Neumora Therapeutics, Inc. (NMRA) Earnings Call Transcript & Summary

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 conference over to Helen Rubinstein, Vice President Investor Relations and Communications of Neumora. Please go ahead.

Good morning, everyone, and thank you for joining us for today's event. Before we begin, I'd like to point out that this presentation contains forward-looking statements, which are based on our current expectations and beliefs. We have a number of important disclosures on this slide, which we urge you to read. In addition, I'd like to note that the event today will be held in lieu of our formal earnings call for this quarter. We plan to report our third quarter 2025 financial results on Thursday, November 6. The press release detailing this information will be available on the Investor Relations section of our website. With me today are several members of Neumora's management team, including Co-Founder, Chief Executive Officer and Chairman, Paul Berns; President, Josh Pinto; Chief Scientific Officer, Nick Brandon; and Chief Operating and Development Officer, Bill Aurora. We're also thrilled to be joined by a leading expert on Alzheimer's disease, Dr. Anton P. Porsteinsson, William B. and Sheila Konar, Professor of Psychiatry, Neurology, Neuroscience and Medicine, Director Alzheimer's disease Care, Research and Education Program at the University of Rochester School of Medicine and Dentistry to discuss the potential of NMRA-511 in Alzheimer's disease agitation. We have an exciting agenda this morning that includes several updates across our portfolio. To start, Paul will provide a brief introduction and outline Neumora's strategic vision. Next, Josh and Nick will review NMRA-215 for the treatment of obesity and walk through the class-leading DIO mouse data we announced this morning. Following that, Bill will review the NMRA-511 program and host a fireside chat with Dr. Porsteinsson focused on its potential in Alzheimer's disease agitation. Additional sessions will provide an update on our M4 PAM franchise and progress with Navacaprant in the Phase III KOASTAL Program. I'll now turn it over to Paul to begin the event. Paul?

Thanks, Helen. Good morning, everyone, and thank you for joining us today. Neumora was founded with a clear purpose to tackle the brain disease crisis, one of the largest population health challenges of our time at scale. From the start, we knew that to deliver on our mission to improve the quality of life for millions of patients we needed to advance differentiated medicines with the potential to enable better outcomes. Our approach is centered on advancing programs with best-in-class pharmacology and brain penetrant chemistry, targeting novel mechanisms of action with the potential to improve upon the current standard of care for hundreds of millions of people. I believe we've made important progress toward that goal, which I'm pleased to be here to review with you today. In particular, this morning, we announced class-leading weight loss data from our diet-induced obesity studies with NMRA-215, our highly brain penetrant NLRP3 inhibitor. With NMRA-215, we believe we've engineered the next generation NLRP3 inhibitor. NMRA-215 has the potential to be a best-in-class new oral therapeutic for obesity that improves upon the challenges with current treatments. We also announced this morning that NMRA-898 has entered into the clinic, marking a major milestone as we are now advancing 2 potentially best-in-class M4 PAM candidates for the treatment of schizophrenia. In addition to this morning's announcement, we have several clinical data readouts within our cash runway guidance period, which extends into 2027. First, we are looking forward to the top line data readout of the Phase Ib signal-seeking study with NMRA-511 in Alzheimer's disease agitation around the end of the year. Now this study will provide important data on the potential utility of NMRA-511 for reducing agitation symptoms. Next, we remain on track to report top line data from the KOASTAL-3 and KOASTAL-2 studies with Navacaprant in the first and second quarters of next year. And finally, we expect to initiate Phase I studies with NMRA-215 in obesity in the first quarter of 2026 and share important updates from our M4 PAM franchise by mid-2026. I believe that we've assembled an industry-leading pipeline with immense potential impact for patients, and we are in a strong position to translate that science into real world therapeutic breakthroughs. As you can see, we believe our pipeline progress has set the stage to unlock tremendous value for patients, health care providers and shareholders. We've made great strides toward our strategic goals and are well positioned to achieve multiple value-creating catalysts over the next 12 months, all within our cash runway. With multiple clinical data readouts and a new study initiation on the horizon, we're excited to maintain strong momentum across our pipeline. The presentations today will provide deeper insight into our novel programs and the catalysts you can expect in the near term. With that, I'll now hand the call over to Josh, in which he'll begin the discussion on our obesity program. So Josh?

Thanks, Paul, and good morning, everyone. We are tackling some of the greatest public health challenges of our generation, and obesity is clearly among the largest epidemics we are facing worldwide. Over 1 billion people are living with obesity, and that number is set to grow to 4 billion by 2035. However, despite the availability of first-generation treatments, significant unmet need exists. Although injectable GLP-1s have become widely used, they're not perfect. Many patients experienced GI side effects, don't respond to treatment with these agents or regain weight after treatment cessation. Oral forms of GLP-1 have not been able to demonstrate the same weight loss as their injectable counterparts, but still drive the same GI side effects. In fact, according to real-world data, 68% of patients discontinue GLP-1 within a year and 58% stop before reaching a clinically meaningful weight loss benefit. Clearly, there is significant opportunity for next-generation oral treatments that work differently to provide improved outcomes for patients. We believe NLRP3 inhibition is the answer. NLRP3 inhibitors may hold the potential for incretin-like weight loss, increased response rates and better tolerability in an oral formulation with no requirement for cold chain storage. That's why we're so excited about our oral NLRP3 inhibitor NMRA-215, which we have designed with best-in-class CNS penetrant pharmacology that has translated to class-leading weight loss in DIO models and we believe will translate to the clinic. Supporting that hypothesis are the class-leading weight loss data we announced this morning with NRMA-215. As you can see from this slide, we ran 3 DIO models. In these studies, NMRA-215 drove dose-dependent body weight loss up to 19% as a monotherapy. This weight loss is quite compelling as publications from Eli Lilly and Novo Nordisk on leading injectable GLP-1, such as tirzepatide and semaglutide, have demonstrated 15% to 20% weight loss in DIO models. And publications from Eli Lilly on leading oral therapeutics, such as orforglipron, have demonstrated approximately 10% weight loss in DIO studies. Importantly, monotherapy NMRA-215 demonstrated incretin-light induction with equivalent early weight loss to semaglutide. This is a feature that no other NLRP3 inhibitor has replicated in multiple DIO studies to date. In the combination setting, NMRA-215 and a therapeutic dose of semaglutide drove 26% body weight loss at day 28, an additive effect resulting in greater body weight loss than semaglutide alone. When the target dose of NMRA-215 was combined with a subtherapeutic dose of semaglutide, it drove 18% body weight loss, suggesting the potential for an incretin-sparing combination that may offer better tolerability than high-dose semaglutide alone. Additionally, NMRA-215 demonstrated positive effects on biomarkers in the 28-day study, suggesting higher quality weight loss. In particular, NMRA-215 drove reduced food intake equivalent to semaglutide, match semaglutide fat loss while demonstrating a statistically significant preservation of lean mass and improved the range of biomarkers. These data are compelling given the high translatability of DIO models to the clinical setting. In fact, a recent Nature publication showed a high correlation with an R equal to 0.93 from DIO rodent models to clinical studies. Based on these results, we believe NMRA-215 has the potential to reshape the oral treatment of obesity. These data clearly show that an NLRP3 inhibitor that is optimized for achieving IC90 coverage in the brain can drive not only class-leading weight loss, but also provide peripheral benefit on a range of biomarkers, including cardiovascular ones. I'll now turn the program over to Nick to dive into these data in more detail. Nick?

Thanks, Josh. I'll start with some brief remarks on the NLRP3 mechanism. NLRP3 is a key regulator of inflammation acting as a critical part of the innate immune system in response to both pathogens and cellular damage and is implicated in disorders involving multiple systems. It's known that NLRP3 mediated inflammation is driven by a range of factors as shown on the left-hand side of this slide. These include factors related to the aging process, underlying genetics, environmental factors and importantly, for today diets. Specifically in obesity, lipids, fatty acids and glutose amongst other obesity-related metabolites activate NLRP3. In turn, the system NLRP3 activation is linked to a range of diseases, including cardiometabolic conditions, like obesity, and neurodegenerative diseases such as Parkinson's disease. Our approach focuses on NLRP3 inhibition in the CNS with NMRA-215 designed for high CNS penetration, so that can act directly in the brain. This is critical for its activity and obesity. NLRP3 mediated neuroinflammation specifically in hypothalamus has been linked to obesity. So targeting NLRP3 in the hypothalamus will modulate dysfunctional neuronal circuitry related to appetite and lead to decreased food intake. Literature suggests that IC90 concentration over 24 hours are required to drive reduced inflammation in the brain to impact food intake. Beyond the brain, NLRP3 inhibition also works in the periphery, protecting organs and blood vessels from inflammation-related damage. These peripheral effects can reduce the risk of comorbid disease, for example, by improving cardiovascular outcomes and enhancing insulin sensitivity. The requirement for IC90 concentration for activity in the brain is why we believe other NLRP3 inhibitors such as VTX3232 have demonstrated peripheral benefits on cardiovascular biomarkers, while not improving body weight, which requires both IC90 exposures in the CNS. NMRA-215's best-in-class pharmacology enables IC90 coverage in the brain and periphery, which is why we demonstrated the class-leading weight loss and benefits in triple biomarkers we're sharing with you today. The pharmacology of NMRA-215 is what sets this program apart from our peers. We believe we've engineered the next-generation NLRP3 inhibitor with this molecule. NRMA-215 was designed to be highly potent, highly selective and optimized for brain exposure, features which contribute to its potential best-in-class profile and which we believe enables the groundbreaking weight loss data we're sharing today. Looking at this slide, the left-hand column shows high potency of NMRA-215 across a range of assays and the middle column highlights the exquisite selectivity of NMRA-215. The right-hand column demonstrates that brain exposure is best-in-class amongst other NLRP3 inhibitors. NRMA-215 is highly permeable, has no PGP liability and with a Kpuu of 0.9, all points to high and sustained CNS penetration and achievement of IC90 concentrations in the brain, which we don't believe other sponsors such as Ventyx can achieve. Before I review the data from our DIO model, I'll take a moment to review how the doses were selected for these studies. When selecting doses for NRMA-215, our goal was to determine the target coverage necessary for weight loss. Literature and other sponsors data suggested that you need to hit IC90 levels of target inhibition in the CNS to drive weight loss. So in our studies, we included a target dose in each study that achieved IC90 concentrations for 24 hours. Note, this target dose of NRMA-215 achieves IC90 concentrates in both the CNS and periphery based on the stringent whole blood assay. We believe this was not achieved by other NLRP3 inhibitors such as VTX3232 in recent clinical studies. This supports our hypothesis that NMRA-215 can show best-in-class benefits in obesity, which is driven centrally as well as other benefits, including cardio protection driven in the periphery. We also tested mid and low doses of NRMA-215. As you can see from the graph on the left on this slide, NMRA-215 is metabolized rapidly in rodents. So we opted for twice daily dosing in the DIO models to ensure 24-hour coverage. However, we plan to develop NRMA-215 as a once-daily oral treatment in humans. All characteristics of the compounding human systems and subsequent projected human doses and exposures are consistent with that. For semaglutide, we tested a subtherapeutic dose of 1 nanomole per kg and a therapeutic dose of 3 nanomole per kg. This approach allowed us to evaluate the potential of NMRA-215 across 2 combination therapy paradigms. With a therapeutic dose combination focused on maximizing weight loss and the sub-therapeutic dose combination evaluating the potential for an incretin-sparing paradigm. Now turning to the results of the DIO models. I'll start with the monotherapy setting. The target dose of NMRA-215 is shown in pink in each of these graphs. Across all 3 studies, NMRA-215 drove impressive body weight loss ranging from 15% to 19%. It's not just the total weight loss that's exciting though, as you can see from the Study 2 and 3 data in the middle and right-hand columns, the target dose of NRMA-215 monotherapy drug semaglutide like induction. The therapeutic dose of semaglutide is showing dark gray on these graphs. And as you can see, the NRMA-215 target dose line matches the semaglutide results throughout the entire study period. Due to the optimized properties of NMRA-215, we may be showing for the first time the full potential of NLRP3 inhibition for incretin-like weight loss induction and overall weight loss in the monotherapy setting. So how do these data compare to other NLRP3 inhibitors in development? First, looking at end of study results in the green roads, NMRA-215 monotherapy demonstrates class-leading weight loss, reaching a similar total of semaglutide. This is a bar, which no other NLRP3 inhibitor has been able to reach today. Turning to day 7 results shown in blue, NMRA-215 monotherapy is best-in-class weight loss induction. You can see that NMRA-215 results at Day 7 match semaglutide across 2 independent studies, while other market participants showed dramatically less weight loss at that time point with semaglutide. An important factor in comparing these studies is a starting way of the mice, where approximately 50 grams is generally considered standard. The mice we use were 49 grams at the start of Study 2 and 48 grams at the start of Study 3. Ventus and Ventyx also started with mice in a similar way range. In contrast, NodThera and BioAge started with a much heavier mice, weighing approximately 53 grams, which may influence the study outcome. We believe that NMRA-215's superior pharmacological properties that enables these overall strong weight loss data. Now turning to data on NMRA-215 combined with semaglutide from the 28-day study. As you can see on the left, both the mid- and target doses of NMRA-215, combined with a therapeutic dose of semaglutide, drove greater weight loss in semaglutide alone with 26% weight loss seen in a target dose combination arm. This demonstrates that NMRA-215 produced additive weight loss beyond semaglutide alone. On the right of the page, you can see that NMRA-215, combined with a subtherapeutic dose of semaglutide, drove significant weight loss of 18%. This suggests the potential for NMRA-215 to be combined with low dose GLP-1s in an incretin-sparing treatment regimen that may be more tolerable for patients. Looking again at how these data compared to others in the class. NMRA-215 in the combination setting drove best-in-class weight loss, surpassing what was demonstrated by Ventyx and BioAge, who critically also use equivalent 3 nanomolar per kg doses of semaglutide in their DIO studies. Ventus used a super therapeutic semaglutide dose of 10 nanomolar per kg more than 3x higher than a semaglutide dose of 3 nanomolar per kg that NMRA-215 was combined with. We have conducted additional analysis of these studies to understand underlying mechanisms and also related by market changes from the 28-day study. First, the graph on the left shows that NMRA-215 drove reduced food intake similar to semaglutide. These results reinforce that the weight loss seen in our DIO studies was driven by reduced appetite. When thinking about the future of obesity treatment, it's clear that quality of weight loss will be a key driver of success for new market entrants. Body composition data is shown on the right of this slide. Here, you can see that NMRA-215 is driving high-quality weight loss, NMRA-215 and semaglutide drive equivalent fat mass loss, but when it comes to preservation of lean mass, NMRA-215 demonstrated a statistically significant preservation of lean mass compared to semaglutide. While these data are shown comparing NMRA-215 monotherapy, semaglutide monotherapy, results were consistent in the combination setting as well. We will now dig deeper into the positive effects NMRA-215 drove across key peripheral biomarkers. As you can see on the left, in a 28-day study, NMRA-215 drove reduced liver weight equivalent to semaglutide. This is a key measure of liver health. The middle column shows that NMRA-215 drove statistically significant reductions in total cholesterol compared to semaglutide with equivalent reductions in LDL. However, NMRA-215 demonstrated a statistically significant preservation of HDL compared to semaglutide. These results suggest that treatment with NMRA-215 may have cardioprotective benefits. On the right of data from the insulin tolerance test showing that NMRA-215 improved insulin sensitivity equivalent to semaglutide. Note these biomarker data are highly consistent with cardioprotective findings from the DIO model Ventyx conducted with VTX3232, supporting the expected class effect of NLRP3 inhibition on CV biomarkers. Together with the impressive weight loss results we shared today, these biomarker data suggest that NMRA-215 has potential as a next-generation oral treatment that offers weight loss and benefits on key cardioprotective, liver health and insulin sensitivity biomarkers. In summary, we set out to evaluate the potential of NMRA-215 across 3 paradigms; monotherapy, combination therapy with GLP-1s and as a maintenance treatment. The data we shared today validate the potential of this program in monotherapy with class-leading weight loss with similar induction and total magnitude results to semaglutide. These data also validates the best-in-class potential of NMRA-215 in the combination setting. Additionally, they showcase the potential of NMRA-215 to drive high-quality weight loss that preserves lean mass, differentiating it from available treatments. Given the strong correlation in weight loss between DIO rodent studies and clinical studies, we're excited to initiate a clinical program with NMRA-215 in the first quarter of 2026. We will evaluate NMRA-215 as a monotherapy and combination therapy for obesity. We expect to deliver 12-week proof-of-concept data in humans in 2026. Now let's transition the discussion to our V1a antagonist, NMRA-511. I will hand over to Bill, who will provide an overview of the program and host a fireside chat with Dr. Anton P. Porsteinsson. Thanks, Bill.

Thank you, Nick, and good morning, everyone. It is well established that the vasopressin system is involved in regulating complex social and emotional behaviors across species. Within the brain, the V1a receptor is the predominant vasopressin receptor subtype, and it's been implicated in regulating anxiety, threat-related behavior, aggression and social and emotional processing. With NMRA-511, we believe we have the best-in-class vasopressin 1a receptor antagonist to modulate the vasopressin system and potentially provide a treatment option for agitation in Alzheimer's disease. Agitation in Alzheimer's disease affects over 70% of individuals living with Alzheimer's disease dementia and is among the most disruptive of AD symptoms. Managing behavioral symptoms of the disease such as agitation is an important treatment consideration as it's associated with greater carryover stress, earlier placement in long-term care facilities and increased morbidity and mortality. As the population ages, the unmet need will continue to increase for patients, their caregivers and the health care system. Several lines of evidence indicate that V1a receptor antagonists have the therapeutic potential to reduce symptoms of agitation. These lines of evidence include preclinical and clinical studies. Preclinical studies across species support the involvement of the vasopressin system in mediating behaviors, including physiologic stress response, aggression, fear and anxiety. Rodent selectively in-bread for ultra degression and stress coping showed dysregulated vasopressin release and HPA functioning. Vasopressin-deficient rodents displayed impaired responses to threat stimuli, reduced anxiety and impaired aggression towards intruders. Clinical studies include 2 studies in healthy volunteers and one of the studies, administration of intranasal vasopressin, increased autonomic responsiveness to threat stimuli and increased anxiety. In another study in healthy volunteers, administration of an oral V1a receptor antagonist suppressed anxiety induced by a threat test. In the third clinical study, concentrations of vasopressin in the CSF were positively correlated with levels of aggression in individuals with personality disorders. And finally, additional evidence from a Phase II placebo-controlled trial with a V1a receptor antagonist showed reduced aggressive behaviors in a subgroup of patients with Huntington's disease and irritability who demonstrated violent outbursts. Turning now to NMRA-511 data. To date, we've evaluated the PK profile of NMRA-511 in a Phase I SAD/MAD study in healthy adults as well as healthy elderly participants in Part A of the ongoing Phase Ib study. In these populations, all doses of 511 were safe and well tolerated. There were no SAEs or discontinuations due to treatment-related AEs, and 20 milligrams of 511 BID is projected to achieve upwards of 98% receptor occupancy. On the left, you'll see NMRA-511 demonstrated a dose-dependent PK profile in healthy adults. The graph on the right compares 40 milligrams of 511 dosed once daily in healthy adults to 20 milligrams of 511 dosed twice daily in healthy elderly participants. You can see that once-daily dosing was associated with the bigger peak-to-trough variation compared to twice-daily dosing. Combined, these data supported the selection of 20 milligrams of NMRA-511 twice daily for the Phase Ib study to maximize receptor occupancy throughout the 24-hour dosing period. Looking more closely at the Phase Ib study design. It's important to remember that this is a 2-part signal-seeking study that is now powered to detect statistical significance. Part A is the 2-week randomized, double-blind, placebo-controlled part of the study that was designed to assess the safety and tolerability, PK and cardiodynamics in healthy elderly participants. Part B is the 8-week randomized, double-blind, placebo-controlled part of the study. The primary endpoint for Part B is the change from baseline to week 8 in CMAI total score. We're also looking to evaluate a broader range of efficacy with other endpoints like CGI and NPI as well as safety and tolerability. The results of this study will help us to better understand the potential benefit of NMRA-511 in Alzheimer's disease agitation and to inform next steps for the program. It's well established that there is a significant unmet need for patients with agitation related to Alzheimer's dementia and their caregivers. And as a result, we believe there's a highly compelling opportunity for a product with a differentiated benefit risk profile. The approved products have limited efficacy, carry a box warning for increased mortality in elderly patients with dementia-related psychosis and have tolerability issues that can be concerning in a vulnerable population. This treatment landscape reinforces the opportunity to improve on the benefit risk profile of available therapies that can reduce agitation and possibly improve functional outcomes. Our goal is to achieve a meaningful reduction in agitation symptoms, improve patient quality of life and reduce caregiver burden. If NMRA-511 delivers a differentiated benefit risk profile, we believe it could become a go-to option for patients and clinicians seeking alternatives for the treatment of agitation in Alzheimer's disease. To dive into this further, I'm pleased to be joined today by Dr. Anton Porsteinsson. Dr. Porsteinsson is a leading expert in Alzheimer's disease and joins us to discuss the unmet needs in this space and the potential role for emerging therapies. Welcome, Dr. Porsteinsson. It's great to have you here with us today.

Good morning, Bill and good morning, everyone, who's on the call.

Excellent. Maybe we can kick things off and I could ask if you could please share a bit about your background and experience with Alzheimer's disease.

Absolutely. My pleasure. Again, good morning, everyone. My name is Dr. Anton Porsteinsson. I'm trained as a geriatric neuropsychiatrist, and I completed my training back in the mid-1990s. Since that time, I've singularly focused on the care and study of people with Alzheimer's disease and related dementias. I spent about 25% of my time in an academic based, specialized memory disorders clinic and 75% of my time I spend on doing clinical research. I've done somewhere north of 350 clinical trials in my career. And the work I focus on ranges from biomarkers and imaging to prevention studies in Alzheimer's disease, intervention studies for early symptomatic Alzheimer's disease, MCI, mild, moderate disease. And with my background coming out of psychiatry, I've always been particularly interested in it as well in neuropsychiatric symptoms in Alzheimer's disease such as agitation and aggression, psychosis, depression, apathy, et cetera. And within that space, I've helped with defining diagnostic guidelines, refine clinical trials and their operations as well as kind of the regulatory process. So glad to be here.

Great. Thank you so much. Let's discuss -- let's start off by discussing the impact of agitation in Alzheimer's disease and how it affects your patients? Specifically, how often do 80 patients present with agitation? And how does it clinically manifest and progress over the course of the disease?

Yes. Thanks, Bill. You highlighted some of it, but agitation and aggression is almost ubiquitous for patients with Alzheimer's disease as well as related dementias and that is that at some time during the course of their disease, 70% of people will experience agitation and aggression. And that can be enduring, that can be short-lived. It tends to increase as the disease wears on, becomes most frequent in the moderate stage and as well into the severe stage. But you can see agitation in particular and sometimes aggressiveness as early as the mild cognitive impairment stage. So no stage is kind of immune to it. When you talk to patients, they experience the agitation and the distress that comes with it and caregivers identify this as probably the most disruptive component of the disease. There's one thing being kind of happily confused and working with your care partner, be that family or a professional caregiver. But if you are agitated, oppositional, angry let alone physically or verbally aggressive, it increases the burden monumentally. And this, along with incontinence, relentless incontinence are the main reasons why patients get moved to higher level of care and higher level of care is emergency rooms, urgent care, hospitalizations and admissions to memory care units as well as skilled nursing facilities. And there's nothing about going into any of these institutions that somehow minimizes the behavior. In fact, it may make the behavior even more intense because it's a new environment unfamiliar to them. So the treatment needs are not only in the outpatient setting, but they extend to these institutional settings as well.

Thank you so much for painting a picture of the clinical presentation for these patients. Can you elaborate a bit on the current treatment landscape for Alzheimer's agitation? And where do you see opportunities for emerging therapies or limitations with existing therapies?

Yes. Let me quickly step back, and there was one thing that I want to highlight, and that is that agitation and aggression at this point is a well-defined condition. We have a solid diagnostic criteria that have been explored and refined over a decade that are now accepted by regulatory bodies. So that means that we have a regulatory process here as well. Despite that, we have very limited options in terms of anything that is FDA approved. There is only 1 medication that is FDA approved for agitation and aggression in Alzheimer's disease. We have a number of medications that are used off label. I should point out that the standard of treatment is to use nonpharmacological interventions first. And that sounds easy, but it isn't. First of all, there is no set of nonpharmacological interventions or behavioral interventions that work for everyone. Number 2, they mostly work when there is mild disease, not if there is moderate or acute disease. Doesn't mean that we don't try them, but you have to augment them very frequently with medications. And they're not easy to do. You need the people to do the interventions. They need to have training. They need to have understanding. And in most places, these resources aren't available. So we resort to medications. And the medications that are used are in some degree dictated by the treatment necessity here that you cannot not treat this even if, for the longest term, no medications were available. And it's important to understand that the treatments we use have very limited evidence of efficacy, maybe more evidence that they're not that efficacious, but they have solid evidence that they are associated with complications. And let me highlight a few of them. So conventional antipsychotics like Haldol, that was, to some degree, replaced by atypical antipsychotics like risperidone and quetiapine, medications that showed very variable benefit, but clear problems in terms of increased all-cause mortality in terms of cerebrovascular events, in terms of worsening of disease progression, in terms of falls, increased sedation, acute kidney injury, et cetera. You mentioned that those are conventionally typical antipsychotics have boxed warnings to kind of highlight that. I also want to point that other medications. I've done a lot of work with SSRI antidepressants, and it was disappointing that last year, we showed that treatment with escitalopram did not separate from placebo and retained some of the problems that we saw with citalopram such as QTC prolongation and falls. So even medications that are in wide use are associated with different kinds of risks in this population. And let me not start with people that are still using benzodiazepines, mood stabilizing anticonvulsants, et cetera, that have their own clear set of limitations. So we need more medications that are safe and well tolerated and have a differentiated type of action from the ones we have currently because there is so much pathophysiological variance in terms of what leads to agitation and aggression in the brain.

Great. Dr. Porsteinsson. As you sort of think a bit about emerging therapies or investigational therapies, can you please comment a bit about V1a receptor antagonism? And what interests you or appeals to you about that mechanism, really what makes this a potentially promising therapy for individuals with agitation in Alzheimer's disease?

Well, Bill, for those that know me, and I'm sure that a few of the people in the audience know me and have spoken with me before. I'm kind of a pharmacology nerd and pathway nerd. I really am intrigued by that. And I'm particularly intrigued by us discovering more and more pathways that may have a high relevance in terms of memory disease in general as well as the emotional control that is so often lost with the disease. And I highlighted the kind of pathophysiological variance before. And that pathophysiological variance actually translates into the agitation and aggression as rarely alone. It often travels with anxiety, depressive features, psychotic features, but it's the agitation that brings the kind of care needs in. So we need other options. And what I like about the vasopressin pathway and the V1a receptor potential is that these are so strategically located. We have such a density of these receptors in the amygdala, the hippocampi areas that really have a major role in emotional control. It's kind of where the strategic sectors of that. We have the animal studies that you mentioned before in both mice and marmoset. We have the human studies that if you stimulate the AVP process, basically, you get this increased behavioral and physiological reactivity to threaten a stimuli in stressful situations. So the pathway has face validity. Now the pathway is relatively clear, but AVP has a number of different areas of impact, for example, the kidneys. And that's why the drug that you're using has to be very specific, have high affinity for the receptor of interest. So we want to target the V1a receptor. And one of the things that interested me about the NMRA-511, and I'll probably call it 511 from now on is the high specificity for that receptor and the lack of engagement of the other receptors and particularly some of the receptors in the kidneys. So that's what interests me. And we also have just a medication that seems to be -- or a molecule that behaves well. We have the data from kind of "normal humans," we're getting the elderly PK/PD data. And soon, some of the first data about the target of interest in patients with Alzheimer's disease and meaningful agitation and aggression.

Dr. Porsteinsson you highlight the selectivity of NMRA-511 for V1a. That's really one of the differentiating features and one of the reasons we believe this is a best-in-class therapy due to selectivity for V1a over V2 or oxytocin. But when we shift and we look at clinical data, what are you hoping to see? What would you like to see achieved with 511 in the ongoing Phase Ib study that would give you confidence and data that you would want to be able to evaluate further?

Yes. So Part B of your Phase Ib study has clearly the group of interest to me, that is patients with Alzheimer's disease and agitation and aggression. You have done a good job in designing this because you need to design the study so that it's going to provide the information that you want. So you'll have the right population. You'll have a good number for a Phase Ib study, so 44 in each group. And you have multiple outcomes that all are very informative. You have the CMAI, which is an outcome that gives you granular information about the type of behaviors, the type of agitation and aggression that might be responding. And you can look at 3 different domains to see which domain might respond the best and also confirm, is this a scale that is optimal moving forward. But then, in addition to that, because the CMAI is a caregiver only-based scale, you have a secondary outcome measures basically the CGIS, which is a clinician global impression score of severity. So an expert clinician will evaluate the patients, get history from the patient as well as the caregiver and establish specifically the severity of the agitation and aggression. You have the CGIC, or the Clinician Global Impression of Change. Now this is the modified ADCS version that targets or centers on agitation and depression. So you have an expert clinician also saying, I think this person is improved, same or worsened. And you furthermore, have a broad-based behavioral scale, the NPI, which gives you information about other behavioral domains. Like I said before, agitation and aggression is rarely alone. We haven't talked about different types of agitation and aggression. Some fall into the effective domain, often alongside the anxiety and depression, some fall in the dysexecutive domain that is dyscontrol because people can't make sense of what's happening around them and can't control their emotions and then a domain that has a psychotic element, et cetera, et cetera. So you want to know, are we only having an impact on agitation or aggression or does it kind of spread to these other areas that are incredibly important as well to the well-being of patients and the comfort of caregivers? So you will get a broad set of information that will give you what you need to basically take it to the next stage of development. And that's exactly and more what I would expect and hope for from a Phase Ib study. So I'm excited to see the results hopefully in the near term.

So if I hear you correctly, Dr. Porsteinsson, it's really about the overall evidence package. CMAI total score will be important, but the factors, individual factors will be things that you would look at along with CGI severity as well as the NPI and the broader set of data to help inform how you might think about the target and the data overall from the Ib study.

Absolutely. I want to be thoughtful about the fact that the CMAI is definitely not the alpha and the omega. It's one tool of many. And particularly at the early stage as we understand what targeting this pathway does. We need to look at this from multiple different viewpoints and have a well-informed foundation so that we can design the Phase II, Phase III studies that hopefully will follow. And we will also understand a lot more. We are doing a Phase Ib study. We want to understand a lot more about safety and tolerability. So far, that looks good. And if you think about the pathway, it ought to look good and the selectivity of the drug. But we want to see that in the healthy elderly population and in this population, if basically the occasional headache is the most common side effect or is the one that we kind of see emerging that overall it's a fairly benign safety and tolerability profile because it's such a vulnerable population.

Great. Dr. Porsteinsson. Really appreciate your perspective here this morning, delighted you're able to join us and also to stay for the Q&A session, which we'll look forward to shortly. Now I'd like to invite Nick back to review our M4 PAM franchise. Nick, over to you.

Thank you, Bill. I'm pleased to dive into our M4 franchise starting with the news announced this morning that we initiated a Phase I SAD/MAD study with NMRA-898 bringing us to 2 clinical programs in the M4 franchise. NMRA-861 and NMRA-898, structurally distinct compounds, have both shown a compelling preclinical profile, being very potent and selective for the M4 receptor with the potential for oral once-daily dosing for the treatment of schizophrenia. Given that both programs are now in the clinic with SAD/MAD studies advancing, I also want to highlight an update to our guidance for the franchise. Instead of providing piecemeal updates on each program individually, we will provide a comprehensive franchise update by mid-2026, potentially including advancing development of one or both of these programs. So let's talk about what gives us confidence in the M4 PAM approach. Over the past 17 months, we've taken a deep and deliberate look at our M4 program, including revisiting data across the field to ensure our conviction in the target and the PAM mechanism remains strong. There are really 3 reasons why we believe. First, we believe this is a validated target with supported preclinical and clinical evidence that shows M4 is critical for antipsychotic activity. Next, nonselective muscarinic agents are unsatisfactory with respect to unwanted side effects limiting their utility. And finally, we believe targeting the allosteric site offers a more selective approach that can potentially deliver enhanced efficacy while minimizing off-target effects. On the next couple of slides, I'll walk through each of these points in greater detail. Data from both the preclinical and clinical settings support the role of M4 as a key driver of antipsychotic activity, as shown on this slide. On the left-hand side, this preclinical data demonstrates that the M4 receptor is needed for xanomeline, the active component of Cobenfy, to have an effect in preclinical models of antipsychotic activity. While the right-hand side shows the clinical data in schizophrenia patients published by Cerevel with their M4 PAM and neurocrine with their selective M4 agonist. However, it's no secret that nonselective muscarinic agents are associated with a wide range of peripheral adverse effects. We have seen that targeted M1, M2 and M3 receptors can lead to cardiovascular, GI and endocrine-based side effects. In contrast, M4 selective agents like our compounds show a transient cardiovascular effect with increased blood pressure and heart rate without additional peripheral side effects, highlighting the importance of receptor selectivity, which brings me to our third key point. We believe PAMs offer a clear advantage in selectivity by targeting the allosteric site on the M4 receptor, we enable greater precision in modulating M4 activity while avoiding off-target effects from other muscarinic subtypes. In contrast, agonists in the orthosteric site often showed partial agonism, which may lead to variable clinical responses and reduced consistency of therapeutic outcomes, whereas PAMs allow for more controlled potentiation of M4 preserving the natural temporal dynamics of acetylcholine signaling, a key factor in achieving both efficacy and tolerability. This selectivity is central to our differentiated approach and supports our conviction in M4 as a best-in-class target for antipsychotic activity. We believe our M4 PAM have the potential to be best-in-class based on both basic pharmacology and also brain penetration. As shown on this slide, our molecules have demonstrated high potency across multiple assays, which we think to be very important and is different from other sponsors are shown. Additionally, we've engineered, both NMRA-861 and 898 for high CNS exposure, optimizing for greater permeability and lower efflux so the drug is able to not only get into the brain, but importantly, stay there. This combination of potency selectivity and brain exposure is critical for achieving robust antipsychotic activity with a cleaner safety profile, which is why we believe both compounds have best-in-class potential. On this final slide, I wanted to briefly review 3 key objectives for the NMRA-861 and NMRA-898 SAD/MAD studies. First, confirming once-daily dosing based on the PK profile in humans; second, evaluating tolerable doses, including in people with stable schizophrenia; and finally, establish CNS penetration based on CSF exposure. As I stated, we look forward to sharing a franchise update by mid-2026. I'll now welcome Bill back to review Navacaprant and our Phase III KOASTAL Program. Thanks, Bill.

Thank you, Nick. We are investigating Navacaprant, our kappa opioid receptor antagonist for the treatment of major depressive disorder or MDD. Kappa opioid receptors, along with their endogenous ligand, dynorphin, form a well-characterized pathway that preclinical data suggests has the potential to modulate depression, anhedonia and anxiety. The figure on the left depicts the downstream effects of KOR activation on multiple neurotransmitters, including dopamine. This activation has been shown to trigger symptoms of anxiety, depression and a mood state known as dysphoria. Conversely, KOR antagonism is believed to restore the regulation of these neurotransmitters and reward processing pathways, which is an important role in regulating mood, cognition, reward and behavior. As a reminder, our Phase III KOASTAL Program is designed to evaluate Navacaprant monotherapy in moderate to severe MDD. We reported KOASTAL-1 data earlier this year and we've made important changes to KOASTAL-2 and 3 based on learnings from the first study. Before I dive into optimizations for KOASTAL-2 and 3, I'll briefly review the coastal study design. KOASTAL-1, 2 and 3 are each 6-week placebo-controlled double-blind randomized trials in adult patients with MDD, who have a MADRS total score greater than or equal to 25 at baseline. Primary endpoint for these studies is the change from baseline to week 6 in the MADRS total score, and the key secondary endpoint is the change from baseline to week 6 in the SHAPS total score, which is a measure of anhedonia. Other secondary efficacy endpoints include the CGIS, the CGI-I, PHQ-9, HAM-A, SDS. In addition, key exploratory efficacy endpoints include quality of life measures. The study design for the KOASTAL studies is consistent with FDA guidance on MDD pivotal studies and will allow us to elucidate the potential benefits of Navacaprant including efficacy on symptoms of depression as measured by the MADRS and the potential benefits on anhedonia as measured by SHAPS as well as safety and tolerability. Turning to study optimizations based on learnings from KOASTAL-1. First, we enhanced engagement with sites around medical monitoring to confirm that patients enrolled in the studies have an independently verified diagnosis of MDD. That helps to ensure that we're appropriately engaging and enrolling patients who meet the eligibility criteria for these studies. We've added in the clinician-rated Mass General Hospital SAFER approach. SAFER is an independent review conducted by clinicians to verify the diagnosis and appropriateness of the patient population. Second, we added an additional tool called the Verified Clinical Trial screening database, aimed at identifying and excluding patients -- participants who enroll in multiple clinical trials. This is additive to the clinical trial subject database we used in KOASTAL-1 and we believe it will help to ensure appropriate patients are enrolled in our ongoing studies. Third, we reduced the number of clinical sites to those that we believe have the greatest level of expertise in conducting MDD studies. We have already seen benefits from the added measures in KOASTAL 2 and 3. For example, SAFER and VCT have identified multiple potential participants who are not appropriate for inclusion, enabling us to exclude them from the studies. It's also important to remember that KOASTAL-2 and 3 had key differences from KOASTAL-1 before the pause earlier this year. For example, they both enrolled a higher proportion of females that is more aligned with historical MDD studies. Additionally, the ex U.S. sites, we believe, are less likely to run into issues of professional patients given the different dynamics with sites in the European and ex U.S. regions. We look forward to sharing top line data next year when the studies read out. Thank you for joining us today. I'll now hand the call over to Josh for closing remarks. Josh?

Thank you, Bill, and thank you, everyone, for being here today. As you've heard throughout today's presentation, Neumora has reached a critical juncture in our mission of redefining neuroscience drug development with an industry-leading pipeline and IP protection into the 2040s. Our team's hard work and momentum is captured by this outline of the multiple catalysts we expect over the next 12 months. We anticipate up to 6 distinct catalysts, each serving as a key inflection point with the potential to create significant value across our portfolio. These include additional preclinical and human proof-of-concept data with NMRA-215 in obesity, which we are excited to progress given the strong correlation and weight loss between DIO rodent studies and clinical studies, Phase Ib data in Alzheimer's disease agitation, Phase III data from Navacaprant in the KOASTAL Program. This is a pivotal time for Neumora, and we are poised for meaningful growth. Thank you.

Thank you for all your time and participation today. I'll now turn the call back over to the operator to host our Q&A session, where all of today's speakers, including Dr. Porsteinsson, will be on the line to answer your questions. Operator?

[Operator Instructions] And the first question will come from Myles Minter with William Blair.

Congrats on the updates. Just 2 questions for me, if I may, one for the company and one for Dr. Porsteinsson. First one is just you mentioned your confidence in the correlation between the DIO mouse models correlating to what you would potentially see clinically on weight loss for 215. Can you just sort of like give us an update on where that confidence stands specifically for the NLRP3 inhibitor class, obviously, considering one of your peers last week did report a Phase II study that didn't show weight loss seen in monotherapy or in a combo setting? So that's the first one. And then the second one, Dr. Porsteinsson, would love your opinion on if there's any sort of overlap between Alzheimer's disease, agitation and psychosis? It's a question that we get a lot from investors considering some pretty heavy news flow on the psychosis side with the upcoming ADEPT-2 study for Cobenfy. So just wondering how you treat patients between agitation and psychosis? And whether they're individual indications or you would treat them together?

Myles, it's Josh here from the company. I'll take the first question, and then I'll turn it over to Dr. Porsteinsson for the second question. And so in terms of what really drives our confidence in the correlation that the DIO data is predictable what we'll see in clinical studies, I think first and foremost, as a model, the DIO is heavily predictive with what we see in clinical studies. As we referenced in the prepared remarks, the recent Nature publication has highlighted a correlation of about 0.93 and there are a range of other publications out there, all kind of pointing to a very high degree of correlation between the clinical -- the weight losses seen in DIO studies and ultimately what's seen in the clinical setting. And so in terms of the weight loss we've seen across other NLRP3 inhibitors clinically, it frankly wasn't surprising to us that Ventyx did not show a weight loss with VTX3232 in the clinic. As you recall, they only showed about 2% weight loss in DIO studies, which actually supports that the DIO studies and the weight loss seen are correlated with what we see in the clinic. And part of the rationale behind this as we walk through it, it's clear based on evidence in the literature as well as information from other sponsors that you need IC90 concentrations in the brain ultimately to drive weight loss in these models and clinically as well as hitting high concentrations like IC90s in the periphery to drive the cardiovascular benefit. And so based on the best-in-class pharmacology that we have for NMRA-215, we achieve IC90 concentrations both in the brain, which drives the reduction in weight and in the periphery, which as we saw and demonstrated today improves the range of peripheral biomarkers. Other sponsors with NLRP3 inhibitors do not have the same pharmacology as we do. As we've highlighted, we've really engineered for CNS penetration. And so as we've seen other sponsors are able to achieve IC90 concentration in the periphery, which really drives the cardiovascular benefits, but they do not achieve IC90 concentration based on the whole blood assays, which is a very stringent measure in the CNS, which we think is going to be critical for driving weight loss. And so Myles, that's really kind of the fulsome answer in terms of what gives us confidence as we look at moving from the DIO model into the clinic. And Dr. Porsteinsson, I'll turn it over to you to answer the second part of Myles's question. Thank you.

Absolutely, Myles. Good question. So yes, I mean, agitation and aggression really coexist with other behaviors very frequently. That can be anxiety, irritability, mood disorders as well as psychosis. So if we think about the overlap between agitation and aggression and psychosis, then let's start by looking at psychosis. If there is psychotic beliefs, but there is no emotional reactivity to it, no distress, no kind of upset with the participant not getting in the way of caregiving. We call those kind of quiet or silent psychosis. And it very often exists, but goes unnoticed. And people are loath to intervene with treatment because of the trouble that the current medications that are available bring. So it is really when you see psychotic features commingle with agitation and aggression that the urgency to treat emerges. How do I deal with that? It depends on what's the stronger flavor. If someone is more nonspecifically agitated, aggressive with some mild suspiciousness, mild hesitancy about others intentions, I would focus on the agitation and the aggression alone. If this is clearly driven by a high level of paranoia or visual hallucinations or auditory hallucinations, which aren't all that common in Alzheimer's disease more maybe in dementia with Lewy bodies, I would lean more towards the psychosis spectrum. So that's kind of how I look at it. You see a lot of overlap between this, agitation and aggression as a whole kind of universe that doesn't have much of psychotic features to them. But when we look at the overlap then it depends on which type of behavior predominates and seems to maybe drive the other one.

And the next question will come from Yatin Suneja with Guggenheim.

Maybe just a couple for me. Could you also comment on how you are viewing the cardiovascular-related strategy given that there, we have seen a clear clinical biomarker data, which seems pretty robust. So that's 1 question. And then a different flavor of this question that Myles just asked, I think we get the Ventyx story. But if you look at the NodThera DIO result and you try to compare it with their clinical results, there seems to be some disconnect there. So I would love to understand from you, how do we sort of tie those 2 pieces together as it relates to sort of your molecule? And then if you can also talk about what would you like to see from a POC study that you're going to be running in Phase II obesity study?

Great. Yatin, thank you, and it's Josh here. In terms of your first question kind of on cardiovascular strategy. So our view is that NMRA-215 can offer a multitude of benefits. One is acting centrally, improving body weight loss in obesity as well as providing the peripheral benefit. And so as we think about our development strategy, we'll be coming forward probably in the early new year as we initiate first-in-human studies and providing a comprehensive overview of what we're going to do. But our plan is to look at that proof-of-concept study both in the monotherapy setting as well as the combination setting. In terms of what we're going to think about from our overall franchise strategy, we will look at a range of indications. I do think obesity will be the lead for NRMA-215, but we'll look at additional areas such as cardiovascular and inflammation where we could have added benefit as well. We do also, Yatin, have been working on a range of follow-on molecules, distinct chemical structure. This is an area where Nick and our research team have been working for a range of years. And ultimately, we think we've got a set of good follow-on molecules that we could look at different indications whether thinking about a neurodegenerative specific condition or something specific for cardiovascular, if we wanted to go after a niche indication there where ultimately the commercial overlap on pricing and reimbursement wouldn't fit with obesity. And so I think, Yatin, that really covers kind of the CV strategy, as I mentioned on the clinical proof of concept. We're going to look to establish it before the end of '26 in both monotherapy in combination from a 12-week perspective, but we'll come out with more specifics on study design when we pick off the first-in-human studies in the first quarter of next year. In terms of your second question on kind of thinking about how the NodThera's DIO results translate to the clinic, I'd remind everybody of a couple of things. First and foremost, NodThera's program is a pro drug. And so ultimately, to run the DIO model, they have to use engineered humanized mice to be able to show the benefit of the pro drug. And so we don't necessarily think that it's a pure apples-to-apples comparison between what NodThera has demonstrated and what the other NLRP3 inhibitors have demonstrated. The other thing I would remind you of is that when running these DIO studies, there are things that can impact the overall weight loss seen. One of the most important factors, Yatin, is the starting body weight. Ideally, in these studies, you want to have the starting body weight hit around 50 grams. For our Study 2 and Study 3, they were at about 49 and 48 grams, respectively. And we saw that both Ventus and Ventyx had their starting body weight in the same range. NodThera as well as BioAge had their mice slightly higher at about 53 grams. And so ultimately, they started with a heavier mice that could have impacted the results that they landed with overall in the DIO study, which could have ultimately impacted why it didn't translate to the clinic. And then finally, I would just remind everyone the most important thing to look at in these studies beyond cross-trial comparison is within study comparisons to active control and every sponsor runs semaglutide is an active control. NRMA-215 is the only NLRP3 inhibitor that is showing that it provides total body weight loss as well as induction in the first 7 days equivalent to semaglutide. And so we think it's clear based on this evidence that NMRA-215 has shown added body weight loss benefits beyond what anyone else has seen, and we think it will fit more with the historical translation to the clinic that we've seen from other obesity products.

And the next question will come from Douglas Tsao with H.C. Wainright.

Sorry about that, I was on mute. Can you hear me?

Yes, sir.

Okay. Sorry about that. Congrats on the progress. Maybe as a starting point, Josh, I'd just be curious how you're thinking about development? I know it's still early, but obviously, there are so many different use cases you sort of outlined some as well sort of induction, subtherapeutic combination with the GLP-1 as well as maintenance. How many of those do you necessarily need to run studies and get sort of labeled indications versus an expectation that it will simply be adopted in the marketplace just given the fact this is so big, and we've already seen clinicians experiment with micro dosing, et cetera? And then I have a follow-up for Dr. Porsteinsson on 511, if I can.

Yes, absolutely. So Doug, I think you're absolutely correct. We have seen physicians within the obesity market start to get creative and look at things like micro dosing and other combinations. So we definitely view this is an area where, as physicians get comfortable with products, they will experiment in terms of how they're thinking about utilization. In terms of our strategy, you highlighted, there's really the potential from obesity and monotherapy combination and maintenance, which I think we clearly demonstrated this morning that NMRA-215 has best-in-class potential and is equivalent to semaglutide in driving monotherapy weight loss in DIO studies as well as having an additive combination effect. And as we move into first-in-human studies, Doug, that's going to really be what we look to define a proof-of-concept over 12 weeks, both on the monotherapy and the combination setting. We will have data from a 12-week DIO study looking at maintenance therapy in the first quarter of 2026. And so as you come out with that data, we'll look at the added paradigm. Ultimately, I think, Doug, we're going to let the clinical data guide us here, but our view is this is a product that we think could work broadly across obesity, whether you think about monotherapy combination and/or switch. And so ultimately, what is required to be on label versus investigator-sponsored studies to provide evidence, we'll hit that as we move later in development. But ultimately, we think that the path forward here for NRMA-215 is to look at it as a broad opportunity in terms of improving obesity across a range of measures, whether monotherapy combination. And then we'll also look at additional benefits. We've seen products such as semaglutide demonstrate cardiovascular benefits in larger studies. And so we will look at kind of a breadth and range of studies we have to run in late-stage development. But we completely agree with you, there is a lot to be done here, and that's why we're really excited about the data we've generated from 215 as well as the follow-on molecules that we're working on for different potential indications.

And so I guess this is a quick follow-up on that. So I guess, Josh, maybe you would sort of try to hit some sort of the big buckets knowing that you're not going to necessarily be able to cover every scenario of use of 215. But if you hit those big buckets, clinicians can then sort of do what they may in terms of if they have sort of particular niches they might want to pursue on their own?

Yes, Doug, I think that's a fair assumption for now. I do think our development strategy will look at the big markets, frankly, to get it approved for the broadest label in use that we can and then more niche indications will follow after as I mentioned, whether it's things that we take on in terms of running randomized controlled trials ourselves or whether it's in partnership with investigators as they look at investigator sponsor studies. There's a range of ways that we could ultimately look to unlock the broad potential here.

And a question for Dr. Porsteinsson. Obviously, I think you alluded to it. The primary indication is of sort of the agitation with 511. I guess, I think you sort of alluded that in these patients, and I know obviously, sort of indications like MDD are not necessarily a primary focus, but do you see a benefit by sort of reducing the level of agitation with these patients that we would ultimately see a better sort of overall mental health status with that?

Yes, Douglas, thank you. Astute question. So because of the heterogeneity, both within just a simple domain of agitation and aggression as well as the overlap with multiple other types of behaviors. And I rattled off a few anxiety depressive features, irritability, psychosis. These all layer on top of each other. And then you want to see actually a broad-based benefit. What is driving that is always a little unclear. Is it just the reduction in the agitation and depression? But I think that if we have a kind of a medication with the potential for a broader impact so that we will see some benefit in mood symptoms, some benefit in anxiety, some benefit in irritability, fearfulness, alongside the agitation and aggression, that is something that clinicians truly appreciate. They want a broad-based benefit that decreases the distress across the system. And by that, I mean not only for the patient, but also the burden for the family or professional caregivers depending on the setting.

And the next question will come from Graig Suvannavejh with Mizuho Securities.

Can you hear me okay?

Yes.

Yes, we can.

Okay. Thanks for the R&D Day updates. These were fantastic. I have lots of questions. I'll try to keep mine limited, maybe to the 511 program initially. I was just curious, and I might have missed it during your presentation, but any studies that have been done or any evidence with 511 in particular as to whether it's associated with any potential cardiovascular depression? I'm basically just trying to get at whether there's any color around the potential for falls, which particularly is an issue with an Alzheimer's patient population. Also, a next question. I know that you had mentioned in terms of the lines of evidence that 511 could be impactful here. You mentioned there was some study related to Huntington's disease. I was wondering if 511 would be considered for Huntington's disease. And then maybe lastly on 511, with your data coming up in the fourth quarter, what are we ideally looking for? In other words, what would be good for us in terms of an outcome here for you to want to take this forward?

Great. Thanks, Doug. And I'll -- this is Josh. I'll turn it over to Bill to address the 511 questions. Bill, over to you.

Sure. When we step back and we look at the cardiodynamics, and the impact of 511. We did, as a part of Part A of the ongoing Phase Ib study, evaluate cardiodynamic effects in healthy elderly participants. Those data, as reported today, were favorable and allowed us to move forward with the 20-milligram BID dose as a part of Part B. So we are pleased with what we've seen with the tolerability and safety profile with the agent thus far. With respect to what we hope to see with the Phase Ib data, I think as part of the overall discussion we have with Dr. Porsteinsson today, I think clinically, folks want to take a look at the overall evidence package. So there's not one specific outcome measure on the rating scale assessments that we would look at in isolation. For example, CMAI total score is an important factor. But the 3 subfactors will be quite important as will be the NPI and CGIS. So we're looking forward to taking a look at the overall data package is reflecting a fair amount of information that's clinically relevant as a part of the overall Phase Ib program that will help us to understand and identify what the next steps are as we think about the development of the agent.

And Graig, in terms of your question on would we consider Huntington's disease as the potential future indication, we're focused right now on the Alzheimer's disease agitation space. But as you noted, a publication from AzVAN did highlight some compelling and supportive evidence in HD irritability. That could be a potential indication that we would expand into downstream as well.

Great. And if I could just ask our KOL, Dr. Porsteinsson, a question. If you could comment on his experience treating Alzheimer's patients with Rexulti in terms of his experience with regards to its efficacy, safety and perhaps more interestingly, any kind of reimbursement challenges he's faced with trying to use Rexulti for Alzheimer's patients with agitation?

Yes. Let me just address that quickly. So obviously, Rexulti is an atypical antipsychotic we can probably call it a third-generation atypical antipsychotic. So it has some of the basically category burden associated with that. So the boxed warning for use in patients with Alzheimer's disease and psychosis. From a use perspective, maybe one of the challenge is that this drug was first approved for use in conditions where there are already 30, 40, 50 drugs available. So the coverage for this medication was not very generous, which was unfortunate because it is the first medication that is approved for agitation and aggression, but it carries over the tight coverage from insurance companies. So one of the main challenges has been basically the high cost and co-pay and the hoops that you need to go through with that. And also patients kind of therefore asking to have something, kind of something similar that maybe is a little bit cheaper. So that has been in the clinic a challenge. For what's been my experience with it, in patients that have more kind of psychosis overtones or more aggressiveness, particularly physical aggressiveness. That's the spot that it has shown particular efficacy maybe in both the clinical trials and the clinical practice, which kind of, again, leaves a lot of "agitation and aggression" unmanaged.

And the next question will come from Brian Abrahams with RBC Capital Markets.

Congrats on all the progress and on the initial NLRP3 data. Two questions from me. I guess, first, both on 215. How are you thinking about the therapeutic index and your level of confidence there for the target dose of 215? I guess it seems like based on the exposure curves and the oral DIO experiment, the target dose might be substantially higher than the mid- and low doses that you looked at. So I was wondering if you could comment on that, and then the dosing that you're planning to explore in the Phase I to maintain IC90 for the full 24 hours, whether you predict you'll need BID dosing? Would you look at TID or even maybe QD dosing? And then secondarily, just also wondering if you could comment on what you guys are going to be looking for out of the 12-week DIO maintenance study as well as the 28-day cytokine data in order to guide and shape the future opportunities that you might be exploring for the drug?

Brian, this is Josh here. Maybe I'll hit your last question first, then I'll turn it over to Nick to hit the therapeutic index and dose exploration in Phase I to hit IC90. But in terms of what we're going to be looking for out of the 12-week DIO study, really, this study is to assess a maintenance paradigm. And so as we can think about it, 1 paradigm would be to look at if we dose NMRA-215 and semaglutide in combination to see the same combination weight loss we had, and then we take semaglutide away, can 215 maintain that weight loss? I think as we've seen from recent publications from other NLRP3 sponsors that is a paradigm that I do think NLRP3 inhibitors that are able to achieve IC90 in the brain can hit. We'll also look at another paradigm, which is ultimately, if you are -- if a mouse is taking semaglutide and reaches target weight loss, could we switch them to NMRA-215 ultimately to maintain that weight loss. And really, the rationale behind this is, as we know the biggest challenge right now with the GLP-1 therapies are the GI AEs. And as we commented on at the beginning of the presentation, about 68% of patients based on real-world evidence do not stay on GLP therapies post 1 year and about 58% don't reach the target weight loss. And it's really from the GI side effects. So the paradigms we're looking to test in the maintenance is, could you drive induction with a GLP-1 or in combination with an NLRP3 and then switch to an NLRP3 alone, which will allow long-term continuation of the weight loss without the continuation of the GI side effect. So that's really what we're looking out for in that study. And then in terms of the 28-day cytokine panel that will be available at the end of the month, I think we'll be looking for updates consistent with what we've seen from other sponsors. But maybe I'll let Nick quickly comment just around IL-1 beta and what we've seen from that and other studies.

Yes, Josh. So in terms of work we've done prior to DIO study, we always look at IL-beta and IL-18 is critical downstream endpoints. And in all those prime models, we see very, very fast reversal of elevation in both of those site declines. We'll have the DIO 28-day data panel very in the near term. So we're looking forward to getting that data.

And then, Brian, I think your other 2 questions were around the therapeutic index that we're running in the DIO models. And then ultimately, I think the real question here is, how are we thinking about dose exploration to maintain IC90 in the clinic?

Yes. Brian. So yes, looking at the data we have on Slide 16, really for us, that target dose is the critical one. I think in all of our work now and as I mentioned, other sponsors, you have to be at IC90 over the whole 24 hours. And because of how 215 behaves in rodents, we had to do the BID dosing. The other 2 doses, I don't think there's anything untoward about them there. There were 2 doses as we just really tried to understand, as I mentioned, what we needed to achieve with 215 to get really strong weight loss data. And I think with the target that we really think we're looking now that we're maximizing that potential of this mechanism. As we look to our clinical dosing, obviously, NRMA-215 behaves very different in all of our human system studies we've done. And so we've booked on a lot of work as we try and look at our projected human doses. And because of how 215 will behave in man, we're confident that we will have a once-a-day drug, which will achieve IC90 in the brain over 24 hours. In terms of therapeutic index, we feel we're in a very good spot as of now, whether it's looking at a safety of this mechanism in the hands of other sponsors, but also the data we have in our non-GLP and GLP studies today, we feel our human projected dose, we have really great margins to where we see anything in the preclinical model. So yes, I feel really good where we are right now.

And the next question is going to come from Paul Matteis with Stifel.

This is Matthew on for Paul. Congrats on all the progress. So my question is on the 215 mouse data. Could you help us understand the rationale for using oral formulation in 1 study and subcutaneous for 2 study? And does the target dose use the same for both oral and subcutaneous, or was it adjusted for bioavailability? And then how much should we read into the differences in the weight loss between the oral and subcutaneous? Were there any differences in the protocol there?

So Matt, this is Josh. I'll hit those really quick. So we wanted to look at oral and subcu, just look, frankly, at 2 different dosage forms to see if we could get similar results, which we absolutely did. And in terms of comparing the results, we did a PK study to look at the target dose subcu and make sure that it matched the target dose that we were using orally. And so ultimately, we feel like the oral subcu and the -- or the oral target and the subcu target are delivering the same IC90 coverage over the full 24-hour period.

And our next question comes from Ami Fadia with Needham.

Congrats on all the updates, particularly on NRMA-215. Maybe if I can just start with a quick follow-up on NRMA-215. As you enter the clinic, would you be studying multiple QD doses? Or do you believe that you have done the work to really identify the 1 dose that can help achieve IC90? And then with regards to NMRA-511, can you talk about sort of what you believe is going to be in the regulatory requirement in terms of the endpoints that the FDA would like to see ultimately for registration? And from a mechanism perspective, do you expect to see variability in the -- sort of in the magnitude of effect across patients based on the severity levels? And maybe if you could talk to how you're thinking about kind of the mix of mild, moderate and severe patients in the Phase I?

Ami, this is Josh. I'll answer the 215 question, then I'll turn it over to Bill for the 511 component. So in terms of what we're planning to do in the clinic, what we do put NMRA-215 into the clinic, we will conduct a standard SAD/MAD study, where we'll look at dose escalation. So obviously, in first-in-human studies, the primary purpose is to establish safety and tolerability. Our plan, though, does involve us looking to dose escalate up to levels where we do achieve IC90 concentrations in the brain. And then once we have that confirmed, looking to running longer term, potentially MAD studies up to 12 weeks, that will really help us generate the human proof-of-concept in both the monotherapy and the combination setting. And so that's what we're planning to do. As Nick mentioned previously, we've got a high degree of confidence that we'll be able to dose once-daily, achieving IC90 concentrations in the brain in humans. So Bill, I'll turn it over to you now to address the 511 questions on regulatory requirements for registration and how we think about variability of results just based on baseline patient severity.

Sure. Thanks, Ami, for the question. So when we think about the 1 agent that is currently FDA approved, it was based on the CMAI total score, but we do know from the FDA correspondence that they do want to take a look at the factors within the CMAI. So we'll be taking a look at those factors as well as the NPI, CGI severity, but we do know the primary efficacy endpoint for regulatory approval is CMAI total score, but much of this, given the unmet need and limited treatment options that are available, will really result in us wanting to look at the overall evidence package as we think about the next phase of development and our overall regulatory strategy.

Got it. That's helpful. If I have time for 1 more question, just with regards to the 2 M4s. Can you sort of talk about where you see the differences translate between the two? Obviously, the Slide 38, lays out the differences across multiple metrics between 861 and 898. But I guess what's the hypothesis for picking these 2 to move forward to this stage? And what do you hope to sort of test out by evaluating both of them?

Ami. it's Nick here. So I think on that slide, you talk to, if you look at the information we've put out on the 2 compounds. When you look at basic properties, they both share a set of features, which we optimized around. So we really like the profile of both whether it's potency and selectivity, but also the CNS penetration attributes to both compounds critically for us as we were bringing forward these 2 new compounds, it was to have 2 structurally distinct molecules. And these molecules are very, very different. So that was our key feature. As we move forward, as we get data in our SAD/MAD studies, there may be data which makes us select one or try to bring both of them forward into further development. As of right now, we were really focused on a set of KOR properties, which we thought would distinguish these from our competitors. So we're really pleased with the profiles of both.

Can I just comment on one thing. This is Anton Porsteinsson because Ami mentioned the magnitude of effect based on severity as part of her question as well. So I basically want to kind of highlight that you need to have a certain degree of severity so that you can see a treatment response. And I think that for the Phase Ib study, we have to understand that there -- it's a sizable Phase Ib study, but it's not the power that we expect to be able remotely to look at subgroups. But I would like to have people with moderate and maybe close to severe level of behavioral disruptions. And if the mean score on the CMAI at baseline is somewhere in the high 60s to high 70s, that will be very informative because it also allows us to kind of compare a little bit what we might see in someone that is kind of on the lower intensity of behavior versus higher intensity of behavior. And I know that the inclusion criteria allowed for that in the Phase Ib study.

This does conclude today's question-and-answer session. I would now like to turn the call back to Paul Berns for closing remarks.

Well, thank you, operator, and thank you to all participants this morning for your time and participation today. And a big thank you to the entire Neumora team for their relentless commitment to make novel new therapies, which have the potential to extend and enhance human life. So with that, I wish everyone a good day.

This concludes today's conference call. Thank you for participating. You now disconnect.