All right. Good afternoon, everyone. Welcome to Guggenheim Healthcare Innovation Conference. My name is Yatin Suneja, one of the Biotech Analysts here at Guggenheim. It is my pleasure to welcome our next presenting company, Neumora. From the company, we have a few executives here in the room, but we will be chatting here with Josh Pinto, who is the President, and Nick Brandon, who is the Chief Scientific Officer. Josh, why don't you maybe make some opening comments? Tell us some of the key updates that you have provided and what we should be focusing on, and then we'll go into the fireside chat session.
Yeah, absolutely. Thanks, Yatin, for having us today. We really appreciate the invite. We've made tremendous progress at Neumora across 2025 and really set us up for what we think can be a very impactful 2026. As we announced at our R&D day recently, a couple of weeks ago, we have completed the DIO studies for NMRA-215, which is our NLRP3 inhibitor that we're going to move into obesity. We produced at our R&D day class-leading weight loss in the DIO studies, not only compared to other NLRP3 inhibitors, but we also produced data that shows our NLRP3 inhibitor is the only one in the class that is showing data that it has semaglutide-like weight loss, not only in terms of where the drug ends finally, but within the first 7-10 day induction period as well.
We're really excited about the class-leading weight loss and think ultimately that that can support NMRI- 215 moving forward as potentially the oral solution in this large market opportunity. We will be moving the program into a first-in-human study in the first quarter of 2026. Ultimately, we expect to generate 12-week human proof-of-concept data by the end of 2026 in both the monotherapy and combination with GLP-1 setting. Beyond NMRI- 215, we are progressing NMRI- 511, which is a V1a receptor antagonist, in a phase IB study right now with patients suffering from Alzheimer's disease agitation. We plan to have data from that signal-seeking study around year-end. We announced at R&D day as well that we moved a second M4 PAM program, NMRI- 898, into the clinic. In addition to NMRI- 898, we have NMRI- 861.
We have two M4 PAMs now that have entered the clinic. We plan to provide a franchise update on those studies by the middle of 2026. Finally, navacaprant, which is our best-in-class kappa opioid receptor antagonist for the monotherapy treatment of MDD. We've implemented the changes to the studies earlier in the year. We're seeing great progress in terms of the quality of patients coming in through the implementation of SAFER and VCT and feel really confident that we are getting a higher quality patient population in KOASTAL-II and III. We ultimately plan to topline those data in the first quarter and second quarter of 2026. We're entering a period with a number of clinical readouts, up to six over the next 12 months.
I would just also add our balance sheet currently has, as of the end of the third quarter, about $170 million on it, which gives us runway into 2027. All the clinical catalysts I just highlighted are fully funded within our operating plan. Yatin, really entering a critical time for Neumora where we're going to be releasing clinical data from most of our core four clinical-stage programs. Really, really exciting time for us.
Got it. Very good. Thank you for that. Yes, I think the R&D day that you hosted was pretty interesting. The question that I have is that could you put in perspective the preclinical data that you have generated on your NLRP3 relative to what we have seen and how well they translate in clinic?
Yatin, I'll tackle the second part of your question first, just on the translatability. This is one of the most highly translatable preclinical models we have within the pharmaceutical industry. If you look at publications, there is a Nature publication that was put out recently, showed across a range of classes, including incretins as well as three other mechanisms, that the correlation between weight loss seen in DIO models and what is ultimately seen in the clinic is very highly correlated. The correlation was north of 0.9. I think what it does is it validates that this is a mechanism that ultimately does translate from preclinical studies into the clinic.
In terms of the data that we put out at R&D day, what we've highlighted is we ran three DIO studies and in the monotherapy setting saw anywhere from 15%-19% weight loss, which is class-leading as we look at other NLRP3 inhibitors in the space. More importantly, what we also showed is that each of these studies has an active comparator in them. We were the only NLRP3 inhibitor that showed equivalent weight loss at the end of study, as well as equivalent weight loss within the first 7 days-10 days to semaglutide to show that we can drive ultimately incretin-like weight loss and induction.
In the combination setting with semaglutide, we showed that combination of NMRI- 215 with a clinically effective dose of semaglutide could drive up to 26% weight loss, which is far greater than either of the two components on their own, which highlights the two mechanisms have the potential to be combinable and drive additional weight loss. Finally, we looked at a paradigm in which we spared the dose of semaglutide to a subtherapeutic level. Commercially, you could think about this as a level that might not be driving the significant GI adverse events that we do see with clinical practice. Ultimately, what that could do is show a paradigm where you could have an incretin-sparing dose paired with a high dose of 215 to alleviate the GIAEs but drive pretty material weight loss.
What we saw in that study as well is that you can drive pretty substantial weight loss superior to the low dose or 215 alone. There is a lot of potential as we think about moving it into the clinic. That is ultimately going to be what we test in our first-in-human study, the monotherapy potential of NMRA-215 in humans as well as the combination potential.
Got it. I think what we hear from investors, or there is still some reservation in terms of their belief on the translatability of this DIO model. I think the main question comes down to some of the data that prodrugs have generated, right? Can you just talk about what are some nuances with the prodrug approach? Because in the prodrug approach with NodThera, they did show improvement in DIO model, but I think there were some mixed clinical results.
Yep. Yatin, as you've highlighted, there are a couple NLRP3 participants that have shown DIO data as well as clinical weight loss data. I'll tackle the Ventyx compound first. In DIO studies, they showed about 2% weight loss. Ultimately, as they reported in the last month, did not see weight loss in the clinic. We think that that evidence continues to support the translatability of the DIO study to the clinic. As you've mentioned with NodThera, that is, as you highlighted, a prodrug. Our understanding is that they have to run humanized engineered mice to see a weight loss reduction with the compound. From our perspective, that makes it hard to do an apples-to-apples comparison.
The one thing I would note, though, is that despite seeing 17% weight loss in their DIO studies, they still did not hit the same level of weight reduction that semaglutide did. We think it's clear based on their data, they are not driving semaglutide-like weight loss or induction, which is what we're seeing with NMRA-215. I think the question behind why we see it with NMRA-215 and the competitors don't is really driven off of the pharmacology. We are a neuroscience company through and through, and our focus has always been to develop novel chemical entities that have access to the brain, which is not something that is always easily achievable. We have developed what we believe is best-in-class CNS-penetrant pharmacology for NLRP3 inhibitors.
We've put some of this data out publicly, which enables us to achieve an IC90 concentration in the brain over 24 hours, which we believe and other sponsors have published data on is required ultimately to drive weight loss. Based on data we've seen from some of the companies that have put out clinical weight loss data with NLRP3 inhibitors, we do not believe any of those compounds necessarily hit the IC90 threshold for 24 hours. We wouldn't expect them ultimately to drive weight loss given it's due to central mechanisms here.
Got it. Just on the biological rationale, what is the central hypothesis? What is the hypothesis that central NLRP3 inhibition is needed for appetite suppression?
Yeah, maybe I'll take this one. Josh has touched on a bit of this already. I think what we see both from the DIO model, but also from human studies, it's clear that neuroinflammation, in particular in the hypothalamus, is likely a key driver in obesity. As Josh said, what we are now learning from other sponsors, but also our own data, to decrease NLRP3 to show weight loss, you need to have covered NLRP3 at the IC90 for 24 hours. You put these pieces together, it's very clear it's a centrally driven mechanism with the hypothalamus likely to be the core axis of it.
Okay. All right. Again, I think if we step back and look at the space in general, I think we are beginning to see some, I think some really remarkable biomarker data on the cardiovascular side. What is your view on the cardiovascular applicability of this molecule? How are you thinking? I know you're going into obesity, but just how would you capture that?
Yeah, absolutely, Yatin. I think a molecule that can achieve IC90 concentrations in the brain as well as in the periphery can achieve not only the weight loss objectives, but also the peripheral cardiovascular benefits. That is what we have designed NMRA-215 to do. We believe with NMRA-215, not only will we see all the peripheral cardiovascular benefits that other sponsors have seen, but we are able to dose the drug at a level that achieves IC90 concentrations in the brain for 24 hours. It should also be able to see the weight loss benefits. As we think about moving the program forward, our first-in-human studies are very much going to focus on obesity. It is the largest therapeutic market I think any of us have seen, and it is only continuing to grow.
From a commercial perspective, it makes a lot of sense if you have a drug that can truly drive weight loss to look at the obesity market first. We will obviously look at follow-on indications and other areas we can go. We are starting to think about ways that we can capture biomarker data that could be useful for the program's future development, but in this first-in-human study. When we initiate the study in the first quarter of next year, we'll come up with more specifics around study design and how we're thinking about capturing some of this early peripheral biomarker data as well.
Got it. So just the study that you're going to run in obese patients, can you just talk structurally how you're thinking, how big the study size and scope of the study?
We have not commented yet on the study size. Yatin, what I will highlight is we are planning to run a first-in-human study consistent with what we have seen other obesity sponsors do. We are looking at running single ascending dose and multiple ascending dose, and then looking at potentially expanding out the multiple ascending dose cohorts, where ultimately we will look to deliver data that is 12 weeks in duration in both the monotherapy and the combination with GLP-1 settings. When we initiate the studies in the new year, we will provide more specifics on the exact kind of design paradigm and exactly what we are looking to achieve.
Got it. Anything else on the NLRP3 that you're watching out or that could have some read-through to you in the meantime?
In terms of read-through, I think our pharmacology really stands out against the rest of the class. As we've put out in our corporate materials, we believe that our access to the brain is far superior to everybody else in the clinic. I know that there will be additional NLRP3 data sets coming. I think with how proximal we are within 12 months of being able to produce our own human proof of concept, at this point, that's really kind of the next major data set that we're looking for to de-risk our molecule and continue to show progress moving forward.
Got it. Very good. Moving on to the neuro side 511. I think there is some data coming up relatively soon in Alzheimer's disease agitation. I think one of the endpoints there is the CMAI total score. What exactly do you need to see in order for you to advance forward in second stage?
Absolutely, Yatin. I just want to remind everybody, this phase IB is a signal-seeking study, and it is not powered for statistical significance. What we are really going to look to gain out of this study is a broad spectrum of data, not only the CMAI, but the factor scores within the CMAI, the NPP, and other measures to get a holistic view of the potential that we think NMRA-511, a highly selective V1a receptor antagonist, could have in Alzheimer's disease agitation. As we think about expectation setting for this readout, what we know is there are really two molecules that have been through RCTs in this space and shown some success. First is REXULTI. If you look at their RCTs, they showed about a 20-point reduction on CMAI to week eight.
We know with REXULTI, they looked at it studying a much more severe population, capturing patients that were not only in the outpatient setting, but patients that were in the inpatient long-term care. It was a more severe patient population. The placebo response they ultimately saw in their study was in the high teens. If you think about what Axsome's done with Auvelity and their program, they have shown more like a 13-point to 14-point reduction in CMAI with Auvelity. Their placebo response tended to be much more in the low double digits. Auvelity, from our perspective, is a much more safe and well-tolerated compound relative to what you see from REXULTI.
We think that our bar, which could be an even safer level and more tolerable over Auvelity, could mean that if we see something in the same range as what Axsome has seen with Auvelity, we should view that we have got a path to move it forward in terms of being able to generate the clinical evidence ultimately required for future registration. I think, Yatin, what we are going to be looking at is probably a broad range of measures. Seeing a CMAI score that is in the same zip code that Axsome saw with Auvelity, I think is something that could give us a lot of confidence.
Got it. Would you move then into a phase III or you need another phase II?
We have flexibility in our design. As we thought about the plans moving forward, we're going to let the data really guide what we do next. If the data is very robust, we could consider moving it into potentially pivotal studies. If the data is compelling but needs more interrogation, we could look to move it into a phase II study and then ultimately pivotals. We have not, in this phase I signal-seeking study, done robust dose ranging yet. We just moved forward with a single dose, which was the highest dose we tested in phase I studies. We'll really see what the data tells us, Yatin, and then think about the development path after that.
Okay. Okay. On the M4 side, I think you have two assets, right, that you are advancing. Just can you talk about the differences between these two assets or similarities? Just focus also on the M4 versus M1, M4, like how you think about that pharmacology.
Yeah, Yatin. You know, over the last four or five months, we put quite a lot of information out on our two clinical candidates. Initially NMRA-861, and then more recently, during today, NMRA-898. Very excited about both molecules. In the data we've put out, there are key features. Look at potency. Importantly, we run a number of assays, and we really optimized around having equity potency across those assays. That is different from what we see with some of the main competitors in this space. Importantly as well, we really optimized around CNS penetration. That was really because we thought other sponsors may have issues there. If you see the data we put out, our compounds are highly permeable, low PGP risk, and look like really good CNS molecules. Again, not dissimilar to the discussion around 215 and NLRP3.
For us, there are two critical features. Selectivity, I think, is on a par with others, but really puts us in a really good position with, we think, really nice molecules to sort of test the hypothesis.
Got it. And then as you advance these two assets, what is the strategy? Eventually, are you going to prioritize one for a certain indication?
I think as we've looked at the muscarinic space, we've always felt there's a range of indications that could be viable for this pharmacology. We're going to prioritize acute treatment of schizophrenia first. That is the clinically validated area for this. I think really what having two compounds does is it provides us the ability to do a best horse race to see, is there one compound that looks more appropriate to prioritize for acute schizophrenia? Then we can look at the second compound. If it looks like it has compelling properties and is continuing to progress well, we could think about other indications to potentially prioritize for that program, whether neurodegenerative conditions that might require a different product profile or SKU ultimately as we move to the commercial setting.
I think, Yatin, ultimately what having two M4 PAMs offers us is just flexibility as we move forward.
Yeah, yeah. What are the next steps for both these assets?
They're currently running in phase I SAD/MAD studies, and we've communicated that we'll provide a franchise update by the middle of 2026.
That's one. Both of them would have SAD/MAD data by that time?
Yeah. Now that both programs are in the clinic, we're going to try to run them in parallel with one another so we can see just how is the data performing comparatively. Do both molecules look like they have a path forward, or is one separated itself from the other?
Just on high level, how differentiated or how differentiated are they relative to Emraclidine?
Yeah, Yatin, back to my prior answer. I think if we look at potency across assays, they're very different. I’d point you towards our corporate deck, our R&D day deck, where we've shown that both our compounds are very potent in our two key cell-based assays. Emraclidine in our hands, potent in one, not very potent in another. This is why we had this data for a long time, and it's only more recently we've started to talk about it. What does that show? Is the compound less potent than we thought, or is there some biased positive allosteric mode of action of that compound compared to us? If you look at the properties, particularly around CNS penetration, we always were concerned about Emraclidine's CNS access.
If you may remember, they, Cerevel published some PET human data, and it was clear that even though they upped the dose, they did not increase the receptor occupancy. We think that compound may have some CNS penetration issues. Again, we optimize around getting really good CNS penetrant molecules. When we think about the key competitors there, particularly on the PAM side, there are two of the key features.
On the safety side, at least in the preclinical model, like how high have you gone on the doses? The issue with the first generation has been ruled out completely?
Yeah, no, good question. So again, we've put out that information. Obviously, over the last 15, 16 months, we had our first compound, NMRI- 266, which had unexpected convulsions in rabbits. So we spent a long time trying to understand that molecule and obviously bringing forward molecules which did not have that risk. I will say our most compelling de-risking data came in vivo itself in rabbits. We've gone to much higher exposures for much longer duration to truly de-risk that. It was clear what we saw with 266 was unique to that molecule.
Got it. Got it. Very good. Okay. To the KOASTAL program, could you talk about the modification that you have made in KOASTAL-II and III? I think III is running ahead of II. Just anything you are able to share, how is that translating into better patients?
Absolutely. Yatin, I think you hit the key point there, which is getting the right patients into the studies. As we communicated after the KOASTAL- I readout, we did not feel like we got the right patients into this study due to kind of the medical oversight of this study and just really qualifying, is this the optimized patient for this study? What we did to address that is we added a couple of components. One is we partnered with Massachusetts General Hospital and the CTNI network, which is run by Maurizio Fava, to implement the SAFER protocol, which effectively has the Massachusetts General Hospital clinical psychiatry team review the patient history and medical records of patients going into deem if they are appropriate, as well as conduct interviews, proprietary interviews with the patient to feel out, does this patient truly have the characteristics that they have put down on paper?
What we feel is that we are now, with the partnership with SAFER CTNI, getting a much higher quality of patient into the study that we believe truly does have MDD. The other thing we added to weed out patients that could be professional is we added the VCT database to complement the CTS database, which we have been using before. We have seen a number of flags in the VCT database for patients that otherwise would have gotten in. We feel like both of the measures are doing what we want, and we are gaining confidence that we are getting a much higher quality of patient and the right patients into the study versus what we saw in KOASTAL- I.
Got it. In the KOASTAL- I, were there sites that had the particular site that had patient issues, and are you able to take them out completely in KOASTAL- II and III?
The sites are different in KOASTAL- I versus KOASTAL- II and III. There are a handful of sites that overlap, but really the goal with running three studies in parallel is you want to replicate the studies. You cannot necessarily just have the same sites running two studies at the same time. As we looked at KOASTAL- I, sites that had enrolled a good number of patients and performed well were the ones that we have then added to KOASTAL- II and III, and we have stayed away from any sites that we felt did not perform well in KOASTAL- I. Ultimately, the goal here is to run independent but replicable studies.
Got it. What is the size of II and III? I think you have some ability to go higher. How much you can go higher, and would you go higher or not?
The base study size for each of the KOASTAL studies is 332 patients. As you noted, Yatin, within the protocols, we have the flexibility to increase the size by up to 25%. In KOASTAL- I, we ultimately enrolled 383 patients, so it was approximately a 13%-15% over-enrollment. We have not communicated what we are going to do in KOASTAL- II and III yet, but we are gaining confidence that we are putting better patients into those studies now than was originally the case under the KOASTAL- I scenario.
Is it that III is coming in Q1? So you'll have one-by-one announcement, or you wait for both?
Yes. Our current guidance is that we'll have KOASTAL- III top line in the first quarter of 2026 and KOASTAL- II top line in the second quarter of 2026.
From a filing perspective, you need both studies?
The base case in neuropsychiatry is you need two studies positive to file for an NDA. There have been examples where one positive study and supportive evidence has enabled approval. VRAYLAR is a good example of that. Our base case right now is two positive. As we communicated to the R&D, one positive plus supportive evidence could give the basis to start engaging with the agency.
Engaging with them. Got it. Very good. Very good. Lots going on. The company is going to be very busy for the next 12 months to 18 months at least.
I completely agree, Yatin. Having six clinical catalysts across our important programs that are all funded within our existing cash runway is a great position to be in. We are excited to start flipping more of the data cards as we hit year-end.
Very good. Thank you, Josh. Thank you, Nick. Appreciate it.