NMRA

LLM Evaluations

Transcript Summary

Neumora Therapeutics' Q4 2025 earnings call highlighted a transition from clinical execution to a catalyst-rich 2026. The primary focus remains on navacaprant, a KOR antagonist for major depressive disorder, which has completed enrollment for its two pivotal Phase III studies (KOASTAL-2 and KOASTAL-3). Management expects top-line data in Q2 2026, noting that enhanced screening protocols have likely improved the quality of the patient population compared to previous trials. Additionally, NMRA-511 showed promising signal-seeking data in Alzheimer’s agitation, demonstrating an effect size on par with current standards of care but with a more favorable safety profile. In schizophrenia, NMRA-898 has been prioritized as the lead M4 PAM due to its long half-life and once-daily dosing potential. However, the company’s obesity program, NMRA-215, encountered a delay due to unexpected findings in a rat toxicology study, pushing its clinical entry to Q1 2027. Neumora ended the year with $182.5 million in cash, providing a runway into the third quarter of 2027. The upcoming year is critical, as data from navacaprant and NMRA-898 will serve as major milestones for the company's valuation and strategic direction in the neuropsychiatry space.

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Full Earnings Call Transcript — Q4 • 2026-03-30

Operator: Ladies and gentlemen, thank you for standing by. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to turn the call over to Helen Rubinstein, Vice President of Investor Relations and Corporate Strategy at Neumora. Please go ahead.
Helen Rubinstein: Good afternoon, and thank you for joining Neumora Therapeutics Fourth Quarter and Full Year 2025 Financial Results Conference Call. Before we begin, I encourage everyone to visit the Investors and Media section of our website at neumoratx.com, where you can find the press release related to today's call. With me on the call today are Chief Executive Officer, Paul Berns; President, Josh Pinto; Chief Operating and Development Officer, Bill Aurora; Chief Scientific Officer, Nick Brandon; and Chief Financial Officer, Mike Milligan. I'd like to point out that we will be making forward-looking statements during today's call, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. Please review the risk factors discussed in today's press release and in our SEC filings for additional detail. With that, I'll now turn the call over to Paul.
Paul Berns: Thanks, Helen. Good morning, everyone, and thank you for joining us. 2025 marked a year of important clinical progress and execution for Neumora. We made meaningful strides in advancing our diverse pipeline of novel mechanism therapies, reported compelling data for NMRA-511, our oral highly potent brain-penetrant and selective vasopressin 1a receptor antagonist, progressed our Phase III program for navacaprant with optimizations based on key learnings from prior studies, expanded our M4 PAM franchise with 2 new programs in clinical development and prioritized obesity as the lead indication for our brain-penetrant NLRP3 inhibitor, NMRA-215 and reported class-leading DIO data, all while continuing to strengthen our financial foundation. Our mission at Neumora remains clear: to advance the next generation of novel therapies that offer improved treatment outcomes and quality of life for patients living with brain diseases. We believe through our differentiated approach centered on advancing programs with best-in-class pharmacology and brain-penetrant chemistry targeting novel mechanisms of action, we have the potential to deliver transformative therapies to millions of patients in need of better options. Now as we move into 2026, Neumora is well positioned to achieve multiple potentially value-creating milestones within the next 12 months. As we approach these near-term catalysts, I am confident in the strength of our science, the focus of our strategy and the dedication of our distinguished Neumora team to deliver revolutionized therapies for patients living with brain diseases. I will now turn the call over to Josh to review our pipeline updates. Josh?
Joshua Pinto: Thank you, Paul. We are poised to build on the strong momentum from 2025 as we enter a catalyst-rich period with multiple clinical data readouts expected this year. Leading with NMRA-511, our oral highly potent brain-penetrant and selective antagonist of the vasopressin 1a receptor in Alzheimer's disease agitation. In January, we announced positive results from the Phase Ib signal-seeking study of NMRA-511. NMRA-511 demonstrated a clinically meaningful effect size in people with Alzheimer's disease and a favorable safety and tolerability profile with no reports of somnolence or sedation. Today, we built upon those positive findings with new data from a prespecified analysis of the Phase Ib study in patients with a neuropsychiatric inventory agitation aggression or NPI-AA score of 4 or greater, which aligns with the enrollment criteria from the Rexulti and Auvelity pivotal studies. These data further reinforce the potential for an unsurpassed profile of NMRA-511 in AD agitation, an area with significant unmet need for new treatments. As a next step, we are exploring higher doses of NMRA-511 in a MAD extension cohort from which we expect to report data in the second half of 2026. From there, we plan to initiate a Phase II study with NMRA-511 in the first quarter of 2027. Turning to navacaprant, our kappa opioid receptor antagonist for the monotherapy treatment of major depressive disorder. The KOASTAL-2 and 3 studies are now fully enrolled with more than 400 patients enrolled in each study. We look forward to reporting data from these studies in the second quarter. Additionally, on our M4 PAM franchise, we announced today that we have selected NMRA-898 as our lead program. We believe that NMRA-898 is well suited for continued development in schizophrenia based on promising clinical results from an ongoing Phase I study. We are currently conducting a multiple ascending dose study of NMRA-898 in healthy volunteers and patients with stable schizophrenia, and we expect to report data in the second half of 2026. Turning to our metabolic franchise. We announced 2 key updates today regarding NMRA-215, our highly brain-penetrant oral NLRP3 inhibitor for the treatment of obesity. The first update and a very exciting one for us is new positive data from a 12-week diet-induced obesity or DIO mouse study that reinforces the potential of NMRA-215 for the treatment of obesity in both the mechanism of action switch and the weight loss maintenance paradigm. These encouraging results further validate what we reported previously, class-leading weight loss as a monotherapy, additive weight loss in combination settings, potential for an incretin-sparing and/or switch treatment paradigm and weight loss maintenance that matches semaglutide. We are eager to advance next steps for NMRA-215. However, as we shared this morning, there were unexpected adverse findings from a separate 13-week rat tox study in a small number of animals. We have opened a for-cause audit of this study and expect to bring NMRA-215 into the clinic in the first quarter of 2027. Nick will go into more detail on both of these updates shortly. But first, I will turn the call over to Bill to provide additional detail on our clinical programs. Bill?
Daljit Aurora: Thank you, Josh. We are excited about the data from NMRA-511, which demonstrated a differentiated profile for the treatment of agitation in Alzheimer's disease. In January, we shared top line results from our Phase Ib signal-seeking study of 511. This was a 2-part signal-seeking study that was not powered to detect statistical significance. Instead, we evaluated the effect size of 511 on a variety of clinical measures to inform additional development in AD agitation. In the Phase Ib study, 511 demonstrated an unsurpassed clinical effect size on CMAI total score and a range of other endpoints in a prespecified population with elevated anxiety at baseline. Today, we announced new data from a prespecified analysis from the Phase Ib in 53 patients with an NPI-AA score of greater than or equal to 4 at baseline. This population is similar to the group studied in pivotal trials with Rexulti and Auvelity. 511 treated patients demonstrated a clinical benefit and had a Cohen's d effect size of 0.32 to 0.34 on CMAI total score, a similar magnitude to Rexulti. Additionally, in this population, 511 showed an unsurpassed effect size across the CMAI aggressive behavior subfactor score and CGI-S agitation score. Notably, 511 demonstrated a favorable tolerability and safety profile in Phase Ib, which we believe provides an opportunity for us to test higher doses. We are advancing a MAD extension study this year with data expected in the second half of the year before moving to a Phase II study in the first quarter of 2027. Transitioning to navacaprant, we are pleased with the significant progress we have made with the navacaprant KOASTAL program for the treatment of major depressive disorder. Today, we announced that KOASTAL-2 and KOASTAL-3 studies are fully enrolled with more than 400 patients enrolled in each study. We expect to report a joint top line data readout for KOASTAL-2 and KOASTAL-3 in the second quarter of 2026. As a reminder, KOASTAL-2 and KOASTAL-3 are Phase III studies being run both in the U.S. and in ex-U.S. territories. The design for these studies incorporated key learnings that we implemented in early 2025 following the KOASTAL-1 readout. This included enhanced medical monitoring to verify inclusion of appropriate patients, screening tools to rule out professional patients and site selection that focused on sites with expertise in conducting MDD studies. We believe that these optimizations facilitated appropriate patient enrollment in these trials. For example, we saw an approximately 10% higher screen fail rate in the KOASTAL-2 and KOASTAL-3 studies compared to KOASTAL 1. Overall, we are confident that these changes will result in a stronger data set and look forward to the results. In the joint top line readout, we expect to include top line results for each individual study as well as prespecified analyses with more than 450 patients enrolled after study optimizations occurred in early 2025. We believe this approach will provide a comprehensive view of the data and help us better assess navacaprant's clinical profile. We will assess next steps regarding regulatory submission once we have the data in hand, but we believe that with the FDA's recent commentary, one positive study plus supportive evidence may be sufficient for approval. With one positive study, we would request a pre-NDA meeting with the FDA. Lastly, on our M4 positive allosteric modulator franchise, today, we announced that we have designated NMRA-898 as the lead program in the franchise and plan to advance it for development in schizophrenia. This decision is supported by the encouraging data we have seen to date from our ongoing Phase I study. In that study, NMRA-898 demonstrated an approximately 80 to 100-hour half-life in humans, which confirms the potential for once-daily dosing and is within a similar range to the half-lives of highly successful neuropsychiatry medications like Vraylar, Abilify and Rexulti. We also observed dose proportional exposures with low variability as well as predicted free brain exposure significantly above the in vitro M4 EC50 levels. In addition, we saw on-target changes in heart rate that were similar to those demonstrated by Cobenfy, which we believe provide pharmacodynamic evidence of target engagement. Taken together, these findings strengthen our confidence in NMRA-898 and support our view that it has a potential best-in-class pharmacologic profile. We are conducting a multiple ascending dose study of 898 in healthy volunteers and patients with stable schizophrenia. The goals of this study are to identify a maximum tolerated dose and to confirm CNS penetration through CSF exposure. We expect to report data from this MAD study in the second half of 2026. While we have paused development of our other M4 PAM, NMRA-861, we believe it has a profile that could support development in the future. We are pleased to have this optionality in our portfolio. As you can see, we are making significant progress across our clinical pipeline that I believe has the potential to translate to meaningful medicines for patients. With that, I'll now turn it over to Nick to walk through our NLRP3 update in more detail. Nick?
Nicholas Brandon: Thanks, Bill. I'll begin with our 12-week DIO data with our NLRP3 inhibitor, NMRA-215. As Josh noted, the results from this study further highlight our CNS penetrant pharmacology that translated to class-leading weight loss in these models. In earlier DIO studies, NMRA-215 drove dose-dependent class-leading weight loss as a monotherapy and in the combination setting with semaglutide. The 12-week DIO data we announced today provides supportive evidence for potential use of NMRA-215 in both the mechanism of action switch and maintenance treatment paradigms. DIO mice that was switched from a combination of NMRA-215 plus semaglutide to NMRA-215 monotherapy at week 8 maintained weight loss similar to mice who received semaglutide monotherapy for the entire study duration. NMRA-215 also demonstrated sustained semaglutide-like weight loss at 12 weeks following the switch from semaglutide monotherapy to NMRA-215 monotherapy at week 8. These findings, along with our previously reported data are very encouraging and supports our view that central NLRP3 inhibition may offer an important new mechanism for weight loss. Additionally, with data from multiple sponsors in the space showing reductions in hsCRP, it's become clear that NLRP3 inhibitors offer potentially compelling cardioprotective benefits. We believe that this is a class effect, and we are likely to see hsCRP reductions with NMRA-215 when it enters the clinic. Now as Josh mentioned, we also shared that unexpected adverse findings were observed in a very small number of animals in a 13-week rat toxicology study. A few details to highlight. The observations were not dose dependent and not associated with a known molecule-related or on-target effect, but did occur in conjunction with documented study conduct issues. We have opened a for-cause audit into the study. We have also completed 28-day rat and dog and 13-week dog toxicology studies with no similar findings and sufficient margins to achieve IC90 concentrations in the brain, which we believe are needed for weight loss. We remain confident in the potential of NLRP3 inhibition for the treatment of obesity and have started dosing in a repeat 13-week rat toxicology study. We now expect to bring NMRA-215 into the clinic in the first quarter of 2027. From here, I will turn it over to Mike to review the financials. Mike?
Michael Milligan: Thanks, Nick, and good afternoon, everyone. As of December 31, 2025, we ended the year with $182.5 million in cash, cash equivalents and marketable securities. We expect our current cash position to support operations into the third quarter of 2027. Additional financial results are available for review in the press release that we issued this morning, including detailed information on our fourth quarter and full year 2025 operating expenses. Our total net loss for 2025 was comparable to the same period in 2024. With that, I'll now hand the call over to Helen to manage Q&A with the operator. Helen?
Michael Milligan: Thanks, Mike. Before I turn it over to the operator, I'll ask that you limit yourself to 1 question. If you have an additional question, please feel free to return to the queue. With that, I'll turn it over to the operator to handle Q&A. Operator?
Operator: [Operator Instructions] Our first question today comes from the line of Myles Minter from William Blair.
Myles Minter: Congrats on the progress. I'll keep it to one. Just wanted to follow up on comments that potentially 1 study and supportive evidence would be sufficient for the navacaprant filing in MDD. Did want to confirm that just means that a positive KOASTAL-2 or 3 would be that one study. And then the source of supportive evidence, maybe that comes from the combined trial analysis of those more than 450 patients enrolled post protocol amendment? Or is that coming from something like the Phase II you've already got in hand or even external data like from the [indiscernible] that supports the core antagonist mechanism here?
Daljit Aurora: Myles, this is Bill. Thank you for your question. Yes, we do believe that with 1 positive study, either KOASTAL-2 or plus supportive data, we'd be in a strong position to proceed in requesting a pre-NDA meeting. Supportive data could take a variety of forms, whether that's an improvement on anhedonia as measured by SHAPS, whether it is tolerability safety profile that's quite compelling in an untreated large population. So there are a variety of ways by which we believe supportive data could play an important role, but 1 of the 2 studies being positive puts us in that position to move ahead of the meeting.
Operator: And the next question comes from the line of Brian Abrahams from RBC Capital Markets.
Brian Abrahams: Congrats on the continued progress. Maybe just on 215, can you give us any color around these conduct issues that you mentioned, like what these were, why you suspect them and how these might relate to the toxicity findings? And I guess I'm curious, would the onus be on you to prove that the findings here were spurious? Or historically, has the FDA been fine with progressing a program if a redo of a 13-week tox study comes up clean?
Nicholas Brandon: Brian, it's Nick here. So because we do have an ongoing audit into the initial 13-week rat study, we can't really provide too many more details. Clearly, we have stated today that we do believe they are procedure-related and we are now completing -- well, we've now started a second repeat study with a different CRO. And that -- in that second study, we have made some changes. I think importantly, these types of findings in top studies are very common in the industry. They're well documented in the literature. And we know that other sponsors have repeated studies and have been able to move their programs forward. So we're obviously looking forward to completing this second study and progressing 215.
Operator: Your next question today comes from the line of Douglas Tsao from H.C. Wainwright.
Douglas Tsao: Just on the M4 program, I'm curious if you could provide a little bit more in terms of what sort of put 898 in the lead. And also, I think Bill mentioned that you continue to see opportunity potentially for 861. I'm just curious, do you see that largely as a backup molecule right now? Or do you potentially envision development in alternative indications?
Joshua Pinto: Yes. Doug, it's Josh here. And so as we mentioned, we're prioritizing NMRA-898 this morning as our lead in schizophrenia. And really, it's not because of anything that we saw with 861. Really, it's because 898 looks so compelling based on the data that we put out today, and both compounds are structurally distinct. So with our focus being on schizophrenia, we're going to progress 898 as the lead in that indication. But we do view 861 as a viable compound for future indications. And so as we think about indication expansion in LCM within this franchise, we could look to bring another compound like 861 forward in that. But for the time being, Doug, 898 is -- will be the lead for schizophrenia. And based on the data that we've published today, the compound is behaving exceedingly well in early clinical studies.
Operator: Your next question today comes from the line of Marc Goodman from Leerink.
Alyssa Larios: This is Alyssa on for Marc. I was just wondering if you could give a little bit more details on the prespecified analysis for the KOASTAL-2 and 3 readouts. What exactly are we going to see? And how do you imagine interpreting those results compared to kind of the entire top line analysis?
Joshua Pinto: Yes. Alyssa, it's Josh here. And so in terms of the KOASTAL studies for the prespecified analysis, what you can really expect is that we will be putting out top line data for the KOASTAL-2 study, top line data for the KOASTAL-3 study. And then we will be looking at those patients that were in a post-pause pooled population, so those that have gone through the SAFER process since the KOASTAL-1 study read out. Bill, maybe you want to just add a bit more in terms of what we'll see from the prespecified top line and what we're really going to be looking for in the KOASTAL results in the second quarter.
Daljit Aurora: Sure. Thanks for the question, Alyssa. So with respect to the KOASTAL-2 and 3 study, just as a quick reminder, when we paused those studies, we did implement a series of measures that were designed to enhance the quality of the patients coming in. And those included things such as working with MGH and implementing the SAFER process. It included implementing VCT as a screening database and paring back the number of sites overall. We're pleased with the measures that we had taken, and we've seen higher rates of screen failure as a consequence, for example, approximately 10% higher than in KOASTAL-1. These would have otherwise been patients that would have been randomized into the study. So it gives us confidence that, in fact, we've done a better job in making sure that we get the quality of patients consistent with what the protocol and our expectations were. With respect to the post-pause population, we'll have an opportunity in each of the individual studies to take a look at how those patients performed as well as taking a look at the pooled population post pause. So those will be added measures on top of looking, of course, at the individual study results for K2 and K3.
Operator: And the next question comes from the line of Paul Matteis from Stifel.
Julian Pino: Congrats on the progress. This is Julian on for Paul. Do you mind just walking us through really quickly the update that you shared with respect to the maintenance data for 215? I guess, was this your expectation? And how did you get to sort of modeling that target dose where you're showing an estimated 23% reduction in weight loss in the DIO model? And then really quickly, if I may, just how does the delay on the sort of tox-related issue for the program factor into your capital allocation strategy?
Joshua Pinto: Yes. Thanks, Julian. And so -- this is Josh here. Maybe I'll answer the second part of your question first. So obviously, our spend this year for 215 will be reduced as we're not going to be moving the program into the clinic until the first quarter of 2027. So it will free up capital as we think about allocation to other areas. In terms of the maintenance data, I think the data is exactly what we would expect, and it built on what we think was the best-in-class monotherapy and combination DIO data that we presented in October at our R&D Day. In terms of what we showed in this DIO study, it was completely focused on longer-term combination paradigms. And so we demonstrated that you could switch from being on a GLP-1 to NMRA-215 and maintain the same level of weight loss, which commercially could be very important. We also looked at a paradigm where if you were on a combination of the 2 products, and you took one off, could you maintain weight loss? We absolutely validated there that, yes, if you're on a combo and you take away semaglutide, you can maintain monotherapy level weight loss with 215. And so in terms of how we selected the target dose, it was really around achieving IC90 concentrations in the brain, as we've highlighted previously. And so Julian, as you look at what we achieved in the 12-week DIO study, the combination of semaglutide and 215 alone, highly consistent with the 28-day data we previously put out, where you saw about a 20% to 25% reduction in combination therapy over the study. So Julian, I would say very validating, hits exactly what we'd expect to see out of the study and exceedingly consistent with what we have shown previously for 215 and DIO studies.
Operator: Your next question today comes from the line of Yatin Suneja from Guggenheim.
Maddalena Delma Caiati: This is Delma for Yatin. So a clarification on the 215 tox study. So have you received any specific guidance from the FDA on what would be required to clear the IND? Or are you proactively rerunning the studies based on your own assessment?
Nicholas Brandon: Yes. Nick here again. Yes. So we haven't discussed the studies with the FDA, but we have consulted multiple consultants and KOLs around what was the appropriate path forward. So repeating the study was clearly the clear guidance we were given. And I would say, based on the experience of our internal team, including myself and our consultants, we're confident that this repeat study could -- will allow us to get the FDA to approve the IND. Yes, there's a lot of precedent for it. And first, I can look back on my own prior experiences at other companies where we've done similar things. So we're confident that this repeat study would allow us to get the IND cleared.
Operator: Your next question today comes from the line of Ami Fadia from Needham & Company.
Poorna Kannan: This is Poorna on for Ami. On NMRA-511, could you help us understand how the effect size changed at the different time points, week 4 and 6 in the subpopulation? And how are you envisioning the Phase II study design in terms of the patient population and trial duration?
Daljit Aurora: Sure. With respect to the effect size that we have seen in the trial overall, we're really pleased with the consistency of the results and looking at the effect size. The effect size, whether it be at week 4 or 8 depending on the various measures was quite consistent, and we're pleased with what we've been seeing here. With respect to the next steps of the program, we've communicated that we'll be moving forward with another MAD cohort where we believe we've got room to push the dose given the favorable tolerability seen. And then from there, we'll describe in further detail what our plans are for Phase II, including the design, inclusion criteria and the alike. But suffice it to say, the data that we put out today showing the NPI-AA of 4 or greater is consistent with what other sponsors have used as a part of their inclusion criteria and been able to maintain a broad label. So that is one where one could expect to follow the path of other sponsors and where there's a regulatory path that's been well defined.
Joshua Pinto: Yes. And Bill, I would just add, I think the data today that we put out is really quite compelling for NMRA-511. I think it shows that in the total population, our data is consistent and just as compelling as what we've seen in patients with elevated anxiety. And Bill, to your point, this new data that we've highlighted today shows that we can develop NMRA-511 down a well-established regulatory pathway while still preserving the ability for a broad label in patients with AD agitation. So we actually view this data as the most compelling data set we've put out thus far for 511 and are really excited about this being the launching point for the program going forward.
Operator: Your next question comes from the line of Graig Suvannavejh from Mizuho.
Graig Suvannavejh: I wanted to ask about 898 and the M4 PAM space. Could you just remind us how you're thinking about its differentiation versus, say, the Neurosterix's program? And if you could provide what you think the latest is with emraclidine, just as we think about the M4 PAM class and again, vis-a-vis the broader muscarinic space and any kind of thoughts you have on the Cobenfy launch and what that means about how doctors are thinking about muscarinics in the schizophrenia landscape?
Nicholas Brandon: Greg, it's Nick here. Thanks for the question on the M4. In terms of the differentiation of 898 in particular, compared to some of the other competitors, even including emerging companies like Neurosterix. I think I'd point to a number of key bits of data which we've put out, knowing that we don't know a lot about a Neurosterix's compound. 898 and 861 have a very, very potent and equipotent across assays, which is critical. Those compounds are also optimized for CNS penetration. And we've put out some data around that, which is in our corporate deck. We really -- the more data comes out there, it really holds up. And now critically, we've got early clinical data and particularly with 898, it's really showed its hands [indiscernible] in the initial cohorts. Clearly, the half-life allows us for once-a-day dosing, which is critical. And I may hand over to Bill in a second to talk about some of the other elements that may drive -- we see really nice dose-dependent exposure. Variability is really, really low. And that's important. Other compounds in this class haven't had that quality. We also see really nice pharmacodynamic effects, and this is by the surrogate heart rate increases we see. So overall now, the profile of 898 just looks really good as we compare to what we know about other sponsors in the field. But maybe, Bill, do you want to add?
Daljit Aurora: Sure, Nick. I would just simply add, Graig, that the half-life for 898 is within a similar range of half-lives of highly successful neuropsych meds like Vraylar, Abilify and Rexulti. We conducted market research with community prescribers that also has underscored some of the potential advantages of the profile that they've seen. And as an example, we know we have the ability to maintain steady state in the situations where a patient may miss dose of medication, which we know is a common phenomenon in schizophrenia. The half-life also has the potential to reduce withdrawal symptoms if patients discontinue medication. And so we're really pleased with the profile and the excitement is certainly one that's been underscored through some of the work we've done with physicians treating schizophrenia patients and the profile they've seen with 898.
Joshua Pinto: Yes. And Graig, this is Josh. I would just add, we're really compelled by the data that's been put out this morning. I think as we look at it in the SAD study, we have not hit an MTD yet, so continue to move forward. And we're already seeing across the pharmacodynamic measures, activity elevated from what we've seen with emraclidine and even at levels relative to Cobenfy. If you look at what we've seen at the 15-milligram level in terms of heart rate elevation and beats per minute, that's comparable to what we've seen from Cobenfy at its highest doses. And so we feel like we are absolutely getting into a really good pharmacodynamic range while also having a compound that is behaving very well from a safety and tolerability perspective.
Operator: Our next question today is from the line of Myles Minter from William Blair.
Myles Minter: For the quick follow-up on Graig's question as well. On 898, did you also see any sort of transient increases in blood pressure in that single ascending dose study?
Daljit Aurora: The changes that we've seen in blood pressure are consistent with what we have expected, nothing that is different from what's been seen with the class. So it underscores that in the Phase Ib, we plan to move forward as other muscarinics have with routine monitoring. We do anticipate as the molecule progresses in development, like other muscarinics have done, we would look to do an ambulatory blood pressure monitoring study as others have in the space.
Joshua Pinto: Yes. But just to be clear, Myles, in the single ascending dose study, we have not seen blood pressure changes thus far. So we are seeing the positive changes in heart rate as we believe the pharmacodynamic measure is as it's related to a measure of target engagement for M4 in the class. But in these doses, we have not seen the elevated blood pressure yet. So we'll continue to monitor and move forward. But to Bill's point, we -- our assumption is that blood pressure could be a class effect, and we baked into our plans having to run an ambulatory blood pressure monitoring study if needed.
Operator: And our final question comes from the line of Douglas Tsao from H.C. Wainwright.
Douglas Tsao: I was just curious in terms of the combination -- or for 215, sorry, for the combination to 215 maintenance study, I'm just curious about the dosing that was utilized and are things that you think you might be able to do to sort of further optimize the maintaining of the weight loss that was seen when it was used in combination with semaglutide?
Joshua Pinto: Yes. Doug, this is Josh here. As I mentioned before, I think in the 12-week DIO study, it's validated the hypothesis that we absolutely wanted. And the combo data, I think, is consistent where we saw over 12 weeks about a 23% reduction in weight loss on the combo. That's consistent with the roughly 25-ish percent we've seen in the earlier studies. And as we know in these DIO studies, as you continue to feed mice high fat diet over time, the weight does tend to rebound, whereas that's not necessarily the case in the clinic. I think as we're looking at ways to optimize the molecule, Doug, moving forward, really, the next step is to get it into the clinic, start to understand how it's behaving in humans from a PK perspective, and then we can look to move it forward there. But what I would say is the data we put out today continues to validate that NMRA-215 does have a best-in-class weight loss potential, at least as it relates to the DIO data we've put out between the R&D Day [indiscernible].
Douglas Tsao: And if I can, Josh, just as a follow-up. I mean, obviously, you've sort of outlined in the DIO models a number of different use cases. How many do you anticipate ultimately bringing forward? Or do you think that this is more of a situation where you'll just sort of validate the 215's ability to drive weight loss and maintain weight loss and then kind of leave it up to clinicians to figure out their own particular dosing regimens and sort of ways of using the molecule?
Joshua Pinto: Yes, Doug. And so there's obviously -- our view is there's going to be a lot of different things and paradigms that can be tested out with this molecule in combination potential. I think in terms of what you can expect from us moving forward, what you can expect from us is consistent with what we've highlighted before, which is we're going to now be moving the program into the clinic in the first quarter of 2027. And initially at weight loss, you can expect data to come out from us in a standard monotherapy as well as combination approach. We'll talk about future paradigms downstream after we validated the hypothesis of weight loss clinically.
Operator: That will conclude the Q&A portion of today's call. I will now hand the call back to Paul Berns, CEO, for closing remarks.
Paul Berns: Okay. Thank you, operator, and thanks to all who joined us for this morning's call. We appreciate your interest and support. Have a lovely day.
Operator: Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.