We're on? All right, great. All right, thank you, everyone. My name is Faisal Khurshid. I'm a senior biotech analyst with Leerink Partners, and we're here in Miami at the 2025 Leerink Partners Global Healthcare Conference. Really pleased to have with us today Carmine Stengone, CEO of Contineum Therapeutics. Carmine, you guys have so many moving parts right now. It's an exciting time for the company. Could you kind of lay the groundwork for us, give a quick intro to yourself and the company, and what's in store for 2025? Sure. Happy to. Again, thank you for inviting us to the conference and for the opportunity for this discussion. As Faisal said, my name is Carmine Stengone, and I'm President and CEO of Contineum. I've been with the organization for this year, we'll make seven years. As you know, we recently went public in April of 2024. I guess the one thing that we should hit right away is this is a really big clinical year for us. We have two clinical stage assets, and over the course of this year, we will be running seven clinical studies. This encompasses everything from healthy volunteer and PET receptor occupancy studies to exploratory studies, and then, of course, some larger clinical proof of concept studies. Six of them are being run by Contineum alone. We are partnered with J&J on one of our assets, and they are in the middle right now of an MDD study with PIPE-307. A little bit of how the company is established. We are a clinical stage biopharmaceutical company in San Diego, and we currently have two clinical stage assets. I think the bulk of the discussion will be around these. Just to lay that out a bit, our lead wholly owned asset is PIPE-791. This is a first-in-class brain penetrant inhibitor of the LPA1 receptor. Our initial interest in this target was actually driven by its expression profile in the brain, specifically on glial cells, microglia, and oligodendrocytes. We felt by inhibiting this target, we could have an impact on remyelination, leading through OPC differentiation into fully functioning and remyelinating oligos. Equally, if not more important, having an impact on the microglia and being able to have a reduction in neuroinflammation through inhibition of the LPA1 receptor in the brain. What we saw as the profile of this compound started to come along was the data that BMS presented in 2023 at ATS. They have an LPA1 receptor. I can't pronounce the name of it, so I will just call it 278. At any rate. Yeah, 278. BMS-986278 showed an impact in IPF in a clinical proof of concept study, phase two. When we looked at this in more detail, we saw that it was likely underpowered. As we compared the profile of that compound against the profile, both pharmacokinetic dosing and safety with 791, we realized that we had a very interesting opportunity here to move within the idiopathic pulmonary fibrosis space. What really drew us in here is that, and we'll talk about this, I'm sure, later on in the discussion, there is a high degree of clinical validation through three phase two studies and now two ongoing phase three studies that LPA1 antagonism is a powerful mechanism in IPF and its ability to reduce the decline in FVC. The next step for 791 is completion of a Phase 1b PET receptor occupancy study. We want to link that PK receptor occupancy relationship to help us de-risk the dose selection heading into our clinical proof of concept study. We also have chronic tox that will read out in Q2 of this year, and that will launch us then into those phase two clinical proof of concept for IPF and then the phase two for progressive MS as well. What we had recently announced as well, we are bringing 791 into a third indication. Less clinical validation here, really an exploratory study, a Phase 1b study in chronic pain and specifically in osteoarthritis and chronic lower back pain. Three clinical, actually, sorry, four clinical studies for 791 that will start or end over the course of 2025. Our second clinical asset for which we signed a partnership in the first half of 2023 with Johnson & Johnson is PIPE-307. This is a first-in-class selective inhibitor, brain penetrant inhibitor of the M1 receptor, so within the anti-muscarinic class that we are currently enrolling. Actually, we've just finished enrolling a phase two clinical proof of concept study focused on relapsing-remitting MS and specifically addressing the biggest hole in that treatment paradigm, which is demyelination. We are anticipating data coming through that study in the second half of this year. With our partner, Johnson & Johnson, they are currently running a phase two clinical proof of concept study with PIPE-307 in their hands as J&J 5120 focused on MDD, a 124-patient study. Like LPA1 with IPF, there's a high degree of clinical validation for M1 antagonism in both relapsing-remitting MS and remyelination, as well as neuroplastic changes associated with MDD. Got it. That's super helpful intro. Really kind of impressive clinical breadth for kind of the stage as a company that you're at. We'd love to kind of talk about the IPF hypothesis for LPA1 and kind of cool you guys are sort of following where the data is telling you to go. Can you talk about the rationale and level of validation for LPA1 and IPF with what Bristol has done here and how investors should kind of be comfortable with this just given investors unfortunately have a lot of scar tissue around IPF? It's been a tough space. Yeah. Yeah. The rationale for LPA1 and IPF really came to the forefront in 2008. Andy Tager was at Harvard Medical School. What he was able to show is that upon lung injury, there is an upregulation in LPA. LPA is a bioactive lipid. It activates the LPA1 receptor, and that starts a cascade of inflammation and subsequently fibroblast recruitment and collagen secretion. That then leads to lung damage. There is another aspect to this as well where LPA can also lead to breaking down of the endothelial layer, epithelial layer, which then leads to another cause for inflammation in this. What we were able to demonstrate preclinically and has been shown now in the clinic, by inhibiting LPA's impact on LPA1, we can attack at least two avenues of the fibrotic process in IPF and potentially in other fibrotic diseases. From a clinical validation perspective, yeah, you're right, IPF is a very challenging space, and we've seen some pretty significant hiccups over the last couple of years. I think that LPA1 inhibition is a little different here. We have now had three successful clinical studies demonstrating an improvement in FVC through the inhibition of LPA1. BMS has brought two compounds forward, three phase two clinical proof of concept studies, over 500 patients in aggregate, and the data are pretty indisputable. I'm not going to say that that drug doesn't have its liabilities, but the data is pretty indisputable that if you can inhibit LPA1 in the lung, you can have a positive impact in patients. From what BMS has shown, the side effect profile is fairly benign. We can talk a little bit about what they've seen heading into the phase three program, which is another 2,000 patients over two trials. Yeah. Yeah, that's great. The setup here is kind of cool, right? Like we're kind of Bristol sort of sets the precedent for the mechanism, and then your pitch is that you have the better molecule, the better mousetrap against this target. Can you talk a little bit about the design of your molecule and how you believe it to be sort of better and differentiated from what's out there? Then we can talk about the Bristol data after that. Yeah. Right now, in terms of compounds moving into phase two, there's really only two LPA1 receptor antagonists. It's us and BMS. I think Structure is a little bit behind in a phase one study. Yeah. I think they're focusing on bigger things as well. Yeah. Unintended. As we look at BMS's molecules, there's a few things that we think can be improved upon. The easiest one here is, one, it's BID dosing. With that BID dosing, you are going to be breaching a trough level every 12 hours or so. Some of the other question marks that come up with the BMS program is that it has a high peak to trough. That could potentially be why they are starting to see, or they've told us that over all the studies that they've run, they have seen hypotension. In their phase three study right now, they're running a lead-in cohort that dose titrates up to their highest dose. Specifically, they're looking at events of syncope in that. They've clearly seen something that we believe to be drug and not unknown, but we haven't seen anything on a cardiac ECG, telemetry, or anything relating to hypotension. I think the biggest place that we can differentiate, and again, this plays into the receptor occupancy study, is we believe that they missed their doses heading into the phase two. If you recall the data in the phase two study that they ran, they chose two doses. There was a 30 mg BID and a 60 mg BID. The 30 mg BID didn't show anything. It was no different than placebo. That was a clear miss. The 60 mg BID definitely showed an impact, but it wasn't maximized. If you compare that data with the original 020 data from their first-generation compound, 020 actually performed quite a bit better. We believe that the 60-mg BID dose, while having an impact on FVC, doesn't have the requisite receptor occupancy to be able to drive a full signal in that. When we looked at PIPE-791, this is a QD dose. It's a very low dose. In our preclinical work, when we map our PK curves from the healthy volunteer MAD on top of the projected EC50 and EC90, we get 24 hours of coverage above EC90 with a single dose. We have a lot of flexibility on our dosing. It would be QD. It would be full receptor occupancy, which we believe can drive efficacy. From a safety perspective, as I mentioned, we haven't seen any signals on cardiac or really anything in general from our healthy volunteer study. A key factor here are the pharmacokinetics of the molecule. It has a very slow on-and-off rate. It is not a covalent binder. It does disassociate. That slow on-and-off rate builds a very low peak to trough and a steady state that can last for an extended period of time. Got it. I want to talk about the, you mentioned kind of the importance of finding the right dose and getting the right kind of target inhibition over the dosing timeframe. You have your Phase 1b imaging trial coming up. What do you hope to learn from that study? Does that help de-risk the kind of question around optimal dosing of the target? We have a lot of confidence in the dosing regimen right now just from what we've done preclinically and in looking at the PK from the healthy volunteer. That said, we want to supplement that with some receptor occupancy work looking at both healthy volunteers and diseased patients. We're looking at healthy volunteer data in the PET receptor occupancy out of eight patients looking at both brain and lung. We know that lung is going to be challenging from a PET perspective, right? It's an aerated organ. It moves. It's full of blood. The signal will be more challenging than in the brain, which is a more solid organ. Thankfully, we also know that it is a one-to-one ratio with this molecule brain to lung. The brain can serve as a surrogate for the lung here. After the healthy volunteer work, we'll start feathering in patients, both progressive MS and IPF. We believe that you will see an upregulation of LPA1 in diseased patients. It's not that different than what Pliant showed with alpha-v beta- 6. The signal is very different between a healthy patient and those who have idiopathic pulmonary fibrosis. Got it. One question that comes up around, you mentioned kind of the blood pressure liabilities associated with the Bristol drug. A question that comes up is, how do we have confidence that that is drug-related, not target-related? I am curious on that. Also, I guess kind of derivative questions to that, did the Bristol program see some of these issues at the same stage that you are at now, or have you been able to compare preclinically to show that it might have some liabilities that you successfully avoid? We have not seen anything preclinically, and I'm not aware of anything preclinically from the Bristol-Myers Squibb compound. The peak to trough ratio is probably a big driver of the, I'm not going to call it toxicity because it's not, but of the hypotension that we see. I don't think anyone is positive whether it is on or off target. We know based on the IP that they filed that it is an event that happens early on in dosing, so potentially first dose, and it's at Tmax. It is something that is associated with the pharmacokinetics there. What they have done now is they have implemented a dose titration strategy in their phase three. Again, 60 milligram BID, 120 milligram BID. They seem to look to wash the signal out with a 10 milligram dose, which is obviously sub-efficacious, and potentially they can wash that hypotension signal out. Again, in the intellectual property where the dose titration is discussed, they also say that they have seen hypotension across all doses in all studies. Yes, they saw it in their healthy volunteer work. We also know in the healthy volunteer work that at their 250 mg SAD patients, so single dose, there was a DLT in the Sentinel patient, which we believe is syncope. That is something that they're looking at in the phase three is cases of syncope associated with the drug. Again, the dose titration, I think the hope there is that we can wash all of that out. Got it. Makes sense. I think you've guided to starting a phase two study in IPF in the second half. Can you talk a little bit to how you're thinking about some of the key variables around that, like dose selection and length of the study, things like that? Yeah. We'll be able to talk more about dose selection after we evaluate the receptor occupancy. I think the big discussion here is in all likelihood, we'll be doing dose range finding, so two doses. We haven't fully worked that through yet. I'm sorry, I missed a second. Yeah. So you're going to do two doses and placebo. Oh, and. You mean like three months, six months? What are you thinking on that? Six months. We have the chronic tox reading out imminently. We want to make sure we know that we will be measured against 278. We want to make sure that we run a study that is an apples-to-apples comparison, similar sort of patient numbers per dose. Importantly, the primary driver here will be changes in FVC. Yep. Okay. Yeah, makes sense. I want to talk about a couple of the other interesting opportunities for 791 that you mentioned, like the progressive MS opportunity and then kind of the newer proof of concept you're generating in pain. On progressive MS, can you speak just a little bit to the hypothesis for LPA1 receptor antagonism in progressive MS? I guess I'm curious as well, is that like an internally developed hypothesis, or is this supported by external literature as well? There is support by external literature, but it is all preclinical, right? This is unlike the IPF space where LPA1 is highly validated. This is more of a white space opportunity. As I mentioned before, what really drew us in here is the expression profile of the target in the brain. As we switch from a relapse-remitting setting to a progressive MS setting, you're switching from the adaptive immune system to the innate immune system. You have a more solid blood-brain barrier and so forth. Within progressive MS, the disability is driven through neuroinflammation and demyelination. That is where our initial hypothesis came out is, can we have an impact on microglia and in all likelihood, paramagnetic rim lesions, kind of like what Sanofi was looking at in their BTK program, and also have an impact on remyelination that can then have a more profound impact on progressive MS patients? As we look at the market here, there's only one drug approved for primary progressive, and it's Ocrevus. Their data in relapse-remitting is spectacular. I would say that it is less so in a progressive MS setting where you're looking at the clinical disability change of between, I think, about a 6% delta between drug and placebo. Got it. Makes sense. You're now advancing, or sorry, I want to talk about your phase two plans in progressive MS. Historically, there haven't been a ton of phase two specifically looking at the progressive MS population. How are you thinking about trial design and kind of balancing, getting some nice de-risking while balancing kind of time, size of the study, et cetera? Yeah. So again, we're looking at a bare minimum of a six-month study. It may go longer than that. Importantly, having seen some of the BTK work, that kind of sets the stage for us a bit. We know that imaging endpoints here will be pretty important. Can we demonstrate a reduction in paramagnetic rim lesions? Can we show a change in remyelination and whether we're looking at that through some sort of visual acuity or potentially through MRI metrics like myelin water fraction, DTI, MTR? I think that is the starting point here. The longer we go, the more that we can really start doing clinical disability measurements. Got it. That makes sense. I want to shift gears. We're about 10 minutes left on the J&J partnered M1 drug PIPE-307. You have kind of like two interesting shots on goal here in relapsing MS and then in the depression phase two as well. Curious how you're thinking about the difference between those two opportunities. Is there one you're more excited about? I think from the investor perspective, they see a little bit of a different risk profile across the two studies. Yeah. I don't know that I agree with investors on that. I'm equally excited about both. Like I said, Contineum started on a hypothesis that M1 receptor antagonism can lead to remyelination. There's clinical validation around this through one of our academic founders running a study with a dirty anti-muscarinic, actually a first-generation antihistamine called clemastine. That clinical validation for us, we find that to be pretty important in a de-risking event. We went into this phase two study looking to interrogate two separate doses in relapsing-remitting, 168 subjects. Much to our delight, we were able to enroll the study two quarters ahead of schedule. To me, that means a couple of things. There is enthusiasm from the investigators. There's enthusiasm from the patients. This is also a unique way to address what is the hallmark of relapsing-remitting MS, demyelination of the axon. We are able to do this without impacting patients' current therapy. You are on an immune modulator. This is just an adjunctive. It addresses a completely different aspect of the disease than the 20 immune modulators out there are able to address. We are excited with the speed with which this recruited. We are really excited to look at the data in the second half of this year. Great. Can you set expectations on what does a winning outcome look like in the phase two data, given this is like a six-month relapsing MS study? Yeah. The primary endpoint here, what we looked at was visual acuity. A lot of the preclinical work that we've done was focused on visual evoked potential. In MS patients, there's demyelination in the anterior visual pathway. How that manifests itself functionally is a latency in the signaling from the retina to the visual cortex. In our animal models, we were able to demonstrate that we could normalize those with PIPE-307. The clinical disability from that demyelination is an impact on vision. Our goal here is to be able to show an actual improvement, a regenerative effect in remyelination that changes that visual parameter. That is the main endpoint. We'll be looking at the typical MS metrics as well. We'll look at NfL. We'll look at various MRIs. Importantly, the MS Functional Composite, which is comprised of agility and dexterity, so nine-hole peg test, 25-foot walk score, SDMT for cognition, and then the visual metric. Got it. Can you just remind us high level of the structure of the collaboration agreement with J&J? In particular, are there any opt-ins or anything kind of tied to this phase two readout? Yeah. They have been a really great partner. They have been very collaborative. They have shared with us information. The overall deal that we signed with them was just over about $1.1 billion, $50 million upfront. JJDC contributed into the crossover round as well, as well as into the IPO. We have about $1 billion left in milestones. Like I said, we're running the relapse-remitting study. J&J is running the depression study. Heading into the phase three, we have the option to co-develop, less than 50%, but to co-fund into that to increase our economics even more from a royalty perspective. Got it. Okay. There is not an opt-in decision on their side, but it would be something that you could kind of choose to. We review the data and then decide. That opt-in would be for all applications. Got it. Does it have to occur at a certain time point? I don't know that we have publicly disclosed that. Okay. Can you talk a little bit about the, obviously, the kind of thesis for M1 antagonism in depression? I think people at least perceive it to be a little bit more well-validated. Can you just talk about that a little bit? Yeah. A lot of this started in the 2000s, early 2000s at NIH. There were two investigators there, Maura Furey and Wayne Drevets. Wayne actually heads up the neuropsych unit at Johnson & Johnson now. What they were able to show over multiple studies with, again, a dirty anti-muscarinic called scopolamine that everyone's familiar with, motion sickness drug, that in treating patients with, in the literature, it was MDD, TRD, and bipolar depression. With the appropriate dose of scopolamine, you can lead to a rapid and prolonged impact on MADRS. Within a week, you see a very rapid drop in the MADRS score. When patients were crossed over onto placebo, you saw that that benefit actually had a prolonged impact. On the other crossover side, the placebo showed no impact. As soon as the dosing started, there was an impact on MADRS. At the time that that work was done, no one knew what the mechanism was. Scopolamine is equal potent across all of the muscarinic receptor subtypes. It was through work from J&J and Lilly and, to some extent, at Contineum as well, that we were able to elucidate that that impact driven by scopolamine was solely driven through the M1 receptor, changing glutamate burst, leading to a neuroplastic change. If you look at the outcome here or the benefit here, it's not all that different than esketamine. This is a compound that you would be able to take at home without dissociative effects and so forth. I think a big factor for the J&J collaboration is we take a lot of pride in Contineum of trying to wash out as much risk as we possibly can. It is a highly selective compound. It truly is a first in class as far as we know of selective M1 receptor. One of the biggest questions people have with anti-muscarinics is, is there a cognitive liability associated with hitting M1 or M4? In our healthy volunteer studies, we subjected all subjects in the studies to a cognitive battery of tests across five different domains of cognition at some fairly significant doses. We saw nothing different than placebo. I think that that was that next step in getting this collaboration up and running. Got it. Super interesting. We have two minutes. I want to wrap up with two final questions. One, I want to come back to the pain opportunity for PIPE-791. Can you talk a little bit about what the rationale is for that proof of concept study that you're running and what would kind of support advancing in what is a very, could be potentially huge, but very different kind of phenotype of an indication? Yeah. I don't want to oversell the pain study right now. We have set this up as purely an exploratory phase 1B. It's a 40-patient crossover study. The two areas that we're focused on are osteoarthritis and chronic lower back pain. The literature out there for LPA and activation of LPA1 in chronic pain is pretty interesting. We took a step further and ran fMRI studies in non-human primates looking at neuropathic pain associated with LPA. We could mitigate some of that pain through an LPA1 receptor antagonist. That's what got us there. In choosing these two indications, the level of LPA in the synovial fluid or in the CSF correlates with pain severity. That was part of the step for us getting there. Again, we're dipping a toe in the pool. Where are these models? Generally. It's in patients. We're dipping our foot in the pool. This is not a powered study. It is placebo-controlled. If we didn't placebo-control it, it didn't solve a signal, no one would believe us. We look forward to hopefully presenting data on this, the top-line data, in the early part of 2026. As we look to the next 12 months, we have three, potentially four, pretty significant clinical readouts that are on the horizon. Got it. Super interesting. Just one question that I always like to wrap up with. What do you think investors misunderstand most about the Contineum story? I think it's odd for a company of our size to have such a breadth of clinical activity going on right now. These were all chosen very purposely. If you look at our portfolio, I think from where we stand heading into these proof of concept studies or running these proof of concept studies, we have a pretty de-risked approach. It's a conservative company where you have clinical validation across three of the opportunities that we're looking at. Some of them have pretty compelling pharma validation behind it. Yeah, that's it. Just to, I guess, finish up, we have the cash in hand that funds us through 2027. That means all of the clinical programs that we've discussed during this, as well as another healthy volunteer study, is all covered with our current budget. All right. Great. Thank you so much for joining us, Carmine. Really appreciate it. This was a helpful overview of the company. All right. Thank you.