Hey, everybody. I'm Cory Kasimov, one of the senior biotech analysts here at Evercore ISI, and it's my pleasure to host our next discussion with Contineum Therapeutics. Excited to have the company's CEO, Carmine Stengone, here with us in Miami today. So, Carmine, why don't I hand it off to you to kick things off? Maybe a quick overview of Contineum and kind of the company's overarching strategy. Yep, absolutely. And Cory, Evercore team, thanks so much for inviting us to the fireside chat. As Cory said, I'm Carmine Stengone, and I'm President and CEO of Contineum. A little bit about the company. So the focus of the company is within the area of NI&I, so neuroscience, inflammation, and immunology. As we choose targets, we always start with a neuroscience component. As luck would have it, a lot of these targets have applications within the I&I space as well, and that'll be particularly relevant as we talk about LPA1. We currently have two clinical stage assets. So one is a first-in-class selective inhibitor of the M1 receptor, so the muscarinic 1 receptor. We have a partnership with J&J around this program. We are currently running a Phase II clinical proof of concept study with PIPE-307 in relapse-remitting patients. That study, as of our last Q filing, so end of September, was a little bit more than two-thirds enrolled, and we are guiding to full enrollment for that study in the first half of next year. The second disease area for this target is depression. And I need to be a little bit coy about it, just given our relationship with J&J, but Johnson & Johnson has reconfirmed that they are aiming to initiate their Phase II clinical proof of concept study later this year, focused on depression. A key point for this M1 program, and it'll come up in the LPA1 program as well, is that there is clinical validation for M1 receptor antagonism in both relapse-remitting MS and in a depression setting, including MDD, TRD, and bipolar. Our second clinical asset is PIPE-791. This is a first-in-class brain-penetrating inhibitor of the LPA1 receptor. As I mentioned, we always start with a neuroscience angle. So our initial interest in this target was driven by the expression of it in glial cells, and specifically on oligodendrocytes and microglia. And it was through that potential augmentation of remyelination and reduction in neuroinflammation that we thought the natural starting point was progressive MS, where demyelination and neuroinflammation are the key drivers of disability. As we started to see the profile of this compound come through and the history that the company has, as we have a number of scientists who were founders of Amira Biosciences, we saw the BMS IPF data come out with their LPA1 receptor antagonist. And we thought the data was fine, but we thought that we could maximize it with the profile that we have with PIPE-791. For 2025, we will be kicking off a Phase II clinical proof of concept study in IPF, another study later in the year in progressive MS. The IPF study obviously has clinical validation through BMS. Then we've recently announced an exploratory phase 1b study with PIPE-791 in pain, specifically looking at osteoarthritis and lower back pain. All right, terrific. So let's talk about PIPE-791 first and maybe the rationale for LPA1 antagonism in IPF and how you think you differentiated from the Bristol compound. Yeah, and I think when we think about LPA1 as a target in general, the bad actor here is always LPA. And a lot of the mechanistic rationale in IPF was teased out by Andy Tager at Harvard Medical School back in 2008. What he was able to show is that an insult to the lung leads to expression of LPA, higher expression of LPA in the lung. This leads to fibroblast recruitment and then eventually collagen secretion, leading to IPF in the lung. What he was also able to show is that the lung fluid is upregulated in LPA in IPF patients. So by inhibiting LPA's impact, activating the LPA1 receptor, one can possibly reverse or mitigate the effects of lung fibrosis. Okay. And Amgen had a setback in here. What's your take on that? I would say we weren't surprised. So we've profiled all of the LPA1 receptor programs out there. So the two BMS programs, Amgen's program, we've looked into Structure's program as well. Just to take a step back with Amgen, I think we need to look at the history of it. So this started out as a Sanofi compound that was sold to Curzion, which went to Horizon in an acquisition, which then went to Amgen in an acquisition. And throughout the process, kind of reading Amgen's body language, it was always one of the last things that they talked about in their rare disease discussions. So we felt like there may be some trouble there, but I think the most important thing for us is when we profiled this compound, the compound properties were likely to lead to a negative result. And specifically, it is highly, highly protein-bound. So in our rodent models, it was 99.93% protein-bound. And in our human evaluation of it, it was higher than that. It had about 0.2% free and less than 5% oral bioavailability. And combine that with trying to drive the pharmacokinetics by having the patients take a high-fat diet with each dose, it was going to be very hard for this compound to be able to achieve the target exposure to drive any sort of antifibrotic effect. Got it. Got it. So how does PET receptor occupancy help de-risk the clinical development of 791? Yeah, and so when we started this company, there were a few things that we focused on. And how can we clinically de-risk these assets early? Some of it's through clinical validation, and we have that in three of the disease areas that we're looking at over our two clinical assets. The other is making sure that you correctly choose the phase 2 doses. And this started with PIPE-307. Prior to doing the J&J deal, we ran a PET receptor occupancy study. And we crafted this radioligand in-house. And in this case, we were looking to build a full receptor occupancy curve because we felt that the dosing regimen and the required receptor occupancy would be different between relapse-remitting MS, where you're driving oligodendrocyte differentiation, versus a synaptic plasticity change in depression. With that, we now have two different dosing regimens that are heading into our clinical POC studies there. For 791, it's a little bit different, so anti-muscarinics, there are properties where if you hit multiple receptors, you can lead to cognitive liabilities and things like that, so we were mitigating that in the dosing. In this case, there's no liabilities that we're aware of with LPA1 receptor antagonism, but we want to make sure that we choose doses that fully maximize the receptor, so hopefully 90% occupancy plus. And that is a key differentiator against other LPA1 receptor antagonists that are BID and have high peak to trough, so they're always breaching a certain threshold over the course of the day. Okay. And you mentioned this is going to a new trial kicking off next year. Can you kind of go into sort of the key elements of the design, at least the anticipated design of that? For the receptor occupancy study? No, for your Phase II trial that you mentioned for. For IPF. IPF, yes. Yeah, so we haven't disclosed a whole lot about this, but this will be a pretty plain vanilla IPF study. We're looking at a couple hundred patients at a minimum. I think what differentiates us against some of the other ones is we're not relying on 12 weeks of data. We want to make sure that we run a robust, fully powered, or full phase 2 of 26 weeks of dosing. We're looking at over 100 sites, and the goal is to have this ready for the clinic in the middle of 2025. Do you have an anticipation of how long it would take to run a study like that? Obviously, the accrual is the key. Thankfully, with Amgen gone, that's 2,000 patients that they're not recruiting. So that helps us. You know, realistically, we are looking at a 2027 readout. These are patients that are in pretty high demand, and we're going to put as many sites out worldwide as we can to accelerate the development. Okay, terrific. So wanted to ask next about progressive MS and 791's potential there. And kind of, I guess to start, where's the hole in the treatment paradigm right now? What does this fill? Yeah, there isn't much out there to treat progressive MS. So you have, for primary progressive MS, you have one approval. Ocrevus got their approval. Ocrevus is a hell of a relapse-remitting drug in that CD20 space. But if you look at the change in clinical disability score by EDSS for Ocrevus in primary progressive patients, you have a 39% versus a 33% reduction in decline. So pretty minor impact there. Where we see the difference here and where we think the hole is, is when you move from relapse-remitting MS to progressive MS, it is a switch from an adaptive immune response to an innate immune response. Within that innate immune response in the brain, you have a more conserved blood-brain barrier, but you also have these activated microglial paramagnetic rim lesions that drive a lot of the clinical disability here. So we have basically two drugs in one with LPA1. Given the expression profiles I mentioned before on oligos, by inhibiting LPA1 on the OPCs, we can lead to OPC differentiation. And we've been able to demonstrate this preclinically, increasing remyelination in animals. Arguably more important is a reduction in neuroinflammation, and we've been able to demonstrate this in animals. As we think to that phase 2, this will be a smaller study, and the main endpoints here are going to be built around imaging. So we'll look at the regular MS functional composite, where you're looking at SDMT, the Peg test, and the 25-foot walk score. We'll look at NFL because I think everyone looks at it at this point in these disease areas. And then for remyelination, we'll have some MRI metrics like myelin-water fraction, MTR, DTI. For us, probably the most important part of this is looking at TSPO PET and identifying these chronically active smoldering lesions that are driven through microglial activation and through LPA1 inhibition there. We expect to be able to dampen down that neuroinflammation and have an impact on these lesions. But this is a six-month treatment regimen in these patients still. Okay, and when should we expect the next update in this program? We will have the PET study done in the first half of this upcoming year. We will have the chronic tox done in the first half of this year. The IPF will kick off before PET. I'm sorry, before progressive MS. Just, we're a small company, and getting 100-150 sites up and running is somewhat daunting. We'll have the progressive MS study up and running by the end of 2025. Okay. And you mentioned pain upfront and this kind of recent indication expansion for 791. Can you kind of speak to the biology and the rationale for LPA1 in pain? Yeah, so I guess, like everything else, LPA is the bad actor here. And if you look into the specific disease areas that we're investigating here, osteoarthritis and lower back pain, in the literature, what you find is that LPA is elevated in the synovial fluid behind the knee. And that elevation is correlated with pain score. And similarly, you have that same impact in spinal stenosis. So for us, we didn't go into this indication lightly. There is no clinical validation here. We have a lot of preclinical work in the literature in our own hands, as well as functional MRI data that we had in the non-human primate that convinced us that this was the right thing to do. But we're taking a very metered approach here. So this is a small, trend-seeking, unpowered study. What we want to see is there a difference between baseline and drug-treated in 40 patients and a crossover design of four weeks of dosing? Again, we understand the pitfalls in doing pain studies. But in taking this calculated bet, this does not impact our cash-out date. We're still fully funded through 2027. And we are placebo-controlling this. If we do see a signal, obviously we need the placebo control or no one will believe it. And we want to make sure that we are running an appropriate study, but not over-engineering it, given that this is a first step in the space. Given it's placebo-controlled but not adequately powered, what is a signal that you'd be happy with seeing? I mean, I'm sure it's the totality of the data and the evidence. It is. Listen, being able to see a difference between baseline and treated and potentially baseline and placebo. Okay. Okay, makes sense. All right, so moving over to PIPE-307, can you speak to the dynamics of this J&J partnership? Yeah, so this J&J partnership was really transformational for us. So one, it gave us the ability to funnel a lot of our resources into 791, which that compound, we can get into the properties at another time, but it really is, from a pharmacokinetic standpoint and a receptor occupancy standpoint, it is a standout drug. We started discussing with J&J pretty early in my tenure at Contineum. They clearly had an interest in M1 receptor antagonism. And the clinical validation that comes from M1 for depression was actually validation performed by the current disease area head, Wayne Drevets, at J&J when he was at NIH. So it was a long negotiation with them. We had several term sheets that we were discussing in parallel. But for us, they were always the group that we targeted, given their expertise in neuropsychiatry. To take a drug like esketamine and turn that into a billion-dollar drug is pretty remarkable on its own right. They had validated this mechanism. The overall economics of the deal, we had $50 million upfront, $25 million into our crossover round, and then they supported into the IPO as well. We have about $1 billion of milestones that are still on the table, and that is split between developmental, regulatory, and commercial. We have a co-funding option that we can trigger before the phase 3 studies commence. The way that we negotiated this is we were never going to be able to do much on a co-commercialization agreement in a relapse-remitting and a depression setting. We were unwilling to bear P&L risk in the launch years in these indications as well. So we negotiated what we call a synthetic profit split, where we ramp the royalties to the very high teens. And then with a trigger on the co-development, we can push those royalties even further. Okay. And that's Pre-Phase III, you opt in for that? It's before the Phase III starts. Okay. And so can you describe the ongoing studies now in relapsing-remitting MS as well as depression? Relapse-remitting MS, yes. And depression, I can speak to it at a high level. We started this study near the end of last year. This is 168 patients with relapse-remitting. It is powered one-to-one-to-one, so two drug-treated groups, one placebo group. The primary endpoints here are tolerability, safety, and then a change in low contrast letter acuity. In MS patients, there is demyelination of the optic nerve. The signaling from the retina to the visual cortex is blunted. You can measure that visual evoked potential latency. We've been able to do that in animals. In humans, it's much more complicated. If some of you follow the old Biogen anti-lingo program, having that at multiple sites can be cumbersome. The functional output of an improvement in VEP latency is an improvement in low contrast letter acuity. The ability to see stairs in a dim setting or driving at night, and we can measure that through an eye test during the study. Then we'll have all of the other typical MS readouts there on MSFC, NFL, and so forth. Okay. So we're running out of time. I mean, it is a small company, but there's a lot going on. So as we look ahead to 2025, you've mentioned some of the events you have coming up. Can you kind of speak to what you see as the key value drivers for the company next year? Yeah, well, so next year, we're less than 50 people right now. We're continuing to grow. We have seven clinical studies completing or starting in 2025. So that is four for LPA1, so the PET study, the progressive MS, the IPF, and the pain study. We have two studies with 307, the relapse-remitting study, which we're running, the depression study with J&J is getting kicked off. And then we have another asset in the portfolio, a peripherally restricted LPA1 receptor antagonist that will hopefully complete healthy volunteer studies next year. I think for the near term, the relapse-remitting, I'm sorry, the receptor occupancy readout along with the chronic tox data, I think is absolutely critical. And I think that those are inflectional for the company. And then there's the potential of readouts in the second half of the year as well. Okay. And then the cash runway you have at this point to kind of support all this, in addition to the support from J&J, of course? Yeah, so we have funded. Again, as of the end of September, we had just under $215 million in the bank that funds us through 2027, so all of the studies that we had discussed are fully funded with the current cash on hand. Perfect. Well, it seems like it's going to be a very exciting time. So thank you for being here with us and best of luck in 2025. I appreciate it. Thanks, Cory. Thanks, Brian. Good timing.