were female. The efficacy that was achieved for our top dose, which was 60 milligrams of daily CRB-913, was an average of 5% at two weeks with no sign of plateauing. All participants who had completed treatment at that top dose lost weight. Of course, equally important, the emerging safety and tolerability profile appears to be favorable, with a favorable GI tolerability profile versus published data, especially on oral GLP-1s. Most importantly, psychiatric AEs that are broadly in line with the GLP class and markedly different than the older generation, or for that matter, Mounjaro, of CB1 inverse agonist. This is a very simple schema of study design. It is a perfectly ordinary initial proof-of-concept dose range finding study in obesity with three doses as well as a placebo, and using a titration window of two weeks, which is fairly standard for these earlier-stage studies. These are baseline demographics, and as you can imagine, and as you have seen in so many other U.S.-based studies, the average patient that the study ended up with was female, typically middle-aged, and weighing just over 100 kilos with a BMI of about 37. We will start with the efficacy, because at the core of this question is, does it actually still work? Can you exclude the CB1 inverse agonist from the brain without compromising its efficacy? The first signs of that were with Mounjaro, but we are delighted that a much more extreme or much more pronounced exclusion from the brain yielded the same type of efficacy or in line with what was seen with Mounjaro. First thing I will point out to you is a very well-behaved placebo cohort. Then we have what appears to be a very satisfactory dose response with nice separation between the three doses explored. All three doses were statistically significant compared to placebo, as you can see. We have a nice separation as the titration comes into effect between the doses. A reminder that very similarly to what you see with the GLP-1 titration scheme, initially, all the patients are on the lower dose, and then as time passes by, more and more patients get to experience a higher dose of the drug. Importantly, in a 12-week period, there is no sign of plateauing. That, of course, is very satisfactory for us to see. The mean weight loss using an efficacy estimate that was seen in our top dose was 5%. Another very common way of looking at this would be a threshold analysis. In other words, how many patients lost X amount of weight at 12 weeks? A reminder, this is a short study. It is just 12 weeks. We are delighted that it appears like so many other weight loss studies that you have seen recently from GLP-1s, with the vast majority of patients losing a certain amount of weight, and then as we move those thresholds upwards, we start to see the real differences between the doses. There were high single-digit patient members who lost more than 7.5% of their weight in 12 weeks, which is, of course, very encouraging. The highest weight loss seen in the study was in the 60-milligram cohort; that was an individual that lost just north of 13% of their weight. So obviously an outlier, but it is always nice to see that. This is a slide that, of course, has a caveat. These are cross-trial comparisons, so we need to be careful and cautious as we approach it. Nevertheless, it gives us a certain amount of taste for the context of what does a 5% weight loss in 12 weeks look like compared to oral GLP-1s, which, after all, are the most relevant comparison in terms of efficacy or comparing a daily tablet to a daily tablet. I think what we can say is what is emerging so far in this period of time is something that looks to be in line with an oral GLP-1. Of course, I will reemphasize, this is not a GLP-1. It is not an incretin-targeting drug. CB1 is not part of the incretin superfamily. It is a completely orthogonal, completely different target that does very different things. So we found this to be very satisfactory and encouraging as we begin the journey with CRB-913 in terms of what could it eventually yield in terms of weight loss. Of course, this story is not about efficacy. It is really the safety that is so important. CB1 inverse agonism has been known to cause weight loss for decades. The question is: have we managed to engineer out some of the safety issues that plagued that first generation, and for that matter, plagued monlunabant? This is a slide where we focus on the worst possible adverse events that could happen. So severe TEAEs and serious TEAEs and their equivalent for TRAE. We had very few severe TEAEs. None of them was psychiatric or gastrointestinal, which was wonderful to see. We had very, very few serious TEAEs, treatment-emerging adverse events. When we look at the treatment-related adverse events, in other words, adverse events are adjudicated as being as a result of the treatment, the picture improves even further. We have the sum total of just one single severe TRAE in the 40-milligram dose; that was a headache. We had no serious TRAEs whatsoever in any of the cohorts. Lastly, looking at treatment discontinuations due to AEs. So due to any AEs, we had some ranging from 3.1% all the way to 13%. You will notice that we have those in placebo as well. This is obviously a double-blind, placebo-controlled study. Patients do not know, nor does the physician know, if they are on active or placebo. And then if we dig further into the type of AEs that cause discontinuations, we see that we have some that are psychiatric in nature, although remember, none of them was serious or severe. These were all mild or moderate. We even have one such event, for example, in placebo. So this was a participant who judged themselves or were judged to have a psychiatric adverse event that led to discontinuation while being on placebo. We similarly have even fewer GI causes of discontinuations. The total rate of discontinuation for any reason, be it an AE or not, was on average about 20%, which is about standard for obesity studies these days. Of course, a similar number was seen for placebo as well. Let's dig a little bit deeper into this. If we focus on every single psychiatric AE that we had in this study, and a reminder, they were all either mild or moderate. None were severe or serious. The following picture emerges. Suicidality: there was no traces of suicidality. Much to our delight, we had just one case of depressive symptoms. It was moderate, and like all the psychiatric AEs here, that case was transient and resolved. It was a moderate case of depressive symptoms at the 60-milligram dose. We had low values for anxiety, as did placebo. Our anxiety does not seem to be either dose-dependent or particularly different than placebo. Similarly for insomnia, low values as are seen in placebo. Lastly, irritability. Irritability does seem to be a hallmark here. Our irritability was all mild. It was seen only with a drug not on placebo. One of the further analyses that we'd be so keen to do would be to understand how it relates to weight loss. Is this an effect of our drug, or is this an effect of the weight loss that our drug triggers? All of these, again, were mild, and every single one of these side effects was resolved. Probably the most important way to look at our psychiatric adverse events is to contextualize what do they look like compared, for example, to the commercial injectable incretin analogs, because that will give us a feel to whether or not they fall outside of the ordinary. What we see is our depression falls within the norm, as does anxiety, as does insomnia. Irritability presents an interesting challenge. It is not typically measured or reported with the injectable incretin analogs. So we need to understand better what is typically seen there. Again, whether this is an effect of our drug or whether this is an effect of the weight loss that we elicit. A reminder that with CANYON-1, we measure these effects every single visit. They are measured every two weeks, and there is a very heightened emphasis on testing for psychiatric adverse events at a very high frequency, something that's not always the case because it's not necessary with GLP-1 or the incretin mechanisms of action. Here's an example, though, of what CRB-913 does not look like. We can juxtapose it compared to Novo Nordisk's recently discontinued CB1 inverse agonist, monlunabant. A reminder that the drugs are in many ways very similar. Their main difference is the degree to which they penetrate the brain. CRB-913 is 15 times less brain penetrant than monlunabant. It is not a subtle difference. It is over an order of magnitude difference in brain penetration. We found it very striking to see how that brain penetration difference translated into a safety profile for psychiatric adverse events. It is not only this marked difference in the number or the degree of psychiatric adverse events, but the nature of them. None of our psychiatric adverse events was severe. That was not the case for rimonabant. All of our psychiatric adverse events, moderate as well as mild, were resolved. Again, not the case for rimonabant. If we think of this as a hypothesis of removing a CB1 inverse agonist from the brain and preserving not only its efficacy but also very dramatically changing the adverse event profile for psychiatric adverse events, this is a very striking data set for us as scientists. Let's turn our attention now to a different set of safety measurements: gastrointestinal. We've known for 20 years, since the days of the first CB1 inverse agonist, that they tend to be milder in terms of their gastrointestinal adverse events. CB1 is not a particular gut GPCR and doesn't seem to have much of an effect on gastric motility. We were really delighted. Diarrhea, a reminder that they're always also found typically in placebo, often found in placebo, but we of course have more of them on the active trial. It is the next slide that contextualizes them. What we've done in this slide is compare them to the oral GLP-1s, oral semaglutide, and then two cohorts of orforglipron using two titration schemes. This is where we see some very dramatic differences. We have markedly less vomiting. Our nausea rate has been cut by half. We have markedly less constipation. Our diarrhea seems to be either at the same or slightly higher levels. As we start to experiment with longer titration periods, it will be interesting to explore. Again, a reminder that all of our GI adverse events were mild to moderate. We did not have any severe, let alone serious adverse events. Lastly, looking at discontinuations. Here what we've done is we tried to find shorter studies for our, as it were, counterparts, the oral semaglutide and orforglipron. What we see is that treatment discontinuations for any reasons ranges from about 17%-26% for our case. We've also pointed out what the placebos are. I will remind everyone that in this study, as is typical in early-stage obesity studies, patients and physicians do not get the opportunity to dose down. In other words, if a patient is in a blinded fashion titrated to a high dose, they are unable to be titrated down to their previous dose. That, of course, is one of the ways that you can reduce discontinuations. In terms of adverse events, it is a very different. It is a range from, in terms of our analogs, 6.9% all the way to 20%. Notice the difference with orforglipron with the titration schema. Again, as we move from a two-week titration, which is a relatively short, aggressive one, to a longer titration period, it stands to reason that our discontinuation rate will follow the same logic, which is to be reduced as patients have more time to adjust to the dose. What did we learn from this study? There are a number of important takeaway messages. We achieved up to an average of 5% placebo-adjusted weight loss in a period of just 12 weeks with no evidence of plateauing, which seems to be in a cross-study comparison comparable to what we see with oral GLP-1s. Our psychiatric AE profile supports the benefit of peripheral restriction of CB1 therapy. That, of course, is immensely satisfactory to see. That has been a 20-year voyage for this class. Of course, not surprisingly, although the extent of it is really gratifying, a favorable GI profile, certainly different in terms of some of the GI effects from the GLP-1, oral GLP-1 class. Our next steps: I am delighted to let you know that we have been selected as a late breaker for ObesityWeek in about two months' time. We look forward to being there in Washington, D.C., and presenting this data. We will engage FDA regarding the next clinical study, which we will name CANYON-2. That will be a phase II monotherapy study starting as quickly as we can next year. Last but not least, we will evaluate the potential to combine CB1 inverse agonism in the form of CRB-913 with other therapies, orthogonal therapies from the incretin pathway. For example, obvious combination to consider to contemplate would be with oral GLP-1. Lastly, a slide that is familiar to all members of this audience. Just to remember what is at stake here. Obesity is probably one of the greatest challenges to healthcare in the 21st century. There is an extraordinary number of people on the planet who are overweight, and of those, an extraordinary number of people who are obese. With over 200 associated comorbidities, and a reminder to everyone that while the GLP class has been transformational for medicine and for these patients, there are a significant number of patients whose more weight than is just provided by the GLP-1 class that could benefit from combination therapies. With that, I am going to turn it over to Professor Bays and start with some questions before we open it up to our audience. Professor Bays, thank you again for being here this morning. You were there at the start of the CB1 journey. We are talking about nearly 25 years ago. I think that a lot of our audiences do not remember it, or they were not quite adults at the time. I wonder if you, having seen the initial rise and then fall of that class, if you could share some thoughts of what were the aspects back in the day that you and collectively found intriguing about the biology? What were some of the lessons that were learned? How does our data sort of fit with all of that? Well, first of all, thanks for the opportunity to be here today, and that was a very nice presentation. It's a very objective presentation. I really appreciated that. You're right. I was there in the day. Prior to the rimonabant experience with Sanofi and such, there had been limited involvement of big pharma in obesity medication development. There had been some smaller companies and such, but again, not very many people were wanting to take the plunge into this space. There are a lot of reasons for that. There was a lot going on; this just disastrous history of development of obesity drugs, where it just seemed every way we turned, problem, problem. Okay, so finally we have these new agents out there, cannabinoid receptor antagonists. The endocannabinoid system is ubiquitous. There was also the, I like the word you said there, hypothesis. The hypothesis was if you administered cannabinoids, people get hungry. You know what I'm talking about. People get hungry. And so the hypothesis was if you were to impair that, disrupt that, instead of getting hungry, you would not be hungry. And so I guess what I really want to emphasize, my perception at the time was that the central nervous system was an essential component of the hypothesis, right? It was not a side effect. It was the intent, okay? That there would be effects on the brain that would reduce hunger, and thus there would be weight reduction. So that's how we went into it. And for those of you that don't know, one of the big things to come out of the whole rimonabant experience is that's where we really started using word "cardiometabolic," because that was going to be the big thing going forward. It's not just the weight of the patient; it's the health of the patient. And so we're looking into cardiovascular disease risk factors and such. Again, entire development program, hypothesis, everything seemed to be going in a direction. We finally had big pharma engaged. And then there were other companies, Merck and other companies, that had their own cannabinoid receptor antagonists and such. So we felt like we really had some traction. And then, even though it got approved in Europe, it did not get approved by the FDA here in the U.S. because of depression, suicidality, these types of things. So that one development program really set us back. I'm talking about medical science. It set us back because there were so many people that were thinking about going into obesity that says, "Here we go again. Just another problem. "We went for over a decade, until finally we truly did get traction with some of the newer GLP-1 receptor agonists. So the question is now, how does this fit into the hypothesis? Well, I remember when they—I don't know if it was you guys, but other people came to me, and they said, "Look, we got this theory that instead of having effects on the brain," which now we know is maybe not the greatest thing, particularly with regard to depression and suicidality, these things. Given that the endocannabinoid system is just ubiquitous, which was the story, why don't we exploit that? Why don't we say we're going to take the brain out of the picture, and we're going to look at these effects upon peripheral tissues and see how that goes? And we looked at preclinical data, and it looked amazing. I must say, I was a skeptic. I guess because I had been burned with the previous efforts and such, and I was like, "I do not know. Sure, we will do the trial. That is why you do science, but and yes, it does look good, and I am not doubting the data, but wow, okay." We do this CANYON-1 study, and what was the hypothesis? The hypothesis was you have the brain, and then you have not the brain. We can go over what the other tissues are, but that is what it came down to, right? It is like brain effects, not brain effects. We are going to take the brain out of the picture, and we are going to see if we can have efficacy and safety based upon the peripheral effects. That is what I believe was the hypothesis development program. Then sure enough, what do we find? We find, I think, some rather remarkable efficacy. If you look at depression and such, I think even more remarkable effects on that aspect of safety. At least for me, as you mentioned, I have been an investigator over 700 clinical trials spanning about 35, 40 years, and I cannot say that I predicted this. Matter of fact, I did not predict this. It is always better to be surprised on the favorable side than be surprised on the not-so-favorable sides. Overall, what I would say is this study, I think, realized the hypothesis of this sort of approach towards implementing therapeutics based upon cannabinoid receptors. Thank you for that. We are scientists at heart, and it is really hard for us to not get very excited because you are quite right, there is a hypothesis here, and that hypothesis has been around for 20 years. I think what has been missing was the tool, was the instrument. We are delighted. We are absolutely delighted. Thank you for that. Well, let me just say. I think in retrospect, we can say this now. I think there is perhaps a disconnect. You have heard cognitive dissonance, where you are thinking two things at the same time that do not really go together. Back in the day, there was clearly an understanding that the endocannabinoid system was ubiquitous. We talked about that all the time. I must say, I think as much as we said that, I think that there was a gravitation towards the belief that if there was going to be weight reduction, it had to be due to effect on the brain, right? And this other stuff, as interesting as it is, the endocannabinoid system is ubiquitous, and it clearly has effects on other body tissues that could have favorable. We kind of put that aside, and we said, "No, but it all comes down to the brain." Well, as it turns out, obviously we need to do confirmatory clinical trials and such, but at least for the data that we're given, my goodness, this does seem to validate the scientific hypothesis that the effects upon the endocannabinoid system in peripheral tissues does seem to have clinical application. I think that's the biggest takeaway for me. It's great that you're not in the brain, and that's fabulous. But what I'm saying is, I don't know too many. I'll just speak for myself. I don't know that I really thought that strictly and restrictively targeting the peripheral tissues with no effects upon the brain was going to result in clinically meaningful weight reduction. I was skeptical. I think that's fair. I think, again, as you mentioned, sort of the trauma of that first generation relegated this to corners of academia in mice. So we're delighted. So thank you for that. I guess my second question for you before we open it up is, okay, so we have preliminary data, of course. We have a drug that induces weight loss. It is not in the incretin pathway or superfamily. This is a completely separate GPCR. It's an oral daily drug. What do you do, putting on your hat as a clinician, as a physician, how do you use a drug like that in a paradigm where obesity is exclusively dominated in a wonderful way by the incretin pathway at the moment? Who needs this? Who gets this? What do you do with this? Okay, so here's where, I guess this is a good thing, where I might have a little bit of disagreement, is that one of your first slides says, "We want to develop something that was going to be competitive against GLP-1 receptor agonist."I think that's fair. We don't know, like you mentioned, there's not been a plateau, which I think is probably one of the big takeaway messages, I think from the efficacy standpoint. Yes. Yeah. There are people that are intolerant to the GLP-1 receptor agonist. GLP-1 receptor agonist, particularly injectables, massive amounts of data, substantial amount of weight reduction, got all kinds of outcome data and everything. I don't think it is necessary that this be competitive to GLP, particularly not the injectables. I don't think having a competitive weight reduction that's comparable to injectable GLP-1 receptor agonists is what's necessary for success of this drug or clinical utility of drug. I don't think we have done studies, okay? What I will say is, I think that there's clearly a role for different obesity medications having, I would say, different but potentially complementary mechanisms of action. Now when you go back and you focus on the oral, okay, so now let's focus on the oral GLP-1 receptor agonist, okay? Is it possible that the clinicians would say, "If possible, I would really like to have the ability, through use of oral administration, to have comparable weight reduction as the injectables." If you were to extend what we've seen here, yes, monotherapy may be useful for people intolerant to GLP-1 receptor agonists. I get that, okay? I think what's also exciting to me is say, what happens if you were to have this combined with an oral GLP-1 receptor agonist? How about this? How about an oral amylin analog? What we're coming to realize is the amylin analogs are at least way more effective than I thought they would be, and in addition, their safety and tolerability profile is really good as well. I think there's opportunities for combining with other oral therapeutics. If that's true, and you were to even just get additive effects, now I'm not saying you're going to get 25%, 30% weight reduction, but what if you were to get 15% weight reduction and such, or 15%, 20% weight reduction, through a pill, through a combination therapeutic agent, I think that would be profound. Now, the caveat with all this is you got to do the studies, you got to look at the efficacy, got to look at safety. I can only go by the data that's presented to me. What I see here is I'm not seeing the psychiatric side effects that we saw with the older agents, which fulfills the hypothesis or supports the hypothesis. What I'm also seeing is you're seeing that weight reduction of 5% in 12 weeks without evidence of a plateau. That's what I'm seeing. What I'm also seeing is this is an entirely different mechanism of action compared to the incretin therapy. Historically, whether you look at diabetes or hypertension or dyslipidemia, we have routinely had combination therapy, often within fixed-dose combination therapeutics. That just seems like a very understandable approach to be taking. A reminder to our audience: both Corbus and separately Novo Nordisk published with our respective CB1 inverse agonist data in DIO mice that was co-administration of our respective CB1 inverse agonists with GLP-1 agonist peptides. As you just said, Dr. Bays, these two orthogonal mechanisms of action for both cases were very promising in their additivity because they just do such different things. When you put them together, those two different things led to meaningfully greater weight loss than just each one of them on their own. Yes, that would be fascinating to explore. Agreed wholeheartedly, I think that we look at this within the universe of an oral daily therapy and what is available and what could be available. With that, I am going to turn to our audience. Tara, if you can open it up to our first questions. Absolutely. Thank you, Yuval. Yes, at this time, we will be hosting a question and answer session with Dr. Bays and Yuval. Please hold for a brief moment while we pull for questions. Our first question comes from Paul Jeng at Guggenheim. Please go ahead, Paul. Hey, thanks for taking the question and for providing this great and really interesting update today. I had a couple on safety. First, understanding that the CANYON-1 study was conscious of the class history and had some key screen out criteria based on psychiatric parameters. I am just curious how you think about the generalizability of the safety data and how representative it is of the broader obesity population. The second part to the question is sort of what gives you confidence that the psychiatric AEs will not be cumulative or perhaps worsen with longer exposure to treatment? I can certainly start on that. Thank you, Paul, for your question. We had a more stringent PHQ-9 screening criteria than you would normally find. A normal threshold is, I believe, over 15, so that would be moderate. Our threshold was over four. One of the things that we wanted to understand was did we create an out of the ordinarily non-depressed population of patients? There is a very easy way to find that out. We looked at our screen failures for PHQ-9, and they are minuscule. I believe they are about 4%. Just randomly selecting 254 adult Americans living with obesity in this study, we barely had anybody fail for PHQ-9. In terms of the length of the study, could we see more as studies lengthen? One thing to think about is when do these happen? If we look at either the published data for the injectable GLP-1s, just because there's so much more data there. If we look at the published data of the injectable GLP-1s, or for that matter, the published data from Mounjaro, it's a very similar pattern. The pattern is a median time to onset, Paul, which is very short. For the injectable incretins, it's 11 days on average. For Mounjaro, that was about 14 days. We look forward to sharing ours, but it's in the same ballpark, and that's not surprising. These things arise when you first encounter the mechanism of action. It's rare to have them happen later. Mounjaro had no events past, I believe, eight or 10 weeks, and as you'll see with ours, it's a very similar effect. Longer studies, and of course you can never predict entirely, but longer studies don't seem to offer a risk in terms of having effects happen later, simply because by that stage the participant has been exposed to the mechanism. The last thing I'll say, Paul, is again, titration, titration. This was a very aggressive two-week titration because the study was short, of course. As we go into longer studies, we will emulate that, allow patients to catch up, as it were, with the mechanism of action before moving to a higher dose. Oh, great. Thank you for that. Then perhaps a quick follow-up. On the efficacy, can you speak to any impact you've observed or qualitatively perhaps on this call on metabolic parameters beyond weight, blood pressure, lipid levels, et cetera? As you think about the phase II, how do you think about potentially exploring higher dose levels? I believe you went as high as 150 milligrams in the phase I-A MAD cohort, and there's been some dose-dependent weight loss. Just curious how you think about the next steps. Thank you. Dr. Bays will be there presenting the data at ObesityWeek. There's a lot more data that we have, as well as data that we're still waiting for. We look forward to sharing all of that at ObesityWeek. Maybe I'll turn that question, the second question, to Dr. Bays. It's a new mechanism. This is where we are at 60, sort of baby steps. What are your thoughts? You are making me short of breath. That is what is making it to me. I am like, here. Okay, so for those folks on the phone, you are all experienced people. Look, I just got this data, right? I am still kind of coming to grips with it. Here we have this wonderful. I do not want to characterize things. Okay, here we have this favor. I think it is reasonably characterized this as favorable response, and now people want to go to higher doses. I am like, oh my gosh, let us be happy with what we got. Look, I think that any decision as to going forward with higher doses needs to take in consideration as to why these doses were changed or chosen to start with, okay? I guess maybe I am too cautious. I am a cautious guy or whatever. I just would not want to enter. Let us say you do go to, say, 120 milligrams or whatever, okay? Now you do start to see some signals. Well, I mean, I would just think that would just mess up everything, right? It would just mess. Then people wouldn't say, "Well, it is because you went too high on the dose." They would just know that it existed. I do not know. I think, just again, I just recently saw this data. For me, as a cautious person and having the experience of the past, I think I would really like to know. The first thing I would want to know is what happens when a person is on 60 milligrams for longer time? One thing, Yuval, you did not really. I do not think you mentioned this. Can you go back to the titration? Certainly. Yeah, look at that. I mean, the first four weeks were titration, right? So the people were only on the 60-milligram dose for what? Eight weeks? Four. Right? Only on it for. I mean, so I am just at a disadvantage here because I just really do not know where it is going. I do not know where the efficacy is going. So if you were to truly get 5%-10%, maybe closer to 10% with extended use, wow. I do not know. I would be cautious in risking it. But again, I am risk-averse. You guys know better than what your risk tolerance is. I am just, again, still trying to come to grips with this data. And just to add to that, Mounjaro in some ways did us a tremendous service. Mounjaro went out there into the wild, as it were, and stepped on a bunch of landmines. Kudos to them for doing so. In other words, it took a lot of courage. It really did. Those landmines have been immensely helpful to us, and one of the most important ones was titration matters. Give patients time to adjust to this mechanism of action, just as you do with the incretin pathway. Early days, we look forward to sharing more data. I will say where monlunabant ended, and it is worth remembering because that was a subsequent, far less noticed paper. At 12 months of 20 milligrams a day monlunabant, their change from baseline was nearly 13%. That is a different drug, but that certainly is something to aspire to. And that would be a meaningful weight loss, even in the context of the current landscape. Our next question. Yes. The next question comes from Brian Abrahams at RBC. Please go ahead. Hey, good morning. Congrats on the data. Thanks so much for taking our question. Just a few from me. Wondering if you could talk a little bit more about the typical duration of the psychiatric side effects that you see here, and then just in terms of the PK/PD, trying to tie it all together, the observations there in terms of consistency, exposures, when you get to steady state at the 60 mg dose, and maybe how that all kind of relates to your observations of both the weight loss and the AE timeline. Thanks. Thanks, Brian. These were all, as I mentioned, mild to moderate. In terms of irritability, because that's the one that kind of stands out, they were all mild, short in duration, all were transient, and every single one of these on the screen resolved. I know everybody wants to see PK. I would remind everybody that we live now in a very different world than we lived a few years ago. It's a world of very fast followers. PK is something that I think is worthwhile keeping confidential to the extent that is possible, of course, and appropriate. I will say that the history of CB1s is they behave very, very nicely. They tend to have a longish half-life. They're very stable compounds. They reach steady state in a reasonable amount of time. There's never been one that had a very peculiar PK. We're no different to that. But it is something that's immensely valuable, Brian, to competitors. I do predict that this sort of 20-year drought of this field might actually change now, if this is indeed perceived as being the return of this class. I think it's unlikely that we're going to be the only ones pursuing it. Thanks. Thank you for the questions. Our next question comes from Graig Suvannavejh at Mizuho. Please go ahead, Graig. Thanks. Good morning. Thanks for the presentation and thanks for taking the questions. Congrats on the day as well. Just maybe a couple questions for Dr. Bays, if I could. Dr. Bays, good to hear from you. We've spoken in the past, and I was curious about comments you'd made, at least to us in the past, where, when you look at safety in these earlier phase I-ish studies, what can you really extrapolate from these findings? I think in the past you've mentioned, at least to us, that you'd ideally like to get a sense of what safety tolerability looks like from studies of perhaps thousands of patients or experience in thousands of patients. Just trying to get a sense of the totality of the data you're seeing, and then maybe as a follow-up, just on specifically if we just took neuropsych, the TRAEs out of the picture here. But on GI, if we were to think about this asset being perhaps very combinable with an injectable incretin, how do you look at the GI profile here, if it might be put on top of one of the injectable incretins? Thanks. Okay, so the first question is, as a clinical trialist, do I favor larger clinical trials over a more extended period of time in order to provide me greater confidence in both efficacy and safety? And the answer is yeah, of course. Yes, absolutely. That's what we want are the large clinical trials over a long period of time. I think what might be a little bit unique here is, I don't remember exactly what the past conversations we've had, but I'll bet they were maybe more related to other types of metabolic drug treatments. For example, like lipid therapies or diabetes treatments or these types of things. And there, what we're more often looking at are things like liver toxicity and muscle toxicity and these types of things. So there, yes, absolutely. You have to look at thousands of patients, maybe even 10,000 patients, over a longer period of time and such, because all it takes is 2K. Some of you may remember a squalene synthase inhibitor, lapaquistat. All it had was two cases of Hyams-Stawell on thousands of patients. Drug is done. All right? So you're absolutely correct that having larger clinical studies over extended periods of time, always more reassuring with regard to efficacy and safety. I think what might be unique here is you've not seen a whole lot of concern here about liver enzymes. I suppose that could pop up or whatever, but what I think most people are zeroed in on are the psychiatric things, because that's what shut down the other programs. Right? That was the mechanism of action. Remember we talked about how it is that effects on the brain; that wasn't a side effect, that was thought to be the mechanism of action. That was the intent. Having effects on the brain was the intent of the older cannabinoid receptor antagonist. So, this hypothesis was, we're going to take the brain out of the picture and see if peripheral effects on the endocannabinoid system can assist with weight reduction. So you're going to say, "But how do you assess that clinically from a side effect standpoint?" And what you do is, you do exactly what you see here on the slide. You evaluate those things. You just heard from Yuval Cohen that those, typically, those psychiatric events occur relatively soon. Okay? Now, I don't mean it can't happen in the future; of course it can. But I think to the extent that we can glean some information, the fact that I would characterize the data with regard to depression as being relatively clean. I'll just throw the opposite. What if there had been 10-15% to 20% across the board of depression symptoms and maybe one or two cases of suicidality? I think we all know what we'd think. The drug's done, right? Drug's done. But the fact is that we have the data as you see it here. Couple that with the fact that it was the intent of this study, as opposed to the intent of the older studies, to say we're going to take the brain out of the picture, and hopefully we're not going to have those CNS effects because we're not in the brain. Hopefully, we will have effects on the peripheral endocannabinoid system, because that's what we're told is important. Maybe we can do that and achieve clinically meaningful weight reduction without the depressive symptoms. I can't tell you what's going to happen in a larger clinical trial over an extended period of time. What I can say is the data that we have thus far in the CANYON-1 study in 12 weeks seems to validate the hypothesis. If you can comment on the GI profile? Yeah. The GI profile, what I would say, can you I think that to me is maybe a little bit tougher because I know what happens with oral GLP-1s by themselves, and I know what happens with CRB-913 by itself. But what happens when you combine the two together? The answer is, I just don't know. Or if you were to add this to, like I said, an oral amylin analog, what do you get there? I just don't know. So I think this has been on your all's mind anyway. Yes, I think the efficacy is going to be important. But if it is true that you've really solved the psychiatric situation, I'm not saying you have; I'm just saying if that's true, if the attention to that hypothesis continues to be supported by the data, I think that's a very fair question. I think the main thing that is going to be focused on is when you add this to that, what happens when you put them together with regard to the GI side effects? Wouldn't that be ironic if it turns out being that it is the GI side effect that is the main focus as far as AEs, and we don't even really much care about the I am not saying that is true; I am just saying that isn't it interesting if that is the direction we are going in the future. The answer to your question is, I have no idea, and I wouldn't even know how to speculate. Anyway, with that, we have run the clock, as it were. Thank you, everyone. Thank you, Professor Bays. Immensely grateful. Very much looking forward to seeing you present this at ObesityWeek®. Of course, thank you to the Corbus team, to the clinicians, and of course, the patients that took the time and effort to participate in this study. We are immensely grateful for that, and we look forward to this journey now continuing. Yes, we are cautiously very optimistic. We are really delighted with this data. Thank you so much. Tara, thank you for organizing this call for us. Our pleasure. Thanks, everyone. The meeting has ended. You may now disconnect. Take care. Bye-bye.