Great. Good morning, everyone. My name is Ted Tenthoff. I'm a Senior Biotech Analyst at Piper Sandler, and before I begin, I am required to point out certain disclosures regarding the relationship between Piper Sandler and Skye, our next presenting company, which are posted at the back of the room and at the registration desk. A s you may know, Skye is developing CB1 antibody and nimacimab for obesity. It's a really cool program that I think is being underappreciated by the street currently and has a lot of potential upside. Here with us from the company are Skye's CEO, Punit Dhillon, and also the Chief Operating Officer, Tu Diep. T hank you both for being with us.
Thanks, Ted.
I thought maybe a good place to start would be by describing the cannabinoid system and its role in energy, metabolism, and storage. Walk us through the rimonabant saga because it really is sort of the proof of concept for weight loss. And then we can kind of pick up some of the CNS stuff in a minute. But tell us about that fundamental mechanism.
Yeah . That's a great place to start. Y eah, the saga of rimonabant continues to carry into the current generation of CB1. But going back in terms of just understanding the biology of CB1, you can think of it as kind of this conserved pathway that has been linked to energy storage and fat storage and slowing down metabolism. Back in the famine, this was obviously important. But that switch has been essentially left on. And what rimonabant did was turn off that switch and reverse that. And it actually showed, like you said, a strong efficacy to do that. And that's why this is an interesting pathway because it's unlocking that link, that those brakes connect to fat storage. W e believe that that helps set the stage in terms of this particular target being a really attractive one.
It, unfortunately, was delivered as a small molecule, and small molecule in that instance was actually targeting the receptor in the brain, so not only did it turn off the switch on in terms of fat storage, it also turned off the switch in terms of the joy side of what this target is linked to, and that exacerbated these neuropsychiatric concerns like depression in severe situations, even having suicide ideation. I t wasn't approved in the U.S. FDA stopped it. Europe basically pulled it off the shelf, and we had this withdrawal of interest in CB1. Fast forward, there has been a lot of appreciation that small molecules can be modified, be peripherally restricted, and then fast forward a little further, and you have an antibody that's developed, which is the one that we're developing, which is the first antibody that is truly peripherally restricted.
The difference, I think, is it's kind of an interesting segue is that the small molecules still have a tendency to be able to cross the blood-brain barrier and penetrate into the brain, which is what we're seeing even in the current new data sets that are coming out. Whereas the data that we've been able to produce has continued to show unequivocally no concern of crossing the blood-brain barrier and also showing that it's safe, that we've had zero neuropsychiatric adverse events in two different clinical trials now.
Picking up on that and focusing in on the nimacimab, walk us through the extensive preclinical data that you guys have generated here because you created this human CB1 receptor knockout, DIO mice. You really have done a lot of work to kind of characterize this. Walk us through some of that preclinical data on the nimacimab.
Yeah. T he big kind of leap for us was that up until generating that data, we didn't have a true POC, a true proof of concept of this particular pathway. W e saw something remarkable that we actually can drive weight loss by a completely different mechanism in terms of targeting that receptor. B y us approaching it through this antibody and allosteric modulation, we are not only able to see driving weight loss, but what we've been able to generate over this past year is four important pillars that help to substantiate why that weight loss is happening. And the four things that we really try to stress on is that this is a coordinated approach that's happening. T his is a much broader metabolic rewiring. And why it's important to stress this is this is different than how the other drugs to date have worked.
The current incretin class of drugs are primarily focused on appetite satiety or stopping people from eating. I t's really a completely different pathway. Where we're focused on is we're able to not only regulate these appetite-regulating hormones, just like the incretins, we're also able to drive lipid metabolism and show that there's this energy expenditure kind of pathway. We're able to show that there's improvement in inflammatory markers and other inflammatory cytokines. And then, importantly, we're also managing glycemic control. Y ou see multiple things happening, those four being critical to help drive a broader weight loss. Now, that data, that POC on the mechanism has then translated into what I would say three important findings that now are starting to prove themselves out clinically.
One has been that there's a correlation in terms of dose response, that when we dose higher, we do see an improvement in dose. Tu can elaborate on kind of technically and from what we're seeing from an IC90 perspective. The other second point is that we're seeing it being competitive to the small molecules. We actually have done a head-to-head experiment with these brain-penetrated small molecules. We're showing that the steepness of our weight loss is sustained and that when the DIO mice are taken off the drug, that the rebound is less with the antibody versus the small molecules. We've also proven that in combination with incretins in both semaglutide with GLP-1 and with tirzepatide, that we've seen improvement in terms of weight loss. We've seen a synergistic effect.
Lastly, what we've also now started to show from preclinical and also in clinical is that rebound weight regain, the weight regain piece, we've been able to blunt the weight regain. In the clinical, sorry, in the preclinical experiments, it's shown about 7% regain versus, was it 40%?
40%.
Yeah, 40% regain for tirzepatide. And then we've just recently shown some clinical data that has a similar type of curve in terms of the weight regain. T he preclinical story has been really important this last year because now we finally have all of that base work that has helped us establish a clinical piece that helps to reiterate and recapitulate that data.
You guys reported the Phase II CB1 data. What did you learn from that human clinical experience?
I mean, quite bluntly, we didn't dose enough.
Yeah.
But in our mind, that's not a bad thing. What we have been saying all along from the perspective of what our next steps needed to be was that the intention was to deliver higher doses in a dose range of the study. The study that we conducted, the CB1 study, was evaluated a single dose. W e've obviously believed that that dose that we selected would have been effective. Unfortunately, it wasn't. But at the end of the day, it was a proof of concept study. And we proved a lot that the drug is safe. And then there is some effect. And then the biology, we believe, based on the clinical data, even though the monotherapy didn't show real effectiveness on its own, what we see in combination with the tirzepatide was extremely exciting and extremely competitive. That, we believe, certainly shows the biology is effective when you're targeting the peripheral CB1 receptors alone.
I really think it was high expectations going into CB1.
Yeah.
Excuse me. And the thing is, too, nothing's really being developed in monotherapy going forward. The whole goal is to develop these drugs in combination. M aybe to dig in a little bit more into what you saw, because I thought the synergistic effect with Wegovy, with semaglutide, was very, very compelling.
Absolutely.
And truthfully, is the more important piece of the puzzle to solve anyway.
Right.
Maybe get a little deeper into monotherapy.
Yeah. I think if you just look at the numbers themselves, right, semaglutide showed about, in our study, showed about a 10% weight loss. We showed about a 13.5% weight loss. T hat's a 30% improvement in weight loss at 26 weeks. And then you sort of zoom out a little bit more and you look at the combination weight loss, you compare it against other drugs at around that same time frame, even drugs like tirzepatide and other combinations, we are very competitive. We're right in line with tirzepatide at about six months. We're better than CagriSema at six months. W hat we're projecting, and we have the extension study ongoing, as you know, that if we, with the additional 26 weeks of dosing with the combination patients, we think we're going to see a very competitive weight loss at that point.
If we can see somewhere in the range of about 20% weight loss with the combination, with, as we just said earlier, a suboptimal dose of the nimacimab, then this could be a really compelling combination, especially as we look towards dosing higher, because we know, again, that even with the additional weight loss that we've seen, we're not seeing any additional adverse events, right? We didn't drive additional GI issues, and we didn't have any neuropsychiatric adverse events, and the last two pieces I'll point out is that that 30% increase in weight loss was really driven by a 30% increase in fat mass loss.
Yeah.
Right? There wasn't any additional lean mass loss in that combination group. T hat's extremely exciting as well and also speaks to the mechanism that Punit was speaking to, that we think CB1 is driving preferential fat mass loss. And the last is that more durable response. When we look at those patients that went off therapy in the combination group versus the semaglutide group alone, that combination group actually maintained their weight loss over 12 weeks pretty well, right? What you would expect in the Sema group, from what we've seen in other studies and what we saw in our study, is that patients gained back the majority of their weight within that first 12 weeks. And in our case, with the combination group, when they go off both drugs, they only gained about 8-10%, I think is what it was, or 18% of their weight back. That's a significant difference.
True.
And we think that that's, again, a nice sort of tip of the hat to the biology of the CB1.
Yeah. I want to just expand on one thing. T he thing to summarize it really well was to kind of take it to what do we learn in terms of what do we have to do next? It comes down to putting our foot on the gas pedal in terms of being able to really have a strong rationale for dosing higher. T here's three critical learnings that are important from the data set that safety really is our leverage. We have a wonderful safety base here with this data set. And we have ability and a sufficient therapeutic window to go higher. Mechanism has been validated. Mechanism shows that it works in terms of the monotherapy. And it really is highlighted in terms of the synergy with the combo. And that finally, that the dose matters.
The dose matters because we not only learned from what's happened in this clinical trial, but we also have all of this preclinical data that we just walked through, which we didn't have when we started the study, right? There's a really interesting correlation now with dose response that wasn't available to us, which enables us to build a stronger PK model that allows us the rationale to move higher. Our main prerogative right now is to put the gas pedal down and continue really solid execution on this next part of the study, which is going to reveal the durability of this signal that we saw. Interesting to kind of get into these next steps in a little bit more detail. We do have the open-label extension.
I think patients escalated a little bit there to 300 weekly nimacimab for an additional 26 weeks. When do we get that data? What does that show us? But then what do we really expect in this next series of studies?
Yeah, so there's three parts to this next, this current 26 weeks of what we would refer to as the 52-week time point.
Yeah.
First is that you will have this broader evidence of exposure of the drug for patients that went from the first 26 weeks onto the next 26 weeks. There is a small difference there that those patients went to a 300 milligram dose. W e'll have a deeper understanding of what that drug exposure looks like from a PK perspective. What's going to be interesting is there is a separate cohort that was the placebo group that crossed into a 300 milligram dose. I t'd be also a fresh or a new cohort of patients that will have first data for the 300 milligram dose. And what we're interested to see there beyond a more robust understanding of our PK is if there is this correlation in terms of incremental weight loss.
We're not obviously going to see a sea change in weight loss based on what we saw in the top line on the monotherapy. But if there is a dose response there, then that obviously signals that the biology is working. This hypothesis that we have of a linear increasing of exposure leading to deeper weight loss holds true. Third important thing is the combination. And the combination trajectory, as Tu pointed out, was really interesting at 26 weeks where we didn't see any plateau of weight loss, 13.5% weight loss at 26 weeks. And we want to see that continue to get to that trajectory of the 20%, which is the important competitive number, we think, as first evidence of POC on this combination synergy.
If you get to the 20% mark in this unique differentiated approach where CB1 combined with GLP-1, we believe that's a very competitive product profile, especially with better tolerability. No concerns of any of the safety. There's exciting things that really unlock by us achieving that. As we showed in preclinical data, there's interest in looking at suboptimal dosing of an incretins and seeing what that result would look like. Obviously, there's interest in us dosing higher on the nimacimab. What would that look like? It really positions us well for a strong Phase II-B.
Yeah.
That's what we're geared towards in terms of learning from our extension study.
On the other side of this next data set, you really do get to a development crossroads here where there's a lot of different directions that you could go. What do you really see as the optimal development path for nimacimab if we had to make that decision today? And I know you've had, there's a lot of interest in this space from pharma. There's a lot of competitive mechanisms that are sort of giving you additional data sets to look at. Is the best way to take this forward is combo? Are you looking at maintenance? Is that something you maybe evaluate further in the future? What do you really see as the development path for nimacimab?
I'll let Tu take the development question. But I just want to set the stage there in terms of there's, I think, a first question to your question, which is kind of like a why not, because there's a piece of this that if you look at the pipeline, it's still all dominated by the incretin class, right?
Yeah.
We know that the GLP-1 market and the GLP-1 combo market is under severe pressure for price compression, something we talked about in July of 2024 with you when we launched, right before we launched the trial. It was like, we expect that GLP-1 pricing is going to come down. That is playing out as we speak, and if you look at the pipeline after that, it's all other combos, just other double incretins or even a triple incretins, and even CagriSema, which would be the first combo of a non-incretin, is more or less the same mechanism, so what's exciting for us from a development standpoint is our plan, our timeline, believe it or not, fits really well in terms of being a near-term drug and capturing a market.
For me, from our strategy, I don't think it's right to rule out that combo for us is a first-line opportunity, especially in such a heterogeneous market. Y ou can tell us about the development.
I mean, I think, again, I don't think it changes from what we've been speaking to is that we do need to do sort of a dose ranging evaluation of nimacimab. I think what we've established is 200 milligram is probably our minimally effective dose. But we want to continue to evaluate higher doses of nimacimab and then find that right dose to then move it into the right combination. O nce we find that right dose, then moving it into a combination allows us to then evaluate the combination dose, right Because I think there's also opportunity here to look at a GLP-1, whether it's semaglutide or tirzepatide, and still sort of reduce that dose, right?
Yeah.
Improve the adverse event profile while still maintaining really good weight loss. I think one challenge that we continue to deal with, but I think the market will eventually catch up with, is we don't need 30% weight loss. It's not like, that's really not the realistic goal, I think, when you speak to physicians. Physicians are like, "I'm really happy if my patient loses 10%." But they need to maintain that weight loss, right?
Yeah.
I don't want them to lose 20% and gain 10% back, and then lose 5% and then gain 10% back. That's not meaningful to them. That's not healthy. T he real goal for patients and physicians are, I want patients to be able to lose weight. I want them to maintain that weight loss and do it in a healthy way. I f we can find the right combination to be able to support that, I think that's really the goal for us.
Yeah. Absolutely. I know it's still not totally finalized, and we'll get more data that will help with the modeling. What doses are you envisioning? How high do you think you could go?
There's plenty of room to go higher because we do have a pretty sufficient safety window. W e don't think we need to dose that high in order to see that efficacy. But right now, what we believe, based on our PK modeling, is that sweet spot is around 600 milligrams or a little higher than that. But it also could be lower than that. T here's a kind of the equation for us right now is also looking at the frequency of the dosing.
Yeah.
We, from a development standpoint, haven't ruled out lowering the frequency but increasing the dose as a way to build more features that are amenable for a product profile that's convenient for patients.
Less frequent than once weekly.
Yeah. But a higher dose in order to make sure that there's enough drug exposure. T hose are going to be explored in the Phase II-B in the dose ranging. And this data that we just talked through in terms of the current extension study and what that gives us is it gives us a very robust PK understanding. T hings that we didn't have when we started the study, we didn't have preclinical data. We had a Phase I that wasn't an obesity that gave us a sense of understanding around PK. But the current data based on 52 weeks gives us a way better modeling for our PK exposure. So.
Plus concern about potential CNS side effects, probably.
Yeah .
We always did how high you were willing to go in CB1. And now you really have established that safety database.
Yeah. Exactly.
Where you have a lot of room to go. I'm excited to see this next trial. In the time we have left, I know you guys ended the quarter with around $35 million in cash. How long does this fund the company? What's it enable you guys to accomplish?
Right now, that's sufficient capital to get us through all these near-term inflection points that we're talking about, including the data from the extension study where we also are continuing to fund some other work that we're doing preclinically as well as on our manufacturing and CMC side. W e're kind of laser-focused on how that capital allocation is at the moment. We're really focused on spending the capital on data generation and directly de-risking kind of these next steps that we're taking. T hat's what we believe is the equation to directly create value. We have to drive value quickly, and we, I think, have a really interesting window coming up in Q1 where we should be able to unlock some value with some way better understanding than going into what we just had in the first 26.
Yeah. I think it's a really compelling opportunity. Thank you guys so much for being with us today.
Thank you.
Excited for more data next year.
Thanks.