All right. Thanks very much. We'll get going with our next half-hour session. My name is Dae Gon Ha, one of the biotech analysts here. Next company we have, Skye Biosciences. And with me right now is Punit Dhillon, the Chief Executive Officer. So, Punit, I'll turn it over to you for a brief intro of the Skye story, and then we'll dive into Q&A.
Great, Dae Gon. Thank you so much for inviting us to the conference. It's really a pleasure to be here again in New York and here at the Stifel Conference. I'm going to just give a quick overview just so we get everybody oriented, but then we can dive into questions. The reference here to the disclaimers is important because I have a tendency as a CEO to make forward-looking remarks. It's important to look at our risk factors. Please always contact us if you have any questions. Just as a company, it's really come together really well over the last year and a half. We've been working hard on building a very comprehensive metabolic pipeline. It's led by nimacimab, which is our lead program. That's now in Phase 2 studies. We'll talk more about that in detail.
Underneath that is obviously a broader pipeline that's coming together, where we're continuing to look at GPCR targets, biologic targets, that are focused in the metabolic realm. We're really excited about how that there's a differentiated story here. As the header alludes to in this slide, a new generation of CB1 inhibitors. We do think that there's a CB1 plus type of story that's also evolving, especially in the non-incretin space. So you think about the landscape, GLP-1 and amylin has certainly gotten a lot more attention this year because of CagriSema. It's going to continue with amycretin and even there's DACRA type of targets. But there's I think an opportunity where CB1 plays a backbone as well, as long as we continue to uphold that benchmark of safety that Skye has. So in terms of what have we accomplished?
What, where are we headed? We're really focused on building a comprehensive company here. It's based on the backbone of nimacimab intellectual property and additional life cycle management that they have, we have ongoing there. We're continuing to build on that. We have a good group of experts that have experience in metabolic diseases as well as obesity specifically, as well as the leadership team. We've continued to expand our leadership team to have all of the expertise from CMC, regulatory, you know, clinical development that has experience bringing drugs to market, and we're continuing to spend a lot of effort in the background on full CMC capabilities. Part of the opportunity here in obesity is to really have a differentiated target product profile.
So not only is that important in the class of CB1, but I think just generally in the overall anti-obesity landscape and certainly in the non-incretin landscape where there's still a really shallow, shallow set of data points. In 2024, I think we saw a lot of GLP-1 data points, and that's given us a good baseline of where the tolerability and discontinuation rates are. So for us, when we look at CB1 inhibition, safety is the most important benchmark that we put first in terms of our product profile, certainly to overcome some of the historic limitations with this class. And then after that, obviously we're looking for meaningful weight loss, as well as improving on GI tolerability. And then we believe CB1 inhibition has ability to demonstrate a lean mass preservation compared to other mechanistic approaches.
There is a product profile here that is looking towards a less frequent dosing. So right now, the current clinical trial dosing is a weekly injection, but we want to get to a monthly injection. And as you will get into this in terms of the clinical trial design, we're currently looking at a combination in the trial with GLP-1. In the real world opportunity, I think there is a real solid case to be made that you can potentially lower the dose of GLP-1 and then make up for that delta that we lose for weight loss by going to lower dose with CB1. So combination rationale is there. The roadmap here is really aggressive. So this is a competitive roadmap relative to our peers. 2024 has been a great year.
I'm looking forward to updating everyone as this year continues and going into JP Morgan on all the progress. We just announced surpassing 50% enrollment on that trial. That sets us up really well for the interim data point in Q2 of 2025, followed by top line data on that trial. Then we'll be initiating a Phase 2B, and the Phase 2b is going to continue to look at dose optimization, as well as other opportunities for product positioning. Following that study, depending on how large we want to make that study, we would have all the information necessary to go and have an EOP2 meeting. So when you think about cramming all of that in, it's underway. We have the cash runway. We're pushing forward aggressively on that plan.
Team, I won't spend too much time here, but I'm really lucky to have such a great, experienced board and management team around the organization. We're going to continue to see, you know, where else we need enhancement in terms of expertise, but a solid group in terms of metabolic experience, R&D experience, CMC experience, especially, and as well as the G&A side. Just in terms of financial metrics, lots has been done in this last year in terms of capital access. Well positioned there from the cash runway to get through to Q3 2027, which is an enviable position relative to, I think, the overall markets. We're continuing to be very judicious on capital deployment. We are focused on clinical. We're keeping our burn rate low and very targeted towards where we expect to really drive value, which is the clinical program.
Other things have also been accomplished this year. Really, you know, it's a pleasure to continue to tell the story and see how we enhance from here. So that's a general overview. Happy to dive into any of the details, and we can refer to the slides if we need to.
Yeah, so thanks for the overview. Certainly with CB1, let's just address the 800 lb gorilla in the room, which is rimonabant. The memory that gave us a lot of learnings, but also draws a lot of question marks around what we should be expecting on the CB1 targeting space, so we're now seeing sort of a renaissance almost, right? With you, Corbus, as well as Novo's in there as well. What was the rimonabant issue that you're trying to really distance yourself from with this nimacimab approach? And what are sort of the characteristics of nimacimab that you believe really makes it a peripherally restricted rather than central leakage that rimonabant had?
So I'm going to approach one aspect of that question from a glass half full perspective, is that CB1 inhibition has certainly been a great validated target because of the Acomplia/ rimonabant experience. And you're, you know, referring to the Sanofi drug. Even more broadly than that, there was another pharma that was spending a lot of time resources on CB1 inhibition. So certainly a great target, but the basis on all of those first generation targets is central CB1 inhibition. So it focused on the brain, focused on inhibiting the signal in the brain. And that obviously went a little too far, and in some cases patients experienced suicidal ideation. There were extreme situations where there were fatalities. That product was removed from the market.
Fast forward, you know, you had a group of researchers at the NIH that continued to advance the science and looking at peripherally restricted small molecules. And out of that came, I think two, you know, interesting approaches that are on the market today. You referred to one, which is Novo's monlunabant, which came from Inversago. And then the other is Corbus's drug, where they modified JD5037 and they continued advancing. But the lineage goes back to this NIH lab. There's another side of the story where Bird Rock Bio was interested in exploring CB1 inhibition as well, but really thinking about how do you overcome, even if there is, as you put it before, you know, the risk of brain exposure or, you know, not shaking off this neuropsychiatric adverse event and coming at it from a large molecule standpoint.
They developed an antibody, which happens to be the first antibody that's allosteric modulating, negative allosteric modulator, and it's inhibiting the CB1 signal and differentiated from the small molecule. We can get into that. So that's kind of a backdrop. What's exciting here now is the data points that point to how the peripheral mechanism, meaning outside of the central compartment, is driving meaningful weight loss. The first data point we saw, the major data point, was the 16-week data that Novo reported on September 20th. I would say that, look, from a glass half full perspective, very exciting data because it's to me a watershed moment for a truly peripheral mechanism driving weight loss.
And we've, when we're comfortable kind of making that remark is because we've done a broader PK analysis to look at what would be, have been the potential central activity versus the peripheral activity. And I would say even Novo themselves has really leaned into saying this is a peripheral driven mechanism. And subsequent to that data, Skye has now come up with additional preclinical evidence that shows with nimacimab that weight loss, that peripheral sufficiency is adequate. So there's still some open questions. Some of the feedback that has come up has still been, is there a central component required to drive that kind of same activity that rimonabant had? And we have a good picture, I think, that's coming together that shows that no, that's not required. Central is not a requirement and peripheral sufficiency is plenty.
And that's the safer way to go. And that's where nimacimab should really set the benchmark.
So that was actually one of the key data that you guys presented sort of coinciding with the ObesityW eek. Chris walked us through various data and modeling predominantly of how the central exposure differs in the rimonabant case and compare that to peripheral exposure. Maybe for those of us that weren't there, can you just briefly remind us what the key findings were as it pertains to brain exposure? Yeah. And peripheral and why that leads you more towards peripheral being more responsible for weight loss?
Yeah, that's a great, great question. So we can segue to that really quickly here. So in the, in the deck, by the way, this, more comprehensive presentation that Dae Gon's referring to is on the website and there's a video related to the obesity week presentation now. So please dig into it, and take your time reviewing the slides and the audio and video. But, here's a quick executive summary. There's, the question of peripheral exposure, and making sure there's adequate saturation of the receptor is the key, key factor that we want to look at. So when you look at the left side of this slide, we're seeing adequate, saturation of the receptor at 10 milligrams, 20 milligrams, and the 50 milligram dose. These are the three doses that were evaluated, by, Novo in the, in the, in the Phase 2 monlunabant study.
On the right side is the same, you know, evidence with nimacimab, but the dark blue line refers to our clinical dose, the once weekly. We've also modeled some other scenarios here showing that in each of these modeling, there is adequate saturation. Peripheral works and what's the takeaway here is that in the press release that Novo noted that they didn't see a dose-dependent weight response. That's what we're kind of indicating here is that there's adequate receptor engagement and we don't need to see higher. You won't see any difference at higher doses. However, when you're increasing the doses, you're also increasing the brain exposure. On the lowest dose, it was above IC 75. In the middle dose, it's between IC 75 and IC 90 and above 50 milligrams, it's above IC 90.
So you know, when you're thinking about these adverse events that were quoted, sleep disturbance, anxiety, agitation, I forgot, irritability or something like that, that was worded, there's a clear reason that you're getting that. But that's clear, but let's go back to the 10 milligram dose. The 10 milligram dose is also below IC90. So it wasn't a centrally mediated weight response. And we'll come back to that in one second as to your question on rimonabant. The key thing on the right-hand part of the slide is the nimacimab is 600-fold below IC90. So we're really, if you're looking at from a stacking numbers to numbers, the differentiation here is that you have a large therapeutic window available for nimacimab and still stays out of the brain.
Now coming back to, do you need central activity? Well, we can look at the rimonabant exposure as information or a data point on why that isn't necessary. For those that don't have those data points 14 years ago at their fingertips, which is what I'll tell you, and this is all published, the five milligram dose of rimonabant showed about a kilogram drop in weight after 52 weeks. And the 20 milligram dose showed about a three kilogram drop in weight at 52 weeks. And you can see on this slide that there was adequate coverage above IC90 on the central exposure. So at five milligrams, it's getting into the brain, 20 milligrams getting in the brain. On the right side though, the five milligram is not getting to IC90 in the periphery, but the 20 milligram is.
I think contrary to the thinking, yes, we agree that the bias for rimonabant was a centrally mediated, maybe anorexigenic pathway, but you also shut down the signal in the periphery as well. And that's what drove the weight loss, not the five milligram dose. So that's the key takeaway is that central inhibition, in going back to the monlunabant data, the 10 milligram dose would not have been adequate enough to have any shutdown of the central receptors in the brain.
Okay. So on that point, I guess a couple of questions to follow up, but maybe I'll start with this. To what extent should we be looking at the magnitude of weight loss that monlunabant showed in their Phase 2a data, recognizing there was no real dose response, right? 10, 20, and 50 seem fairly similar. Is that the bogey? And is that kind of the limit that we should be expecting from a CB1 inhibition? Maybe we'll start with that before we think about some of the other questions.
No, I don't think so. I think that the 16-week data is still, I mean, one thing we don't have is any dose curves. So we're all shooting in the dark in terms of estimates. The only other thing that we can backdrop to is that Novo themselves were, I guess, giving guidance to maybe, you know, higher numbers. So I would say that we still need to see the 52-week data to make any of those conclusions. But going back to rimonabant, you know, we did see 8%-10% depending on what way you look at the protocol and the intent to treat population. There was a pretty sufficient 50 at a 52-week, it was a meaningful number.
So I think that there is a lot of room and in the case of nimacimab, there is an even more interesting opportunity there where we have a lot of room on the therapeutic window. So when you think about the PK profile and where we can still see if there's if we can dose higher and see a difference in terms of how that curve looks like, we'll get that evidence after this study. So the interim data is going to be the first time now with 26-week data. It's encouraging the 6% placebo adjusted at 16 weeks for it to translate to what we're expecting, 8% at 26 weeks. So I think that we didn't have that data point going into that, but I'm glad, you know, we powered the study accordingly. I think it's in the right ballpark.
And the other thing, I mean, I'm not an endocrinologist, so the other Puneet, our CMO, does a better job explaining, you know, in terms of this component. But I think that the way I look at it simply is that, you know, a peripheral, a truly peripheral driven response, you get like a the two for one approach. You do get an indirect engagement in terms of appetite regulating hormones. So you still have, but by targeting fat, focusing on CB1, converting this fat to energy and reducing these adipocytes, you get that leptin signaling. So you're reducing leptin levels and you are engaging in terms of leptin sensitivity.
So indirectly, it's not a direct thing like how GLP-1s are driving the caloric restriction through the brain signaling, but indirectly we're doing that. Coming back to the metabolic gains, you get a broader metabolic gain. You get the weight loss, but you also get the leptin sensitivity adjacent, insulin sensitivity, and other metabolic gains that we think are going to drive a deeper weight loss. I would say, I think there's been this obsession with fast, quick weight loss and it's been fast, quick weight loss in a short amount of timeframe. I think having spent time with Dr.
Arora, and just spent with these other obesity doctors, it's really clear that smarter, sustainable weight loss, slower, is actually the way that these patients are going to see that it stays off versus what, you know, the incretin approaches are. So I think the CB1 has a really cool role to play in the overall landscape.
I guess another distinction you guys have with nimacimab is, to your earlier point, this is a negative allosteric modulator versus a small molecule that is competitive binding inhibitor, to the receptor. So what kind of drew you into this particular approach when we think about downstream effects, i.e., weight loss, and why not pursue a small molecule given that, you know, there are other companies that are clearly pursuing small molecules?
Yeah. So, well, funny enough, the small molecule activity drew us into the overall CB. So go back, rewind, Skye had a fair amount of experience with CB1, but in the agonist space. So we had a good understanding of what the mechanism was around CB1 and the small molecule activity, in terms of the companies that were involved. We followed Inversago closely. There was a substantial deal in Q4 of 2022 that was the light bulb for management that says, okay, hold on, there's some interest again in CB1 inhibition. We already knew that CB1 was not an exciting therapeutic area. Inhibition wasn't exciting because of the rimonabant story, but with an $80 million deal that Inversago had done and then launched a Phase 2 study, it certainly popped, in terms of interest.
So there we knew a Bird Rock sitting there with an asset that had a really good data package. It was developed by Janssen for a NASH program that Janssen decided that they're not going to pursue. So we had the opportunity to take that, repackage the IND and all of the regulatory information to go into obesity. I will say to be transparent, we were looking beyond obesity. We were looking at comorbid indications as well. I think it was nice to see that the buy side was really keen on obesity and it made our development plan very simple in terms of being able to drive towards a data point. And then that led us to the trial design, which I think this trial excuse my language is like a no BS trial.
Like it's asking all the right questions. It's the first non-incretin data point that we're going to see in the space in the first half of the year. It gives us 26-week data and it gives us the CB1 data. So, you're going to see that a comparison across three different active arms as well as the body composition data point. So, I think we're, you know, getting, we're going to get to the answers that everybody wants to follow. And everybody that's following the CB1 inhibition space that still has that burning question about, is central inhibition required? Well, we're going to answer that question here as well.
And if we can show that we can drive eight% weight loss and without neuropsychiatric side effects, with a better GI profile, with lean mass preservation, that's a home run in terms of the overall landscape at this point in time.
Yeah, so on the CB1 trial, which you mentioned interim data in Q2 of next year, you recently announced more than 50% enrollment completed. So we're kind of taking down to that Q2 readout. Just do the back of the envelope math, but 50% enrollment with multiple arms where you're dealing with mono as well as combo therapy raises the question, how compelling slash definitive is that readout going to be? Is that going to be a lot of noise? Can we really reinterpret coming out of that interim readout or is it more likely to come out sort of in the full data set in Q4? So help set some expectations around those multiple arms that we're going to be expecting.
Yeah. So to be clear, first of all, like we saw from our satellite event at obesity, we take the data presentations of anything we're doing very seriously. So we do feel there's a responsibility to set the tone for what CB1 inhibition and how the overall market and the doctors and patients and everyone gets comfortable around this access. So the safety has always been paramount. And I think that that's the number one thing that we want to make sure that we re-read out and report. And obviously we'll have that information, but the interim, specifically on the interim data, you should expect that you will see, when we say 50%, based on 50% enrollment, it will be on 50% of each of these arms.
So approximately 60 patients, and it'll be on the full 26 weeks of data, but it'll be only the top line weight loss, and maybe we don't know yet. I don't know the specifics around whether body composition will be included in that data point, but I hope so. And but certainly the safety information, whereas the top line information on the full data set will probably give us a bit more time to clean the information and have all of the follow-up and other things that are necessary to report the finer data points on secondary and exploratory endpoints. So none of the exploratory endpoints I'd expect in the interim data.
Fair enough. On the combo therapy arm, I mean, the 8% weight loss is presumably for the monotherapy that you've powered for. For the combo, what's the goal or profile that we should be looking out for? Is it additive benefit? And if so, to what extent? Like what magnitude on top of the GLP-1 should we be expecting to get you excited?
Yeah. So I'm expecting an additive benefit, but I think when we spoke, when we're speaking to doctors and seeing how that translates into a real world setting, the expectation is that patients are going to have a better tolerability profile, better lean mass preservation, and be able to get to the desired weight loss over perhaps a longer period of time rather than that drastic drop that they're experiencing. So we don't have a specific number that we've given guidance to, but we expect it to be higher than 8%. And that would be, I think, achievable given Wegovy's profile and evidence of that mechanism.
So certainly, you know, we expect the nimacimab with everything that we have now with the preclinical data and the Phase 1 data to support that it's going to be an additive effect. The synergistic effect, I think, is a further down the road question, in terms of what I was alluding to earlier about whether we can drop the dose to a more lower dose instead of the titration dose that patients have to take and then make up for that deficit with CB1. In this current trial, the way it's designed is that patients are still coming on as a titration and then they get to 2.4. If they can't handle 2.4, then they go back to 1.7. So the 1.7 is the bare minimum for the maintenance dose.
Okay. That seems to complicate the situation. Why not just bring in people who have been on stable dose for say like six months on Sema?
Yeah. So we went for this trial design. We went patient naive, just so we don't have any prior, you know, data points that are conflating. So all of these patients are naive to any anti-obesity medication, drug.
Okay, so is it safe to say that the interim readout is going to be a good barometer for what to expect by Q4, or do you expect material evolution from the Q2 interim to Q4?
I believe it's going to be a really good barometer. I think the interim data readout is what most people are waiting for in terms of it's a well-established mechanism in terms of validation. It's a good number of patients. Like even looking at the GLP-1 data, our interim data will have more patients than some of these Phase 2 data points that have been read out in GLP-1, so I'm excited about that. I think it is going to be a good barometer and I'm going to stand behind that it's an exciting non-incretin mechanism and it's a first in class in CB1, so I think we will see certainly the more of the depth that we need on all of the top line information in Q4, and we're looking forward to doing that.
And plus, I think, I don't want to speak on behalf of the R&D group, but there's, you know, very much interest in terms of publishing this. So we want to, as you have highlighted, like we've crammed so much information in this trial. So there's going to be a lot of different data points that I think will come out, including that follow-up period for 13 weeks, right? So we're not going to have that 13-week data at that 26-week time point. So you'll have even evidence of durability, later on, in the year.
But presumably by Q4, you would have updates from the interim cohort that would've had the 13-week follow-up, right?
Yeah, but not for everyone. Yeah. Yeah.
Okay. Looks like we're out of time.