All right. Thanks very much. It's my pleasure to be hosting this panel with Carmine Stengone, President and CEO of Contineum Therapeutics. Always good to see you, man.
Thank you.
Maybe, Carmine, you can just give a quick overview of the company, and then we can do Q&A. Sound good?
Sure. Yeah. So Contineum, we are a small molecule discovery and development company. Focus of the company is within NI&I, so neuroscience, inflammation, and immunology. We have two clinical stage assets. One that we've partnered with J&J is an M1 receptor antagonist that's currently enrolling a phase two clinical proof of concept study in relapsing-remitting MS. J&J is on the verge of kicking off a phase two clinical proof of concept study in depression. Our second asset is a first-in-class brain penetrant inhibitor of the LPA1 receptor. This is PIPE-791. That compound recently, well, not so recently, about six to nine months ago, completed a phase one healthy volunteer study. We are on the verge of starting a Phase 1b PET study looking at receptor occupancy in lung and brain.
We will advance into two phase 2 studies next year, one in idiopathic pulmonary fibrosis and the other in progressive MS. Today we announced a third indication for 791 in an exploratory phase 1b study focused on osteoarthritis and chronic lower back pain.
Great. So maybe let's start with IPF. Obviously, a challenging space. Do you want to talk a little bit about the scientific rationale of targeting LPA1 receptor and how it's different than some of the things that have been kind of thrown at the wall in this area before?
Yeah. And I think something important to note here is that LPA1 receptor antagonism is clinically validated within IPF. So BMS has run three studies across two separate drugs in over 500 patients. And they show an impact on reducing the decline associated with FVC. We think that we have a better approach than BMS with our compound. But LPA1 is a driver of fibrosis due to LPA. So in patients who experience lung injury, there's an increase in LPA. You actually see an increase in lung fluid. That LPA activates the LPA1 receptor. That leads to an accumulation of fibroblasts and then subsequently collagen secretion driving the disease state.
Okay. Makes sense. And so as it relates to the data that we have so far, maybe talk a little bit about the Bristol data that you described as validating. And how do you make sense of the recent failure of the Amgen compound?
Sure. Yeah. So with Bristol, there's resident knowledge within Contineum around this. So the first LPA1 receptor antagonist that went into the clinic originated with Contineum scientists when they were at Amira Biosciences. And Amira was a San Diego-based company. They sold to BMS back in 2011 for $400+ million for that LPA1 receptor antagonist. BMS brought that compound. It was relabeled. I'm sorry, BMS-020 brought that into the clinic and demonstrated clinical proof of concept, actually a pretty nice impact on FVC decline in the IPF patients. There were some issues associated with the drug, the biggest of which was there was an off-target toxicity associated with it where they had two patients, I believe, with cholecystitis and liver injuries. So that was later found out to be driven through inhibition of BSEP, which was an off-target effect. And now all LPA1 receptor antagonists are screened against BSEP.
So ours, BMS's new one, Amgen, and we, based on their S1 structure as well, all screen against BSEP. But we know that with that program, there was a PET study run. So they were able to look at these doses, assess the receptor occupancy to drive the maximum impact that they could. There were issues associated with the drug, really highly protein-bound, that necessitated high doses of 600 mg QD and 600 mg BID. Once that failed due to the cholecystitis issues, BMS transitioned over to another compound, BMS-278. Last year, they reported data at ATS. They looked at two separate doses here, 30 mg BID and 60 mg BID. Surprisingly, the 30 mg BID dose showed nothing. It was pretty similar to placebo. The 60 mg started to show an impact, but it certainly wasn't maximized to the way that 020 was.
Nonetheless, they showed an improvement in FVC decline and now have moved into two larger-scale phase 3s in both IPF and PPF
They're dosing higher too, correct?
Yeah. So.
Or we think.
No, no, no, we know.
Yeah. Okay.
The interesting thing here is they killed the 30 mg BID dose, which makes sense because it didn't really have an impact, but they added in a 120 mg BID dose, and as far as we know, that dose has never been tested in patients before, so it's not really common for pharma to add a new higher dose heading into a phase three registration program. A few other things that we've learned through this. So BMS had a healthy volunteer study that they published on: the 125 mg BID in the MAD portion was ostensibly clean outside of what we believe may have been a hypotension signal, but the 250 mg QD in the SAD portion was discontinued early on due to DLTs, so they are now pushing forward with a higher dose, and what we also recently learned is they are implementing a dose titration scheme.
So it appears that they have hypotension signals across all doses that they've tested over both studies. So this dose titration can take up to 21 days to get up to that 120 mg BID dose.
Yeah. Yep. Okay. So if we take a step back, at what level of LPA1 receptor occupancy has Bristol established the efficacy of this mechanism? And with 791, where do you think you can get?
Yeah. So Bristol has never talked about their PET studies.
Okay. So we just don't.
We don't know if they ran a PET study in the 278 in the newest program.
Do you have a guess as to how much better you can be based on your own clinical work and modeling?
We assume that their 30 mg BID never breached the IC50.
Got it.
The compound, that Bristol compound, has a really high peak to trough. That's what's necessitating a BID dosing regimen here, and given the signal that we saw, we don't believe that they are achieving anywhere close to full receptor occupancy. I think that's a differentiating factor with PIPE-791. This is a QD oral drug. What we've been able to demonstrate preclinically is at very low doses being able to achieve IC90 coverage 24 hours a day, and some of the other unique properties here is it has a really slow association-dissociation rate, and so that leads to a pretty steady shallow peak to trough ratio and continued target coverage over 24 hours.
Yep. Okay. Makes sense. So maybe dig a little bit deeper now into the properties of 791.
Sure. So a lot of this, if you look at the current treatment regimen in IPF, there's two drugs approved, pirfenidone, which is off-patent, and then Ofev, which is a BI drug. The tolerability profiles here are pretty negative. You have about 30%-40% of patients who never go on either of those drugs because of tolerability issues. And then you have another 30%-40% of patients who roll off within a year. So you have a huge unmet medical need here in a disease that is fatal. Once you're diagnosed, the average lifespan post-diagnosis is three to five years. Nonetheless, even with all of these issues, the BI drug's going to do close to $5 billion in sales this year. So for us, what we wanted to do is make the most convenient regimen possible.
We have, based on our healthy volunteer data, a 1 mg dose that we believe, with a single dose, covers the receptor to 90%. We've gone as high as 10 mg in the MAD, where it's an order of magnitude or more higher than that 1 mg dose. That slow association-dissociation rate allows for a very smooth curve in the pharmacokinetics and allows us to interrogate the receptor unlike anybody else, where we are able to achieve, we believe we'll be able to achieve in patients 90% receptor occupancy through the entire dosing regimen. I think if you believe in the receptor occupancy that higher exposure leads to higher benefit, and that seems to be what has played out with the BMS drugs, it's probably what caused the demise of the Amgen drug, is it didn't have much receptor occupancy at all.
I think we have the best-in-class approach in this disease as well as PPF and other ILDs.
Yep. Okay. So you want to talk a little bit about the PET study you're conducting and the data we're going to get from that?
Yeah. So we now have MHRA approval to start our PET study. We'll look to get our first doses in healthy volunteers done in December. Really, the focus here is looking at receptor occupancy. So this will have two components to it, one, a healthy volunteer portion of it. We'll look at several doses and look to identify the doses that allow for full target coverage. This is a little bit different than what we did with 307, our M1 program. In that case, we were looking to build a full receptor occupancy curve because we knew receptor occupancy at different levels, one can promote remyelination, the other one can lead to a synaptic plasticity change in depressed patients. So in this case, we'll interrogate both lung and brain, looking to achieve maximal occupancy there, and then we'll feather in some IPF and progressive MS patients as well.
Yep. Yep. Okay. And so after that study, assuming it validates your thesis here related to the properties of the drug, what are the next steps in development?
Yeah. So that'll lead us into a phase two clinical proof of concept study. And this PET study supports both IPF and progressive MS. Just to put it out there, the PET imaging in the brain is a lot easier than in the lung. It's a conserved organ. There's blood running through it. It doesn't move while you're doing the assessment. So we expect the data to be cleaner in brain than in lung. The lung is an aerated organ. It's moving the entire time. But thankfully, we know that the receptor occupancy between brain and lung are tightly correlated with our compound. So in a pinch, we can use the brain data to estimate the receptor occupancy in lung as well.
Okay. Okay. When you say it might be noisy in the lung data, what do you mean exactly?
So it's an imaging study, right? It's a radiology one that you're using. And if it is a single dose, it is a single picture. And if the lung is moving, you'll get different resolution depending on where it is on the scale.
Like the data might not be interpretable or it might give you a receptor occupancy number that's just way off?
I think it'll probably be murky.
Murky.
Murky or.
Like harder to interpret.
Yeah.
Okay.
Whereas if you look at the receptor occupancy curve that we did in the brain for 307, it was extraordinarily clean.
Yep. Okay. And then maybe touch upon the mechanistic rationale for this in progressive MS and some of the animal data you have.
Yeah. So when we choose targets at Contineum, it always starts with an angle of neuroscience. So our initial interest in LPA1 was not for IPF. It just happened that when we saw the BMS data and we compared it to what we had, we knew we had a better drug. Our initial interest in LPA1 was driven by the expression profile in the brain. And specifically, LPA1 is highly expressed in glial cells, microglia, which drive neuroinflammation, and then on oligodendrocytes, which drive remyelination. And so that was a big reason for us going into this. And mechanistically, LPA is a bioactive phospholipid. It leads to inflammation, leads to a range of different issues. And in and around lesions in MS patients, there is an upregulation of autotaxin, which catalyzes the formation of LPA from LPC.
It is that bioactive phospholipid that leads to an increase in neuroinflammation and also prevents OPC differentiation. Hitting the two main aspects associated with clinical disability in progressive MS.
Makes sense. Okay. And for progressive MS, what could a proof of concept study look like? And how are you thinking about things like MRI or neurofilament as sort of ways to get faster, cheaper proof of concept?
Yep. So this will be a smaller study than IPF. As I said, in IPF, we're probably looking at 200 to 300 patients. In this case, this will be a scaled-back study, but we're looking at two different forms of the drivers of clinical disability in these patients. So we will have a number of MRI metrics built around remyelination. So DTI, MTR, potentially myelin water fraction in this as well. And then we'll do the typical MS functional composite. So walk test, peg score, SDMT, and visual acuity. So that is one part of it. For me, the more exciting part here is that progressive MS is a transition from the adaptive immune system to the innate immune system. And it is within this that the microglia are overactivated and lead to neuroinflammation. And we now have TSPO PET where we can image this.
And we're able to show these smoldering lesions. And so a lot of this will be built around TSPO PET and QSM, being able to demonstrate over a six-month treatment regimen potential reduction in neuroinflammation. So being able to hit on either one of those two, remyelination or neuroinflammation, is huge. But by having an impact in neuroinflammation, this is really a keyhole approach into other neurodegenerative diseases.
Yep. Okay. Makes sense. Should we switch gears to 307?
Sure.
All right. You want to give a snapshot of where that's at?
Yeah. So PIPE-307, this was an internal, all of these are internally derived programs. This is a first-in-class selective inhibitor of the M1 receptor. And I think most people are probably familiar with anticholinergics. Anticholinergic drugs have a range of different peripheral and central side effects. M1 is one of five muscarinic subreceptors. We started this program, it was really the foundation of Contineum Therapeutics. And we're the first group to be able to identify a selective M1 receptor antagonist. We went into this initially given existing clinical validation through one of our academic founders, where he was able to show in MS patients an improvement in visual acuity and a functional metric of remyelination in these patients. So there was outstanding clinical validation there. What was missing was a selective M1 antagonist to actually test in patients.
So we are currently enrolling a phase 2 clinical proof of concept study in relapsing-remitting patients, about 168 patients. Per our most recent quarterly earnings, at the end of September, we were about a little bit more than two-thirds enrolled. We are anticipating this study to wrap up enrollment in the first half of 2025. And we are running this in collaboration with J&J. Separately, J&J has validated through work at NIH using a dirty anti-muscarinic scopolamine, that M1 antagonism can drive a benefit in depressed patients. And this has been run through one of their disease area heads in neuropsychiatry, Wayne Drevets, when he was at NIH, showing that at certain doses of scopolamine, there is a rapid and prolonged benefit in MDDs. And they've repeated this over multiple studies in MDD, TRD, bipolar as well.
So with 307 and the partnership with J&J, there's two different indications, both of which have clinical validation. So a truly de-risked molecule.
Yep. Yep. Okay. So the J&J study, anything more you can say about how that study's power, the types of patients being enrolled, or the answer's no, the answer's no?
The answer's no. Yes, we have information. We're not allowed to share it.
Right. Okay. Okay.
All I can say is that the study will be initiated this year.
Yeah. Okay. And then as it relates to just blocking M1, right, there's been this thesis out there for a while that M1 agonism could benefit cognition. What do we know about the safety of blocking M1?
Yeah. So you have generally the anti-muscarinics out there. The anticholinergic agents are pretty dirty. So drugs like scopolamine, benztropine, they hit all of the muscarinic subreceptors.
Right.
When we started the M1 program, we knew that we wanted to focus on M1 solely. We also had the hypothesis that if you can selectively antagonize that single receptor without hitting M2 through M5, you can limit the cognitive deficits that you see with scopolamine. We were able to show some of this in animal models, but rodent models are rodent models. So when we ran our healthy volunteer study with PIPE-307, we put every subject in that study through a pretty comprehensive battery of cognitive testing throughout the study, five different domains of cognition, everything from simple learning and memory through executive function. And these were at some pretty high doses. And thankfully, the output of that study was we saw no change in cognition when compared to placebo or any sort of dose or PK correlation here.
Okay. Makes sense. So I think in the MDD study, it's pretty self-evident what constitutes proof of concept. How are you thinking about what constitutes proof of concept in MS?
Yeah. So the first and most important area that we're looking at, it's only a six-month study. So having a remyelination impact, it may require a longer endpoint. But what we see is the first change when you remyelinate is likely in the anterior visual pathway. So in animals, we used a functional biomarker to assess remyelination called visual evoked potential latency. So in MS patients, as in EAE animals, there's demyelination of the optic nerve. And what that does is it blunts the latency or it increases the latency period on the signaling from the retina to the visual cortex. You can reverse that by remyelinating those axons. So we were able to demonstrate that in animals. In humans, VEP is really cumbersome. And we would have to have probably only looked at two sites rather than.
Is that what Biogen tried to do?
That's what they tried.
That looks messy.
Site-to-site variability is really tough there, but the readout there should be an improvement in visual acuity, so that functional biomarker leads, if it's successful, should lead to an improvement in visual acuity. The first benefit that we think we'll see is on low-contrast letter acuity. Of course, we'll be looking at NfL. We'll be looking at MRI measures as well.
Right. Okay. Okay. Makes sense. Any questions? Always a shy audience.
Yeah. I guess the last thing for me is today we announced a new IND.
You're talking about your new pain announcement.
Yeah. Sorry. And I don't want to oversell it because it's pain. The probability of success is low. We are running an exploratory study. But we announced today an open IND for PIPE-791 in pain focused on osteoarthritis and chronic lower back pain. The literature precedent is there. The preclinical models that we've done and others have done are pretty compelling. Again, not overselling this because we know the probabilities of success, but there's a huge unmet medical need just between those two indications about 80 million patients in the United States. And this has no read-through on IPF. It has no read-through on progressive MS. And it doesn't impact our cash-out runway. So it's a smaller study. It is purely exploratory.
Placebo-controlled?
Placebo-controlled, but not powered. So this is a trend-seeking study. Can we show a difference between baseline and treated? And with any luck there, that would launch us into a bigger phase two study. But we're taking this step by step, really just using this study to dip our toe in the pool before we were to expand the scope of it.
What underlies the scientific rationale that got you excited about this?
All of this, every time we talk about an LPA1 receptor antagonist, the bad actor is always LPA, so it's the same in this case. There's literature data from patients where you see an increase in LPA in the synovial fluid of osteoarthritis patients. You also see LPA in spinal stenosis patients, and that level of LPA is correlated with the pain score. Internally, we have done animal modeling, including non-human primate. I think in CNS disorders, relying on rodent models is sometimes troublesome, but the readouts that we saw out of our non-human primate studies were pretty interesting as well.
Yep. Makes sense. So what are the timelines there?
The goal is to get the study up and running in Q1, and we're currently guiding to finalization of the study in Q1 of 2026.
Okay. Okay. Great. And cash runway, Carmine?
End of 2027.
Okay. All right.
Yeah. I think we, as of the last Q, have about $214 million in the bank. IPF is one portion of this. We'd love to be able to investigate other ILDs in the long run as well.
Right. Okay. Makes sense. Thank you very much. Appreciate it.