Have you figured out how, you know, like admilparant? Nope. All right. Hello, everyone. My name is Charlie Moore. I'm a Senior Biotech Associate here at Baird, and I'm pleased to welcome here today Carmine Stengone from Contineum Therapeutics. He's the CEO, and he will be telling us more about his company and the assets they have under development. Carmine, if you wouldn't mind, could you just kind of give some overview of the company and just a quick look at where everything is in terms of clinical development? Yeah, absolutely. Thank you to Baird for inviting us to the fireside chat. As Charlie mentioned, I'm Carmine Stengone. I am President and CEO of Contineum. I've been with the organization for just about seven years now. It recently went public, so we went public in the first half of last year. A little bit about the company: the main focus that we have is in NINI, so neuroscience, inflammation, and immunology. We have two clinical stage assets, w e have multiple near-term readouts on the horizon, and ju st to touch on these assets briefly, some things that we do to de-risk these programs at an early stage: one, we'll be talking about IPF, MDD, and relapsing-remitting MS. With the mechanisms that we are advancing in these indications, there is a high degree of clinical validation. We feel that helps to de-risk some of the clinical development risk that we have. In addition to that, we spend a lot of extra time early on in development making sure that we choose the right doses heading into phase II. What we've found, especially in neuroscience indications, is people choosing the wrong doses into the phase II and possibly killing drugs that were somewhat efficacious, so w e do that. We help to validate those doses using PET receptor occupancy studies to make sure that we have the requisite level of target engagement to drive what we believe will be an efficacious readout. With respect to the two programs, the program that is fully owned right now is PIPE-791. This is a first-in-class brain-penetrant inhibitor of the LPA-1 receptor, and we are currently advancing this in IPF. We expect to initiate a phase II clinical proof-of-concept study in IPF before the end of this year. Later this month, we will be putting out data on our phase 1b PET receptor occupancy data. In addition to IPF, we currently have an exploratory phase 1B running with this same asset in the area of chronic pain. We are doing a crossover design, 40 patients, up to 40 patients, looking at the pain response on a numeric pain rating scale in both osteoarthritic pain as well as in chronic lower back pain, including back pain with radiculopathies. PIPE-307 is a first-in-class selective inhibitor of the M1 receptor, so it's in the muscarinic class. This was actually the mechanism that helped form the foundation for Contineum Therapeutics. In early 2023, we signed a collaboration agreement with Johnson & Johnson around this, and we are currently in the midst of two separate phase II clinical proof-of-concept studies. One, which we'll be reading out before the end of this year, is focused on remyelination, in a relapsing-remitting MS setting. The other, which J & J is running right now, is focused on MDD. Very different diseases, but mechanistically, M1 has a significant impact in each. From a corporate perspective, we have cash through the end of 2027, and that allows us to execute on all the inflection points that we'll talk about during the course of this fireside. Wonderful. Thank you for that overview, Carmine. You know, why don't we get started with PIPE-791, since that's your wholly owned asset? As you mentioned, it's an LPA-1 receptor antagonist that you plan to develop for IPF and explore in pain. Could you kind of give us a little bit of background on this mechanism as well as some of the history of other LPA-1 R antagonist programs? Sure. A lot of the understanding of LPA-1 and LPA generally in IPF came through Andy Tager back in the 2008 timeframe at Harvard Medical School. What he saw in IPF patients was an increase in LPA in the bronchoalveolar fluid. What he subsequently was able to elucidate here was that it was LPA that activates the LPA-1 receptor. What this leads to is, through an activation of LPA-1, a recruitment of fibroblasts, which then leads to collagen secretion. In addition to that, there's an impact on the epithelial layer, which allows for further inflammation. He was able to demonstrate that this was driven through LPA-1 through a number of different knockout models. From a preclinical perspective, knocking out LPA-1 improves fibrosis in bleomycin. Subsequently, we've had three compounds now that have generated data with this target in IPF. Probably the most important are through BMS. BMS had a first-generation LPA-1 receptor antagonist, the first one to go into an IPF patient population. As luck would have it, that asset actually came from a company based in San Diego called Amira, and my CSO was one of the founding scientists there. There's a lot of requisite knowledge internally around LPA-1 and IPF. That compound showed some pretty impressive efficacy until the study had to be stopped due to an off-target toxicity. There was an inhibition of BSEP that led to hepatobiliary tox. BMS quickly nominated another development candidate, and this is BMS-278, now known as Admilparant. This compound is currently in a phase III, actually two phase III studies focused on IPF and PPF. There are question marks around some of the aspects of the company that we believe we can address with PIPE-791 through differentiation. Wonderful, t hat's a great overview. As you mentioned, differentiation, if we could just take a quick look at the pharmacokinetic profile of PIPE- 791, could you kind of give us a quick overview of how it compares to these other LPA-1 antagonists? As we look at BMS' lead program, it's a BID drug, i t's a relatively high dose. There are some question marks around a hypotension signal that they have. We believe in this case that even in their phase II study, they missed on the appropriate doses. They're currently in a phase III study investigating a dose that had never been previously tested in patients. It's not really a common occurrence for pharma. With 791, we think we can address all of these deficiencies. The easiest thing here is we have a very unique pharmacokinetic signature. We have extended coverage above EC90, and that is driven by a slow association-dissociation rate, so i t takes a little bit of time for PIPE-791 to attach to the receptor. When it does, it has a very long half-life. We believe that this can lead to, we know that this is going to be a QD dose. We believe that having that low peak to trough ratio relative to BM S and others, we can mitigate any safety or tolerability issues. The fact that we can achieve 90+ receptor occupancy with a single dose, we believe will lead to a stronger efficacy profile as well. Wonderful, and there are also different approaches in the clinic. When you think about, say, small molecule versus a targeted antibody, do you have any thoughts in terms of how those different approaches could differentiate as well as what advantages you think the small molecule approach may have? As far as we know, anything that's gone into patients has been a small molecule. Through BMS, through Amgen, through the Horizon acquisition in our program, I think there's benefits to this. Tissue penetration is much easier with a small molecule. Clearance is easier through a small molecule. From a financial perspective, obviously, it's easier as well. The drawbacks on a small molecule is they can be more promiscuous than something that is selective like an antibody. Antibody has a longer half-life as well. What we like about 791 is it is a small molecule. We have a high degree of selectivity. The half-life makes it almost like an antibody, but the drug does clear over time. We feel like this is the perfect mix of a small molecule with some antibody-like properties. Lugol-Diloxone. Yeah. Yeah. Makes sense. You have a phase one study that you alluded to with PET scans looking at receptor occupancy, and you have enrolled healthy volunteers as well as multiple sclerosis patients. Could you tell us a little bit more about what you hope to learn from this and thinking about, for example, your IPF phase II program that you plan to initiate later this year? Does this serve as a gating factor in terms of dose selection, or can you begin independent of this readout? This was never a gating clinical study for us. Honestly, the gating clinical factor for us moving into a phase II was getting our chronic tox done to be able to dose at least six months in patients. What we had here was a period of time where we could try and validate the doses that we had already had a high degree of confidence in from our non-clinical work. We were able to do that with this PET study. The majority of the data here, when you're looking at establishing receptor occupancy, is built through healthy volunteers. We're waiting on putting out the data later this month, but we believe that should this work the way that we hope, we will have doses that achieve high levels of receptor occupancy that serve as a differentiator and hopefully improve efficacy in this particular mechanism. Great. As we kind of think about the use of 791 in IPF and IPF more broadly, can you just give us a little bit of background at a high level on the disease itself as well as the gaps that are left by current management strategies? Sure. From a prevalence perspective, there's about 130,000 patients in the U.S., with idiopathic pulmonary fibrosis. It qualifies as an orphan disease. The incidence rate is about 30,000- 40,000 annually. The stark statistic for me here is once you're diagnosed with IPF, you have a greater than 50% chance of being dead within three to five years, and that is even when on top of current therapies. There are two approved treatments for IPF: o ne is pirfenidone, t he other one is a drug called Ofev, known as nintedanib. They do have an impact on forced vital capacity. As we age, our forced vital capacity decreases, but this is accelerated in IPF patients. Eventually, over time, that is what leads to death, that chronic fibrosis in the lungs. Nintedanib and pirfenidone have a degree of decreasing that rate of forced vital decline, but they come with a lot of baggage with them as well. The tolerability issues with both of these are pretty detrimental, so t here's transaminitis, t here are GI issues associated with it, t here's liver monitoring that is required as well, t hey are also either TID or BID dosing. One of the issues here, even in having that impact on forced vital capacity, is patients don't feel better. If you are extending someone's life by six months or a year, but the quality of life isn't there, you can look to pirfenidone and nintedanib as being comparable to the first-generation chemotherapeutics where, yes, you can extend life, but is that life, does it have much quality to it? The goal here now is to introduce new therapeutics in here that, from an ideal standpoint, can actually stabilize forced vital capacity once these patients are diagnosed and put on treatment. Great. Yeah. Speaking of the mechanism, as you've mentioned, has some de-risking due to Bristol's work in IPF. They showed about a 1.5% difference from placebo in terms of reducing the decline of PP FVC. However, as you've alluded to, it seems like potentially they left efficacy on the table. Yeah. Could you talk a little bit more about your thoughts there, as well as how you intend to ensure that you aren't yourself leaving efficacy on the table? Yeah. When they ran their phase II study, they chose two doses. From what we understand, they probably did not run a PET study. This was based solely on internal work from them. They chose a dose of 30 mg twice a day and then 60 mg twice a day. When their IPF study ran out, what we saw was that the 30 mg BID dose was no different than placebo. It had zero impact on FVC. The 60 mg dose started to show an impact, but it was clear that this was not maximized. Our hypothesis was that they didn't have the right level of receptor occupancy or target coverage. More recently, they put data out on clinicaltrials.gov that substantiates that. When you look at the 30 mg BID dose, the important metric to look at is what was the concentration at trough. The concentration at trough suggested that you're having maybe 20% target engagement. Yeah. is still sub 50% at that 60 mg BID dose. They have now moved into 120 mg BID. Again, it is not really common for pharma to do that, a new dose into a registration study. We expect that will lead to better target coverage, but it also imparts some risk into the program as well. Yeah. In terms of the risk, as you also alluded to earlier, hypotension has been a concern here. In quite a large proportion of patients in the phase II, almost 20%. Could you just kind of help us contextualize that within IPF, even if asymptomatic? What does this mean for patients and physicians as well as, you spoke a little bit about how your peak to trough may help you avoid this adverse event, but is this something that you're going to be keeping an eye on as well as you proceed through a phase II? FVC decline is what we're looking for. Sure. The way to maximize that through this mechanism is to hit the target as hard as you can. BMS, through what, now three studies that have read out, their healthy volunteer as well as an IPF and a PPF study, they saw cases of hypotension across the board. They actually had a dose-limiting toxicity in their healthy volunteer study for one of their doses as well that led to syncope. Obviously, these are older, frail patients, and having a hypotension signal is not ideal. We don't know whether this is on or off target. What we do know is that the pharmacokinetic profile that their 278 compound had, their '020 program had, and then Amgen's compound as well had, had a very high peak to trough. With the BMS drug, it looks like that hypotension signal comes up at Cmax early on in dosing. Their peak to trough, like I said, goes very high. It could be that it is hitting other receptors. It could be that it is just peak related with respect to LPA-1. What we know with our compound is in our healthy volunteers, we did not see any issues similar to what they had. We have a very slow onset of action for our molecule, so there's a low peak to trough. In addition to that, it almost is like a titration effect heading into it. One way that BMS is trying to wash out the hypotension signal in their phase III is through a dose titration strategy. Commercially, that is perfectly reasonable, but implementing that in a commercial, I'm sorry, clinically, it's very reasonable. In a commercial setting with an older, frail patient population, it's tough to do a titration that can last a week or two. Makes perfect sense. Just to confirm, when you're thinking about your trial design for IPF, you are taking care to ensure it has high comparability with Bristol. Is that correct? We want to make sure that at the end of this, people can do an apples-to-apples comparison. Wonderful. Yeah, that sounds great. Just moving on, since I want to make sure we can get to more of your pipeline, I know as well you have a really interesting exploratory trial with 791 in pain, as you mentioned at the outset. You're expecting a readout from that early next year in the first half. Could you just give us a little bit more about the rationale here, the design, and as well what you are hoping to learn from this signal finding study? Absolutely. We didn't take this study lightly. This is, we understand the probability of success in pain studies. Based on data that we generated in-house in non-human primates, looking at fMRI, as well as literature precedent around LPA and LPA-1 in specific pain settings, we thought this was a good opportunity to do an exploratory study, so t his is a smaller study, i t's up to 40 patients, w e'll run it as a crossover design at four weeks of dosing. The goal here is really just looking at trends. This is really dipping our toe in the pool to see, can we treat each of these 40 patients as an N of 1 and pull out a signal that then would convince us to move into a larger pain study as a phase II? We chose osteoarthritic pain and chronic lower back pain because if you read in the literature, the level of LPA is increased in both of those compartments, and the concentration level of LPA correlates with the disease severity and pain severity. Great. Makes sense. Definitely looking forward to that one. Before we move on to 307, which is another exciting compound, we'd just love to touch on the recent decision to postpone initiations of 791 in progressive MS as well as CTX-343, which is a peripheral LPA-1 antagonist. Could you just give us some more color on your thinking there and any insight you may be able to give us in terms of when we might be able to see those clinical programs initiate? Yeah. You positioned it right. These are just postponements, not cancellations of these programs. What really forced us to do this or compelled us to do this was the IPF study we're going to run is going to look a lot more like a phase III. We're looking at 100+ sites worldwide. We want to make sure that we focus our clinical and operational resources on getting that study up and running. Absolutely. Once we hit some steady state there, we will re-engage on progressive MS and on CTX-343. The dollars associated with both of those studies are still in our budget. This was not an issue with cash runway. We are funded through the end of 2027, it was more making sure that we focus on running the right study and not just rapidly running through it. Perfect. Yeah. Great. All right. Let's turn to 307 now, which, as you mentioned, is an M1-specific antagonist that you are exploring in both relapsing, remitting MS as well as major depressive disorder and is in a collaboration with J&J. Could you just kind of give us a high-level overview of these programs as well as the agreement you have with Johnson & Johnson? Yeah. As I said, M1 receptor antagonism was the start of Contineum. For the two diseases that we're interrogating, there is clinical validation. What we initially looked at was remyelination in a relapsing-remitting setting. In relapsing-remitting patients, there are infiltrating immune cells that end up expressing CHAT, releasing acetylcholine, and acetylcholine activates the M1 receptor on OPCs. OPCs are oligodendrocyte precursor cells. These are cells that are fated to become fully functioning oligos, and those oligos remyelinate axons. We believe that in inhibiting that M1 receptor on the OPC, we can take the brakes off of that process, lead to the differentiation, and lead to remyelination. This all started through some academic work at UCSF, where an investigator there ran a clinical study with a dirty antimuscarinic called clemastine and was able to show in relapsing-remitting patients with chronic optic neuropathy remyelination for the first time. The way he measured this was through something called visual-evoked potential latencies. MS patients, one of the first areas that get demyelinated is through the optic nerve. When that demyelination happens, the signal from the retina to the visual cortex is blunted. You increase that latency. With clemastine, he was able to show remyelination, and the way that he was able to do that is through that functional biomarker of VEP. That latency was decreased, leading to that remyelination. That leads to some of the clinical measures there around vision, so low contrast letter acuity. That is what you'll be looking at in your drugs. That'll be our primary endpoint, yes. Correct. All right. Great. Speaking of, you have the VISTA study coming up with an expectation of data in the fourth quarter of this year. We've already gone over the rationale, but when it comes to what remyelination really means in MS, could you just help us contextualize the clinical meaningfulness of that in this disease that really kind of lacks a therapy that can achieve that? Yeah. There are a ton of agents that work in relapsing-remitting MS. There are about 20 drugs approved. They're all immune modulators, though, so they're all focusing on the same thing. Amongst those 20 drugs, you have about $27 billion a year in sales. What is missing from the treatment paradigm in these patients is addressing the true hallmark of this disease. This disease is known for demyelination that leads to axonal degeneration, which leads to the clinical disability. By reversing that, we can add another weapon to the arsenal, really addressing the hallmark of the disease and hopefully having a much better impact on patient outcomes. Wonderful. When we get the data from this upcoming readout, what do you think that is going to look like in terms of the type of data we might see? Is it going to primarily be that primary endpoint? Will we get a fuller slate of endpoints? How should we think about the bar for success here in terms of this somewhat unique endpoint? Yeah. For the top-line data, we're still working through what will be released. At a bare minimum, we will talk about the primary endpoints, so safety and tolerability, and then mean change in low contrast letter acuity. That's what this is powered for. We do have a range of different exploratory endpoints. Some of them, another measure of LCLA, so percentage of patients who have a five or greater letter improvement on their LCLA, so t hat's about one line on the eye chart. We'll be looking at neurofilament light. In that case, that is actually pretty well validated in multiple sclerosis. NFL increases with axonal degeneration and neurodegeneration, so being able to show a reduction in that. We have the typical MS functional composite that is vision, which we're already doing, SDMT, which is cognition, and then strength and dexterity through the 25 ft walk score and the nine-hole PEG test. Lastly, MRI metrics where we can look at myelination as well. Wonderful. Can't wait to see that readout. Really exciting stuff. Alongside the MS program, you also have a depression program. Could you just give us a quick overview in terms of the rationale here as well as when you think about the profile that an M1 antagonist might have? Would it be more of a slow buildup like an SSRI, or do you think it could resemble something more like a ketamine-type treatment that has a faster onset? Yeah. It's interesting that you bring up ketamine because this is J&J is running this program. They have Spravato, which is an esketamine, which they use in TRD. The start for M1 in depression started at NIH back in the 2000s, and t here was an investigator there by the name of Wayne Drevets. He used scopolamine, which is a dirty antimuscarinic drug. There was always an anticholinergic thesis around depression. Wayne actually went forward and ran a number of studies with Maura Furey. What he showed with scopolamine in an MDD patient population is with a single dose, you can lead to a rapid decline in MADRS. His studies were 28 days, but two weeks on dosing, and it was only dosed twice a week. Saw a rapid decline in MADRS that continued through the dosing period. For the two weeks after dosing, you retained that benefit. You saw the opposite on the crossover side. That clinical validation through Wayne, Wayne is actually now the Head of Neuropsychiatry at J&J, so t hey have a strong belief in M1 receptor antagonism in this specific setting. The expectation here, if you look on clinicaltrials.gov for their program, they're running a four-week study as well, but t heir primary endpoint is the MADRS change at day five, so t hey're expecting or hoping to see a very rapid improvement in patients. Great. Let's hope they do see that. That would be very exciting. Just to wrap up on 307 and the collaboration agreement, could you give us a little bit of information on how the development costs are divided between the two parties, as well as should 307 succeed in the clinic, would you be able to take part in the upside from commercialization? Yeah. As I said, we signed this deal in the first half of 2023. Overall deal size was just over $1.1 billion, $50 million in cash upfront, $25 million in equity when we were still a private company, and they also supported into the IPO. There are a good mix of developmental, regulatory, and commercial milestones. We will look at the phase II together. J&J makes a decision as how to proceed. When they move into registration studies, we have the ability to co-fund on this, and t hat would allow us to increase the economics in the deal even further. In that case, we would be able to put 1-2 additional percentage points on our current royalty rate, and that would push us at the high end up to that 20% number. Great. Just to wrap up, could you give us a quick reminder in terms of the intellectual property position for both of your lead compounds? Sure. Yeah. It's still a lot of runway on those. With 307, the initial patent gives us coverage through 2040. A secondary polymorph patent pushes that to 2042, and that's before other patent term extensions. Same with LPA-1, 2042- 2044, and then additional patent term extensions. Great. Yeah. Seems strong. I think we've covered just about all of my questions, but as we look to wrap up here, is there anything that you think investors need to know about Contineum and where the company's headed? Yeah. There are a number of inflection points on the horizon. We have the PET study reading out this month. We have the relapse-remitting study reading out by the end of the year. We have the pain study in the first half of next year. I encourage you to look on clinicaltrials.gov to see J&J's timing on their study. Unfortunately, I do not want to piss off our partner. Arguably, one of the bigger catalysts for us is not one that we're generating, so BMS is seeking to put data out of their phase III study by the end of next year. Okay. Looking at what Mineralys was able to do and what Cerevel did based on Karuna data, that is a key inflection point for us as well. Wonderful. That about does it for us. Thank you so much, Carmine, for your time and your expertise. Thank you, everyone, for attending and listening. I really appreciate it. All right.