Well, thank you, everyone, for joining us. I'm Andrea Tan, biotech analyst at Goldman Sachs. I'm really pleased to be joined by Carmine Stengone, CEO of Contineum. Thank you. Carmine, maybe given the recent IPO, we can start by you providing us a brief description of the company, the transition from private to public, how that's been going? Sure. Yeah, absolutely. And thank you again for inviting us to present here at the conference. As Andrea mentioned, my name is Carmine Stengone, and I'm President and CEO of Contineum Therapeutics. Contineum is a biopharma company focused on unmet medical needs in the area of NI&I, so neuroscience, inflammation, and immunology. We have consistently focused on targets that we think, when modulated, can lead to an impact in clinical disability in these various diseases that we're investigating. So from a clinical standpoint, we have two clinical stage assets. Everything in our portfolio is internally derived. The first asset we'll probably be talking about today is PIPE-791. This is a first-in-class brain penetrant inhibitor of the LPA1 receptor. And we are advancing this in two separate indications, one in the CNS and one peripherally. So the first application, and really the driver of our interest in the target initially, was within progressive MS. So by inhibiting this target, we believe that we can have an impact in remyelination as well as reducing neuroinflammation. And those are the key clinical disability drivers in progressive MS. Secondly, and a lot of this built on history within the company as well as external clinical validation, we're advancing 791 in idiopathic pulmonary fibrosis. So we've completed a healthy volunteer study to support both of these indications, and we plan on initiating phase 2s in both of these indications in 2025. Separately, the program that started Contineum Therapeutics was built around M1 receptor antagonism. And this is a pure-play CNS program. Our interest here initially, again, was driven through remyelination and through some clinical validation that came from some of our academic founders at UCSF. They were able to demonstrate in patients that by inhibiting the M1 receptor, this can lead to a positive impact demonstrating remyelination in relapsing-remitting MS patients. As that story began to evolve, we started to see something else coming along for M1 as well. And in this case, inhibition of M1 can lead to a, we believe, will lead to a rapid and prolonged response in depression. And based on both of those two applications, last year, we signed a collaboration with Johnson & Johnson to advance these CNS programs. So that's where we currently stand. I think one of the key features for our company is that we do have two clinical stage assets. These are four different diseases, three of which have clinical validation. So we focus early on on de-risking these programs as much as possible. Some of this through clinical validation, some of this running receptor occupancy in PET studies to de-risk dose selection. We've been successful in advancing both of these compounds. Lots of stuff going on. Yes. Maybe we can start with 791 here. The mechanistic rationale between targeting this in IPF versus progressive MS, help us maybe walk us through that? Sure. So I'll start with progressive MS. Since when we first decided to pursue this mechanism, we were focused on the CNS aspects of it. So if you look in progressive MS patients, there is an upregulation in autotaxin. Autotaxin is the key driver that catalyzes LPC to LPA. And LPA is a bioactive phospholipid that is a bad actor in a number of different diseases. If you look into patient data, LPA1 is elevated in the CSF of progressive MS patients. And the drivers here for LPA and activation of LPA1 are driven around the expression profile of LPA1 in the brain. So it is highly expressed in glial cells and relevant to progressive MS and MS generally, oligodendrocytes. So inhibition of OPC differentiation leads to a reduction in remyelination. And then also in neuroinflammation. So in this case, this is with respect to the microglia. So we believe that by inhibiting LPA1 in the CNS, we can address the two main drivers of clinical disability in a progressive MS setting. And that's not to say that this can't move further to the left in the treatment regimen as well. I think any remyelinating agent will be beneficial in a relapsing-remitting setting. Got it. Walk us through the preclinical data, because you have seen the benefit here in preclinical models. We have. But how translatable are animal models in this disease? Yeah. So the most commonly used animal model for MS is the EAE model. That is a model of inflammatory demyelination. And it is a model that is generally used in relapsing-remitting. And that is because there really is a dearth of treatments within the progressive MS landscape. What we focus on from remyelination is on the visual pathway. And what we've been able to do in a remyelination setting is perfect in-house a preclinical model built around visual evoked potential latency. And for those who aren't familiar with this, visual evoked potential latency is looking at the anterior visual pathway. And in MS patients, there is essentially demyelination of the optic nerve that reduces the conduction velocity from the retina to the visual cortex. And that is driven through remyelination. So in animals, and we will be testing this in humans as well, with a drug like PIPE-791 or PIPE-307, which we'll talk about a little bit later, but increasing that or improving that remyelination can normalize the conduction velocity and have an impact there. So I think that that is clinically translatable in that we can look at this in the animals, and there's clinical validation of improvements in VEP latency with a remyelination agent in the clinic. On the neuroinflammatory side here, a lot of this is novel science. And we're really interested in looking into, well, we have a PET ligand that we will use to evaluate in the brain. And that study will kick off later this year in a phase 1b PET study. But what we're really looking at here are rim-positive lesions that are indicative of activated microglia. Being able to demonstrate that with an LPA1 receptor antagonist, we can reduce those lesions in a progressive MS setting. When you think about other therapies that have failed in the progressive MS space, maybe what underpins your confidence that 791 will be successful here? Yeah. And to be frank, there aren't that many that have failed in the progressive MS space as initial progressive MS agents. So there's a host of immune modulators that are used in relapsing-remitting that do not work in a primary progressive setting. There's one drug out there that is, it's a CD20 from Genentech called Ocrevus that looks spectacular in relapsing-remitting MS. It is the only compound that I'm aware of that has a label claim for primary progressive. And the impact there is pretty modest. If you look at the clinical disability, the progression of clinical disability, I think on drug on Ocrevus, it was about a 33% progression rate. And on placebo, it was about a 39% progression rate. So nothing really out there has worked. The reason we have confidence around this is if we hit on either of those endpoints, either a reduction in neuroinflammation or an improvement in remyelination, it is a pretty substantial change from what patients are currently able to achieve. If we can hit on both of those, we think this can be a transformational drug within the progressive MS setting. But being able to demonstrate a change in neuroinflammation opens up a range of other neurodegenerative diseases that are driven through brain inflammation. Help us understand what that pathway looks like. You mentioned initiating a phase 2 trial. What does that trial design look like? What are the endpoints you would look for? Yep. So right now, we're working with KOLs to really refine this. So this study will kick off in 2025. There will be two key components to this. One, looking at remyelination, and it's very similar to the endpoints that we're looking at with PIPE-307. So this will be progressive MS patients. We will be evaluating a range of different measures. There will likely be a small VEP component to this, but also looking at low contrast letter acuity, which is tightly correlated with that anterior visual pathway for remyelination. We'll look at neurofilament light. We know that that's important to FDA and to patients as well. As we look into the neuroinflammation component here, this all starts with imaging. So this will be a minimum of a six-month dosing regimen. We'll look into MRI measures to be able to identify rim-positive lesions, and then correlating that with TSPO PET, and over time, being able, hopefully, to show a reduction in that neuroinflammation through those activated microglia. And then as you think about IPF, so the other indication that you're exploring here with 791, the mechanism has been largely de-risked by others in the field. Maybe based off of the work that you've done, how differentiated do you think 791 is relative to these other agents? Other LPA1 receptor antagonists? I think it can be highly differentiated. So mechanistically, this makes sense. So when you look at this, again, LPA is the bad actor here. In this progressive I'm sorry, in this IPF setting, it was Andy Tager from Harvard Medical School that first described this, where a lung injury increases LPA levels. And that LPA within the lung drives fibroblast accumulation and then collagen secretion. And that is the driver for the disability that these patients have. Currently, in IPF, there are two approved drugs. There's a drug called Ofev from BI, nintedanib, and then Esbriet from Roche. The unmet medical need here is pretty enormous. So this is not a huge patient population. You're looking at about 130,000-140,000 patients in the U.S. Given the liabilities associated with the current drugs, you have upwards of almost 50% of patients who are diagnosed that don't go on drug due to the side effect profile. You have about 30%-50% of patients, depending on what stats you're looking at, of patients who go on drug, but they roll off within a year. When you look at the diagnosis for these patients, it's pretty stark. About 70% of subjects who are diagnosed, even on drug, are dead within 3-5 years. The unmet medical need is there, and we need better drugs for this. BMS laid this out as a starting point. Full disclosure, my CSO and a number of my employees were scientific founders of Amira Biosciences. They developed the first LPA1 receptor antagonist. That company, Amira, was sold to BMS back in 2012, and that was the first drug to go into the clinic. It was eventually AM152, eventually labeled as BMS-986020. And it showed a really nice improvement in FVC decline. It suffered from an off-target toxicity around BSEP that led to cholecystitis, hepatobiliary tox. BMS liked that program, that mechanism enough where they then came up with BMS-986278. And there's a few things to note here. So they reported data last year at ATS. Their 60-milligram b.i.d. dose showed a pretty moderate response in FVC decline, and the 30-milligram b.i.d. didn't really show anything. So they have now moved into a phase 3 and taking a somewhat unpharma-like approach to bringing 120-milligram b.i.d., a drug level that has not been tested in patients before, into the phase 3 study. We believe that they missed, in our opinion, on missing their dose selection into the phase 2. That's why they're going to a higher dose, trying to achieve a higher level of receptor occupancy. We think that drug is interesting mechanistically, but we also think that there's a number of ways where we differentiate. One, and one of the key areas here is the IPF patient population is elderly. Convenience and compliance is important. We're the only low-dose QD drug out there that can achieve high levels of receptor occupancy. In all likelihood, we are going to be in that 1-milligram dose range, which may be very combinable with other mechanisms of action as we look to polypharmacy in these patients. For me, the most important part of 791 that differentiates from other LPA1 receptor antagonists is built around the pharmacokinetics. So with 791, there's a very slow association and dissociation rate. In our healthy volunteer studies, depending on the dose, these numbers, they're close to where they were. But you're looking at a half-life of anywhere from 35 to 55 hours. So with a low dose here, we can get extended coverage above IC90 with a single-milligram dose. If we look at the other programs out there, and I'll include 020, despite the fact that it's no longer moving forward, 020, 278, and then the Amgen molecule, AMG 670. They're all b.i.d. dosed. In our opinion, they're not achieving the target levels of receptor occupancy. They're all probably breaching the IC50 for this mechanism. And we believe that a higher receptor occupancy leads to a better impact on the target, which we hope leads to better efficacy. And you saw that dose response in 020. From their 60-mg QD dose to their 60-mg b.i.d. dose, we know their receptor occupancy is going up. They did a PET study before selecting those doses. But they're still unable to achieve the levels of receptor occupancy that we'll be able to achieve with 791. I believe Amgen will have data on their molecule later this year. They will. What will you be looking for there? How much read-through is there to your program? Honestly, I don't think there's a lot of read-through. Given the unmet need here, we're rooting for everyone to be successful in this space. The Amgen molecule, again, we've profiled it in-house. It's pretty highly protein-bound. It also has really low oral bioavailability. From what we understand, patients are being dosed with a high-fat diet with each dose. So we suspect that there is probably less than ideal PK there. And we'll wait on the data in the second half of this year. But I think that the profile of 791 is so distinct from the other LPA1 receptor antagonist that the read-through is pretty minimal. As you think about 791 coming onto a landscape where there are these other agents, OFEV, Esbriet, presumably Bristol's asset, where does 791 fit in there? Are you thinking monotherapy, combination therapy with background agents? Yeah. So Esbriet's already off patent. OFEV, I think, goes off patent in a year or two. They will remain frontline for the foreseeable future. So I think that we need to be prepared for a situation where we're looking at polypharmacy and we're adding on. But as I mentioned before, there is a huge swath of the IPF patient population that's untreated. They're either treatment naive because they don't want to go on those drugs, or their physicians don't put them on those drugs. And they also roll off given the tolerability issues within a year. So there is a huge group of patients there who need better therapies as frontline. And I think an LPA1 receptor antagonist can fit that bill given a clean safety profile and a good efficacy profile. And then as you think to the phase two trial, is it fair to assume that you'll follow the same framework that Bristol has used, that Amgen is using? How should we think about that? Yeah, pretty similar. So we decided to go straight from, and a lot of this based on our preclinical work as well as our healthy volunteer work. We decided to go straight from a 28-day GLP tox study into a 6- and 9-month chronic dosing study. So we're in the middle of that right now. We know a lot of groups have taken a 12-week look. We wanted to make sure that we were running a robust, by length and by powering, study in both progressive MS patients and IPF patients. So we're using that chronic tox data to run a minimum of a 6-month study. So yes, I think a lot of it will mirror what BMS did. They ran two 26-week studies, 24- or 26-week studies, looking at IPF, and subsequently also looked at progressive pulmonary fibrosis. Patient population there, I think, was about 80-90 patients per cohort, and they ran two different doses. So I think we would probably be in that range. Amgen's phase 2 is actually a 52-week study, and they have a smaller patient population of about 150 patients. The most important metric for here is improvement in FVC. Is comparable efficacy to Bristol's asset sufficient, or would you need, or would you hope to look for improved efficacy? And then, of course, you'll have presumably the benefit of the more convenient once daily. Comparable efficacy is fine. It's good. It's not what we're aiming for, but it's something that can certainly benefit patients, given the other conveniences that you mentioned for 791. But our hope here, and again, we've been able to demonstrate this preclinically in the bleomycin model, that as we increase the receptor occupancy, we have a better impact on the animals in the lung fibrosis. We hope to be able to achieve that in patients as well. So that is our goal. The convenience and the single-day dosing and the safety profile are going to be key. So I'm not going to call that incremental. I think that that's still very important. But we went into this disease state with conviction that having a profile like 791 will lead to better outcomes for patients. Maybe touch really quickly on your phase 1b PET data or the PET study that you're initiating. How to think through, or maybe what should investors be focused on as you conduct this study and the data start to read out? Yeah. And again, a lot of this comes back to the Amira molecule. So there was an understanding of the receptor occupancy that drives efficacy. We have crafted our own PET ligand in-house. We have tested it in animals. We have a very good sense as to what the receptor occupancy will be. That being said, we want to substantiate that in patients. So we will use healthy volunteers to build out that receptor occupancy curve to make sure that we are able to achieve, in a phase 2 study, a high level of receptor occupancy beyond what our competitors are able to do with a QD once daily dose. And we think that's a huge de-risking event. As I mentioned before, 278 looks like a good molecule, but again, in my opinion, they missed the dose in their phase 2. We want to make sure that we don't have a misstep like that along the way. We also are going to take that extra step in looking at the receptor occupancy, or I'm sorry, the PET ligand in patients as well. So later this year, we'll have the healthy volunteer study kicked off early in 2025. We will look at patients with progressive MS and idiopathic pulmonary fibrosis and being able to demonstrate what that ligand is able to show in lung and brain. And maybe are these data sets gating to the initiation of the phase 2 trials? No. No. These are information that we think will be really important to treating physicians and to put out to the investment community, being able to show this for the first time. But is it gating? No. We have a lot of confidence in where we are with this molecule with respect to receptor occupancy. The gating item right now is completion of the chronic tox study, which will happen in the first half of 2025. And then that'll launch us into these larger phase twos. Maybe we can transition to 307. Sure. Maybe to start, if you don't mind, speak about the genesis of this J&J collaboration. To the extent that you are able to share, what was the level of detail or data that they saw to really get them interested? And where do they see the long-term potential here for 307? So I'll be a little bit careful on this because J&J has been a fantastic partner, and we'll be careful with how we position this. So M1 receptor antagonism led to the start of Contineum Therapeutics. A lot of this built around internal work looking at M1 on OPCs. And by inhibiting M1, we can lead to OPC differentiation. So in that inflammatory environment of MS, acetylcholine is brought in through infiltrating immune cells. It activates the M1 receptor, and it puts the brakes on that OPC differentiation process. And we demonstrate this preclinically from the work of some of our academic collaborators at UCSF. They were able to show this clinically with, I'll call it a dirty anti-muscarinic clemastine. So that started everything for us. The biggest question marks that people have around M1 receptor antagonism are driven by tolerability. There's a ton of anti-muscarinics out there. The ones that people think about most commonly are benztropine and scopolamine, where there is a cognitive liability associated with it. When we started this company, we believed that if we can selectively inhibit the M1 receptor, you limit that cognitive issue associated with dirty anti-muscarinics. So not long after I joined Contineum, I was approached by J&J, and they had expressed an interest in M1 receptor antagonism. The big question marks were, can you achieve a selective molecule given the active site homology across the five muscarinic sub-receptors? And then even if you can achieve that level of selectivity, can you limit any sort of cognitive issue? And like I said before, we take a pretty conservative approach as a small 40-person company. So we were able to identify PIPE-307 has a very selective profile against the other muscarinic receptor subtypes. As we went into the healthy volunteer study, we decided that we would run this as a kill experiment. So in addition to looking at safety and tolerability in various doses, every single patient, I'm sorry, every single healthy volunteer who came into the study was subjected to a battery of cognitive assessments, everything from simple learning and memory all the way through executive function. And they were tested at multiple time points. What we were able to show is that all doses, all time points, there was zero impact on cognition. That was a key driver for Johnson & Johnson. They are committed to becoming the world's number 1 neuroscience company. I think they're well on their way, given what they've shown with kappa and orexin and hopefully P2X7. PIPE-307 is the next arrow in their quiver within the depression space. So in addition to looking at OPC differentiation and the impact on remyelination, there is clinical validation out there for scopolamine to demonstrate in the publications from Wayne Drevets while he was at NIH. He's now one of the leaders of the neuropsychiatry group at J&J. He was able to demonstrate that with scopolamine, it can lead to a rapid and prolonged impact in both MDD patients and bipolar depression patients. That was obviously a driver for J&J's interest, being able to have a selective compound that mechanistically was the driver of that improvement, not only in the animal models, but also in patients, was really key to getting that collaboration up and running, the internal validation driven through the work at NIH. Maybe given the understanding that the M1 receptor is linked to cognition, are you surprised by these findings that your asset does not impair cognitive function? No. No. And again, that was the hypothesis in starting the company. It played out preclinically to the extent that you can test cognition in animals. But we had a high degree of confidence. I'm not going to say we weren't nervous going into the healthy volunteer study, but we had a high degree of confidence that given the profile that we saw with 307 and the ability to modulate receptor occupancy needs depending on whether we were going for MS or for a depression setting, we felt really good heading into that. Got it. Then maybe just provide a quick update on where you stand with the phase 2 VISTA trial in RRMS. How has enrollment been going? When can we expect to see some data? Well, that last question I can't answer, but the rest of it I can. So we're enrolling the study. All centers are up and running right now. The recruitment has gone better than we could have hoped. So we're feeling really good about this. The overall patient population here will be right around 160 subjects. Yeah, that's about all that I can say about that. And then on your decision, I mean, you've mentioned the low contrast acuity endpoint. Maybe talk us through the decision to use that as your endpoint. What would be clinically meaningful here? And help us think about what maybe that magnitude of benefit in the context of other agents. Yeah. So very few agents have gone through that path. You see an improvement in low contrast letter acuity with natalizumab and alemtuzumab. So that was able to be demonstrated. We work closely with Laura Balcer, and she has really championed this technique of low contrast letter acuity. It is a big driver of clinical disability in MS patients. This really links back to what we've been able to show in animals and in humans with visual evoked potential. So it is demyelination of that optic nerve that drives that conduction velocity loss. That is also the driver, that demyelination of that loss in low contrast letter acuity. So it is a key metric in the study that we're running. We also do have some VEP work going on in that study. From a clinically meaningful endpoint, you're looking at 5-7 letters of improvement. Perfect. And then just as you think about the landscape for RMS, there are so many agents out there right now. Can you help frame for us what the opportunity would be if 307 were able to show a benefit on remyelination? Yeah. We've seen the enthusiasm from the MS community in the VISTA study. So this is an easy addition to current standard of care. There are no remyelinating agents out there. So if you look at the treatment regimen for relapsing-remitting patients, there's about 20 drugs out there. They generate about $25 billion a year in sales. They all essentially do the same thing. They're really good immune modulators. They increase the time between relapses. What they don't do is change the course of clinical disability, nor do they address the hallmark of this disease, which is demyelination and eventually degeneration of the axon. So from a patient treatment standpoint, this is an add-on. It's an adjunctive to these immune modulators that we think can have a profound impact in the patient population. Now, how are you thinking about the strategy to bring forward both 791 and 307? You've touched a little bit on 791 being able to maybe go a little bit earlier into RMS, but talk to us about that thought process. Yeah. So there's no stepwise change from relapsing-remitting to progressive MS. This is really a continuum. We like 791 in the progressive setting. One, there's very little to treat these patients. And two, to be able to combine remyelination with a reduction in neuroinflammation can be really transformational. We started Contineum around M1 receptor antagonism, and that was driven through the knowledge that inhibiting that OPC differentiation can be switched off with a selective M1 receptor antagonist. The whole in the treatment regimen for relapsing-remitting patients is primarily built around remyelination. So I think that there is an opportunity for 791 to move to the left, and in the long term right now, we're really focused on a progressive setting. But these are two very different profiles of molecule that I think can benefit the entire gamut of multiple sclerosis. Perfect. Maybe in the last minute here, you do have a pipeline of other assets. Anything you'd like to highlight there, whether it's the next-gen, the next-gen LPA1 receptor antagonist? Yeah. And we have a highly productive chemistry and biology group. So everything was internally derived. As we looked at LPA1 receptor antagonism, we knew that there would be questions around CNS penetration and not especially as you look into diseases of the periphery. So we have nominated development candidate CTX-343, which is very similar to 791, but it is peripherally restricted. And that is moving into IND-enabling tox. We also have a number of discovery programs, one of which should be moving into development candidate stages in the not too distant future. Great. Final question. Over the next 12-18 months, you have a number of catalysts, but what are you most excited about and where do you feel investors should focus? I'm super excited about the PET study. This is data that's not out there in the public for anyone. We think that it'll be really important for clinicians to be able to see how an LPA1 receptor antagonist can work within this setting. And then obviously then kicking off the proof of concept studies. But we have a great collaboration with J&J. Stay tuned on some data coming through that. Unfortunately, I can't give any timelines on it, but that was the foundation of this company, and we're really excited to start to be able to present that information. Great. Well, with that, Carmine, thank you so much for joining us. Thank you, everyone. Thanks. Thanks. Thanks.