Thanks. Happy to moderate this catch-up chat with Carmine Stengone, President and CEO of Contineum Therapeutics. Always great to see you. Maybe we'll have Carmine just give a quick sort of overview and update on Contineum and the IPF program, and then we'll do Q&A. Thanks a lot.
Absolutely. Sean, Stifel and Paul, thanks again for inviting us to the conference. A little bit about Contineum. We are a small molecule biopharmaceutical company based in San Diego. The main focus of the company is fibrosis and inflammation. We have one internally derived asset that is currently in a phase II clinical study, that is PIPE-791. The main focus for this clinical study is idiopathic pulmonary fibrosis, and the target is LPA1. I'm sure that a lot of people have heard recently about the admilparant data, and we believe that we have a compound that is very competitive with theirs, with multiple differentiators, and it's not the worst case having a pharma starting build the market before we get there. We also have a program that is partnered with Johnson & Johnson, again, internally derived. This is PIPE-307.
It's a first-in-class inhibitor of the M1 receptor. J&J has brought that into an MDD study, which recently read out, and we can talk about that a little bit later. We're waiting on potential next steps with that program as well.
Great. Well, yeah, I think we'll probably spend most of our time on IPF. Just to kind of set the stage, do you want to review the admilparant top line, and what were your main takeaways? I know there's a lot we can unpack.
Yeah. It's hard to interpret a press release that had two lines on the data. We don't know what we don't know. We don't know the effect size. We don't know the confidence intervals. We don't know the P values. What they did disclose in their study, in my opinion, is unambiguous validation of the target. The admilparant phase II study was about 1,200 patients over 52 weeks with a twice-daily dosed LPA1 receptor antagonist, and they brought in two different doses to the study, a 60 mg BID, which is the top dose that they tested in their phase II, as well as doubling that dose, so introducing a new dose into the phase III at 120 mg BID. Really, the takeaway that we got from this was, again, clinical validation is now established with this target in a phase III for the first time.
We've had issues with other programs around this target, including a previous BMS program, having issues before heading into phase III. They also disclosed that they hit statistical significance and clinical efficacy in the 60 mg BID dose group. They did not hit stat sig at the 120 mg, but they did disclose that they saw a reduction in FVC decline relative to placebo out of that dose group too. I think there's a lot of question marks that hopefully will be answered in the near future, and all likelihood, we're probably waiting till ATS to get all of the information.
Cool. When's that for people?
May.
Okay. Maybe just to start, is it surprising that there wasn't a linear dose response here?
I don't know that it was response. I don't know that it was anticipated. I think that based on what we know about that molecule, we believe that the receptor occupancy and the target coverage that they have is pretty similar between the 60 mg BID dose group and the 120 mg BID dose group. What we don't know is what was the difference between the two doses, and could this be driven by, again, target coverage? Could it be driven by tolerability associated with some of the properties of this molecule which we work around?
Right. These will be the questions for the actual presentation.
Absolutely.
Yeah. Okay. Makes sense. Maybe I can sort of throw at you some of the inferences people are trying to make and see if you pass the smell test, which I'm sure you've heard. One is that, I think there's this inference out there, it's like, "Well, if this dose hit and the other one didn't hit, then the effect size must not be that big." What would you say to that?
I don't know that that makes a whole lot of sense, obviously, without seeing what the data is. Their effect size hit statistical significance and it's clinically relevant. This is the first time an LPA1 receptor antagonist got through this hurdle. If you look at the contemporary clinical studies, so in that I'm including TYVASO, I'm including nerandomilast, even nintedanib. The focus here is trying to have a 50% reduction in FVC decline relative to placebo, and all of these seem to fall within that same category. I think nerandomilast was at about 40%, TYVASO was in the 50% range. I would expect this to fall within that same category, but some of the key differentiators that this mechanism has is there are no overt tox issues and tolerability issues.
With nerandomilast, obviously, there's a little bit of a GI signal that prevents combination therapy, and that's where everybody wants to move within IPF, is the combination therapies that can drive the full impact of all of these targets. We expect that BMS will have a similar signal to those. We're also really interested in knowing what they did on the secondary endpoints, because that is something that no other program has been able to hit on, and that is acute exacerbations, the functional composite around this, cough. We're bullish on the target itself. We think that there's maybe some compound properties that are unknown around BMS that have driven the change between 60 mg and 120 mg. In my opinion, I think that the target coverage is pretty similar, and that is what's driving this. We also don't know the SAP, right?
It was published in the British Medical Journal, but that was then, I guess, changed. We don't know how they're splitting alpha between 120 mg and 60 mg.
Right. Okay. Makes sense. Well, maybe then just set the stage and give people an overview around PIPE-791, what we know about the drug, and what the differentiation thesis is.
Yeah. Looking at it relative to admilparant. Admilparant is a twice-daily dose, either at 60 mg or 120 mg, that we'll see coming up. It has a very high peak-to-trough ratio. They have demonstrated hypotension signals through their phase II study and have worked through that in the phase III, seemingly through a dose titration. With that, they also recently put out some information around a potential hepatic signal, and there was one patient who passed away in the phase III study.
What did you make of that?
Again, without having a lot of information, it is tough to interpret it.
I read that, and I was like, "There is so much else in the context of that. How am I supposed to make a call on if it is DILI or not?
I think the knee-jerk reaction to it was, "Oh my gosh, this is like BMS-986020.
Right.
For those who don't know, BMS-986020 was the first compound that BMS brought into a phase II. It was acquired through Amira Pharmaceuticals, which was a San Diego-based IPF company. That was a very different sort of situation. In BMS-986020, it was an off-target toxicity that was generated because of the compound, not because of the mechanism. BMS has done a really good job at spelling that out and showing that in non-human primate studies. So, it was an inhibition of BSEP, which is bile salt export pump, that led to hepatobiliary tox that discontinued the study. The data before that looked pretty excellent if you look at the curves over the 26 weeks. This case, I think that the biggest questions had initially were around the patient who died, but that patient unfortunately had a ton of different comorbidities.
What I'm more interested in is they did say that there were a number of cases of Hy's law. So, that would be 3X the upper limit of normal for the LFTs and 2X on bilirubin. We don't know much more about that. So, that's also something that we'll be interested in learning about at ATS.
Yep. Okay. At face, what do you think about that? Usually, Hy's law is like, "Oof, that kills a drug.
Yes. Really where I'm most interested in, where did it segregate? Was it in the 120 mg? Because at that point, you are doubling the dose. You are basically doubling your peak concentration. Maybe they're plucking off something else that we're not aware of, but unfortunately, it's all speculation right now.
Right. Okay. Back to PIPE-791. The thesis here is your compound's more potent, it's QD. What can you say about the dose range and your comfort in the overall therapeutic index?
For PIPE-791?
Yes.
We have done a PET study in humans, and we were able to identify the receptor coverage at all of the doses that we've tested through our MAD. That was at 1 mg , 3 mg , and 10 mg. In each of those doses, we have a QD molecule with consistent coverage above 90% receptor occupancy. This is the opportunity to fully test the power of this receptor, and this is as close to an antibody against LPA1 that you can get in a small molecule.
Okay. Great. Do you want to talk about the phase II design that you're running?
Yeah. We are now enrolling our phase II clinical proof of concept study. This is called PROPEL-IPF. It is anticipated to enroll about 324 patients, so 108 patients per arm. It is a global study, 26 weeks. Primary endpoint, not surprisingly, absolute change in FVC relative to placebo, and the study is enrolling really well right now. We have about 109 sites as of yesterday opened worldwide, and the goal for this study is to have completion in the middle of 2028.
Okay. Again, going back to sort of the dose response question with Bristol, I feel like one of the things I think people have wondered with their data is, does that take away anything from the likelihood that a more potent drug with higher receptor coverage could generate better efficacy? Where do you think you are going to be getting in terms of coverage, and do you feel like Bristol tested this hypothesis at all?
Yeah. For us, potency isn't the most important thing. It is that sustained, consistent target coverage over the entire dosing regimen. Again, to highlight Bristol's program right now, it is a QD dose. It is a fast on, fast off rate. I am sorry, it is a BID dose. It is fast on, fast off. It requires a dose titration to help with the hypotension signal. For ours, we have consistent coverage 24 hours a day, greater than 90% receptor occupancy. We do not have a dose titration. We have not seen any adverse signals in our completed studies, and that includes blood pressure. So we think that we are in a good position to differentiate and to provide not only a best-in-class molecule for LPA1, but hopefully a best-in-disease molecule to start the combination therapy discussions.
People have wondered for this class whether changes in blood pressure are on target or off target, and whether a lack of blood pressure change would question that you are actually hitting the target the way you would think. What would you say to that?
Well, I think that it is plausible that it is on target. The LPA1 is expressed on vascular tissue, so there is a thesis that that is what is causing the signal that was seen. We think that a lot of that is driven by, again, the properties of Bristol's versus ours. So Bristol's fast on, fast off. They end up having that hypotension signal, and they are trying to mitigate that through dose titration. We have a molecule that has a very unique PK signature, so it is a slow on and off rate. One benefit there from an efficacy perspective is even as it comes out of the plasma, we are still locked onto the receptor, so we are having that consistent coverage that you can't have with a BID molecule.
We also have this slow on and off rate that essentially functions like a dose titration, so it takes multiple hours to associate to the receptor, and over that period of time, you're basically titrating up to the full concentration.
Makes sense. So the phase II-B study, have you guys said anything about powering or what sort of effect size would be the goal here?
We have not. No.
Okay.
But I guess the easiest way to put this is, it's hard to do cross-trial comparisons. But what we want people to be able to look at is as close to an apples to apples comparison of the admilparant phase II as possible. So I think we probably have 50 or so additional IPF patients, but it's structured very similar to what Bristol did in their phase II.
Okay. Makes sense. I think one of the other sort of bull case theses on this class, which I believe in, is the idea that these drugs look to be a lot better tolerated. Obviously, we'll better understand if there's a liver signal with Bristol, but they look a lot better tolerated, and there are different mechanisms, so you might be able to combine them with a number of other different medications. How do we prove that out? Is there a way, as you guys advance in clinical development, where you can sort of better characterize the safety and synergy with other medications?
Yeah. It starts on a non-clinical side, but yes, in the admilparant phase III, they are allowing nintedanib and pirfenidone, which are the legacy programs out there. We now have nerandomilast, and in all likelihood, TYVASO will be approved in the not-too-distant future. So, this will be tested in the clinic. There are some issues here, obviously. So nerandomilast has a DDI associated with pirfenidone, so it limits the use between those two. And then nintedanib, or Ofev, has a pretty nasty tolerability issue around GI toxicity, and nerandomilast exacerbates that. So right now, what people are looking for is that foundation therapy upon which we can add combinations. And based on what we've seen with admilparant as well as with PIPE-791, we believe the LPA1 class is that cornerstone that then allows for combination, whether it's with a PDE4, whether it's with whatever the mechanism Ofev is.
I don't think anyone really understands it completely. TYVASO's different. We'll have to see how that pairs with a small molecule.
Yeah. Okay. Makes sense. Anything else you want to add on IPF?
No, we are excited for this study. We think that what BMS has done has been a boon for LPA1 receptor antagonism generally. There is clinical validation there, and we look forward to being able to discuss our data as we continue developing it.
How can we track your progress in the next year? Are you going to be giving any enrollment updates or telling us when you are fully enrolled?
We will likely talk about full enrollment. I would encourage people to continue tracking us on clinicaltrials.gov. You will be able to see the sites that we have established as well as the territories. As I said before, we have over 100 sites in almost 20 territories right now.
Yep. Okay, great. You also have this pain angle with PIPE-791. Maybe talk about a little bit of the data you generated there, and how do you see next steps?
Yeah. So we ran a phase I-B exploratory study in pain. There is a lot of rationale for LPA1 receptor antagonism in pain, especially fibrotic pain. This was focused in osteoarthritic patients as well as in chronic lower back pain. We had 43 patients in a crossover design. So all of the patients were on drug for at least four weeks. What we were able to demonstrate here in a purely trend-seeking study was a numeric change in pain scores across the subjects that we tested, and especially in osteoarthritis, we saw a reduction in NRS for average daily pain, worst pain, as well as KOOS, which is a metric that is specific to osteoarthritis. So, we hit the endpoint that we wanted. We are excited about this. Obviously, the biggest driver for the company right now, and the focus of the resources is built around PROPEL-IPF.
But we see pain as, or LPA1-driven pain as an area where we can also add a differentiator in the fibrotic space. So, if we can reduce the rate of FVC decline versus placebo, which then has an improvement on pulmonary function in these patients, they are still getting worse every day. If you look at these patients, if we can increase their lifespan, but also address any sort of additional quality of life. So, in IPF, these patients are generally 75- 85 years old on average. They have osteoarthritic pain. They have chronic lower back pain. If we can not only change their pulmonary function, but also increase their quality of life, we think that is a game-changer. Then the next step for us beyond IPF is progressive pulmonary fibrosis.
In that category of patients, you have subjects who have systemic sclerosis, rheumatoid arthritis, connective tissue disease, all that have serious pain syndromes associated with it. So, we think that having the only CNS-penetrant molecule that can mitigate pain could be a boon for the class as well.
Any secondary endpoints in the PROPEL-IPF study, or any sort of pre-specified subgroup with pain that you could kind of look at?
There are exploratory endpoints around pain, yes.
Okay.
Yeah.
Okay.
We'll also be looking at cough. We'll be looking at, because we want to make sure that we have all of our ducks in a row, we'll be looking at blood pressure. Obviously, in any study, we're looking at LFTs and bilirubin.
Right. Okay, great. Do you want to briefly, before we wrap up here, just talk about the J&J partnership? Anything else to add there?
Yeah. We partnered with J&J in 2023 for our M1 receptor antagonist, PIPE-307. J&J had a longstanding interest in this target, and a lot of this came from their experience with scopolamine. There's an investigator who was at NIH, his name's Wayne Drevets. He is now Head of Neuropsychiatry at J&J. He used scopolamine while he was at NIH in multiple different clinical studies. And what he was able to demonstrate is that molecule, and what was later found out through the M1 receptor, had an impact on MDD, TRD, bipolar depression. And when they realized that this was driven by M1, the goal was to find a selective M1 receptor antagonist. Through our collaboration, we ran the MOONLIGHT-1 study, or J&J ran the MOONLIGHT-1 study. This was focused on MDD. It was a crossover design, two weeks on treatment. Sorry.
It's a two-week treatment regimen here, and we looked at two different dosing regimens. The goal here was change in MADRS at day five, so a really fast readout. Unfortunately, we missed on the primary endpoint. We own that. That being said, there were a number of pre-specified exploratory endpoints that J&J had interest in. So, we're in continued contact with them. I'm not going to say that they are 100% pushing this forward, but I think that they are evaluating it very carefully, and hopefully we will be able to provide more information in the near future.
Okay, great. Maybe before we wrap up here, Carmine, do you want to just touch upon your cash runway?
Sure. We are about $245 million. That gives us funding all the way through the middle of 2029, and that is about a year post-conclusion of the PROPEL-IPF study. From a cash position, we are in pretty good shape.
Okay, great. Thank you very much. Appreciate it. Good to see you.