Welcome everyone. I'm back to the Leerink Global Healthcare Conference. My name is Roanna Ruiz. I'm the Senior Biotech Analyst here at Leerink, and it is my pleasure to introduce Contineum Therapeutics. With me today, I have the CEO, Carmine Stengone, and I also have Tim Watkins, CMO. Thanks for joining me. Yeah, thanks for the invite. Yeah, great to have you. To start, I'll go big picture before we drill into the details. For any investors who are digging more into your story, could you just frame the core strategic focus for you heading into 2026 and beyond, and like, how has the company evolved up to this point? Contineum is a small molecule NI&I-focused company. Neuroscience, inflammation, immunology, and we'll probably talk quite a bit around pulmonary fibrosis today. We have really gone through a transition over the last couple of years from a platform-based drug discovery company against small molecule chemistry into now a company with two clinical-stage assets, and we're prosecuting three different clinical trials at this point. We have PIPE-791. We believe this to be a best-in-class inhibitor of the LPA1 receptor. We have two inflection points around LPA1 over the course of this year. The first is what I will admittedly call an exploratory study, a trend-seeking study with PIPE-791 in chronic pain, and specifically in osteoarthritis as well as in chronic lower back pain. The next readout on this, which is truly inflectional for us, is BMS's data with their phase III LPA1 receptor antagonist, zimilparant, which is expected in Q4 of this year. The target that started Contineum is based around a compound called PIPE-307. This is a first-in-class brain penetrant and selective inhibitor of the M1 receptor. We partnered this program with Johnson & Johnson in the first half of 2023. They are currently running a phase II clinical proof of concept study with this mechanism in MDD, and importantly in IPF and in MDD. For PIPE-791 and PIPE-307, there is clinical validation out there that we think really de-risks the profile of our portfolio. Yeah. Makes sense. I'll start with PIPE-791, 'cause I do get a lot of questions on it, and I assume you do too. Yeah. Maybe could you talk about the specific differentiators here for this PIPE-791 program versus the other LPA1 agent that's being developed by BMS and, you know, what should we be thinking about going forward? Yeah, I can start and Tim can certainly join in. We believe based on BMS's three readouts that they've already had in PPF with 278, in IPF with 278, and then in their first generation compound, 020, in IPF as well. We think that the clinical validation here is extraordinary, but we think that there are holes within the BMS program that we can help address. You know, first and foremost, we're looking to optimize efficacy here, and we know from the pharmacokinetic profile that BMS doesn't achieve the highest levels of target coverage. From what we've seen non-clinically, you know, even if you look at the early BMS data, being able to fully occupy the receptor can drive a benefit in FVC. We think that that is a potential differentiator on the market. BMS has been public about having a hypotension signal across all of the studies that they have done. That has led to a dose titration strategy in their phase III in order to work up to a higher dose at 120 mg BID. We have not seen a hypotension signal in the studies that we have run. We did not see anything in non-clinical work, and we don't expect to have a dose titration through the development of this program. The easy differentiator here that's pretty clear already is we have a QD molecule. At doses as low as 1 mg daily, we are able to achieve 90% receptor occupancy, and we can go up from that. Having a patient population that's generally in their 60s - 70s, convenience is key. Then the last component of this, which is the hardest to predict at this point, was if we see something of interest in our pain study, we think that that can be an additional benefit for patients with pulmonary fibrosis, especially those with RA-ILD or systemic sclerosis. I guess based on current drugs, we look at current IPF drugs as first generation chemos. They do a good job at potentially extending a patient's life, but they don't feel better. If we can do something that actually improves quality of life for these patients, we think that is really revolutionary for these patients. Great. I think you've characterized the PIPE-791 IPF phase II study as operationally similar or phase III-like in size and rigor. Can you just recap just some of the design elements there that you're thinking about, number of patients, et c. What do investors need to remember about this study? Yeah. I mean, it's certainly not phase III like in size. It is phase III like in rigor for sure. It's 108 subjects over three arms, placebo, and two doses of PIPE-791. We're allowing background therapy, a 26-week study. You know, it's fairly sort of bland in some ways in terms of eligibility criteria, very similar to prior designs. I think you know, the eligibility and target sort of enrollment cohort has been pretty well dialed in in IPF in the sort of contemporary environment. We are allowing background therapy. What's really important in this is you know, the execution part of it. I think you got it right when you say rigor there because the monitoring of the kinds of patients that we're bringing into this study, them meeting the guideline criteria for diagnosis of IPF, us looking at FVC and the quality of spirometry all along the way, we are very close to ensuring we protect the tolerability and safety profile, which we think will be at the top of the class, and enable some future things in IPF therapy that have not been able to be done to date, namely sort of future combinations. You know, we are really prepared and are. When I'm not here, I feel like I'm all over the rest of the world here getting this thing up and running and training our investigators, which seem to be really excited about the opportunity. Yeah. Could you elaborate a bit more? Like, how's it going getting this up and running? It's you know, I won't lie, it's a big job to get an IPF phase II study up and running. A lot of technical aspects to ensuring that we get folks trained and engaged, and it is an orphan population. You know, there's a lot of different IPF studies going on. They need to view us as a premium sponsor and somebody who's engaged and able to communicate and available for questions and things like that. We're excited by it. We're up and running. Opened up at the end of last year, got our first patients in, and we're just riding the wave of getting things open and people enthused about it. Nice. That's great. I noticed, Tim, you alluded to combination use and kind of wanted to tag on a question there in terms of, let's say everything works out and you achieve the target profile that you wanna see with seven-nine-one in IPF patients, where do you see it layering into the treatment paradigm going forward in IPF? Yeah. I think it's a great question a lot of folks have to date been thinking about, you know, readouts and would I use this therapy or would I use that therapy, and trying to do something that's inherently difficult, cross-trial comparisons around efficacy or whatnot. We, you know, think this will be an optimized efficacy for this target. We think a non-titratable once-daily molecule will be an ideal sort of foundation. And again, instead of thinking, well, I can't combine these two therapies, which individually are very difficult to tolerate, and most patients are not staying on these drugs after they start them, as much as 50% are not on even nintedanib or pirfenidone after a year, we now will have a drug that patients will be able to remain on. If you could combine therapeutics in the future, again, each one of the currently marketed therapeutics do not stop the disease. They simply slow it down. You're buying time. If you could combine therapeutics and gain further efficacy or really arrest the disease, one would do that, and I think that's where we're positioned, to not only be easily combined with available therapies in the future, but to think about, you know, combination, oral combinations, that could emerge, you know, beyond what's currently available or on the immediate threshold. Yep. Makes sense. One debate that I've heard about a little bit around the LPA1 mechanism is just thinking about BMS' zimilparant, and it's shown hypotension risk, historically, and it requires some monitoring and probably titration dosing. How confident are you that this is drug-specific and not class-specific? You know, I think, we aren't confident that it's not a class. It could be a class effect. You know, we have not seen that with our drug right now, but it could be, you know, a target-specific effect. Again, the way that BMS is navigating this is with a titration. I will call out that they saw sentinel episodes and hypotension in their phase I study of healthy volunteers, whereas we did not. They did report out in their phase II data that there was, you know, there were AEs that did not look sort of biased toward the molecule, but there was a dose-related effect on blood pressure at day one in decreasing that. To get around all that is the titration. We believe there are some. If it is on target, we believe our PK profile maybe avoids that. We have a particularly slow off rate with our molecule and also a slow on rate. Rather than the high peak to troughs that they see, potentially inducing some sort of on-target effect, we think we avoid that. But again, that's something that we're being very thoughtful about as we bring forward doses into our phase II. We believe also with the pain readout, first and foremost, that the safety profile is going to be a solid read-through to, you know, reaffirming our belief in PIPE-791 in IPF. That's interesting. Thinking about read-through, you know, with BMS' phase III reading out later this year in IPF, if that is positive. Yeah How would you guide investors thinking about extrapolating from that data set to your program? I mean, I view it again as just reaffirming kind of the things I've already said. If that is positive, we believe our target coverage, which at our lowest dose is approximating 90% and beating the 120 BID, and at higher doses, we're at multiples of that, the science would play out that indeed the animal models have been confirmed in a human population, and that with optimized target coverage, that should translate over into very robust efficacy. But we will not have a titration profile. There will be none of that, and we believe a solid safety and tolerability profile that we'll be able to build upon. Much akin to what some of your pulmonary colleagues were speaking about earlier today, second generation have optimized efficacy. Second generation has optimized the tolerability safety profile, making it easier for a once-daily molecule and future combinations, and that should carry the day in and of itself. If pain re-reads through or we have other things that are unique to the neuropenetrant aspects of the molecule, that, will be a game changer and something that we're thinking about as we get our phase II readout and how we could incorporate and capture that, as an additional differentiator in phase III when we get there. Yep. Rhona, to be clear, we're rooting for BMS. We wanna see good data coming out of this. In the long run, we think that we have the best-in-class approach, and seven nine one could be the backbone of IPF therapy upon which other drugs are added. Yep. Got it. Running with this scenario, let's say a positive trial from BMS, positive validation for your PIPE program, and targeting the same target, how do you think about the competitive dynamics? Like fast-forward a little bit in terms of commercially like launching after BMS with a similar mechanism agent. Yeah, we've looked at other comps within the space, where this isn't a me too. This is. I'm not gonna call it a me better. This is a best-in-class approach. I think in the long run, looking at the patient population and how fragile they are, having a QD dose, having a non-titratable dose, having a lack of a hypotension signal, and being able to maximize efficacy, right? I think that transition becomes very easy for a physician. Yep. I hear you. I'm gonna switch gears a little bit to PIPE-307. That's partnered with J&J in MDD. Wanted to just like put this a little bit into context because, following the VISTA trial miss in RRMS. You know, the partnership focus seems to be shifting more towards MDD, you know, how would you frame like how you're thinking about the upcoming data set for this program, and like what should investors be looking for when the data set comes out? Yeah. This is a phase II study from J&J. The focus here is MDD. It's 124 patients. This is two different dosing regimens that they're pushing through. Based on their primary efficacy endpoint, they are very aggressive on this. We are looking at a change in MADRS on day five as the primary efficacy endpoint. That puts it kind of in line with what you see with Spravato and what was seen in the clinical validation with scopolamine. As we look at J&J's portfolio, take ITSC out of it for now, the M1 program occupies a really important part of their neuropsych portfolio. When we signed this deal with them a couple of years ago, they had their CGRP program, which is unlikely to move forward. They had a P2X7 program as well. Right now, their internal portfolio includes an orexin program, which is a relatively niche indication of MDD associated with insomnia. When you look at a drug like PIPE-307 and a potential rapid onset of action, this really allows not only for MDD, but expansion into potentially other depressive disorders. Got it. With the MOONLIGHT 1 study readout, what would you think would be a clinically meaningful signal coming out of that study when the results read out? I think that is something that I will rely on J&J to communicate. Okay. Okay. Fair enough. I think in the past, just thinking about, you know, the different programs you've worked on with J&J, I think you advised no efficacy read-through from VISTA to MOONLIGHT. Yep. Given different dosing, etc. Could you talk a bit about anything else that could possibly come from VISTA that might de-risk the MDD program? Yeah. When we started in identifying an M1 selective compound, there were still investors in pharma who had concerns around the anticholinergic profile here. Are we gonna have cardiac issues? Are we gonna have increased cases of dry mouth and things like that? We came into this with the idea that if we can selectively hit the M1 receptor, we can mitigate all the cognitive issues that are associated with anticholinergics. We were able to demonstrate that to J&J through our healthy volunteer studies, looking at cognition across SAD and MAD, and this was multiple areas of cognition, everything from simple learning and memory to executive function, and there was nothing there. That said, those were smaller studies in healthy volunteers. Now, we've been in a patient population, and these subjects have had dosing QD for six months, and the safety and tolerability profile is there to support the path that we're going on. Okay. Sounds great. Can you refresh us or just remind us about the economics of this partnership going forward, assuming that MOONLIGHT is positive? We signed the collaboration with J&J in the first half of 2023. $50 million up front, they put $25 million into a crossover round and then supported us into the IPO. We have just over $1 billion in milestones that are split between development, regulatory, and commercial. We have royalties that start in the low teens% ramp to the high teens, and we still hold on to a potential co-development/co-funding option, far less than 50%, that we can trigger on as we head into later stage development. What that'll allow us to do is put a point or two of additional on the royalty to the point where that top royalty would be at 20%. Yep. Okay, great. I'll pivot again to the upcoming readout for the chronic pain exploratory study. Thinking about that, can you just remind us, you know, about the study design and structure and just the rationale behind it, thinking about it and just, like, how should investors unpack that part? Yep. You want me to take it or you want it? Sure. You know, I think we're first of all, I think that this is, you know, we've made it pretty clear for investors to not have this as their thesis for investment into Contineum. This is a phase I signal-seeking study. The first and most important thing that this will provide is, again, like VISTA for J&J, this is going to be, you know, the first real patient population where we've treated patients up to a month with Pipe seven nine one. So we view the safety and tolerability as central to our hypothesis for how this will work in patients with IPF. The pain readout in and of itself is something that, you know, we're gonna be looking for a trend, a signal. We have NRS, we have a number of other caveats into this placebo-controlled, 40-patient sort of crossover design. We'll be looking for a clear signal that affirms that indeed we have something there. It's a notoriously difficult, you know, indication to navigate with placebo responses at times. We're looking at a variety of different measures, both generalized to pain, but also unique to osteoarthritis of the knee, which is part of the population, and also to patients with chronic low back pain with and without sciatica. Looking for a signal, something that we can rely on, and then again, navigate into what are the next steps. Is that in a dedicated pain population? Is that something that we would try to incorporate into future clinical trial design? What would we learn from the IPF PPF study to how that could differentiate efficacy there from other LPA1 antagonists, sort of the next steps. Okay. Just to clarify, you meant by incorporating into a future trial design, like actually incorporating learnings from this pain study into a future IPF study? Is that what you meant? Sure. I mean, if we did see a signal there, we'd wanna think about how could we measure that reliably in patients with IPF, or where would that line up in patients with diseases like RA-ILD or SSc-ILD who have PPF. That would be something that we would want to measure, in a thoughtful and proactive way. Although there are general measures by which, you know, we would also incorporate. Yeah. Got it. I guess one important thing there as we think about this outside of just pain, this is the only compound that can have an impact on pain from what we have seen in our own testing. This is the only brain-penetrant LPA1 receptor antagonist, and that centrally mediated portion of that pain syndrome is it requires a brain-penetrant compound. Yep. Got it. Digging into the background behind this a little bit, I noticed you had fMRI non-human primate data, and it showed a bit of blunting of the central pain signaling as part of a motivator for the program. How do you explain this to investors in terms of translating that preclinical signal to humans? Are there any risks or any caveats to think about? Oh, in a pain study? In a pain study. Yeah, there's a ton of risks. We were encouraged by what we saw in that non-human primate study. This was really a measure of sciatica here. It was a light ligature around the sciatic nerve, and this was an objective study, this was an fMRI endpoint. What you saw is in that chronic constriction injury, a pretty rapid lighting up of the fMRI. Then as we dosed with 791, that blunted the signal, and when we took 791 away, that signal came roaring back. Does that mean that it will 100% translate into humans? No. The data was interesting enough and the literature precedent of LPA activation of the ascending pain pathway, both around osteoarthritis and in chronic lower back pain gave us one more reason to consider this, but we weren't gonna run a big phase II. This is really just dipping our toe in the pool and seeing, do we see a signal that convinces us that this is real, and do we see a signal that may potentially help out in other diseases? Got it. Daniel Lorrain and team, you know, really devised that to be a pretty rigorous animal model looking at cynomolgus instead of just a rodent model there to try to bolster confidence like, well, we would really need to see something here to move us into testing this in humans. That's passed that bar, but of course, the signal-seeking study here is designed to answer that question of whether or not this is something we continue to pursue or not. Yep. Makes sense. A bigger picture question is how are you thinking about capital allocation priorities between running this phase II in IPF and pushing forward other pipeline initiatives and things like that, and preserving balance sheet flexibility? Yeah. Thankfully, we're in a great position on the balance sheet right now. We are funded through the middle of 2029. The main focus of the company is getting this phase II and IPF up and running and making sure that we are running a proper study. Thankfully, with 307 we have no further financial obligations, so J&J foots the bill. If we are gonna have another financial obligation, it will be on our call for that co-funding option. You know, I'd like to point out that everything that we have done has come from in-house. We have a very prolific drug discovery engine. We will continue feeding that, but the lion's share of the capital, of course, will move into clinical development. That's just the natural progression of any company. Yep. I hear you. Any updated thoughts on potential partnerships on some of the other programs that are not partnered with J&J? We talk to strategics frequently. For earlier stage programs, I think partnerships are a consideration. I think right now we wanna see what kind of firepower we have around PIPE-791 and IPF, so we can reengage after the phase II, but I don't foresee a partnership in the near term right now. Like, this is something that it's an orphan disease. We have expertise in-house. We wanna show that we can run this phase II, have a successful outcome, and then we'll think about the next step. Yep. Got it. Circling back to IPF in the last few minutes, thinking about the phase II and, you know, some of the, your theories behind the mechanism and some of the early data you have and extrapolating from BMS, I mean, what has KOL feedback been so far on the LPA1 mechanism and your program in particular? I mean, I think you heard that earlier today, that the LPA1 mechanism is viewed as sort of a, you know, it's got some pleiotropic effects or multiple avenues to affect pain. It's not just a single sort of feature of or pain rather IPF and fibrosis. You know, there's epithelial injury producing LPA. There's fibroblasts that are attracted and then produce LPA to attracting fibrogenic fibroblasts. There's solid science behind this. I think the other thing that we hear from KOLs is that unlike other programs that have brought smaller, shorter studies or a single phase II to the gamut here, we have two distinct phase II studies, both 26 weeks in design that have looked at three different pulmonary fibrosis populations, two in IPF, and one in PPF. In each one of those studies, there has been a signal, evidence of an effect on attenuation of FVC. That I think is inducing quite a bit of enthusiasm around the mechanism and its ability to translate over, which we believe BMS will readout like later this year. Lastly, a once daily tolerability sort of molecule is something that every KOL is excited about because it'll you know just does not exist right now in the landscape, something that's simple to take and easy to adhere to. That's a really real point of excitement from KOLs. Yep. Got it. Stepping back a bit, I mean, what do you think the market still possibly under appreciates about the Contineum story today? Well, I think some of it is people need to understand the clinical validation from BMS, right? That to me, the data that they have generated over two different molecules is indisputable. We have the ability to execute on this and are really focused on this, IPF program. I think the most important part here is we truly believe that LPA1 antagonism will be the backbone of therapy. I am confident that we have a best in class approach, and with four potential differentiators, hitting on one or two of those can be really transformational for patients. Great. Another last question before we close. Just thinking about some of the most interesting catalysts or data events coming up, like, what would you point investors to first for them to start to do work on? For us or for. For both external and internal. Like, where do you think they should? Yeah. Look first if you're talking to a new investor? In my opinion, there's three potential catalysts this year. Okay. I think the probability of success increases with each one. The pain study, as Tim said, don't let it be your thesis for an investment in Contineum, but there is potential upside there if we see something. We know all of the issues with pain studies, especially exploratory pain studies. There is clinical validation for MDD, and in that case, it's also in the hands of someone who has taken a drug with all of the liabilities of Spravato and turned that into a $1.7 billion drug. We think that is a reasonable and interesting outcome that we're looking forward to late summer or early fall. The biggest catalyst for us is BMS, right? We've seen, you know, I know that there was an issue with SURPASS more recently, but you saw Alumis's stock pop 120% on SURPASS data from Roche. We think that catalyst from BMS can be really important to us, not only to validate this target even further, but to again allow us to continue demonstrating the differentiation versus that molecule. Yeah. Sounds great. I think with that we are at time, so thanks again for joining me. Great. Thanks, Roanna.