Great. Thanks, everybody, for continuing to listen in here. It's my pleasure to be joined by the Contineum Therapeutics Management Team. I think we'll just kind of get right into it, and I'll ask Carmine, the CEO of Contineum, to give a quick overview of the company, the pipeline, you know, catalyst timelines, and then we can dig into the science and do some Q&A. Thank you guys very much, and please take it.
Yeah, absolutely. Thanks, Paul, for the invite to the CNS conference. I'm happy to present slides if you think it'll be useful, but just as a quick background of the company, Contineum is a clinical stage biotherapeutic company, and our main focus areas are NI&I, so neuroscience, inflammation, and immunology. A few things that I just want to point out early on in this discussion is all of the assets that we'll be talking about today were internally derived. I think that highlights the very productive nature of our research and development group. As we start to pick targets of interest for us, we always start with a neuroscience angle. What we have found, though, is that in selecting these targets, many of these targets also have a fair degree of applicability within the NI&I space, and that's what led us down the path with 791, with IPF.
As we lay out 2025, it's a very heavy clinical year for us. We will be running seven different clinical studies, four of them around our lead asset, 791, two with PIPE-307. That is an asset that we'll be talking about that is partnered with J&J, and then a novel program that we'll be heading into healthy volunteer studies. An area that we like to focus on here, and we think is particularly important in what appears to be a heavy risk-off environment right now, is we have clinical validation, a high degree of clinical validation across both assets in three of the disease areas that we're interrogating. Some of that clinical validation comes from pharma, from BMS and J&J, for instance, and some comes from academic work that we have that helped get Contineum started at UCSF.
We think that that allows for a de-risk portfolio coming forward. Of course, we do have areas that have been preclinically validated by us, but more of a white space opportunity.
Yeah. Yep. Okay. Great. Maybe in the spirit, I do want to talk about the IPF program because of how interesting it is and how big that market is. In the spirit of this conference, let's cover your CNS efforts first. As it relates to PIPE-307, do you want to give the historical context on the validation we have for the M1-based approach in depression and RRMS? I guess overall, why you think the probability of success here is better than the industry average pre-phase II asset.
Yeah, I'll start with this, and I'll defer to Dan on some of this as well. PIPE-307, this is a first-in-class selective inhibitor of the M1 receptor. We initially had interest in this target given its potential to remyelinate. What we have found is that by inhibiting the M1 receptor on oligodendrocyte precursor cells, we can advance the differentiation process into fully functioning and remyelinating oligos. The initial proof of concept study here actually came from Dr. Ari Green at UCSF. He ran a study called REBUILD, and he used a drug called clemastine, which is actually a first-generation antihistamine but has broad anti-muscarinic properties. In that crossover design, he was able to demonstrate for the first time remyelination in relapsing-remitting patients. He was able to demonstrate that through a functional biomarker called Visual Evoked Potential Latency.
Demyelination of the optic nerve in relapsing-remitting patients leads to a blunted signal from the retina to the visual cortex. He was able to improve that with clemastine. After that work had been done through scientists at Contineum at UCSF and elsewhere, it was determined that that effect was driven through the M1 receptor. That clinical validation, along with a lot of the work that we've done, has now launched us into a phase II clinical proof of concept study called the VISTA study. This is the largest remyelination program that we're aware of. The goal here was to enroll 168 subjects. We actually over-enrolled that, and we were able to get this study fully enrolled two quarters ahead of schedule.
We are happy to announce that we are going to be able to provide top-line data coming through this, what we think is a really critical study for relapsing-remitting patients in the second half of this year. What we believe, how this fits into the treatment paradigm is we have 20-plus drugs out there to treat relapsing-remitting MS, all efficient immune modulators, all do a good job at increasing the time between relapses, but the hole that is missing in the treatment paradigm for these patients is remyelination of the axon and preventing the neurodegeneration associated with that.
Maybe before we talk about the depression side, do you want to just, remyelination, right, has been this holy grail, and there was excitement years ago about lingo. I think one of the questions in this space is, how do you show it in a clinical trial? Specifically, how do you show it in a study that is not a year or longer, right, given the natural history of the disease? What is your view on the best way to at least preliminarily de-risk something like this?
Yeah. We really like that functional biomarker of VEP. It is very difficult to do that over a multitude of sites because it can lead to confounding results in different ways that people do this. In the REBUILD study, it was a great way to do it. It was a single-site study, so it was very self-contained. As we look at the development of the VISTA study, we're looking at the typical MS components, right? The MSFC, we're going to look at NfL, we'll look at MRI imaging, but this is a six-month study, and we feel like the area that can show the quickest benefit is in the eye. The functional biomarker of VEP, an improvement there should lead to an improvement in low-contrast letter acuity. We've seen this through other compounds at much earlier stages.
If you look at the REBUILD study, that VEP latency improvement occurred in that crossover design anywhere between two and three months post-treatment. We're running a 6-month study. We believe that that will lead to remyelination in that anterior visual pathway and then lead to an improvement in low-contrast letter acuity. This isn't a reduction in degeneration. This is actually a regenerative approach to show remyelinated axons.
Right. So your thesis is that you could show clinical improvement.
Correct. Yeah.
Yeah. Okay. Okay. Do you want to talk about the depression side? We can go scientific and then talk about the clinical development plan to the degree to which you guys can share details.
Yeah. Thankfully, the study is actually on clinicaltrials.gov now. It is PIPE-307. The J&J moniker is JNJ-5120. The clinical validation around M1 receptor antagonism in MDD really started at NIH by two investigators, Maura Furey and Wayne Drevets. Over multiple studies, they were able to demonstrate that a low dose of scopolamine can have a rapid and robust improvement in MADRS. That improvement occurs over the course of days. When patients come off drugs, you see that prolonged improvement. That has been replicated multiple times. They have been able to show this in MDD, bipolar depression, TRD, and so forth. As luck would have it, Wayne Drevets, who led that study, is now the disease area head for neuropsychiatry at J&J and a strong believer in the anti-muscarinic hypothesis of depression. They recently kicked off their phase II B study.
This is a 124-patient study, two different treatment regimens, one placebo regimen. It is a rapid study. If you look on the ClinicalTrials.gov listing, they're expecting to show an impact within a week or two. That study is in full enrollment right now. I'll turn it over to Dan to discuss the scientific rationale for M1 receptor antagonism in the MDD space.
Yeah, it's really kind of an interesting story because it came off of the clinical trial results where there was a significant effort preclinically to try to identify how scopolamine was producing its effects. We have to give a lot of credit to the scientists out of Eli Lilly, who published the initial paper showing that the M1 knockout animals could recapitulate the scopolamine effect. This was replicated by other academics, specifically showing M1 receptors targeting the GABA cells. By inhibiting those receptors, you see a decrease in GABA release and a disinhibition of the glutamate signaling. That leads to an increase in synaptic density. I'd like to say it's very similar to the ketamine biology, but with a safer mechanism.
Yeah. Paul, I guess another important point here is if you look at esketamine and what J&J has been able to do with all of the liabilities associated with that, from reimbursement to dissociation to monitoring, they've turned that drug into a billion-dollar drug, which is pretty remarkable in its own right. This is another arrow in their quiver to treat MDD and other neuropsychiatric conditions. There's a high degree of excitement there. I think that excitement has been amplified now with the loss of the Kappa program, this being a key phase II clinical development program for Johnson & Johnson in the space. Oh, you're on mute, Paul.
Thank you. How were the doses and specifically the dosing regimen for this study chosen?
I wish that we can share that, but unfortunately, that is not in the public domain.
Okay. Okay. I guess maybe you can tell me if I'm on to anything, but my understanding is that there's a thesis around the M1 approach that you might not need to hit this pathway every day, that it might lend itself to intermittent use or something that's durable post-treatment. Is that part of the thought process or the thesis here?
I think it's a reasonable hypothesis if you look at the scopolamine work where that was dosed, I think, twice a week.
Yeah. Okay. And then just as it relates to M1 antagonism generally, right? I mean, no one's really proven it, but there's been a lot of smoke around the possibility that M1 agonism benefits cognition. I know that there's mixed data here, but just on the other side of the coin, what's your guys' comfort in the safety of your approach?
Yeah. You've got to consider that we have now dosed for anywhere from a few months all the way to a 6-month period, over 168 patients with a selective M1 receptor antagonist. We haven't had any issues that have been identified by the DSMB. From our healthy volunteer work, we try to de-risk these as early as possible. An important component in the J&J collaboration was phase I work that we ran that was a risky study. It was a kill study because there is a stigma around cognition and anti-muscarinics. Our hypothesis was that if you can selectively hit a single sub-receptor, you can mitigate those issues. We tested that in our healthy volunteers going up to some pretty whopping doses.
All the subjects went through a battery of tests, five different domains of cognition, everything from simple learning and memory through executive function. We saw nothing different than placebo. That gave us and our partner a lot of confidence that this is a safe mechanism to interrogate. I guess going a step further on M1 agonism, a number of pharma have brought forward selective M1 agonists that proved to be safe. They just really did not do anything from a pro-cognitive effect.
Yeah. Yeah. Okay. Fair enough. Before we move on, just maybe remind us the timing of these two data readouts for the M1 compound.
Yeah. For the VISTA study, the relapse-remitting study, the top-line data will be in the second half of this year with the J&J study, which is called Moonlight One. Unfortunately, we're not able to talk about the timing for that.
Okay. Did you say that that's fully enrolled, though?
The relapsing-remitting study is fully enrolled.
I'm sorry. I think I just want to make sure we clarify that, right? You did not say that it was a depression study.
No. No, no.
Okay. All right. Let's switch gears and maybe talk a little about just LPA1. And again, in MS, you have some preclinical data there. What's the underlying thesis and why this could work?
Yeah. Dan, maybe you can talk about some of the profile of LPA1 in the brain.
Yeah. We were quite interested in targeting LPA1 for inflammatory demyelination conditions such as progressive MS based on some findings that we discovered here in the lab. If you look at MS patient tissues, what you'll find is high levels of autotaxin expression in and around lesions. This leads to aberrant LPA production. The LPA1 receptor within the CNS is primarily restricted to glial cells, both microglia and oligodendrocytes. What we show in response to excess LPA activation is an increase in neuroinflammation and inhibition of oligodendrocyte survival and ultimately remyelination failure. Blocking this one receptor within the CNS reverses these events, you see a dampening of neuroinflammation, a promotion of oligodendrocyte survival, and ultimately remyelination.
Great. You guys have EAE data, is that right?
We do, yes. That was the main model that we used to show all of these effects, promotion of remyelination, functional promotion, and also dampening of neuroinflammation.
That model has been pretty predictive for the directly immunomodulating therapies. What do we know about the relevance of that model to a novel mechanism like this?
We have to, it's actually clemastine is quite helpful in this setting as well. Clemastine was effective in the EAE model. It showed a remyelination effect. Of course, that went on to show activity in humans in the REBUILD trial. We can rely on that molecule bridging the gap between remyelination from preclinical to clinical. I can also say from a neuroinflammation perspective, BTKIs are active in the EAE model showing a reduction in neuroinflammation. That now, it seems like that's bearing out clinically.
Yeah. Yeah. Okay. Great. Do you want to talk about the trial that you're running? It feels like to me, right, there's not saying that there aren't ways you can show that the progressive program works in a short study. Certainly make a good case for that, Carmine. Just in relapsing MS, right, there's things like there's things like neurofilament. There's more of a there's a lot more precedent to leverage. Maybe talk about the trial design and how you guys are framing what positive proof of concept might look like.
Yeah. For this study, first of all, we're waiting on our chronic tox. The 6 and 9-month chronic tox is complete. We're just waiting on the draft reports. That'll give us the ability, along with the receptor occupancy study that's currently running, to decide on what doses to bring forward. As a starting point here from the progressive MS side, this will be largely an imaging study. Looking at different MRI metrics for remyelination, myelin water fraction, MTR, MTI. On the neuroinflammation side, we're likely to focus on paramagnetic rim lesions and being able to demonstrate an improvement in those lesions through TSPO-PET or other metrics there as well. This is set up more as a phase II A. We're still debating the length of the study. It could be up to a year. It may be 6 months.
As we continue to generate more data, we'll be able to provide more input there. We anticipate that study starting in the second half of this year.
Okay. Is NFL of interest to you?
Oh, absolutely. Yeah. I think any sort of study that we're doing in the CNS, we will look at NFL, especially given the potential for 791 for remyelination in progressive MS patients and also having a component of that in neuropathic pain as well.
Right. Right. Right. Okay. All right. I know we only have a few minutes left. There is always a lot to talk about with you guys. Just give us the update on IPF. You guys have this PET study ongoing with data coming out. What are you going to learn about this study as it relates to drug in the brain, drug in the lung? What is the utility of it?
Yeah. A key driver for this study from our perspective was looking at the BMS data, right? When we saw their phase II data, it was clear that they missed their doses. They went forward with two separate doses, a 30-mg BID and a 60-mg BID. The 30-mg BID was just mixed in with placebo. It really did not have much of an impact at all. Their 60-mg BID started to show an impact, but it clearly was not maximized. As we saw their PK that came out of clinicaltrials.gov recently, it was clear that the 30-mg dose was well below the EC50. Even the 60-mg dose, there were some patients above that level. There were a lot of patients below that level. That mixed result to us started to make sense.
They have now moved into their phase three study with a 120 mg BID dose, which is a little bit out of the ordinary for pharma to be testing a novel previously untested dose in a registration study. We are very confident in our modeling around what doses we are bringing forward. This was just an additional check-the-box for us to say, "Okay, we've run this study. Now we have another data point to really triangulate on what the appropriate doses are moving into that phase II B." That will pertain to both progressive MS as well as idiopathic pulmonary fibrosis.
Yeah. Okay. What's the latest thinking on whether the lung data from the PET study will be interpretable?
We don't have enough information right now to be able to talk about either progressive MS or the lung. We do have a fair amount of healthy volunteer data. We knew going into the study in healthy volunteers, the expression of LPA1 is less than it is in disease tissue. The nice thing here, we know that lung is tricky. It moves. It's aerated. It's full of blood. It is a much harder organ to interpret than the brain. We also know that the brain can serve a surrogate as a lung here because it is a one-to-one ratio in our hands between brain and lung. That being said, we hope to be able to share the healthy volunteer data demonstrating receptor occupancy and displacement. We are working to feather in some additional patients both from an IPF perspective and from the progressive MS population.
Yeah. Yeah.
We'll be reporting those data in the next quarter.
Yeah. Okay. Makes sense. Maybe lastly, Carmine, I know we're almost out of time, but do you want to just briefly touch upon why you guys chose to go into pain with this approach?
Yeah. I'm going to toss that over to Dan again.
Yeah. The LPA1 pathway has been implicated in pain. Actually, quite a bit of academic research behind this showing that LPA is liberated after nerve injury and tissue injury. That activates LPA1 receptors both peripherally and centrally. Peripherally, there is a demyelination component from LPA1 expressed on Schwann cells. Centrally, as we have been discussing, LPA1 drives neuroinflammation. Collectively, this has been shown to sensitize the ascending pain pathway. A lot of academic literature, we were able to replicate some of the pain findings using a non-human primate model of neuropathic pain. Yeah, we are pretty excited about the possibility of exploring LPA1 in this setting.
Great. You guys have a bunch of readouts coming up.
We do.
Do you want to just briefly touch upon cash runway, which is certainly topical in this biotech market?
Yeah. This is one of the areas that we're really happy with the IPO and our collaboration with J&J. I think we're in a unique position. We are funded through 2027. That hits all of the major inflection points that we had been discussing from proof of concept to the exploratory studies, even getting a peripherally restricted LPA1 receptor antagonist into the clinic. We're happy to be in that situation, especially in what is a pretty tough fundraising market out there right now.
Great. Awesome. Thank you, guys. We covered a lot in 25 minutes. I appreciate you taking the time. We will look forward to catching up soon. Thanks, everybody, for listening.
All right. Thanks, Paul.