Conference Transcript - NMRA 2026-05-19

Speaker 3

Back, everybody, and good afternoon. I'm Brian Abrams, Senior Biotech Analyst at RBC Capital Markets. We're really pleased to have our next presenting company, Nomura Therapeutics, represented by Josh Pinto, the President, Nick Brandon, their Chief Scientific Officer, and Jason Duncan, their Chief Administrative Officer. Thanks so much, guys, for being here.

Speaker 2

Yeah, thanks, Brian, for inviting us. I really appreciate it.

Speaker 3

So, lots to cover, because I know there's a lot of programs that have been moving forward very actively. Maybe we can start with Nebacaprand and MDD. For those new to the story, the data from the Phase 3, Coastal 2 and 3 studies are very close at hand. Can you maybe just remind us around some of the study amendments and some of the changes that you implemented to Coastal 2 and 3 following the Coastal 1 results and maybe how those may be contributing to, I guess, how the conduct has been going so far, how the implementation has been going as we kind of near the end, And how do you think those are contributing to a study population that's more likely to demonstrate statistics and showcase statistical significant effects for the background for the drug?

Speaker 2

Yeah, absolutely. And thanks, Brian, for the question. I think as you think about the Coastal 2 and 3 studies, which are expected to read out later this quarter, they were part of a broader Phase 3 Coastal program that included three Phase 3 studies that we ran. As you mentioned, we got results from the Coastal 1 study in early 2025. what we saw in that study was an overly inflated placebo response, particularly in the male population that led us to dig into that. And a couple of things we noted is that we enrolled more male patients than you historically see in MDD clinical trials. And we don't necessarily think that all of those patients were appropriate or had the right flavor of MDD for a clinical trial. And so the challenges with Coastal One really boiled down to not enrolling the right patients. And so to your point, we made a number of amendments in early 2025 to Coastal Two and Three to help fix that. One of the amendments and changes that we made was we partnered with Mass General Hospital and their SAFER program, which is led by Maurizio Fava, to really help instill the medical monitoring over the study and make sure we're getting the right patients. We also completely rebuilt our clinical development team with a seasoned set of neuropsych drug developers that have brought a range of programs forward, whether Abilify, Vralar or Cabenphi. And so we've brought in the right team. And so, Brian, what you're hearing from us is over the last 12 to 18 months with Coastal 2 and 3, we've had much stringent oversight of every patient that's come into the study. And that's what's giving us optimism as we look forward this quarter. In terms of what we're seeing that gave us confidence to take the studies up to the maximum number of patients we could enroll is, first, we were achieving that two-thirds female population. So as we denoted, we achieved about two-thirds female population in Coastal 2 and 3. As you recall from Coastal 1, the drug actually had an approximately three-point separation in the female population, so where it did work. so we're happy that we normalized that. We also saw a significantly higher screen fail rate with our medical monitoring and the safer process. And so the screen, it's working effectively. And so as we've looked at those measures, the blinded data that we're seeing, that's what gave us the confidence, Brian, to invest the additional dollars and maximize the number of patients in Coastal 2 and 3. Got it.

Speaker 3

Any sense of what the study's powering is now with some of those changes? and then how might you be presenting the top-line data? Will you break down patients who were enrolled prior to the optimization, or will this be kind of the full population? How should we think about interpreting what we'll see?

Speaker 2

Yeah, so the studies were originally powered to 90% to detect about a 3.2-point change on the Madras. Some of the key variables that we haven't disclosed that go into that are obviously the standard deviation, as well as the dropout rate. What I can say, Brian, is that in terms of standard deviation and dropout rate, one is slightly higher than our assumption, whereas one is slightly lower than our assumption. So assuming we've been able to control placebo response in the study, we feel very good about the power that is in the study. In terms of the readout that's coming, what we're going to see is top line data from the Coastal 2 study, top line data from the Coastal 3 study, as well as a pooled analysis of patients that came in under the safer protocol and with the more stringent medical monitoring. And we believe that releasing all of this at once will be able to give us the opportunity to declare what is our path forward with Novacoprint and give investors confidence that the measures that we added to improve the medical monitoring have truly impacted the study results.

Speaker 3

And what do you think you need to show from a clinical robustness and statistical standpoint to support approvability. And is this, will the, will you be discussing primarily the kind of the safer population, the pooled population with the FDA? If it was one trial hitting and one trial missing under kind of the guise of the new FDA guidelines or policy, is that good enough? If you hit on one study in the safer population, just help us understand the different permutations here, because I know, you know, depression studies can be tough, and it's a big deal to show a real signal with a novel mechanism. It's a huge unmet need. So what would be, apart from obviously both studies hitting statistical significance on every population, like what are the different possibilities here?

Speaker 2

Well, I think you hit one of the key points, Brian, which is first you have to look at it from the unmet need perspective within MDD. The current therapies that are available today have good efficacy. They don't treat all of the symptoms. They do not treat anhedonia, which is one of the core symptoms. And the side effect baggage is quite substantial. And that's really what Novakoprant's looking to move forward is bring a program forward that can show a benefit on depressive symptoms, anhedonia benefit, but with a clean safety profile as well. And so in terms of what we believe we'll need to file an NDA, our working assumption is hitting statistical significance on the Madras in one of coastal two and three, so having a hit on the primary endpoint, plus supportive data, which could be the post-pause pooled data I've gone through safer. It could be the Shaps and Anedonia data. It could be the broad tolerability profile, given how clean it's looked in our prior studies. And so we think that there's a lot of permutations that could support moving forward to a pre-NDA meeting and having a discussion with the agency about a path forward with a single pivotal study being successful.

Speaker 3

Got it. Good. And then just remind us of the timelines for the data. Presumably, it's not coming tonight.

Speaker 2

You guys wouldn't be here. Yeah. So I think in terms of when it's coming, we've disclosed that it's coming in the second quarter. Obviously, we're here today. So I think you don't have to hold your breath for this evening, Brian. But we did announce at the end of March when we released our 10K that we had completed enrollment by that point. As you guys know it's a six-week study. And so, you know, you should expect to see the data at some point before the quarter's over.

Speaker 3

Maybe shifting gears to 5.11. You reported some intriguing data relatively recently. So can you talk to your confidence in the signals that you're observing, both in the total population and the high anxiety subgroup where you saw even more robust effects? And I guess where are you now with regards to next steps, exploration of higher doses, this MAD extension study that you're prosecuting now?

Speaker 2

We're really excited about the data that we've seen out of NMRA 511 from the Phase 1B study in patients with Alzheimer's disease agitation. From a top-line perspective, what we've shown is a product profile that has a very mild side effect profile, so definitely competes favorably against a Rexalti or an Avelity within that arena. And from an efficacy perspective, we've seen across a range of measures, not only the CMAI primary, but subfactors and secondary outcomes such as CGIS and NPI, an efficacy profile in the broad population that is comparable to Rex Salty. And that is within a population that is similar to what Rex Salty and Avelity both studied in their pivotal trials. So we think as close as you can come on a head-to-head comparison, 5.11 looks like a much safer version of Rexalti's efficacy profile. We also wanted to look at how the drug performs in patients with elevated anxiety at baseline because the vasopressin 1a antagonist pathway is thought to be anxiolytic. And so this is one of the unique times behind in neuropsychiatry where you can tie a broad clinical result actually to a mechanistic hypothesis. And as you know, that's very challenging. And what we saw in patients with elevated anxiety is across each of the measures, an elevated clinical effect size. And so that gives us confidence that if we can focus on enrolling a population that from an inclusion-exclusion criteria is close or similar to what Rick Salty and Avelady did, and through medical monitoring, ensuring we're getting and balancing appropriate levels of elevated anxiety, should allow us to really test this product in a patient population that it's well-suited for while also preserving potential for a broad label. And so in terms of next steps, we'll be completing a MAD extension study this year. We'll read that out in the second half of the year. As we've mentioned in the release, the 20 milligram BID dose was very safe and well-tolerated, so we want to look to push the dose higher to see if we can capture more efficacy. And so we'll look to do that. After that, we'll look to move into a phase two dose ranging study.

Speaker 3

And what are going to be the key takeaways from the MAD extension? Will it be primarily on safety? Are there kind of biomarkers or anything?

Speaker 2

So what I would say is from a safety and tolerability perspective, that's obviously going to be the primary goal. We want to see what is the maximum tolerated dose. So how far can we push 5.11 up? So that'll be the primary goal. On biomarkers, Brian, we did look at a range of things from the 1B. And so you might see some more data coming out from us as we move forward. And that could be, you know, things that we ultimately look at in the MAD extension and future studies as well. But in terms of biomarkers, you know, we're still doing a bit of work on what we want to study in the MAD extension.

Speaker 3

And so I guess, how are you thinking about what indications might be best suited for the V1AR mechanism here? And I guess, Is there internal data from preclinical models or data from other compounds that can guide your development path? And maybe you could also touch on some of the key differences in 5.11's pharmacological profile relative to other V1A agents that could give it maybe a better likelihood of showing success across whatever indications you may pursue.

Speaker 1

I'll tell you that one. I mean, we've obviously paid very close attention to the literature, both preclinical and clinical data, and obviously tracking other V1A antagonists which have been put into development. I think you go back to what's been published around the vasopressin B1A system, it's so closely associated with stress disorders and anxiety, whether in rodent, non-human primate, through to human experimental systems, increased vasopressin, you drive anxiety, stress-like states, you dampen those with a B1A antagonist. And we have our own data in the non-human primate model, the Marbezet model, which really corroborates that. uh then you know what we've also seen in those studies is and this is i think becoming a common theme is the impact on aggression so there's one clinical compound from azavan srx 246 which in the huntington's disease study did show and you know an effect on aggression we actually look at our non-human primate data it also is very suggestive we could be impacting on aggression like behaviors as a van has recently started a new study in fragile x with enrichment for people you know patients with aggression so for me as well as you've got this anxiety theme you've also got the aggression and that links back to agitation and alzheimer's disease where we had our biggest impact so that's where you know our first study but then as we look forward with this you know really centering around anxiety and stress you know we are thinking about things like general anxiety social anxiety ptsd and these are things we've really thought through very diligently over the last few years and we're in the mix as we decided where to to place 5.11 you know when we think about our compound and how it differentiates there's probably four compounds you did think about roche had balabactan which they took into autism which you know was unfortunately unsuccessful we actually look at a compound similar pharmacology but when you start to we're able to model projected receptor occupancies there's no pet ligand so we can't actually do the empirical experiment but when we project the occupancies 511 is really superior so where with our 20 mig bid dose we're somewhere between 93 and 97 percent over 24 hours you know we think balavaptan which was they could only go up to 10 they were somewhere between 70 and 90 percent uh again it's only modeled but i think what we have the properties of 511 you know really give better cns properties compared to balavaptan srx246 which has been used in a number of studies and particularly some really important clinical ones very old compounds you know we believe that you know their patent life may have you know you know passed uh you look at the structure of that molecule very very different doesn't look particularly cns friendly uh so structurally basic properties very different from 5.11 overall we see 5.11 having the sort of best in class properties from a profile perspective basic pharmacology cns penetration okay good um maybe moving on to uh 215 um there have been a lot of developments in obesity and the metabolic space A number of companies here today and will be here tomorrow playing in that space.

Speaker 3

But there's certainly arguments for continued unmet need. So I guess I'm curious, what do you think is most distinct about the NLRP3 mechanism and where a drug like 215 could fit in in this broader landscape?

Speaker 1

Yeah, so for NLRP3, and this is really the thesis we've worked through and still, you know, still are following, is clearly a role in the brain for NLRP3 inhibition. And what's the story which has emerged in the last 18 months is that inhibiting NLRP3 at high levels, all the work is focused on the hypothalamus, which is, you know, probably the center of regulating key feeding circuitry. if you inhibit it there in preclinical models you see significant weight loss but the key feature here is you need to see very high levels of central inhibition you know there's been some very nice publications which is again you know we've confirmed with our own data you need to be like an icy 90 level of inhibition over 24 hours so there's this piece which we think is critical for the weight loss and we know it's by decreasing food intake you also have the peripheral impact of nlb3 inhibition which we're seeing almost to be a class effect across you know other sponsors impact on critical cardiometabolic biomarkers like hscrp uh and even you know il6 so there's two pieces to this if you then have a compound which has good peripheral exposure You're going to see those peripheral effects. If you also have a really high CNS penetrant compound, we believe you have a chance of seeing, you know, changes to eating behavior and weight loss. And that's certainly backed up by at least our preclinical data today.

Speaker 3

Yeah, so let's talk about those data a little bit more. You recently had 12-week data from a DIO model where 215 maintains semaglutide-like weight loss when switched from a combo to a monotherapy. You've shown some other data showing monotherapy weight loss. I guess, what are the key takeaways from these studies that you've run so far in preclinical models? And I guess what should be a realistic expectation for human weight loss efficacy in phase one, just based on the translatability of this model and for this class in particular?

Speaker 1

Yeah, so maybe just a reminder on our original disclosures last year, you know, we showed both monotherapy and combination weight loss with semaglutide, which looked to be class leading in these preclinical models. when you look at both overall weight loss over 28 days or induction of weight loss it looked incretin-like which looked to distinguish 215 you know more recently we've put out these longer 12-week studies where we've tested a number of paradigms Brian like you mentioned so we've done the maintenance so where we've had animals on samaglutide and 215 and then we've just put them to 215 alone and what we see is maintenance and maintenance of weight loss similar to what you would have with SEMA alone and then we've just done you know a very you know one day to another quick switch from SEMA to 215 again maintaining that weight loss you know our view and I'll let Josh weigh in as well you know it just seems this whether it's monotherapy but particularly in combination very tunable and you know very complementary mechanisms so in terms of what could happen.

Speaker 2

Yeah. And I would say this is a model. I think it's one of the most highly translatable models that we have from the preclinical to the clinical setting. We've seen a number of publications that have been out there that have violated the correlation has been as high as 0.9. And we've seen this not only with GLP-1s, amylins, and older classes. So this isn't necessarily just a GLP-1 mechanistic hypothesis. So I don't necessarily want to state numerically where we think we would ultimately want to go in the clinic because that's challenging to do. But what I would highlight is this is the only NLRP3 inhibitor that has shown semaglutide-like weight loss as well as induction. And so we feel like it's delivered, Nick, the best-in-class preclinical profile. And that's why we're excited, Brian, to test it in the clinic once we get through the repeat three-month rat talks that we're currently working on.

Speaker 3

And can you maybe give us an update there on the status of this repeat talk study in rats with the new CRO? So any color, as you've kind of digested and analyzed the data, what may have happened with that initial study? And have regulators weighed in at all about the potential acceptability of the second tox study to de-risk the program to move into the clinic?

Speaker 1

Yes. So maybe I'll start with the original study. Can't really say too much more than what we've disclosed before. You know, as a reminder, we did see a small number of animals in this three-month study, certain events which were correlated with procedural errors, you know, at the same time. This did lead us to start a full-cause audit, which is still ongoing. But, you know, we've got to remember, you know, these were not dose-dependent, no link to mechanism or the molecule. and the molecule had behaved you know our data in 28 day rat dog and three month dog studies were what we know were really good and supportive of moving forward our belief you know that in 215 clearly led us to reinitiate a repeat study you know which we announced back in march which is which is ongoing so before you know we haven't been to the regulators yet because we obviously want to see the result of the three months plus complete the audit and which will quite us in a good position with the FDA to get our first IND approved here.

Speaker 3

Good. And then just maybe in the last couple of minutes, you have another program, the M4PAM program, you know, two different molecules you're potentially looking at here.

Speaker 1

How do 861 and 898 differentiate both from one another and from some of the predecessor drugs, just in terms of things like potency brain penetration selectivity and what would constitute a go no-go decision point for further invest uh investment in the franchise yeah so maybe just as you know one of our more recent updates was that we have prioritized nmra 898 over 861 that's right just to stay though both molecules are really good uh 861 though we have paused it we could easily bring it back into development. The reason we selected 898 were just a number of attributes which also are key differentiators from other compounds like emraclidine. So 898, very potent across basic pharmacology assays which we don't see with all other compounds but the most selective M4PAM we have seen and certainly of all of our compounds. Then importantly both 861 and 898 were optimized around cns penetration and we believe other sponsors may have may struggle with cns penetration perhaps even with uh cns e-flux challenges which we don't have with with either of those compounds as we went into phase one development 898 the properties we've seen so far just made it stand out so it has a long half-life around 80 to 100 hours in the data we've disclosed today and as we think about schizophrenia you know where compliance could be initially you can clearly think this this could be very helpful if they if individuals miss a day or two of dosing it's also the variability in the human pk is so low i personally haven't worked with a compound like this where not only the variability but when we model out the data pre getting your real data it looks it looks like textbook data so as we've thought about other compounds as we go into clinical development, you know, clinical proof of concepts, we're sort of de-risking a number of other features which other compounds may have faced. So for us then, it's all around, you know, obviously we need to pick the right dose, which we're trying to do with our MAD study, but just actually executing flawlessly. And we think it'll give that, you know, a real good chance of showing efficacy.

Speaker 2

And then in terms of next steps, Brian, we'll come out with the MAD data in the second half of this year. This will include the multiple ascending dose data from healthy volunteers, as well as patients with stable schizophrenia. And then we'll look to very quickly move it into a proof of concept study thereafter. We're really, really excited about 898 and the profile that's been delivering thus far.

Speaker 3

Anything we can read through from the stable schizophrenia patients, just given they're stable versus...

Speaker 2

I don't know if there's anything necessarily on the stable schizophrenia point from an efficacy perspective, but I would say from a pharmacodynamic perspective, we've already delivered some very interesting data. As you think about the increase in beats per minute from a heart rate perspective, it's hypothesized quite strongly that that is driven through M4 central target engagement. And with our 15 milligram dose, which we're continuing to move higher on, we've already seen heart rate level elevations comparable to what Cabenphi's seen at their highest doses. So we feel like we're engaging the M4 target. I think the really interesting data we're going to get out of the MAD cohorts will be some of the CSF work, as well as continuing to see how safety progresses in the two different populations.

Speaker 3

We're out of time, but thank you guys so much.

Speaker 2

Great to get up.