Okay, now we'll get started. Welcome, everybody. I'm Doug Tsao, Senior Analyst at H.C. Wainwright. We are thrilled now to have Neumora with us, represented by the company's CEO, Paul Berns, the company's president, Joshua Pinto, and Nick Brandon from Clinical Development.
CSO.
Not enough coffee this morning, so with that, why don't we sort of start off with a lot that has happened with the company in the last 12 months, in particular with new programs. In particular, I think there's been a lot of interest in the NLRP3 inhibitor program in obesity, and so this is an area that's gotten obviously a lot of attention given the success of the GLP-1s, establishing as a multi-billion dollar category, and there's become a lot of competition with the incretins as well as alternative mechanisms. And Paul, I know you have a lot of experience in the obesity space, so maybe just as a starting point, what excites you about your asset and the NLRP3 mechanism?
Yeah, thanks. Doug, thanks for having us, by the way. Pleasure to be with all of you today. We are quite excited about the utility of NLRP3s and the inflammasome as a CNS-mediated pharmacology in the way that we in the early evidence in the preclinical animal models and even some of the evidence of some of the other NLRP3 sponsors in their early clinical data that have demonstrated beautiful benefits, frankly, in obesity, Doug. The pathway predominantly works in the easiest way to think about it is that it's a CNS-mediated effect. We've learned that. So you need to have an exquisite chemistry that has CNS properties for which it gets into the brain, so highly brain penetrant, and then stays in the brain, and ultimately works through the mechanism of the hypothalamus. Doug simply put it, shuts the food noise off in layman's terms.
And this is complementary to the gut-hormone-brain axis in the way the incretins work or the amylins work. So we're quite excited because for physicians to have a new tool and a completely different mechanism of action for which you could potentially demonstrate good weight loss induction, potentially similar to the incretins, and then have a really convenient once-a-day potential oral small molecule drug. And then from the commercial side, Doug, with a low cost of goods as a small molecule is really quite important because you could imagine on a global basis for those patients for which maybe an injectable might make sense, you're going to have those products. But for many patients, a small molecule oral will be a very, very important therapeutic SKU or brand to bring to the marketplace.
It's one that's going to be more affordable and frankly, one that I believe can demonstrate unsurpassed efficacy with improved tolerability and ease of use and convenience of an oral medication. As we noted most recently in our second quarter investor call, we will look to produce the DIO data in the typical mouse model here later this year and this fall. We'll bring those to the marketplace, share them with all of you as investors. We have a group of well-educated and frankly, exceptionally experienced key opinion leaders in the field of obesity that are quite excited about the mechanism and its complementary benefits to the incretins as well as the monotherapeutic benefits.
And I guess the DIO model has proven to be very effective in terms of predicting weight loss and sort of the trajectory that can be achieved. We've seen from others with NLRP3s that they come in that sort of mid-teens range. I know you sort of hesitated to provide sort of a bar in the past, and so I doubt you'll give one now, but just maybe provide a framework how you're thinking about sort of the lower bounds of what some of the other NLRP3s have shown, as well as sort of the injectables and the GLP-1s. And there's sort of often been this in the investment community, there's sort of focus like, "Oh, we have to hit 20%," or, "Is it as good as what tirzepatide hit?" And is that how you're necessarily thinking about it just given the options you have with your drug?
Yeah. Thanks, Doug. And this is Josh here. I think as we're looking at NLRP3 relative to the current therapeutics and what's emerging in obesity, it's really the benefit-risk profile that we look at. And there's three what we believe are clinical paradigms that we'll ultimately look to test. First is the monotherapy paradigm. And what we're looking for there is you're looking for incretin-level induction. So are you seeing incretin-level weight loss in the DIO model early on that's comparable to a commercially available dose of semaglutide? What we think that could do is also couple well with a product, to Paul's point, that we don't think is going to have the GI AEs that are associated with the incretin therapies and then all the commercial benefits that the oral small molecule brings, not only from a low cost of goods, but does not require cold chain storage.
In the second paradigm, we're really going to look to test is kind of in combination. And so not only could you look to maximize the weight loss benefit of a GLP-1 by adding an NLRP3, but can you dial the dose back of a GLP-1 ultimately to reduce the GI side effects and potentially make it more tolerable? As we know, we've all heard rumors, some of the stats out there, upwards of 60%, 70% of patients that start on the GLP-1s today don't actually get to the target weight loss driven by the GI AEs or just the time it takes ultimately to get through all the titration steps to get there, which can take upwards of six months. The third paradigm I think we're really going to look at is can you switch someone or remove the GLP-1 once they've hit that?
And I think what we'll look at is can you dose an NLRP3, so 215 with a GLP-1, and when you reach the target weight loss, remove the GLP-1 and maintain the weight loss on an NLRP3? As we know today, one of the challenges is that when people stop taking a GLP-1, the weight can tend to rebound. And so this would be looking at a long-term simple oral once-daily maintenance therapy that also does not have the GI AEs. Or could you, frankly, even switch once you get to the target weight loss from incretin induction? Could you switch to an NLRP3 to maintain that going forward? And so I think what we're really going to be looking at in the DIO study, and we're running a few different ones to elucidate all these paradigms, is ultimately seeing can we see GLP-like induction in the monotherapy?
Can we see additive benefit in combination therapy? And then ultimately, can we maintain the benefit of a GLP-1 if we switch or take a GLP-1 away in a maintenance? To your point on the cross-trial comparisons, it's very challenging, particularly in preclinical models. We know there's a couple of factors that can drive it. Frankly, the higher the starting weight of the mice, the higher the proportion of weight loss. And so there's a few factors that make the cross-trial comparison not ideal in these preclinical models. But what we will be coming forward with is a robust data set across multiple factors, not just on the weight loss measures we've talked about, but there's a range of biomarkers that we'll look at. And we'll also look to see is this therapy and mechanism lean muscle mass sparing? We know that that is also one of the key pushbacks and knocks against the incretin.
One of the things I maybe would add to that too, Josh and Doug, when we this goes to Nick's team, they did a fantastic job because, Nick, we've been working on our NLRP3 for four years with a variety of different chemotypes because it was really important to make sure we could optimize the physicochemical properties for CNS activity in particular. We knew that those drugs, those other NLRP3s that had some higher level of peripheral activity were not going to be optimized for the obesity setting per se, and so I would just say that you need a therapy that has unsurpassed brain penetrant characteristics.
It needs to stay in the brain in order to maintain that activity as well because I'll just say this without getting into too much proprietary information, but having inhibitory concentration IC50s is not good enough. You need to have a much better drug than that, and then you have to stay in the brain to optimize its activity. And that was not a trivial task. So we made the investment. We have exquisite IP, by the way, that came through that investment, but we're really quite pleased with the molecule we have.
I guess when we think about that greater brain penetration, will that be largely manifest in just the greater weight loss, or are there other attributes of the molecule that will come to bear?
Nick?
Yeah. No, I do think, as Paul's already mentioned, the brain penetration is a critical factor here, but it's also like the basic pharmacology of the molecule. And we've put this data out, a recent disclosure. We do really feel, across assays, our molecules are very potent, very selective. And as far as we look, again, doing that cross-sponsored comparison, it has the potential to be best in class. So I think a marriage of the two things, basic pharmacology, brain penetration, and I think the two of them, hopefully, with the data we will reveal by the end of the year, we'll see some signs.
I guess I'm curious, when we'll get the data by the end of the year, how quickly will you then move forward? Sort of, Josh, as you outlined sort of the different scenarios or potential uses, would you potentially pursue all of those all at once, or are you going to look to evaluate the data and sort of take an initial step first and then sort of follow additional use cases down the road?
Yeah, absolutely. And so, Doug, we always take a data-driven approach. So we'll look to see what the DIO model really shows us. But assuming that it's consistent with what we think it will be going in, our plan is to get NMRA-215 into the clinic in the first quarter of 2026. In terms of the paradigm we'll test, I think we'll absolutely want to go monotherapy first, assuming that that does support it from the DIO data. But I think we'll ultimately look to run a combo study and a maintenance. And so when we put it in the clinic, we'll come out with a full clinical paradigm. One of the nice things about obesity is we've seen other sponsors move very quickly from first in human to proof of concept within 6-12 months.
And so it's an area where we think we can rapidly get from first in human in the first quarter of 2026 to a clinical proof of concept outcome. And so that's really what we're going to be looking towards. And it might be one of the paradigms that we ultimately test first, but I think our plan will be assuming the DIO data supports it to test monotherapy combination as well as maintenance and switch clinically.
Okay. And so the first would be monotherapy and then subsequently follow with some of the others.
Yeah.
Okay. And I guess the focus obviously is on obesity. The NLRP3 mechanism could have utility more broadly. And I guess even just within the metabolic space, what effects do you think it will have for patients that perhaps they're not getting from GLP-1s?
Yeah. So I think with this mechanism, over the last maybe five to 10 years, we've seen utility, particularly as we think about things like cardio protection. We've seen data in OA. There's other, I'd say, comorbidities where you might see some additional benefit on top of the obesity. And so package all that together, it could be very meaningful. And then when you think about what you get from the incretins together in some of the different paradigms Josh speaks to, it could be really quite interesting the overall benefit you could gain from this as a monotherapy, but also in combination.
Yeah. And I would just also add that in addition to those efficacy benefits, I wouldn't underestimate just the burden that the GI AEs can have on existing patients as well as the potential for lean muscle sparing with this mechanism relative to the incretins, which could be a very important advancement as we just think about how to deliver long-term weight loss solutions to patients.
And I think that's an important point because if you talk to patients who have taken GLP-1s, a lot of times they're really happy with the weight loss, but they're really unhappy with how it got there. And to my point earlier, sometimes we sort of look at these arbitrary benchmarks. Oh, did it hit what tirzepatide did? Did it do it will it do it as quickly? And how do you evaluate that, meaning that perhaps a slower rate of weight gain loss, but in a much more tolerable package might be more commercially viable, certainly for a segment of the market?
I actually think that's going to be the interesting part of coming. We're going to see some of the evidence of what I'll call the induction rate or the rate of weight loss out of the DIO model. What's most important is we get to the phase one, Doug, and we demonstrate that in a human setting, which I'm really excited to get this molecule there that Nick has developed. I think it could go either way, and I think you're going to be able to modulate. What's going to be beautiful about it is I anticipate we'll probably end up actually developing a couple of different doses so that we can put the control of that in the patient as a consumer in the doctor's hands so they can fine-tune the weight loss journey or the weight loss experience they want to optimize for patients.
Because we'll certainly get to a therapeutic dose that, from a risk-benefit perspective, optimizes induction and so forth. But you can imagine we might have a couple of different doses that allow them to dial it in appropriately. Because whether or not the patient gets there quickly or perhaps in certain circumstances with comorbidities, it's better to take a little more time. There's such a diverse group of obese patients with different comorbidities. I think this drug and this class of therapy and this particular molecule within this class, I think it's going to allow us to bring a really great tool that's going to help the physician-patient optimize that. Lastly, I would say we'll have to see how the clinical studies bear this out. But at some point, when you lose weight, if you're an obese patient or clinically obese or just overweight, you have NASH.
I suspect, by the way, you're going to see improvements. Because for most people that have NASH, if you're obese, clinically obese, if you just lose weight, your NASH tends to improve dramatically. So I think you're going to find even more and more come as other sponsors perhaps look beyond the initial indication of obesity of the utility of these drugs.
I guess along those lines, when you think about something like NASH, do you think that that would be sort of a benefit that you would actively pursue in terms of characterizing?
I.
Claimed, or do you think that would sort of be something that would?
I can assure you already that the key opinion leaders that look at this mechanism, the same way that they were looking at the incretins that have demonstrated that benefit, will look, and you'll see some IND-enabled studies and some phase four work. We'll certainly want to support that with the experts in the field. Then we can choose whether or not that becomes an SNDA for an indication. I definitely think you'll see a lot of data come out and a lot of interest in utilizing our product and exploring that there.
Okay. And then maybe shifting gears to the M4 program, which is something that you released early or sort of disclosed a few months ago. And you came forward with two PAMs, not just one. And you've always sort of said that you think that this is a two-molecule franchise. And maybe just exactly what you mean by that. And also, while you've emphasized why you think the PAM approach is the right versus, say, the M4 agonist.
Maybe we should start with that latter piece of the.
Let me start with that. So I can start. So I think, as you remember, 16, 17 months ago, our first compound in the clinic NMRA-266, we were put on clinical hold for unexpected convulsions. In this last 16, 17 months, we've done a lot of thinking, trying to ensure that our conviction in M4 and the PAM approach is still there. And honestly, having revisited all of the preclinical data, a lot of it generated by our group and our collaborators looking at the clinical signals, whether it's Cerevel or the Neurocrine M4, we remain wholly convicted on M4. And I really, truly think, as we start to think what we're seeing with Cobenfy in the real-world use, the allosteric mechanism does get us that selectivity, which gets us away from the AEs. So all that together, our conviction remains steadfast.
Then we obviously needed to bring forward new molecules. The two you've mentioned, 861, which is now in phase one, and 898, which we'll bring into the clinic by the end of the year, they have optimized properties, basic pharmacology, again, brain penetration, which we really focused on as we looked at other sponsors' assets. Importantly, from a Neumora perspective, we had to de-risk the rabbit convulsions. We've done that extensively with 12 months of work, and we feel really confident these molecules do not have the issue. We absolutely know they do not have the issues which 266 had. We feel really good about these two molecules moving forward.
Yeah. And then in terms of the franchise approach, Doug, and it's really around just the broad indication potential that we think M4 PAMs could have. We know that the kind of lead area where the field is de-risked is acute schizophrenia. But beyond acute schizophrenia, there's the dementia-related psychosis. We think there's other neuropsych conditions such as bipolar. But even beyond that, there's potential across some neurodegenerative conditions. And so ultimately, as we think about this target, we think it has broad applicability. And if we're fortunate enough to have two really high-quality compounds that move through early development, we could look at different indications for those products.
Ultimately, they could drive different doses clinically, commercially, and ultimately run into different product SKUs. And so I think that's how we're thinking about it from a franchise perspective. First and foremost, our main goal is to ensure that we have at least one, if not two, very high-quality M4 PAMs moving through early development so we can put that into a schizophrenia proof of concept study.
And so would you anticipate taking both into a schizophrenia study, or at what point do you sort of start to have the assets potentially take different development paths?
Yeah. I think we're going to need to see the phase 1 data play out a bit before we provide our definitive guidance there. There could be a scenario where you could think about running both head-to-head. I think that's not optimal because you want to run multiple doses of each compound, and then all of a sudden, you could get into a paradigm where you've got four active arms against placebo. So I think our goal here ultimately will be to prioritize one to put in as the lead for schizophrenia. But then if we have the other compound that's moved through early development and looks really strong as well, we can move that potentially into some of the neurodegenerative conditions.
With the phase one study, you are growing into some schizophrenia patients, right? Because it does allow you to get to higher doses than you can in healthy volunteers. I'm just curious. It is a small n, going to be a relatively small n, but do you think that there's value, or is that something that you're going to caution us to not parse too much in terms of what you see in that study?
So I would highlight it's a short study. They're Phase 1, so they're only a couple of weeks in length. And they are also patients with stable schizophrenia. So the notion that you're going to see a move on the PANSS score in a couple of weeks in a stable population, probably not a high probability event. I think what we're really going to be looking for in the patients with stable schizophrenia are how much dose can they tolerate? Are the PK characteristics in that population the same as they are in healthy normals? And ultimately, the side effect profile. Because the tried-and-true approach really in CNS drug development is to get to an MTD as high as you possibly can and then look to push that ultimately as the top dose into the proof of concept.
Okay, so we're now in what I've been calling stoppage time.
That's fine.
But we can go over a little bit. I did want to touch on two of the other key assets, right? 511 as well as navacaprant. And maybe just an update on enrollment in the Coastal studies and what you're seeing or gives you some additional confidence based on some of the operational changes you made for that program.
Absolutely, and so as a reminder, when we got the results from KOSTAL-1 at the beginning of this year, we paused KOSTAL-2 and KOSTAL-3 while we were analyzing the data and ultimately making some changes in the study, and the three changes that we really focused on making were one, refining the set of sites we were running the studies at to make sure it was a smaller group and a high-quality group. And so we've done that, and we've refined the sites we're working with. Second was we wanted to really focus on controlling patient quality and making sure we're getting the right patients in the study. As we've come out publicly and said, we just didn't enroll the right patient population in KOSTAL-1 .
We ultimately think that's what drove the outsized placebo response we saw in the population, in particular in the male side of the population. We've added the SAFER interview process, and that's in partnership with MGH and their Clinical Trial Network Initiative. What SAFER really does is it provides a Massachusetts General clinical psychiatrist that reviews the patients. What we're seeing out of SAFER so far is it is driving a much higher screen fail rate, which is exactly what we want to see because it's highlighting that it is weeding out a number of patients that otherwise would have been randomized into the study. We also added a second professional subject database, VCT, and it has caught a number of patients too, and it flagged them as potentially professional patients, which were not allowed to randomize, that otherwise would have been randomizing.
So we feel a lot better that we're doing everything we can to get the high-quality patients into the study and give the drug a chance to succeed. In terms of where we are with enrollment, in the second quarter in August, we came out and reiterated guidance for KOSTAL-3 in the first quarter of 2026 and KOSTAL-2 in the second quarter of 2026.
Okay, and then just touch on quickly 511, which is the asset we expect data by year-end in Alzheimer's disease agitation.
Yeah. Absolutely. And so with NMRA-511, we think that the vasopressin system really has an impact on anxiety and the agitation axis. And so we've prioritized Alzheimer's disease agitation as the first indication we're going into. We will have phase 1B data in patients with Alzheimer's disease agitation around the end of this year. This is an eight-week randomized double-blind placebo-controlled study where we'll have about 40-ish plus or minus patients in each arm. So we will be able to get a good read on effect size. It is not powered for statistical significance, though. And so that study is coming out at the end of the year. Rexulti is the only approved therapeutic in this class. It has shown a fairly robust effect size, but we all know that there's a number of side effects and limitations with that product.
They really studied a severe population, including both inpatient and outpatient in their pivotal studies. I would say Axsome has done some work with Auvelity, which seems to be quite compelling. And so our view is that there's a great opportunity here for a therapeutic that is much more tolerated over what we've seen with Rexulti, but that might not necessarily have to hit that same efficacy bar because the commercial opportunity in our mind is really in that outpatient setting, and so in more of a milder patient population before they end up in a long-term care setting.
Okay. Great. Well, I think with that, we will have to stop. So thank you very much. And it's obviously going to be a very eventful six months for the company.
Yes. Thanks, Doug.
Thank you.
Thanks.