... All right. Good morning, everybody. I'm Alexa Deemer from the Cantor Biotech Equity Research Team, and I'm honored to be sharing the stage this morning with Contineum Therapeutics. We have with us Carmine Stengone and Timothy Watkins. Welcome. Hope you're enjoying our healthcare conference. So, you know, let's just start out with a general introduction. For those less familiar, maybe you can give an overview of the company and what the focus is for the next six to twelve months. Yeah, absolutely. I guess, as a starting point, again, thank you to the Cantor team for inviting us today, and give you a little bit of background on Contineum. So we are a San Diego-based biotech. Our main focus is in the area of neuroscience, inflammation, and immunology, and those seem like disparate areas between neuroscience and I&I, but what we have found is that there are a lot of targets that overlap both segments, and we can dig into that. A couple of important things that we like to point out about the company: One, we have two clinical stage assets. We are pursuing multiple therapeutic areas around these, and we have some pretty important clinical proof of concept readouts coming and initiations coming. Other things that we like to look at is, how do we de-risk these assets early? So our two lead programs, PIPE-307, is a first-in-class selective inhibitor of the M1 receptor that is currently enrolling an MDD study with our partner, J&J, and we recently completed our relapsing-remitting study focused on remyelination. We went into these areas, one, because the science led us there. Two, there was a high degree of clinical validation against using that target against both of those diseases. And what we found from our biology and chemistry team is we do a really good job at enhancing molecules where big pharma hasn't been able to get the right properties, and that's what led to our collaboration with J&J. Similarly, with our other clinical asset, and really with the lead that we'll be talking about most today, PIPE-791, this is what we believe to be a best-in-class inhibitor of the LPA1 receptor. And we can talk about the clinical validation that comes there that de-risks our clinical translation as well, with over 500 patients' worth of data with the BMS's compounds. We firmly believe that our compound has properties that can enhance efficacy, safety, and convenience of dosing in patients. So we look to de-risk early. We also put in additional measures, like looking at target receptor occupancy with our programs, if we're able to do that, to make sure that we are choosing the correct dose and moving into our POC that allow us to maximize the effect of these compounds. Got it. All right, so we'll start with 791 and then go to 307. Sure. So, you know, with IPF, so how big is the unmet need? And perhaps you can comment on the incidence and the prognosis. Sure, I can dive in on some of the unmet need. Obviously, this is an orphan disease. There's about 130,000 patients in the U.S., with another 30,000 to 40,000 patients with new incidences annually. About 3 million worldwide. Two drugs out there to treat patients. I think most would agree that they are suboptimal, not only from an efficacy perspective, but probably more so from a tolerability perspective. So that leaves a large hole in the market that needs to be addressed, and this is an area that we believe will, similar to antiviral therapy and cancer therapy, this will be a polypharmacy approach because there is a lot of heterogeneity between subjects. All right. And, you know, you just touched upon this. Maybe you can dive a bit deeper into the gaps in the treatment landscape that still leave room for innovation. Sure. Yeah. So, I think, you know, just we were chatting ahead of time, I think this market is huge right now. And when you look at the current treatment sort of landscape and what patients are offered, it's a... You know, with idiopathic pulmonary fibrosis, really a silent disease until patients develop symptoms, shortness of breath and cough, that starts to really interfere with their quality of life and being able to conduct their day-to-day activities. They seek out a provider and eventually likely end up in the hands of a pulmonologist, where that diagnosis is made, and they've already lost quite a bit of lung function, and that, you know, continues throughout the course of the disease. The current therapeutics that are available, pirfenidone and nintedanib, were a big step forward, at least in attenuating or slowing the progression of the disease, but not halting it. It doesn't cure the disease. And I think the biggest challenge for patients is that, they don't feel better when they take these medications. The tolerability issues with it include diarrhea, nausea, vomiting, rash, monitoring for liver function, et cetera. And these are challenges for patients with a severe debilitating disease. So, you know, patients are sort of faced with an incurable disease, and I liken it a lot to a cancer diagnosis. And many, comparatively, cancer diagnoses fare much better than IPF. So, again, I think that the opportunity would be to develop therapeutics first and foremost, that patients can tolerate, and that doesn't make them feel worse, that's convenient for them to get, and that significantly attenuate or halt the progression of the disease. And, you know, if we could actually develop something that made them feel better, or relieve symptoms or improve quality of life, that's the holy grail that's out there for not just IPF patients, by the way, but for patients with other forms of progressive pulmonary fibrosis, of which there are more than 200 known conditions that can contribute to that. So plenty of room for innovation. Yeah. I think one important point here is, even with the treatments that are out there, this is a fatal diagnosis, and you have 50% of patients who start on nintedanib or pirfenidone who roll off the therapy within a year because of tolerability. Yep. So large unmet need, really no good treatment options for these patients. So that's where, 791 can come in. So this is a LPA1 receptor antagonist. So what even is LPA, and how does this contribute to fibrosis, and why is this an attractive target for IPF? Yeah, the LPA lysophosphatidic acid is an important sort of element that's been, you know, around and known about for many, many years now. It came out of Andrew Tager's lab really uncovering sort of its relationship with fibrosis. This is higher in patients with IPF and other fibrotic conditions as well. It contributes to inflammation in the lung and recruitment of fibroblasts that subsequently lead to collagen deposition and increase in the matrix and scarring in the lung. So, this particular target has been explored several times, but you know, work that's been done by others and including work that has been done in our own lab show that this is a really a fundamental sort of pathway in the fibrotic sort of schema of IPF and other fibrotic diseases. Okay, so let's touch upon that a bit more. So what were some of the lessons that you learned from previously developed LPA1 receptor antagonists, and how does it compare to those drugs and ones that are also currently being developed? It's a good question. I think that one of the things we know about this target is that high coverage of the target is really, really important if you're gonna stop or attenuate or interrupt that fibrotic process. So I think, you know, if we look clinically, all eyes are on BMS right now. Carmine mentioned an earlier molecule that was in development in a phase 2 study in patients with IPF. That drug actually. That study was actually stopped early because of some hepatobiliary toxicity. But at the time that it stopped, it did show evidence of a dose-related effect on reducing FVC or decline in FVC over time, which is how physicians measure lung function in the clinic. That program was terminated, but the current BMS-986278 sort of program that BMS is running has also come out in a second phase 2 study, a new molecule hitting that same target in two cohorts. One, a cohort of patients with IPF, and two, a cohort of patients with progressive pulmonary fibrosis, and the drug demonstrated some efficacy there. The lower dose was sort of at the margin of efficacy, but the upper dose, the 60 milligrams BID, was demonstrated some efficacy in IPF and then again in a PPF population. Now, I think the interesting thing is that the BMS team must have known that there was still some room for improvement there, so they're testing a higher dose in a phase 3 program to try to reach that target coverage. But as opposed to PIPE-791, our own molecule has got some very unique PK profiles, very potent, very selective, a slow on and slow off rate, and that allows us to reach, you know, testing, you know, 90% target coverage or multiples of that in the clinic, which is something that we're really excited about. And that's key, I think, to demonstrating robust efficacy in the population. Got it, and maybe you can go into a bit more detail about the work that you did to fine-tune the PK profile of PIPE-791. Yeah, this is. Our chemistry team has been amazing at developing these molecules. With 791, we had an interest in this target for a while. Tim mentioned the initial LPA-1 receptor antagonist that BMS brought in, and that was BMS-020. That was actually acquired through a company in San Diego called Amira Pharmaceuticals. A number of our scientists were founding scientists at Amira, so there's a lot of knowledge there. When we started our own research effort around LPA-1, we wanted to move outside of the IP estate that was set up by BMS, by Amgen, by Ono, and others. Our chemistry team focused on a novel IP estate, and with that, we were able to get, as Tim mentioned, a compound that has a very slow on and off rate, and there's a few benefits to this. With that slow on and off rate, we have a very blunted peak-to-trough, and normally, when you see some tolerability issues with these compounds, they generally happen at peak. And having that blunted peak-to-trough improves our tolerability profile. In addition, this is clearly a QD drug. So with that on and off rate, we have target coverage 90% and above, and this is as close as you can get to a human knockout of this. And when you start looking into the literature, knockout animals for LPA-1 demonstrate no changes in bleomycin, anything like that. So it is a proven molecule preclinically, and now with over 500 patients through BMS, this mechanism, we think, is heavily de-risked. Okay. So multiple disease-modifying agents in the pipeline for IPF from numerous companies. So how do you see PIPE-791 carving space out in the IPF treatment landscape, and is this a winner-takes-all market, or are there room for multiple players? Well, as we mentioned, I think right now, the two treatments out there are suboptimal, and they can't be used together at this point, and IPF, especially through, you know, POC studies and phase 3s, has been somewhat of a graveyard for a while, with Biogen and others along the way. Looks like we have hit a bit of momentum here with BI's drug, so we expect that to get approved. We think that it's an incremental benefit, and then we'll wait and see once we learn more information from the Tyvaso program from United, but in the long run, having a safer drug, this will be a polypharmacy approach, and this is really an untapped market, even with all the liabilities that nintedanib has. It generated over $4 billion a year in sales. Got it. So, you know, you're planning on initiating a global phase 2 proof of concept study next quarter. So can you share some details on the design of the study, endpoints, expectations for data? I know it's a pretty broad question. You know, we are in the midst of sort of launching that study. I can share that you know, we're- Yeah ... we're developing a very careful protocol, a very robust protocol, really to offer an apples-to-apples comparison to like the BMS program in their phase 2. You know, the IPF studies, a global IPF study, we're measuring endpoints that, frankly, are the same as those that we'll be measuring in later stage development, like phase 3. Take a lot of care and precision to put people together. So, the team is working at exactly that, which is really developing a very careful, clean protocol that offers the monitoring that we want to be able to demonstrate, you know, robust efficacies compared to BMS. The other thing that we really want to demonstrate is, you know, there's no titration sort of package as a part of PIPE-791. We'll look at a couple of doses in our phase 2, but we want to demonstrate that safety and tolerability profile because we also think that's a real differentiator against what BMS is putting together right now. So again, it's efficacy, but it's also demonstrating the safety, tolerability, and convenience of what we'll be offering by PIPE-791. Okay, so is the BMS trial the best benchmark to use for this study? I would say so. I think that, you know, we certainly don't want to develop anything that's less robust than that kind of trial. So, that's our benchmark, and we're putting some tweaks on this, but I think that's where we're shooting, on an apples-to-apples comparison to that. Okay. And so trial's expected to initiate fourth quarter. How long do you take for enrollment to complete, and when could we see the first look at data for this? Love to share that, but at this point, we can't. Okay. Um- Got it. All right, so moving on to the PET receptor occupancy study. So that's reading out soon, you guided toward third quarter. So, you know, maybe give an overview of this study, what do you hope to learn, and what kind of data would really validate this program? Yeah. So, like I said before, we really want to make sure that we understand the doses that will be optimal for the phase 2. We did this with 307, and we can talk about that, looking at PET receptor occupancy. That was really critical in deciding the doses for two different diseases. In this case, we had the opportunity and the time to be able to run a PET receptor occupancy study. We already had non-clinical information, along with our phase 1 SAD and MAD PK, where we had a high degree of confidence for greater than 90% coverage of the receptor. But we wanted to make sure that we validated this in patients as well. The real goal here was to be able to demonstrate that with PIPE-791 in humans, we can achieve that high level of coverage. And this study was never a gating study for the phase 2. That was always the chronic tox. But we think that this is useful for the community, and in our opinion, BMS's phase 2, they missed on their doses, right? So they are pushing to 120 mg BID to get more robust coverage, and their 30 mg BID really didn't show anything. And what we want to be able to do is, with our unique PK profile here, is demonstrate a higher receptor occupancy without the tolerability issues that we believe BMS has had in the past. Now, is this study something other companies have done? So BMS has run it twice. Okay. You mean, I'm sorry, you mean from a receptor occupancy perspective? Yes. Yes. We are unaware of any other company that has been able to develop a receptor occupancy data set- Okay ... with their program. So really for validation of the doses that you're choosing? Correct. Okay, got it. All right, so, you know, moving away from IPF and onto, chronic pain and MS. So you're also exploring PIPE-791 in chronic pain and progressive MS, so how are you prioritizing these programs relative to IPF? I know you recently postponed the initiation of the phase 2 trial in, progressive MS. So maybe just touch upon, you know, the, the rationale for these studies and, you know, why you're deciding to explore those two indications. Yeah. So the IPF study that we're going to run is a pretty huge study for us. This looks a lot more like a phase 3 than a phase 2, just the number of sites, and we wanted to make sure that we put our clinical and operational needs ahead and allowed us to get that study up and running. So as you mentioned, we postponed the progressive MS study. Want to be clear with everyone, those are not terminated or canceled. They're really just pushed down the road a little bit until we get our feet under us on the IPF program. With chronic pain, this is an exploratory study that we initiated earlier this year. This is one of the areas in our portfolio where there is no existing clinical validation for LPA1 receptor antagonism, but the non-clinical data and the literature precedence for LPA1 in this setting was really compelling for us. Not compelling enough to run a full-scale phase 2, but we wanted to do a really dip our toe in the pool and run a phase 1B exploratory study. This is in up to 40 subjects, crossover design, and the main focus here is to be able to demonstrate an improvement in pain in an osteoarthritis setting, as well as in chronic lower back pain. Got it. And so how does LPA link the pathophysiology of IPF, pain, and MS? Yeah, so in all of these cases, there's one bad actor, and it's LPA itself. So as Tim mentioned, it's a bioactive phospholipid. It's often increased when there's an injury. So when there's a lung injury, LPA1 is increased in the lung, and it activates the LPA1 receptor, driving the fibrosis. In progressive MS, similarly, there is an injury that occurs that then impacts LPA on glial cells, and specifically on microglia, driving neuroinflammation in progressive MS patients, as well as on oligodendrocytes, which then leads to demyelination. With pain, it's focusing on the afferent pathways in the brain, activation of a number of different cortical regions. And again, there's two focuses here. There's a central component and a peripheral component. So with LPA elevation, there's activation on microglia, driving inflammation, and then there's also activation on Schwann cells, which leads to demyelination. What we've been able to demonstrate in the pain setting in a non-human primate model is a chronic constriction injury and a really objective fMRI measurement of reduction in pain in these animals. We chose osteoarthritis and lower back pain because there is literature evidence around increased LPA in those two settings, and the level of LPA is correlated with the pain score and disease severity. Got it. And are these two subsets of pain, osteoarthritic pain and chronic lower back pain, how are they currently treated and, you know, what gives you confidence that PIPE-791 will be able to effectively treat both of those subsets? Yeah, so this is an opportunity at a non-opioid treatment here. So most of these patients will go on opioids or gabapentin. This is, I guess, a cleaner way to be able to treat these disorders. But again, totally an exploratory study. It is not powered. It is placebo-controlled, because if we didn't placebo control it and saw good results, no one would believe it. But we're treating this as forty N of ones, looking for trends that give us the confidence to then move into a more robust POC concept program. Okay. And before we move on to 307, do you just want to take the time to summarize what the catalysts are for 791? Sure. So we have, the pain study is the first readout that we'll have, and we'll have the top-line data of that in the first half of next year. Really important for us is getting the IPF study up and running this year, and arguably the biggest catalyst for PIPE-791 is the potential of BMS's top-line data at the end of next year. So from what we understand, they are now fully enrolled, the estimate is top-line data, probably in the middle of the second half of next year. Okay. Definitely something we'll be on the lookout for. And moving on to 307, this is a muscarinic receptor antagonist being evaluated in relapsing-remitting MS. You know, what prior studies support this mechanism in MS? Yeah, so a lot of this came from one of our academic founders at UCSF. The mechanism through which this clinical validation happened, actually, scientifically, was proved out after the clinical study. But there was a study called the ReBUILD study. The drug was clemastine. So this is actually a first-generation antihistamine, but it has broad antimuscarinic properties. And Ari Green at UCSF brought this compound into a crossover design in relapsing-remitting patients with chronic optic neuropathy. And what he was able to show with clemastine, again, there are tolerability issues and low receptor occupancy here, but even in a small study crossover, he was able to show an improvement in a functional biomarker of remyelination, and that is visual evoked potential latency. So relapsing-remitting patients often have chronic optic neuritis that's driven through demyelination of the optic nerve, and what that means is that the signaling from the retina to the visual cortex is slower due to that demyelination. And the theory was you can improve that visual evoked potential latency through remyelination, and he was able to show that in a crossover design, and I think it was actually in 50 patients. Okay. So, you know, correct me if I'm wrong, but Low Contrast Letter Acuity is the one of the most sensitive tests to detect treatment effects. Mm-hmm. Maybe explain what this is and why that's the case? ... Yeah, so low contrast letter acuity is a visual marker. So it's essentially a reading an eye chart, one called the ETDRS is a diabetic retinopathy standardized sort of eye chart used in those types of studies, but you do it in low light. You know, you're trying to read these letters in low light is a real sensitive marker of vision. This is really important because these patients, you know, with optic neuropathy, this is part of the issue. You know, it's akin to kind of being able to have some vision at night or in a dark corridor and knowing kind of where you are. But changes in these letters, you know, is a marker of if you know that improves actually over time, that's a marker of sort of restoring that remyelination to that optic nerve, and essentially is a translation of that improved visual evoked potential into something that's clinically meaningful for patients. So I like this because and I think the research community likes this, because one, it does signal that improvement in that score is really potent. You're modifying you know the visual sort of access and that remyelination element. But two, this is clinically meaningful for patients as well. So I think that along with several of the other markers we're looking at in that study are going to be potent around remyelination capabilities. Great. So maybe you can just outline this phase II study a bit. You know, talk about trial design and what we can expect in the top line readout in the fourth quarter of- Yeah. At a high level, this is a relapsing-remitting population of patients. It's a 26-week placebo-controlled design, looking at a couple of doses. As you mentioned, low contrast letter acuity is the primary endpoint, binocular. But we're looking at several other sort of elements of this as well, including a Nine- Hole Peg Test, a walking assessment. We're also looking at some biomarkers, including sort of a neurofilament light chain marker, and we're looking at MRI elements of remyelination as well. So, again, several different ways to kind of examine the treatment effect here, capabilities of, along with, of course, safety and tolerability. And then read out fourth quarter of this year? Yes. So that's our plan here and closing the... This program is partnered with J&J, so what role are they playing? Yeah. So we signed the partnership with J&J in the first half of 2023. At that point, we had everything pretty much in place to re-run the relapsing-remitting study. So we have run. We've operationalized that study. We're running it. We will be putting out top line data later this year. Again, there was clinical validation there. J&J was really interested as well for M1 receptor antagonism in a depression setting, and there was clinical validation there that came out of NIH through the lab of Wayne Drevets. Wayne is now the head of neuropsychiatry at J&J. So he showed that with scopolamine, the M1 receptor antagonism component of scopolamine led to a rapid and robust improvement in MADRS through a single dose, actually. They are currently enrolling what is now called the MOONLIGHT-1 study, focused on MDD patients. They are looking to recruit about 124 patients for this study. Given our collaboration with J&J, we can't really talk a lot about what they're doing, but for timelines and more around the design of the study, ClinicalTrials.gov has projected timelines. Awesome. And anything we should be on the lookout in terms of safety for a muscarinic receptor antagonist? No, that's a stigma that we dealt with early on within the company, because people think about scopolamine and benztropine and the cognitive deficits associated with it. Our theory heading into identifying a selective M1 receptor antagonist was we can mitigate that through a selective block. In our healthy volunteer work, we actually put all 72 subjects through a battery of cognitive tests, everything from simple learning and memory all the way through executive function, and we did not see anything different than placebo from a cognition perspective. Got it. All right, we're almost out of time, so anything else we missed that you would like to highlight? No. At this point, we're really in clinical execution phase. So we have four pretty important clinical readouts over the next 12 months to this year, hopefully to next year. And we look forward to updating everyone on top line data as soon as we have it. Awesome. Carmine, Tim, thank you so much for joining us. This was awesome, and we're really looking forward to seeing some more data. Okay. Thanks for having us. Thank you.