All right, thanks everybody, and thank you for joining Guggenheim Securities' inaugural Healthcare Innovation Conference. I'm really pleased to be joined by Skye Bioscience. Skye Bioscience, to my left immediately is Punit Dhillon, the CEO, and Puneet Arora is the Chief Medical Officer to my far left. Just want to introduce myself. I'm Seamus Fernandez, one of the biopharma analysts here at Guggenheim. So Punit, maybe just to kick us off, maybe just give us a little bit of background on Skye and where you're most focused just in development right now. Obviously, obesity is a hot topic right now, for sure. Thanks, Seamus. I really appreciate being here at this conference. You almost said agonist, didn't you? I did. But the awesome thing for Skye is it's been a fantastic year. We're developing a very focused clinical pipeline on metabolic diseases. Our lead program is focused on CB1 inhibition. It's referred to as nimacimab, where we're developing a first-in-class CB1 antibody inhibitor, and that program is currently in phase II for obesity. And then the third area is just there's been quite a bit of work done fundamentally in terms of the company. So I think it is an interesting investment thesis from the broad perspective, certainly being mid-stage, launching the clinical program. Last week, we also came out with additional preclinical evidence that helped to postulate a very clear de-risk component on the efficacy that supports the safety that we've already had. And I think it's an attractive upside relative to the obesity peers, cash runway until Q3 2027. So lots of things have been done, and really happy to have my colleague here, Dr. Arora, join the team less than 90 days ago. He's hit the ground running. Our clinical program's enrolling really well. So lots to do, and 2025 is turning out to be a good year to look ahead to. Great. And if you don't mind, maybe just give us a little bit of the history of nimacimab and where you brought the asset in from, and then also just the specific approach to the treatment of obesity that you're targeting? Yeah, that's a great question. So nimacimab was developed by a company called Bird Rock Bio, a private company out of San Diego, and that company was acquired by Skye last year, last August of 2023. So we were very thankful that Versant and 5AM Ventures came in as investors with that asset. They were previously investors in Bird Rock. And then we basically started to articulate a clinical development strategy around metabolic diseases. For us, nimacimab, the acquisition of that asset was and still is focused on a broader franchise opportunity. But the reason we were interested in that is because of the safety profile and the fact that CB1 inhibition, for those that have been following the class, would immediately recognize that there's actually been clinical validation with this approach just in the small molecule side. And that also had risks associated with it. Acomplia, which was marketed by Sanofi, was launched in Europe and then taken off the market because of neuropsychiatric adverse events and specifically severe events such as suicide ideation. As we've seen new second-generation peripheral-driven CB1 inhibitors that are small molecules, they haven't necessarily shaken off that risk. As I'm talking about the monlunabant data, for us, nimacimab from day one, the safety profile has been a key factor. Then we felt fairly confident around the way that the mechanism works, the fact that it is also not only an antagonist, but it's also an inverse agonist. It's a large molecule that stays out of the brain that we could try to highlight a similar type of weight loss without any of the safety concerns. Going from acquisition, the goal was to get the trial going. We filed an IND, got that approved in Q1, and then we just launched this program in Q3, and it's enrolling now. So really, there's been a lot of momentum from that initial acquisition and that history and having the cash to run all of these programs. That's been important. Now, I think as we've seen, it was interesting timing. If I could say that the Novo, having acquired a similar CB1 or another CB1 asset around the same time frame as our acquisition of Bird Rock, did set the stage for a lot of interest in this particular pathway. And I think that's what's shaping up for 2025 is that we're going to see more of the non-incretin opportunity take shape. Amylin certainly is an exciting non-incretin. But beyond that, when you look at CB1 and its mechanism and its potential to tackle a lot of different areas of maybe additive and synergistic effects with incretins, it certainly sets us up really well. Great. Puneet, can you maybe talk a little bit about the phase II program, what needs to happen to really bring us forward to those data and the differentiation that you see with bringing in the preclinical data that was just revealed? Maybe we can talk a little bit about that as well. Yeah, so let's start by talking about our phase II program. As Punit said, we've already launched our phase II- A study, and this is our proof of mechanism study. It's a robust clinical trial, randomized, placebo-controlled, and we're doing it in two arms. So the primary arm is the monotherapy arm where we're looking at nimacimab, and we're looking to validate its action. Now, Punit described to you and just very briefly, we had the first generation of CB1 antagonists, and there the action was validated. And we also know from the distribution of the CB1 receptors in the body and by their action that they're very important when it comes to energy modulation, weight modulation, and metabolism in general. So we validated that pathway. And then the second generation, as people like to think, is the peripherally restricted drugs, which is ours. What we are doing here is now validating in this 26-week trial the action of an antibody, which is clearly peripherally restricted because antibodies barely will go into the CNS and across the blood-brain barrier. We'll be looking at weight loss. We'll be looking at changes in body composition because we believe that with the CB1 pathway, when you block it, unlike what you see, for example, with the GLP-1s and with any drug that causes a lot of anorexigenic effect predominantly, you don't get the same kind of lean mass loss. For example, if you were getting a 10% weight loss with semaglutide, you could get up to 40% of that, 4% of that as a loss in muscle and bone. Compared to what we know from the rimonabant data, that when you target these alternative pathways like the CB1 pathway, you barely get any of that, so almost all of it is adipose, and that muscle fat ratio makes a big difference to your metabolic well-being, so we'll be looking at that. We'll be looking at all the other exploratory markers, including things that we think are connected closely to this pathway, like leptin levels, which go down as you lose weight, but also leptin sensitivity improves. We want to be able to show that insulin sensitivity improves as well. We're also doing a small study, sub-study, where we're just looking preliminarily at whether sleep quality improves because we know that as weight improves and you get better muscle-to-fat ratios, sleep quality improves as well. The second arm of this study, which is more exploratory, so we are going into what people think of as the third generations of CB1s, which is CB1 Plus. So you bring in a second drug and a second action with it. And we think that the GLP-1s are especially complementary in terms of action because their action is a lot in the CNS. It's a lot to do with reduction in appetite and food intake. And since the CB1s come in with so much peripheral action, the two together should do very well. So we are combining Wegovy and nimacimab versus Wegovy alone, and that will be an arm with 20 patients each as well. So again, randomized and controlled with the Wegovy arm. So that's the design of our trial. We're going to 26 weeks. We're going to have an interim analysis, which is when we've done 50% of the patients have completed the 26 weeks, and then the final analysis when all the patients have completed it. We do have a 13-week follow-up as well, so we'll eventually have 39-week data, including what happens 13 weeks after you've stopped the therapies. Great. And in terms of the data that we've seen so far and the arguments around peripheral restriction, can you just help us understand a little bit of your thought on the process? We haven't actually, I mean, we really haven't seen the full monlunabant dataset yet. We probably won't see it until maybe ADA of next year. So we're a ways off from that. Maybe just can you help us understand a little bit of the differentiation of nimacimab in terms of the level of peripheral restriction versus either rimonabant, monlunabant, or perhaps other potential competitor molecules? Sure. So let's start with rimonabant. Rimonabant, at that time, weight loss was something very difficult to achieve in an effective manner with a drug. Rimonabant was probably the first drug that effectively did that. And therefore, there was a lot of excitement around it. There wasn't a lot of effort to keep down CNS levels. Maybe it wasn't that well understood what could happen if you had the drug widespread in the brain. So we have an example for a drug that was very, in a sense, CNS predominant and didn't have peripheral levels that were that good. So the peripheral levels it did have, and at the appropriate doses, they showed a reasonable weight loss, and they got approval in Europe based on that. And of course, because of the adverse event profile, they never got approved by the FDA. Now, fast forward here, we are looking at the peripherally restricted drugs, right? And the small molecules, we have monlunabant. Monlunabant does leak. It's a small molecule, so it will leak into the CNS. And yet, compared to rimonabant, monlunabant has a lot more peripheral action, right? So it is a second-generation drug, but you still have the liability of the drug leaking into the CNS. So we are seeing with the dose response of monlunabant, and we've modeled this and we've looked at the levels of monlunabant, they don't see a dose response with the doses as they go up in terms of efficacy. And that's because at the dose they started with, they already have a pretty good level at the periphery. So it tells us that if your peripheral levels have already reached where they are, you're already getting a good response. You won't get much of it. They are getting some effect. They haven't given us the details, right? But you don't get significant rises because you're in the periphery, but they're not so much in the CNS. When they increase their doses, by our modeling, their CNS levels go up further and start to reach IC90, and so you see more neuropsych effects. So now the goal is to get better. Now that we see this, if we can increase the peripheral effect and stop that CNS effect, which is what happens when you use an antibody, which would happen with nimacimab, we believe, you will get the robust weight loss action. And you're seeing that already with monlunabant. They've got a 6% change, but not see the neuropsych events because we are not seeing the central actions. So you have a much larger therapeutic window with our drug in terms of differentiation because as they're going up in dose, that's only increasing the exposure in the brain. Yeah. And in terms of having a sort of clear understanding of the level of peripheral restriction that you have with your antibody, we've heard from some folks that there is some exposure to peptide agonists in the brain. We even know that there are antibodies that get into the brain in other areas, but in very, very small quantities, but are still effective. Alzheimer's antibodies is an example. So can you just help us understand the level of peripheral restriction that you think is necessary to avoid those neuropsychiatric events? But then importantly, why isn't some central action with CB1 necessary to actually drive the satiety response or the response from an obesity perspective? We see your peripheral restriction. We're looking at the peripheral receptors in each of the organs, and we're looking at what kinds of levels would achieve an IC90 and be able to effectively block those receptors and eventually be able to show a dose response with that. That's how we'd be looking at peripheral restriction. Now, there's a series of data that has come over time with peripherally restricted molecules, which are available for research, right, which have shown that if you use the peripherally restricted molecules, actually the weight loss in DIO models is exactly the same. It does not change, right? Also, there are adipose knockout models available where if you remove the CB1 receptors altogether from adipose tissue, these mice actually don't gain weight even when you put them on a high-fat diet. So there is data available that shows that this peripheral action is really critical. Now, as far as antibodies going into the CNS is concerned, I think it's a bit more nuanced than people look at. You're asking the question of, does it help to get some CNS action in certain ways? Probably, possibly, but here, the predominant action that we are looking for is peripheral. And that doesn't mean you're not getting central action anyway, even if you had zero, and we'll come to that in a moment, in the brain. I'll take the example of leptin, right? Leptin signaling is very important for satiety. So ordinarily, when we eat, leptin levels go up. They go to the hypothalamus, tell the hypothalamus that we've eaten enough and we are full, and you stop eating. It turns out that when you become obese or insulin resistant or diabetic or you have metabolic disorders, leptin levels are already very high. There was a time when we used to think that we had found the magic drug in leptin, and we quickly realized that leptin levels are already very high in metabolic disorders. So the receptors no longer respond to any increase in leptin. And so that is a defect that you have in obesity. When you bring the leptin levels down as weight is lost, you regain some of that. But there's also an action of blocking CB1 receptors that improves sensitivity to leptin. So we find, and we've shown this in preclinical models, that leptin signaling is resumed when you block the CB1 receptors. So you are getting a central action. You're just not getting it directly. So that's one thing. So you're getting satiety back, and you're changing feeding behavior. The peptides that have central action predominantly have it through limited receptors in the hypothalamus that they're acting on through the fenestrated capillaries that are in certain areas of the brain, right, where you want to sense what's in the blood, and that includes what's in the blood in terms of what you've eaten. It's possible that those kinds of effects might be seen with our antibody as well, which doesn't mean that there will be widespread distribution in the brain because the antibodies are not going to cross. The higher centers in the brain where there is CB1, where endocannabinoids go and modulate your stress responses and your anxiety and how you feel, those are the ones you don't want to hit. And those will happen when you have widespread distribution the way you get it with small molecules. Great. And just on your question about the magnitude, we've shown in our PK modeling 600-fold below inhibitory concentration, below IC90. So there's a very strong difference compared to small molecules. So relative to monlunabant, it's a huge, huge magnitude of difference, 50-fold difference. Great. Yeah. And so when you think about the profile of your molecule, what you'd like to see in the phase II results, what are you most focused on? Is there a magnitude of weight loss that you're specifically focused on? Is it the combinability with GLP-1s? What is the sort of, in the hierarchical order, what would you say are the most important results to see in your data? Is it safety first, then? Yeah. So I think, yeah, it'd certainly be safety first. In the class, safety first is a key factor. The next aspect is what's the requirement for regulatory approval? So the study is powered really well for showing an 8% change in weight loss in the monotherapy versus placebo. So that's what our primary endpoint is. But as you know, this evolution of the entire metabolic space has certainly opened up these possibilities of combinations and looking at the non-responders to GLP-1 or other interesting scientific and clinical questions. For us, we've been very disciplined about a regulatory path towards getting across the finish line in this class is checking the box off on safety. Phase I data showed a really strong safety profile, zero neuropsychiatric adverse events. We want to be able to replicate that in phase II. It does then put us really well positioned in the CB1 class as a development candidate. Our objective from here is going to be to do some dose optimization to look at a higher dose, and then we expect to be able to hit that primary endpoint. There is this exploratory aspect, and maybe you can elaborate on this: the additive effect of what we can have on top of GLP-1 or other incretin combos. We're continuing to evaluate that preclinically and obviously in the clinical side. From a regulatory standpoint, we'll continue to assess how that kind of makes sense from a. So there are different populations to treat in obesity here. It's a large heterogeneous population. There are people who haven't taken another drug and need their first drug, and we'd like to show that nimacimab works. So it's an option. And just like with other large heterogeneous diseases like diabetes or hyperlipidemia, you're going to have a lot of different mechanisms and can individualize treatment. But equally important, if you take those examples, is how you can combine different drugs for different people and bring them together. And because these effects seem so nicely complementary, we are eager to see how these drugs work together. We don't think that nimacimab has any significant GI issues, or at least whatever they are, they're relatively minimal compared to GLP-1. So in that sense, also, it's a good combination to have. And if we can mitigate the lean mass loss, for example, with semaglutide, all of those things coming together would be good because obviously the GLP-1s are effective drugs, and they're once in a generation molecules, and we want to be able to start putting them together. So we're looking at a population in terms of population, in terms of regulatory considerations. We're saying treating people with nimacimab as a therapy for obesity, treating people who are on GLP-1s with nimacimab as a therapy. So that's the beginning of starting to talk about combination therapies. And eventually, we can have ways to actually put them together and maybe conjugate them. And there's a lot of work to be done here. Especially looking at the SELECT data in cardiovascular, there's certainly an opportunity to be additive to those kind of indications. So addressing the comorbidities is another pathway. And nimacimab has the mechanism of anti-inflammation and antifibrotic components that I think need to be continued to be explored in combination. Great. And in terms of just the treatment duration, antibodies tend to have a longer profile. Can you just remind us what duration you're targeting? And as you explore higher doses, is it possible that we could get a longer-acting potential profile? Yeah. So right now, in the proof of mechanism study, we have a once-a-week subcutaneous injection. However, exactly as you pointed out, the antibody does have what seems to be a much larger half-life. We think that half-life could be up to 21 days. So our plan at the moment is, as we go forward and do dose ranging and we can go to higher doses, we'd be looking for up to a monthly injection. So those are things we are definitely going to be exploring. What about sequencing of treatments? We're starting to see maintenance studies emerge. What are other opportunities for your program? We think that there are actually numerous ways in which these other mechanisms that are coming in on top of GLP-1s can be used. And specifically speaking of CB1 and nimacimab, so we're talking about a combination that would get you to the right place metabolically. And then the question is, do you need to keep taking GLP-1s to maintain that weight? If you could keep your muscle mass up and you can just take, say, a once-a-month nimacimab injection, would that keep you metabolically in a great state and keep your weight up? Yeah, that would certainly be something of value. Got it. And I guess as a sort of just to kind of wrap up, as you think about the future of the company, let's assume that the phase II study is positive. You've sort of hit those key metrics on safety and efficacy. What do you see as sort of the next steps for the company? Is it finding a strategic partner because of the cost of development, or is it an area where you feel confident in future development with Skye on a go-alone basis? Yeah. So initially, we're continuing to keep the gas pedal down on our development objective. So we are already working on subsequent study, and partially why the interim data look is built in is so we can quickly move to phase II-B to explore the dose component before we launch our formal phase III. Ultimately, for commercial purposes, I think we would like to work with a partner. But I think there's a great opportunity here in 2025 to hit those objectives and create a bit more value for our shareholders before we explore that commercial opportunity. All right. Great. Yeah. Thank you, Punit and Puneet, for joining us here at our conference, and really look forward to your data next year and an exciting 2025. Thanks, Seamus. Thanks so much. Yeah.