Hello, everyone. I'm Jay Olson, one of the biotech analysts at Oppenheimer, and it's a pleasure to welcome you to Oppenheimer's 35th Annual Healthcare Conference and our discussion with Skye Bioscience. It's my pleasure to introduce Punit Dhillon, CEO of Skye. Thank you for joining us, Punit. I'll turn it over to you. Hey, thanks again, Jay. I appreciate the invitation, and good morning, everyone, and welcome to the presentation. It's really a pleasure to participate in the Oppenheimer Healthcare Conference. I can't believe it's the 35th year. It's an honor. I just want to take a moment to, first of all, just ground everybody in terms of one important aspect of the therapeutic area that we're diving into today. You know, it's been really evident over the last two years that we've seen this incredible shift in the treatment paradigm for obesity and the appreciation of the fact that it's a chronic condition, and drug intervention is really beginning to treat the underlying disease as well as treat and prevent some of the downstream effects of obesity. We're no longer thinking of treating comorbidities symptomatically, which is an important takeaway. I would say that hands down that obesity and metabolic diseases are among the most pressing global health challenges of our time. We can see that in terms of how discussions have evolved over the last few years. I'll dive right into the presentation. Before I begin, we're going to be providing an update that contains forward-looking statements, which are subject to risks and uncertainties. Investors should review our filings with the SEC for detailed risk factors. I also want to make note that the information shared reflects management's current expectations as of today. At the heart of Skye, it's a really simple and powerful idea. We're leveraging the best science to redefine how we treat obesity and metabolic diseases. We're a leader in GPCR-based antibody therapies for metabolic health. Nimacimab is our flagship CB1 inhibitor. It's really designed to provide sustainable weight loss with fewer side effects. Our approach really builds on validated science to really reshape the obesity treatment paradigm. Just briefly on the financial metrics, I want to quickly highlight in terms of capital access and finance and resources. We've been successful in securing the backing from top-tier life science investors and raised over $107 million since August of 2023. That cash position takes us through Q3 of 2027 based on current guidance. We'll discuss where those investments are being made and how really we're harvesting that for incredible value creation developing this particular product. Execution on our entire development plan and strategy is made possible with our entire leadership team. This slide just is highlighting kind of a collective track record of everyone, over 40 different drugs commercialized, multiple successful ventures co-founded, many strategic transactions, and some of those that have literally shaped the industry. I'm really proud to be a part of this team and the broader team. We're confident that we have the expertise and continue to add on that where needed to ensure that there's a pathway to bring nimacimab to the market. In terms of where the investments are being made, over the past year, we've really focused in on obesity and a broader metabolic pipeline. Clearly, this includes the necessary building blocks for value creation through our existing IP, but also generating clinical and preclinical data with really strong collaborators. Now there's a very acute kind of period where we have some near-term clinical milestones. We're working with a fantastic group of obesity experts and collaborators that really are guiding our entire pipeline. We're excited to share some of these insights later on this year. Stay tuned for updates. Another area that we're spending a lot of time and focused on is continuing in the CMC and GMP manufacturing area and the readiness to really support our clinical trials as well as our regulatory strategy. There's quite a bit of effort there over the next few years to get us into that Phase 3 readiness camp. Near-term inflection points obviously include Phase 2 study updates over the coming months and interim clinical data by the end of Q2 2025, as well as final top-line clinical data by the end of Q4 2025. All right, let's explore why the anti-obesity market really offers a compelling opportunity for innovation. If you look at, you can zoom out of our specific product and look at just kind of a wider view at the moment, we really see how the entire obesity market and pipeline is shaping up. There's been an incredible amount of success in the incretin mimetic classes, so drugs like Zepbound, Wegovy, Mounjaro. Obviously, those are drugs that have a GLP-1 backbone and related, some of them are dual or triple agonist combos. After that, when you look at the non-incretin pipeline, the two targets that really stand out in terms of clinical validation are amylin and CB1 inhibition. After that, for the most part, I think it's yet to be still defined in terms of regulatory development strategies, clinical development advancement, or additional safety and efficacy clarity on these additional mechanisms. We think that even though there's been a lot of discussion in obesity, there's still a lot of opportunity. If you focus in on this particular information on this slide, the current market has proven that meaningful weight loss is achievable, but there's really the lingering side effects that are really the concern. Specifically, there's an opportunity to improve on GI tolerability. We can improve the continuation of drug intervention to reach really the long-term sustainable weight loss goals. I think there's an overemphasis in terms of time points and how fast that weight loss needs to be, whereas if you have a more sustainable long-term weight loss, we get to kind of the similar outcomes. One of the key things here in the pink box here is the 30% dropout rate after the first four weeks. That's 30% of patients that aren't staying on the treatment for the minimum 12 weeks, and then they're very unlikely to achieve clinically meaningful weight loss. There are really opportunities to improve on that. When you look at response rates, there's opportunities to improve on response rates for those that don't even respond, as well as continue to have the benefit from the additive response and related kind of metabolic benefits as we see with patients that continue to stay on drugs over a longer period of time. We believe that in order to do this, we can improve on healthier, more sustainable weight loss by having a mechanism that's also addressing preservation of lean mass. When you look at each of these buckets, there's an unmet medical need, and there's a sizable opportunity in the overall obesity treatment paradigm. Now, the other way of looking at this in terms of just the advantages of targeting obesity through additional mechanisms is specifically looking at what the peripheral-driven mechanisms offer rather than the central-driven mechanisms. When you look at overall in obesity, the choice between the central versus peripheral pathways is really more than a scientific debate. I think it's a really important concept to grasp because there is a heterogeneity in obesity. We have many different subtypes of obesity. We obviously have effectiveness around central acting drugs like GLP-1 that rely on caloric restriction, but they cause significant GI side effects among other things that I just went over. Whereas the peripherally targeting agents, such as CB1 inhibition, they promote fat loss and are still indirectly regulating appetite. In this case, we're trying to show that we're reestablishing key metabolic pathways that may have had resistance, for example, insulin resistance. There's a pathway to better sensitivity and leptin resistance. There's a pathway for a productive shift in appetite regulation that basically curbs some of that caloric input that we're trying to shoot for with the GLP-1s, but do so safely. CB1, I think, is the only non-incretin target that's clinically validated by multiple agents. I want to just kind of touch on that. If you look at just going back in terms of CB1 history, a bit of context, both rimonabant and monlunabant have demonstrated the efficacy of CB1 inhibition in achieving significant weight loss. Rimonabant and monlunabant achieved basically up to 6% weight loss. In the case of rimonabant, it was a little lower, but 6% weight loss in 16 weeks for monlunabant. If you think about that from a competitive standpoint, it's actually competitive to oral semaglutide, even relatively close to injectable semaglutide at 16 weeks with a better GI tolerability. However, the key issue that's been faced for these small molecules is dose-dependent neuropsychiatric side effects. Nimacimab is focused on peripheral CB1 inhibition, and we're really avoiding the CNS-related risks while still focused on the overall saturation of the receptor and delivering effective weight loss. I'm going to switch over and transition to talking about nimacimab in more detail. Nimacimab is not only focused on weight loss. Obviously, that's a primary endpoint of our trial, but we're also overall focused on metabolic restoration. Just a bit of color in terms of the antibody itself, it's an antibody engineered for stability and superior tolerability. It's an IgG4 antibody with a half-life of 18 to 21 days, which enables us to evaluate monthly dosing. We're focused on a really peripheral-driven mechanism here, which is minimizing the CNS exposure. This has actually been evaluated in multiple NHP studies showing really background levels of antibody in the CNS and brain with no accumulation of the antibody despite multiple weeks of dosing. Our antibody is also acting both as an inverse agonist and an antagonist. That's a really important point. It's basically ensuring kind of this dual mechanism of action for optimal efficacy. That's been measured in the presence of CB1 agonism with beta-arrestin as an endpoint, evaluating beta-arrestin recruitment, as well as evaluating increase in cyclic AMP. Nimacimab is shown to be twice as potent as rimonabant with that particular endpoint. Lastly, I think just in terms of the way that it's competitively situated relative to small molecules, we're a non-competitive allosteric binding molecule, which really provides for a consistent kind of CB1 inhibition and binding formation regardless of the endocannabinoid levels endogenously. We do not have to compete for the same binding site by focus on allosteric binding. All right, in terms of just nimacimab and peripheral CB1 inhibition, CB1 is expressed in tissue and has in multiple tissues and has a lot of related mechanisms. Specifically in adipose tissue, we're addressing CB1 upregulation, and we're really triggering for reduction of fat storage and promoting fat metabolism and energy expenditure. We have this related kind of opportunity when we talk about this comment about metabolic restoration, we have this opportunity to interrogate some of the other targets in tissues, CB1 target in related tissues that would benefit from anti-inflammatory and antifibrotic pathways that might help in comorbidities associated with obesity. As well as the weight loss component, you're getting this broader metabolic gains and restoration with CB1 inhibition by focusing on these other tissues like liver, pancreas, and the muscle. Now, coming back to the peripheral restriction and exclusion of CB1 inhibition in the brain, again, several preclinical studies confirmed the absence of nimacimab in the brain, even at higher doses. Phase 1 data also demonstrated no neuropsychiatric effects in humans. Together, this really serves as the benchmark of data for the CB1 class. This is the type of precision we would expect from a safety standpoint. I don't think this is something that we want to compromise at all. We believe this opens the door to a completely new mechanism of action for sustainable weight loss by having a sufficient amount of weight loss through a peripheral saturation of the receptor. Now, let's dive into that. There's been quite a bit of work generated overall in the class in different DIO models, but we developed our own DIO model. Now, kind of going beyond safety and the PK data that I just shared, we've begun to generate very important PD data to highlight this concept of peripheral sufficiency for weight loss. This is the first data set, which was shared last November at a satellite event around Obesity Week. We ran an efficacy study in a DIO model using a proprietary human CB1 knock-in mouse model. Here, nimacimab treatment led to a clear dose-dependent reduction in weight loss, with the highest dose of 75 milligrams per kg providing the most dramatic effect. I think critically here, the weight reduction was driven by fat mass loss rather than any muscle wasting. At higher doses, we saw significant preservation of lean mass, and it shows that nimacimab really is targeting the fat without compromising muscle. When you compare it against semaglutide side by side, nimacimab efficacy matches or exceeds semaglutide in terms of weight loss and fat mass loss, both demonstrating really meaningful metabolic improvements in this particular model. We also saw, this is not listed on this slide, but we also saw dose-dependent improvements in glucose tolerance with lower blood glucose levels during the glucose tolerance test, which is another key marker of metabolic health. We are still evaluating a lot of other information from this model, and we are evaluating hormones like leptin and insulin, as well as lipid and inflammation markers. So far, early findings are suggesting benefits that really align with nimacimab in terms of fighting obesity with this particular mechanism. In fact, this is probably a better way to capture this in terms of this slide. We are now working on several simultaneous points of reference and mechanism of nimacimab. All of these different parameters are showing how CB1 inhibition is driving this coordinated metabolic change in multiple tissues. Nimacimab isn't just about this weight loss and not just about the top-line weight loss number. It's about this holistic metabolic health and metabolic restoration by targeting adipose, liver, and muscle tissues. In the adipose tissue, we're seeing reduction in leptin and resistance levels and promoting fat loss and improved energy expenditure. In the liver and pancreas, we're seeing decreases in fibrosis and steatosis while really enhancing insulin sensitivity and glucose regulation. We look forward to kind of outlining more of this data in the coming months. When you look at the unmet need and what's not fulfilled by the current treatment paradigm, and you kind of go back to my earlier comment about the importance of keeping in mind that obesity has many different patient subtypes, there's really a much broader opportunity at play, right? The market, like what we discussed earlier here, was there's opportunity to address the non-responders, address combination, discontinuation, maintenance therapy, all with a real complementary focus on metabolic restoration. There is, I think, an opportunity here in terms of CB1 inhibition isn't just complementary to existing treatments. It's really critical in terms of that overall piece of the metabolic puzzle. This chart kind of outlines where that is. On the right side of the slide, we're outlining kind of the TPP that we're focused on and where the opportunities are for nimacimab. Certainly, TPP towards a monthly dosing, as well as long-term dosing, provides a very strong strategic advantage, and it addresses some of the unmet needs of this diverse population. Again, I kind of touched on this. The key takeaway here is that not every patient is going to need to have a drastic type of weight loss. There is certainly a large opportunity here in the overweight and the Class 1 population. We believe that not every patient will benefit, nor will it be healthy to only think about some sort of benchmark for weight loss based on that bar that has been kind of set by GLP-1 receptor agonist, like in terms of the 20%+ numbers that we hear about. Frankly, I think it is a great opportunity to look at where there is an opportunity to see as a follow-on to those patients that cannot or do not respond to those drugs, especially in that overweight and Class 1 population where that degree of percentage of weight loss is certainly not necessary. This is a good figure to really visualize what we're targeting in our clinical study and how overall we expect to see this drug perform. Again, the criteria and TPP we're looking at, in addition to weight loss, is limited to no neuropsychiatric adverse events, really showing an improvement in tolerability and then improvement in quality of weight loss. We believe that the key to winning in the obesity market is to really demonstrate that it's a sustainable, consistent weight loss over any amount of time. It's not a rush to see 20% + within six months, but instead, patients improving and sustaining weight loss and overall making better health choices with other lifestyle changes and really complementing that with pharmaceutical intervention. The other aspect here is the maintenance, or think about follow-on to GLP-1 or other incretin mimetics. There's also this opportunity of addressing non-responders or refractive patients that are very important patient populations. The CBeyond study, the Phase 2 study that we're running, we feel very optimistic based on our DIO studies to be able to really demonstrate this additive benefit between combo of nimacimab and semaglutide to really achieve that quality of weight loss and improvement in tolerability. Similarly, based on the DIO data, we expect to show how this mechanism preserves weight loss while reducing fat mass and really addressing some of the limitations of these current therapies. I'll jump to the Phase 2 design here. We're currently conducting a Phase 2 study of nimacimab. It's named CBeyond. This program has four different treatment arms, including a double-blinded portion with nimacimab monotherapy and against placebo, which is highlighted in this red box. There is a partially blinded study of nimacimab combination with semaglutide, as well as semaglutide alone plus nimacimab placebo matching. The primary endpoint here is demonstrating 8% mean weight loss difference versus placebo at 26 weeks. The secondary endpoints are looking at safety, including neuropsychiatric evaluations, as well as body composition changes. We are also evaluating changes in key metabolic markers such as insulin sensitivity and triglycerides. This study is also incorporating a 13-week follow-up period to see the durability of weight loss and other endpoints. Now, just in terms of expectations around the data, as I outlined, there are obviously these several endpoints we will be measuring. This is an interim analysis that is expected in late Q2 at 26 weeks for 50% of patients in all the cohorts. This is going to include weight loss data, safety data, as well as the body composition data. We will follow that with top-line data in Q4 2025, which will include all those parameters as well. In terms of just, excuse me, going beyond the strategic kind of vision here of what we're focused on, in addition to nimacimab, we are continuing to work beyond nimacimab where we're looking at building a broader pipeline. In terms of zooming in on the clinical development strategy of nimacimab with the Phase 2 data expected in late Q2 2025, it's really guiding our Phase 2b development plan and subsequent studies, including the Phase 3 programs. The goal here is to be Phase 3 ready by late 2027. We continue to make very active investments in R&D and manufacturing, IP, and other collaborative partnerships to ensure this kind of long-term success. What can you expect here from nimacimab? Obviously, we feel really confident around the benchmark of safety, and this mechanism has proven to have a strong efficacy profile. We believe we have a very competitive target product profile overall. We are working hard on really addressing the gaps in the current market, and we believe that nimacimab should be a drug and product that has uptake and can become really the cornerstone in the future of obesity treatment. The near-term milestones include Phase 2 trial data with a Phase 2b dose escalation study, which we'll provide details on later this year. The ultimate plan is having Phase 3 readiness targeted for 2027. The long-term vision includes expanding into additional metabolic indications and continuing to improve on the TPP and obesity, which we think is important because we want to continue to set new standards in terms of patient outcomes and address some of these unmet needs that I talked about today. That is it. I thank you, and I can take any questions if there are any questions. Yeah, absolutely. Thank you so much, Punit. It is great to come up to speed on all the work you are doing at Skye, and congrats on all the progress. We do have a few questions. One of the most common questions we get from investors lately is about the recent update from Novo Nordisk on their CB1 small molecule, monlunabant, which you mentioned. Can you just talk about your interpretation of those results and if there is any read across to nimacimab? Yeah, I think it's broken up into two areas. On the efficacy side, we're really obviously impressed with the efficacy. I think there hasn't been as much appreciation on that because, unfortunately, the information that Novo provided was very scant. Obviously, we're interested in seeing how those curves are, what is the quality of weight loss, is there lean mass preservation. If you just take the top-line weight loss number at 16 weeks, the 8% is a very competitive number when you look at it, that it's a peripheral-driven mechanism. This is a different mechanism than sema that was focused on caloric restriction alone, whereas monlunabant is driving and saturating that receptor peripherally and driving that reduction in weight through an indirect pathway that's regulating appetite. We feel really that that's only helped to validate the mechanism. The other side of the camp is the safety concern. Obviously, the neuropsychiatric concerns around small molecules go back to the rimonabant days. The fact that the second generation that was supposed to be more peripherally restricted and alleviate that concern is a bit of cold water on the small molecules. It's unfortunately kind of wrapped, I think, I feel like from a perception standpoint, it's wrapped Skye into that situation. For Skye, it's twofold. One is we have to generate obesity data. That's what this trial is about. The other is it's a different mechanism. It's an antibody that's staying outside of the brain. There's, I think, too much emphasis that's been put on that there's some kind of Goldilocks requirement of small molecule saturation or inhibition, sorry, that's required in the brain. In October, as you know, we kind of debunked that with going through an incredible amount of detail that Chris and the team did in terms of demonstrating the PK comparisons of why nimacimab actually had that efficacy driven based on peripheral. And rimonabant, much to most people's surprise, was actually a peripheral-driven mechanism primarily as well. We think we have tried to share that based on our DIO data, which is showing that there's sufficiency in a peripheral-driven mechanism. Now the human data is going to be the key factor. Yeah, that's the good and the ugly related to the nimacimab data, in our opinion. Okay. Thanks for those thoughts. I know we're just about out of time, but maybe one last quick question. You mentioned that as the metabolic landscape evolves beyond GLP-1 and the other Gs, that you thought that in addition to CB1, amylin, those two might be the more promising mechanisms beyond incretins. Can you maybe compare CB1 inhibitions to amylin and what are the pros and cons of each? Yeah, I think it started at EASD last year where amylin really got a lot more attention. It is funny that everything, if you go back a year prior to that, in 2023, there was less claims being made around the mechanism. All of a sudden, you saw amylin mechanism having claims around energy expenditure, around insulin sensitivity, around leptin sensitivity, and all with an improved tolerability profile over GLP-1. As a non-incretin, that is why I am putting a bit of emphasis on it, just because let's face it, Novo is putting a lot of effort on that. They got CagriSema in development. Maybe that's a life cycle management until they have amycretin closer to approval. Certainly, CagriSema seems to be on that path towards approval in the coming years. We think that amylin is going to have a role to play once that drug is approved. That paves the way for the oral version that comes in Novo's pipeline. There are other companies that also have a monotherapy amylin in development. The mechanism has shown improvement in safety, and it's obviously driving weight loss and also having these other metabolic-related improvements or metabolic gains outside of these gut hormones that have been the previous generation. We think that that's relevant. The reason why it's important, Jay, is that if you go back to the front lines, and this is part of the work that's underway at Skye right now, is we have this very comprehensive survey that we're working on with obesity KOLs. And every conversation we have, the conversation most often leads to, "We need more tools in our toolbox in order to treat these patients." There's only seven drugs that are approved. Out of the seven that are approved, there's three that are primarily used. Those three that were primarily used had supply issues in the last two years. Finally, we're seeing normalization around that. Those three that have been recently approved, unfortunately, have millions of patients that aren't being properly addressed because what I went over in my presentation, there's a large discontinuation rate, tolerability issues, and there's, frankly, a large number of patients that don't even respond. We think that there's certainly a market to be grasped there. We'll probably package that and articulate that in the coming months. Stay tuned for our update on that. Excellent. We will look forward to that. We'll wrap things up there. Thank you so much, Punit. It's always a pleasure catching up with you. Really appreciate your sharing your insights with us here today. Great. Thank you so much, Jay. Take care. Bye-bye. Thanks, everybody.