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. With me on the call today are several members of Neumora's management team, including Chief Executive Officer, Henry Gosebruch, Chief Financial Officer, Josh Pinto, Chief Strategy Officer, Bill Aurora, and Head of R&D, Rob Lenz, who will review the data generated with navacaprant to date, as well as share additional detail about the ongoing phase III COASTAL Program. We are also thrilled to be joined for a fireside chat today by Dr. Sanjay Mathew, John Krystal, and Roger McIntyre, who are among the world's leading experts on the treatment of neuropsychiatric conditions. Please feel free to enter Q&A into the chat box on your screen throughout the event. We will answer questions received at the end of the presentation. With that, I'll now turn the call over to Josh Pinto to provide opening remarks. Thanks, Helen. Good morning, everyone, and thank you for joining us for what I'm certain will be an engaging and dynamic discussion. Brain diseases collectively represent one of the greatest medical challenges of our generation, affecting upwards of one point five billion people globally. They are a leading cause of disability, with a significant impact on quality of life, not only for patients, but for their caregivers, families, and society at large. We all know someone affected by brain disease, and at Neumora, our goal is to bring the next wave of medicines forward to alleviate this substantial unmet need. To achieve this goal, we have developed a robust portfolio of seven clinical and preclinical programs, all targeting novel mechanisms of action in their respective indications. Importantly, we believe that each of our programs has the potential to reshape the treatment of its target indication, making a significant difference for the patients we aim to serve. I'm particularly pleased to be here today to discuss our lead program, navacaprant, which we are investigating for the treatment of major depressive disorder, or MDD, and other neuropsychiatric disorders. MDD is the leading cause of disability worldwide, affecting more than 280 million people. Yet, it has been more than 30 years since a drug with a novel mechanism of action has been approved to treat it. As a result, people living with MDD often experience inadequate treatment response or significant tolerability challenges, leading them to discontinue standard of care treatment. In fact, up to 85% of patients either don't receive pharmacological treatment or fail to achieve remission with first-line therapy. More than 70% of people with MDD experience anhedonia, or the lack of ability to experience pleasure from daily activities, which is not adequately treated by existing agents. We believe navacaprant has the potential to reshape the treatment of MDD. Navacaprant is a highly selective, novel, once-daily kappa-opioid receptor antagonist that we are developing as a potential monotherapy treatment. In our phase II study, navacaprant demonstrated a favorable safety and tolerability profile with no weight gain, sexual dysfunction, or other adverse events commonly associated with standard of care. It is designed to be easy to use as an oral, once-daily, 80 mg dose without titration required, and it has shown improvements on depressive symptoms, including anhedonia, that may benefit people with MDD as well as other neuropsychiatric conditions. We believe that navacaprant has the potential to make a difference in the treatment of MDD and beyond, and look forward to reporting the first pivotal data from COASTAL-1 in the fourth quarter of this year. As we think about the potential impact of navacaprant on the MDD treatment landscape, we are fortunate to be joined this morning by Doctors Sanjay Mathew, John Krystal, and Roger McIntyre, who will share their perspectives on the unmet needs in the treatment of MDD and the potential role of kappa-opioid receptor antagonists. Dr. Sanjay Mathew is the Marjorie Bintliff Johnson and Raleigh White Johnson, Jr. Vice Chair for Research and a professor in the Menninger Department of Psychiatry and Behavioral Sciences at Baylor College of Medicine. His research focuses on experimental therapeutics and pathophysiology related to treatment-resistant mood and anxiety disorders and PTSD, with a particular focus on rapid-acting and novel pharmacotherapies. Dr. Mathew graduated from Dartmouth College and Baylor College of Medicine. He then trained in psychiatry and mood and anxiety disorder research at Columbia University and the New York State Psychiatric Institute. Prior to his current position at Baylor College of Medicine, he served as a faculty member at the Icahn School of Medicine at Mount Sinai in New York, where he co-directed the Mood and Anxiety Disorders Program. Dr. Mathew has co-authored or authored over 180 manuscripts and book chapters, serving on the editorial board of several journals. He currently serves on the board of the American Society of Clinical Psychopharmacology and the Anxiety and Depression Association of America, where he serves as the president-elect. He is also an elected fellow of the American College of Neuropsychopharmacology.... John Krystal, MD, is a leading expert in the areas of post-traumatic stress disorder, schizophrenia, and depression. He is the Robert L. McNeil Jr. Professor of Translational Research and Chair of Psychiatry at Yale University, Chief of Psychiatry at Yale New Haven Hospital, and Director of the Clinical Neuroscience Division of the National Center for PTSD, Department of Veterans Affairs. He is best known for leading the discovery of the rapid antidepressant effects of ketamine in depressed patients. He is a member of the U.S. National Academy of Medicine. Additionally, Dr. Krystal is co-chair of the Forum on Neuroscience and Nervous System Disorders, NeuroForum, of the National Academies of Sciences, Engineering, and Medicine, and the editor of the journal Biological Psychiatry. Dr. Roger McIntyre is a professor of psychiatry and pharmacology at the University of Toronto and chairman of the board, Depression and Bipolar Support Alliance, DBSA, in Chicago, Illinois. Dr. McIntyre is among the world's leading experts on anhedonia, having published more than a thousand scientific papers, including over fifty scientific papers on anhedonia. He is also a leading expert on bipolar depression and has been involved in research evaluating novel approaches for treating it. Dr. McIntyre is extensively involved in medical education. He is a highly sought-after speaker at both national and international meetings. He has received several teaching awards from the University of Toronto, Department of Psychiatry, and has been a recipient of the Joint Canadian Psychiatric Association Council of Psychiatric Continuing Education Award for the Most Outstanding Continuing Education Activity in Psychiatry in Canada. Additionally, Dr. McIntyre is the co-chair of the Canadian Network for Mood and Anxiety Treatments, CANMAT Task Force on the treatment of comorbidity in adults with major depressive disorder or bipolar disorder, and as well, a contributor to the CANMAT Guidelines for the treatment of depressive disorders and bipolar disorders. Dr. McIntyre has published hundreds of peer-reviewed articles and has edited and/or co-edited several textbooks on mood disorders. With that, I'll now turn the program over to Bill for a review of navacaprant data to date. Bill? Thank you, Josh, and good morning, everyone. Kappa-opioid receptors, or KORs, along with their endogenous ligand dynorphin, are a well-characterized pathway that preclinical data suggests have the potential to modulate depression, anhedonia, and anxiety. The figure on the right depicts the downstream effects of KOR activation on multiple neurotransmitters, including dopamine. This activation has been shown to trigger dysphoria and symptoms of anxiety and depression. Conversely, KOR antagonism is believed to restore the regulation of these neurotransmitters, which play an important role in regulating mood, cognition, and reward processing pathways. Now, let's shift to the clinical data. Multiple independent sponsors have generated clinical evidence supporting the role of kappa-opioid receptors in mood disorders. First, the NIMH FAST-MAS study, which was designed as a proof of mechanism study to validate KORs as a target for drug development. This study enrolled a transdiagnostic population comprised of patients with a variety of neuropsychiatric disorders and used aticaprant to better understand the impact of KOR antagonism. There were two important findings that emerged from this study. First, administration of a KOR antagonist or a KORA resulted in activation in the ventral striatum, a region of the brain that's associated with reward processing, reinforcing the biological role that KORs play. Second, the study demonstrated that KOR antagonism improved symptoms of anhedonia in a neuropsychiatric population with multiple diagnoses. Additional clinical studies conducted by Neumora and J&J reinforced these findings in participants with MDD, demonstrating that KOR antagonism can improve core depressive symptoms, including anhedonia. Although this target has been of high interest in neuropsychiatric for some time, it has historically been difficult to develop selective KORA molecules. Currently, there are several KORAs in clinical development, and these represent a significant step forward in terms of drugging this target. Importantly, we believe navacaprant has best-in-class pharmacology with three hundred-fold selectivity for kappa-opioid receptors over mu-opioid receptors in preclinical studies, which is significantly higher than other programs in clinical development targeting this mechanism, such as aticaprant and CVL-354, now known as icalcaprant, which are both 30-fold selective for KOR over the mu-opioid receptor. The high selectivity of navacaprant may provide a competitive advantage compared to other KOR programs by enabling the dose to be higher, achieving a 90% receptor occupancy without experiencing mu-mediated adverse events. The navacaprant phase II study was the first to prospectively demonstrate efficacy in treating depressed mood and anhedonia. Robust results from phase II reinforced the potential of navacaprant to treat symptoms of depression, including anhedonia. Starting with the graph on the left side of the slide, you'll note that on the HAM-D17, we saw significant reductions in symptoms of depression at week four and week eight in the moderate to severe MDD population. On the right of the slide, results on the SHAPS, which is the scale used to evaluate impact on anhedonia. We note that navacaprant demonstrated statistically significant reductions in anhedonia at week eight. This is an important finding because current antidepressants do not adequately treat anhedonia, a core symptom that occurs in up to 70% of individuals with MDD. Anhedonia has been associated with greater severity of depressive symptoms, a poor prognosis, as well as higher rates of suicidality. In addition, navacaprant demonstrated on a broad range of measures in the moderate to severe MDD population, efficacy, including response rates and remission. In particular, I'll call out HAM-D6, which measures the core symptoms of depression, where we saw robust results in our phase II study. This measure is known to correlate with the MADRS, which is the scale that we're using to measure the primary endpoint in our phase III program. We're incredibly pleased with the high level of consistency across the range of these outcome measures in our phase II study, further bolstering our confidence in the potential benefits of navacaprant. In addition to efficacy, the tolerability and safety profile are important factors. Navacaprant was well tolerated in our phase II study with a favorable safety profile compared to placebo. In fact, overall discontinuation rates were higher on placebo compared to navacaprant. Treatment-emergent adverse events reported in subjects on navacaprant were mild to moderate in severity and infrequently resulted in discontinuation from study drug. Navacaprant was not associated with common side effects of current antidepressants, such as weight gain or sexual dysfunction, which are often the cause for treatment discontinuation with current agents. We know that these patients are typically in their 20s, their 30s, their 40s, for whom tolerability profile of antidepressant therapy matters greatly. And we believe that the safety profile of navacaprant would be an attractive alternative relative to the existing agents that are approved. Given the compelling profile seen in phase II, we're pleased to be advancing the registrational phase III COASTAL Program, evaluating navacaprant for the treatment of MDD in a phase II study with navacaprant in bipolar depression. I'll now turn the program over to Rob to review the ongoing studies. Rob, over to you. Thanks, Bill. So the COASTAL Program includes three replicate phase III randomized, double-blind, placebo-controlled studies, the so-called COASTAL-1, COASTAL-2, and COASTAL-3. And they're designed to evaluate the efficacy and safety of navacaprant monotherapy in adult patients with moderate to severe MDD. Now, we're also advancing an open-label extension study, so-called COASTAL-LT, which is designed to evaluate the long-term safety of navacaprant. And we believe that by running three replicate studies in the COASTAL Program, we're maximizing the likelihood of two of the studies being positive, providing an increased probability of success across the program. And we look forward to top-line data readout from COASTAL-1 in the fourth quarter of this year and data from COASTAL-2 and COASTAL-3 next year. And if successful, these studies are expected to support a new drug application with the FDA for navacaprant as monotherapy in 2025. Now, we're also exploring the potential of navacaprant as a treatment for bipolar disorder and are pleased to be advancing a phase II signal-seeking study that we expect to read out from the second half of 2025. Now, additionally, there are a number of other neuropsychiatric diseases listed at the bottom of the slide, where we believe that navacaprant may offer potential benefits, and we look forward to providing more detail on the development of navacaprant in these additional indications in the future. Diving into the phase III design, we're evaluating navacaprant in patients who have a Montgomery-Åsberg Depression Rating Scale, or MADRS, total score of 25 or higher at baseline. The primary endpoint of these studies is the change from baseline in MADRS total score at week six, and the key secondary endpoint is the change from baseline to week six on the Snaith-Hamilton Pleasure Scale, or the SHAPS, which is a measure of anhedonia. We believe this design is consistent with FDA guidance on MDD pivotal studies and would enable us to achieve a broad label for the treatment of depression if the studies are successful. This study design really allows us to fully elucidate the most important benefits of navacaprant, including efficacy on treating core symptoms of depression as measured by statistical significance on the MADRS, the safety and tolerability profile of navacaprant, and potential benefits on anhedonia symptoms as measured by SHAPS. Now, importantly, we've designed each of the COASTAL studies with robust powering to achieve statistical significance and clinically meaningful improvements on depressive symptoms. So to support the clinical COASTAL studies, we're deploying really a state-of-the-art approach to maximize the probability of success that incorporates significant enhancements to both the study design and conduct relative to the phase II study. So starting with the study design, we're evaluating a population with moderate to severe MDD with an endpoint at week six, both features that are aligned with FDA guidance and industry best practice to help minimize placebo responses. Now, additionally, we're using the MADRS as the primary endpoint of the study, which is a scale that we believe is best suited to fully capture the benefit of navacaprant's pharmacology. Turning to execution, we're taking numerous measures to ensure high-quality patients and high-quality sites are participating in the trial, including but not limited to selecting trial sites with extensive experience running MDD studies, which we believe will help ensure that the appropriate patients are enrolled in our studies. We're utilizing central raters who help to ensure that the patients who are randomized into the COASTAL studies meet the entry criteria, as well as to help ensure consistency of rating across the sites. We're also using video apps to verify that patients are compliant with taking their study medications, and we're providing training to sites on reducing staff interactions with patients that could potentially lead to placebo responses, and we're deploying a reminder script that sites use with the patients to help reduce expectation bias. The literature demonstrates that these approaches can help contribute to a reduced placebo effects in clinical trials. Now, additionally, we're leveraging our in-house data science team to develop capabilities and applications that allow near real-time operational data oversight for the COASTAL studies. We know that in MDD studies, high-quality study execution is vital to achieve success, and we're definitely pleased to be taking an innovative approach to track, project, and explore blinded data from the COASTAL Program using a suite of applications developed by our data science team. Now, these proprietary applications allow us to explore blinded data to support quality control of the COASTAL studies by allowing us to have near real-time access to key data in the studies and, if needed, to take action in near real time. So for example, if when looking at blinded results for an individual patient in the trial, we see discordant results on two scales that we would expect to normally move in the same direction, we could intervene with actions like retraining a rater at a site before errors are repeatedly more broadly. So overall, we believe that with the design, the placebo mitigation, and the oversight measures we're deploying, we've really optimized the COASTAL studies to support the highest possible probability of success. Now, we're also advancing a phase II study with navacaprant in bipolar depression. And in addition to being a cardinal feature in MDD, anhedonia is also highly prevalent and clinically relevant in bipolar depression, and there's a growing body of research that the pathophysiologic underpinnings of anhedonia in bipolar depression. Now, given that navacaprant demonstrated meaningful improvements in anhedonia symptoms in patients with moderate to severe MDD, we believe it may also be effective in treating anhedonia related to bipolar depression. So the ongoing study will evaluate navacaprant 80 mg monotherapy in approximately 60 people with bipolar II disorder, experiencing a moderate to severe major depressive episode, as defined by a MADRS score of 25 or greater at baseline. The primary endpoint of the study is the change in MADRS from baseline to week 6, and the key secondary endpoints will evaluate the impact of navacaprant on anhedonia, as well as other measures as listed in the slide. Now, the phase II study is powered to provide an estimate of the treatment effect rather than statistical significance, and so it's designed to inform further development of navacaprant in bipolar depression, potentially including development in broader bipolar disorder populations. We expect to report top-line data from the phase II study in the second half of 2025. With that overview, I'll turn the program back to Helen for a KOL Fireside Chat. Thanks, Rob. We're pleased to be joined by Dr. Sanjay Mathew and Dr. John Krystal for today's discussion. Unfortunately, Dr. Roger McIntyre had connectivity issues. Before we begin, I'd like to start with introductions. Maybe I'll ask each of our speakers to introduce themselves. Dr. Mathew? Yes. Hi, I'm Sanjay Mathew. I'm a psychiatrist and serve as Vice Chair for Research at Baylor College of Medicine, where I direct a program in mood and anxiety disorders, where we conduct research in depression, clinical trials, and the neurobiology of these conditions. Dr. Krystal? Yes. Hi, everyone. My name is John Krystal. I'm a professor and chair of psychiatry at Yale, and I've been studying the neurobiology and treatment of psychiatric disorders my entire career. Thank you. We're really pleased to be joined by you both for today's discussion. Let's start with MDD. Dr. Krystal, could you please describe how a typical patient presents with MDD? Sure. As you heard, MDD is very common. As many as one in five people will meet criteria for MDD in the context of MDD or another disorder at some time in their lives. I'm afraid, though, that there is no typical patient. It's an extremely heterogeneous condition with well over two hundred symptom profiles that meet DSM-5 MDD criteria. So in thinking about MDD and MDD patients, it's helpful to think about domains of MDD symptoms. Obviously, an important domain is mood, and people may experience a variety of negative mood states, sadness, anxiousness, guilty, shame, and their mood can either be very flat and unreactive or very reactive, hyperreactive. With regards to vegetative symptoms, you also see this range of kinds of symptoms. People may have decreased energy or increased energy. They might be agitated or restless. They may have reduced appetite, and have weight loss, but sometimes there can be increased appetite and weight gain. Very common and important symptoms, particularly for the discussion today, is the loss of pleasure or anhedonia along with hopelessness. Sleep is frequently impaired, and there can be loss of interest in daily activities, but intensive preoccupations with guilty themes, with ruminating guilty ruminations and other repetitive thoughts. Increasingly, we're aware of cognitive impairments in the domains of attention and learning and memory. Some patients will experience psychosis. We're, of course, aware of suicide risk for self-harm that can be associated with major depression. Depression is often associated with contextual factors such as stress, bereavement, chronic pain, substance use, and history of psychological trauma. These sources of heterogeneity complicate the individual assessment, particularly since with most patients with depression may be treated by primary care practitioners rather than psychiatrists or other mental health practitioners. Thanks, Dr. Krystal. I think that one of the symptom domains you mentioned that's a little bit less familiar to folks is anhedonia. So maybe Dr. Mathew, could you just walk us through how many of your patients experience anhedonia and how they describe its impact on their life? Yeah. So anhedonia is a very common symptom of major depressive disorder, and in fact, is one of the two cardinal symptoms in the DSM diagnosis. So anhedonia, meaning an inability to experience pleasure or reward, or the loss of motivation, is really common, 70%-80% in many sort of epidemiological and clinical surveys. And the challenge associated with anhedonia is that these patients simply do not do as well clinically. They are associated with partial or non-response to standard treatments, such as SSRIs or SNRIs or bupropion. And anhedonia can be a poor prognostic sign and be associated even with mortality by suicide, as well as morbidity and loss of social function. So it is a driver for the negative quality of life and limited psychosocial function in the illness. That's why it remains an important target for novel therapeutics. That makes sense. And what is the current treatment paradigm for people who are experiencing MDD? The standard of practice and all of the treatment guidelines suggest antidepressant monotherapy as the initial choice, and those are conventionally the generic SSRIs or SNRIs as the first-line treatment. Should a patient not respond fully, at that time, there are multiple options, including switching to another monotherapy or augmenting with any number of approved augmentation options, as well as off-label options. Then after that, you could switch to yet another monotherapy or include combination approaches or any number of neurostimulation approaches as you get further down the treatment algorithm. But the unfortunate truth is, as you get further down the treatment algorithm, the proportion of patients who respond and remit go down proportionally. There are high levels of treatment resistance in depression. Do the drugs that are currently available treat anhedonia, or does that remain an unmet need? Unfortunately, the SSRIs, while they're often very effective for patients in some of the, the sadness and anxiety features of depression, what's often left over after a treatment or even a partially successful treatment are these motivational symptoms, the pleasure-seeking symptoms, the anhedonic-type symptoms. So, so this remains a symptom dimension of high unmet need. So what we often see in the clinic are patients who say, "You know, I'm no longer sad. I'm not crying all the time. I'm much less anxious, but I simply don't care," and they've withdrawn from socializing with friends, meeting family members, doing the things they normally like to do. So, that remains a clinical conundrum. One of the things that I think is interesting that you mentioned is that many of the drugs that are available for MDD today work with the same mechanism of action. And so I'm wondering if you could each walk us through your thoughts on some of the challenges with the currently available therapies and what you'd like to see from a new medication. Dr. Krystal, I'll ask you to comment first. Sure. You know, current medications are helpful for many patients, and they have saved many lives. However, unfortunately, even when optimized or used in combination with other standard medications, they can be inadequately effective for too many patients, probably well over half of patients. While some patients have an inadequate overall response, others will experience inadequate response in the particular symptom domains such as anhedonia, anxiety, or insomnia. Thus, despite all the progress that's been made in treating depression, there's still a need for antidepressants that work through novel mechanisms, particularly those that are effective for some of the symptom domains that are common, commonly ineffectively treated by SSRIs. ...Dr. Mathew, do you have anything to add? Yes. Well, I think one of the issues that the clinicians and the patients grapple with are the longer-term side effects associated with the standard of care antidepressants. When we educate patients about the treatment of depression, we tell them upfront that this is not a six-week treatment, but this is perhaps nine months or longer, and in some cases, it can be many, many months. And with chronic treatment for the standard medications, you do see problematic side effects, including gastrointestinal, you see sexual side effects and problematic weight gain, which for some patients is simply a non-starter. We know with augmentation strategies, such as the atypical antipsychotics, we do see a host of metabolic side effects, including propensity for diabetes or hyperlipidemia and some neurologic side effects. And so the long-term safety tolerability is a concern, and it's a reason for non-adherence. We know patients with depression also are on a host of other medications, and for every additional medication a patient's on, the adherence tends to go down. So ultimately, what we're seeking are well-tolerated, effective medications that patients can comfortably use in the long term. I think based on both of your comments, it's really clear that there's a need for novel mechanisms in depression. And so maybe turning to kappa-opioid receptor antagonism, which we're here to discuss today. The NIMH FAST-MAS study was the first study to confirm the role of kappa-opioid receptors in reward processing pathways. And Dr. Mathew, I know that you were part of the team that conducted that study. So starting us off, what made you and the other investigators interested in studying this target? Yes, so the NIMH group of FAST-MAS investigators, the idea was to identify new targets as the field, in many ways, became stuck on the serotonin, norepinephrine, dopamine hypotheses of depression, and there had been a lack of investment in CNS disorders, specifically psychiatric disorders, because of the feeling that the field was stuck, and so when it became clear that the kappa-opioid receptor system offered a potential attractive target to address not only depression but some of the important features of depression, including anhedonia and anxiety, the investigators got together and identified a target, a molecular target, the kappa-opioid receptor, and then an antagonist of that target, and tested it in an fMRI paradigm that looked at the drug's impact on fMRI ventral striatal activation in response to a specific task in the MRI. It turned out that the drug, which was aticaprant, increased ventral striatal activation in anticipation of rewards in this specific task, while also improving symptoms in a transdiagnostic sample, the symptoms of anhedonia, associated with depression or anxiety. This was really a proof of mechanism that this is something worthy of further study, which is, in fact, since that paper was published, has taken place both with the aticaprant program and with the navacaprant program, which we're discussing today. Absolutely. Dr. Krystal, for the folks who may be less familiar with kappa-opioid receptor antagonism, could you walk us through the rationale for using this in MDD? Sure. Kappa-opioid receptors, or KORs, are present throughout the cortex and limbic system. They are completely distinct from mu-opioid receptors, the receptors targeted by morphine. The primary natural ligand for kappa-opioid receptors is dynorphin, which is a downstream product of the prodynorphin gene. In major depression, human imaging studies have suggested that the kappa-opioid receptor may show altered regulation. Similarly, the prodynorphin gene shows altered levels of expression in several brain regions in postmortem brain tissue from depressed patients. So what does this mean for patients? In animals, as you heard, alterations in kappa-opioid receptors and dynorphin can be associated with impaired reward processing and anhedonia, symptoms that are seen in depressed patients. These behaviors can be attenuated in animals with the KORs. In the FAST-MAS study, which you just heard about, it was conducted in patients with anhedonia, but not necessarily depression. A KOR reduced anhedonia and showed signs of enhancing engagement of reward circuits on fMRI. Thus, the positive phase II results with navacaprant and aticaprant in MDD makes sense. They suggest that disturbances in reward circuits can be corrected with KORs in MDD, and this is really exciting and important for the possibility of a new MDD treatment. What is it about this wave of current KORs in development that has you so excited? I think basically it's the right time, and we have the right drugs. As you heard, kappa-opioid receptors are a very hot area of research, driven by advances in neuroimaging, clinical trials, animal research. With respect to the drugs, historically, there's been significant in kappa-opioid receptors as a target. But the drugs that were brought forward had challenging pharmacological profiles, including low selectivity for kappa-opioid receptors over mu-opioid receptors, the target for morphine. In contrast, the current wave of KORAs in development are more selective for kappa-opioid receptors. As you heard, navacaprant has potential best-in-class pharmacology with over 300 -fold selectivity for kappa-opioid receptors over mu-opioid receptors. The high selectivity of navacaprant may provide competitive advantage compared to other kappa-opioid receptor programs by enabling the use of higher doses, achieving 90% receptor occupancy without experiencing side effects that might be related to actions at the mu-opioid receptor. Aticaprant and CVL-354 have each demonstrated approximately 30-fold selectivity for kappa-opioid receptors over mu-opioid receptors. Thanks, Dr. Krystal. We've been discussing the two KORAs that are currently in pivotal studies, navacaprant and aticaprant. And one of the key differences between the two programs is that navacaprant is being studied in the monotherapy setting, whereas aticaprant is being studied in the adjunctive setting. Dr. Mathew, could you talk a little bit about how you think about the use of monotherapy versus adjunctive therapy? Yes. So the majority of patients we treat, certainly first, second line, are administered monotherapy approaches. And the reason for that is the decreased complexity, the increased adherence that's more likely with the monotherapy approach, as opposed to combination or multiple drug strategy approaches. So when all else is equal, we do prefer a monotherapy approach. When a drug ultimately is approved as monotherapy, it does give you an inherent flexibility as a clinician to use it as a monotherapy, but also to use it in the context of adjunctive add-on to a background SSRI or SNRI. So it really maximizes the flexibility. When a drug is initially approved as an augmentation strategy, the inverse is not true. We don't necessarily prescribe those drugs as monotherapy because we need to see the data. Is it, in fact, an antidepressant on its own without the background antidepressant? So, I think the bottom line is a monotherapy drug gives you a maximum clinical flexibility. Sure. That makes sense, and I'd imagine that, the decision to use a drug in MDD is really driven by the data that it demonstrated in clinical studies. So perhaps, Dr. Mathew, I know that you presented the phase II data with navacaprant at ACNP last year. Could you walk us through any data points that you found particularly interesting and your key takeaways from the study? Yeah. I mean, I think the key takeaways are that it clearly had a signal for antidepressant efficacy, as well as improvements in anhedonia. So the Hamilton Depression change from baseline and its difference from placebo was statistically significant in the moderate to severe population, which is really the population of interest in depression trials and the population which will be recruited in the COASTAL Programs. The SHAPS change from baseline and change from placebo was a robust difference, highly statistically significant. So suggesting that the mechanism is holding true, that this is an anti-anhedonic drug, that not only works on the broad symptom of depression, but specifically is targeting the anhedonia profile. Also, as a clinician, I'm interested not only in sort of placebo change from baseline differences. I'm interested in response rates, because ultimately, that's going to drive the decisions on what to do next for a clinician. Here, the response rate differences from placebo were quite robust, about 25% for response and 20% for remission, which was quite a strong response remission rate differences. Then the global impression scale, this is the Clinical Global Impression. What does the clinician overall view how the patient is doing? Those were statistically significant effects. I was also, as mentioned earlier in the presentation, the HAM-D6 was statistically significant, and the HAM-D6 taps into the core depressive items, which are considered to be the drivers of dysfunction and morbidity and depression. There are a lot of items on the Hamilton seventeen which may not be core to the anhedonia and the sadness of depression, and so finding that is quite reassuring because the HAM-D6 correlates quite nicely with the MADRS outcomes. I'd also mention that psychosocial function and disability was measured in the phase II study by the Sheehan Disability Scale, which looks into disability in work, relationships, and social domains, and there was a trend for efficacy, which is something we'll be very interested in looking at for the future phase III studies, because ultimately, that is the goal of treatment, to restore social functioning, and I should mention that the safety profile was really promising. There was no signal for toxicity, certainly with liver or cardiovascular, no change in EKG, no weight gain, and no reported sexual side effects. And so all of those safety parameters were very promising and certainly will be followed closely in the next study. Sure. Dr. Mathew, you mentioned the phase III studies, what we're calling the COASTAL Program. Wondering if we can just dig into your thoughts on that program a little bit further, and, and I'd actually love to hear from each of you for this question. You know, what gives you confidence in the probability of success here? And maybe Dr. Mathew, I'll ask you to comment first. Yes. So first off, having three identically designed studies. These are six-week, single, parallel arm with a single dose, eighty milligrams, with a six-week MADRS endpoint. So these are straightforward designs, really best practice designs in terms of the duration of the trial. Six weeks tends to be more favorable than longer trials. The use of the MADRS as the endpoint, we know that the MADRS taps into the core anhedonic features of depression better than the Hamilton Scale, and has good psychometric properties, good sensitivity to change for these type of trials. And then the requirement for stability of symptoms, that this is not a transient depressive profile, but rather patients from the time of screening to their randomization have some stability of their depressive picture, cannot have had more than a 20% improvement in depressive symptoms, which may predict a future placebo response. The monitoring, the real-time monitoring that Dr. Lenz was discussing, I think that is a rigorous approach to data integrity and trial integrity. And then the use of independent raters to validate the diagnosis, to validate the symptom severity at baseline, to make sure the right patients are selected for the study. And also, the careful attention to site selection, choosing sites for these trials who are highly experienced in the population of interest and are highly motivated to produce excellent data and informative data for the trials. Absolutely. That's really helpful. Dr. Krystal, do you have anything to add? I'd just like to make two points. The first is that a lot of thought and effort went into minimizing the number of assessments and staff interactions for patients in order to reduce the high placebo response. And secondly, as you heard earlier, that Neumora is employing a placebo-controlled reminder script. In other words, reminding people that there's a chance they're going to get placebo to reduce their expectation bias. Sure, and as you think about the COASTAL Program, could you describe for us what success looks like for you? What results would you see as compelling? Dr. Mathew, maybe you first, and then Dr. Krystal. Yeah, I think in terms of risk-benefit. So if two out of the three studies are positive, and there's a very good safety profile that confirms what was found in phase II, with no new emerging AEs of interest or any problematic AEs, and efficacy, as suggested by statistical significance on the pre-specified MADRS six-week endpoint, then I would view that as a highly successful program. Now, of course, we're gonna get long-term information from the COASTAL-LT program, so we'd really be looking at what is the longer-term safety profile beyond the six weeks. But certainly for the COASTAL-1 through 3 programs, really looking at the overall risk-benefit, and how does the statistical efficacy on depression, how does that stack against the safety profile? Sure. Dr. Krystal, anything to add? I don't have much to add here. It's really the overall risk-benefit profile that navacaprant demonstrates in these trials that I'll be focusing on, and of course, if there's improvement in anhedonia, that would be really interesting and exciting. Sure. Dr. Mathew, earlier in our discussion, you mentioned the Sheehan Disability Scale as a measure that you are particularly interested in. Are there any other outcomes from the COASTAL Program that you're interested in looking at? Yeah. We know that anxiety is often comorbid with depression, and patients with moderate to severe depression have worry, have other types of sort of cognitive anxiety. Many of them have diagnoses secondarily of GAD or social anxiety disorder. Both of those diagnoses are allowable in this trial, as long as they're not primary to the MDD. So I'm very interested in looking at how the drug performs on the Hamilton Anxiety Scale, which is one of the secondary and exploratory endpoints. And that would be important because in terms of we want all good antidepressants to also be effective in anxiety, because what we want to avoid is prescribing an antidepressant and then prescribing an anxiolytic, if we can have the same effects in one drug. Sure. This has been a really interesting discussion about MDD, and I'm sure that we'll dig further into MDD during the Q&A session shortly. But before we do that, I wanted to spend some time talking about bipolar depression, because we're also running a phase II signal-seeking study in that indication. So maybe to start, Dr. Mathew, could you walk us through the role of anhedonia in bipolar depression and what the current treatment paradigm is in this indication? Yes. So anhedonia remains a core issue in bipolar depression as well. The diagnosis of a major depressive episode in bipolar disorder is exactly the same in the DSM. You meet five of nine criteria. Anhedonia is a common symptom in bipolar depression as it is in a major depressive disorder. Unfortunately, we have many fewer options for treatments in bipolar depression than we have in MDD. So while we have 30+ antidepressants that are approved for the FDA, only a handful of medications have the FDA indication for bipolar depression. And almost all of those options are drugs that have metabolic concerns: weight gain, as we were talking about earlier, the propensity for diabetes, hyperlipidemia, neurologic side effects, and so on. What the field's unmet need in this area are well-tolerated, safe, efficacious medications that are not in the antipsychotic class. Sure, that makes sense. And as you think about, KORAs, do you view that there's a role for investigating KORAs in bipolar depression? Yeah, I mean, based on the data in depression to date for the KORAs broadly, stemming from the FAST-MAS study, and just as a reminder, the FAST-MAS study included patients with bipolar depression. So there is a prior, some data in a relatively small number of subjects supporting the fact that there are anti-anhedonic effects in bipolar depression using a KORA. And importantly, the use of a KORA did not precipitate a hypomania or trigger any kind of manic destabilization of the illness, which is something you're always concerned about in a bipolar depression study. Will the antidepressant destabilize the course of illness? There was no evidence for that in the FAST-MAS study. Sure. That makes a lot of sense, and we're certainly looking forward to the data from that study in the second half of next year. Dr. Krystal, before we open to broader Q&A, perhaps I'll ask you to comment on the other indications where you think there could be potential for KORAs. This is a great time to ask that question, given the exciting new data that came out from the Abi-Dargham group two weeks ago, showing that kappa-opioid receptor levels are highly correlated with anhedonia symptoms in schizophrenia. This supports the long-standing belief that kappa-opioid receptor antagonists would reduce negative symptoms in schizophrenia patients. There are a number of other indications where kappa-opioid receptor antagonists could be useful, given their anti-stress effects, including substance use disorders, anxiety disorders, and PTSD. Thank you. I'd like to take a moment to thank you both for joining us today and sharing your firsthand experience with treating MDD and your perspectives on neuropsychiatric disorders. I certainly found it to be a productive and interesting discussion. We'll now open to Q&A. Dr. Mathew and Dr. Krystal will be available to answer questions, and we'll also be joined by members of Neumora's management team, including Henry Gosebruch, Joshua Pinto, Bill Arora, and Robert Lenz. As a quick reminder, if you'd like to submit a question, please feel free to enter it in the chat box, and we will take questions as they were received. All right, looks like we have a good number of questions in our queue, so the first question, I think, is for you, Dr. Mathew. How much benefit do you anticipate will be gained by switching from HAM-D17 to MADRS in the COASTAL studies? Yeah, no, I think MADRS is absolutely the most appropriate instrument for a drug that has significant impact on anhedonia. So the MADRS is a 10-item instrument. At least two of the items specifically tap into anhedonia or related constructs. You can develop an anhedonia factor subscale of the MADRS. It's a psychometrically more robust scale than the Hamilton Depression 17, which includes really extraneous, almost irrelevant items, such as insight and other items which have not really been relevant for the vast majority of patients. So I think absolutely the MADRS is the right choice, given the drug and the psychometrics of the scale. Wonderful. Thank you. Our next question is, I think, for Dr. Krystal. Thus far, KORA antagonists, particularly navacaprant, have looked quite safe and well-tolerated. What would be particular adverse events that you'd be looking for with this class and any that you would be reassured to not see in the phase III? ... Sure. Well, so far, we haven't seen signals of things that might be concerning, but any drug that reduces anhedonia has the possibility of producing euphoria, and we haven't seen that with these drugs. People aren't hyperactive or overly activated. They don't have disruption of sleep. So far, the safety signals, even though these drugs are enhancing reward circuit function, we haven't seen any concerns related to that effect. Sure. I don't know if I could add something to that. Please do. Yeah. So, I'll be particularly interested in looking at the COWS, which is the Clinical Opioid Withdrawal Scale, to really look at is there any evidence of opioid-related withdrawal? Literally, which would confirm the hypothesis that this is a kappa-specific and non-mu acting agent. I'd also be interested in looking at the pruritus, which was not reported in the phase II study, but has been reported with the aticaprant. Sure. That's a great point, Dr. Mathew, and it makes me think of one thing that I think would be good to remind the listeners of. Josh, perhaps you could walk through the FDA feedback we've received regarding abuse potential studies. Yes, absolutely, and this was disclosed in our 10-K press release in March of this year. We had received feedback from the FDA from a Type D meeting that we don't have to run any future abuse liability and/or physical dependence studies. You know, and this was based on the selective pharmacology for navacaprant. It doesn't have any mu agonist properties, and as has been mentioned through this call, you know, it's highly selective antagonist for kappa opioid receptor, three hundredfold over the mu opioid receptor. And so, we feel like we're in a very good position with the product on that sense right now. Thanks, Josh. Next question, I'll ask both Dr. Mathew and Dr. Krystal to comment on. How important is it for navacaprant to demonstrate a placebo-normalized benefit on MADRS that appears superior to other agents in terms of, effect size, versus having an agent that is active with a benign safety profile and novel mechanism of action? Maybe Dr. Mathew, if you want to go first. Yeah. I think comparative analyses for these type of studies are very difficult to do, because obviously, each study is different. They're designed slightly different, different populations of interest. And so to compare a four-point difference from placebo on COASTAL-1 to something else of a different drug, so it's very difficult to do those type of comparative claims. And so what I'm looking for is statistical significance that's meaningful, and have the good safety profile that was found in the earlier study. Yeah, just to jump here, I would say having statistical significance in phase II is really very exciting, particularly in the context of this really promising safety profile. I think it's probably premature to evaluate the true effect size based on phase II. That's sort of what we look for in phase III. And when you have a heterogeneous patient population, as we do in depression, it can be very difficult to compare sizes across studies. So, you know, you really kind of need head-to-head comparisons to make some of these fine-grained comparison across drugs in terms of effect size. But overall, statistical significance, great clinical profile coming out of phase II is very exciting. Sure. And sticking with the theme of trying to compare drugs across pivotal studies, we did receive a question about aticaprant data and how you would think about any potential read-through from the aticaprant data, if it were to come out before the navacaprant data. So maybe Dr. Mathew, if you want to comment there. Yeah. I see very little read-through, either on the positive or the negative side for the aticaprant study. It's a different design. First of all, it's adjunctive design, which, and the effect sizes for adjunctive studies can sometimes be quite different than monotherapy studies. But fundamentally, it's a different drug. I mean, as discussed earlier, the selectivity for navacaprant is 300 fold, kappa over mu versus 30 fold, for aticaprant. So it's a different design and a different drug. So whether or not it's positive or negative, I think has actually very little read-through to the coastal program. Absolutely. Another question for both Dr. Krystal and Dr. Mathew. Assuming that navacaprant continues to demonstrate the overall favorable benefit-risk profile that we've discussed to date, where in your practice would you envision using this drug? First line, second line, et cetera. Maybe Dr. Krystal, if you want to comment first. Yeah, sure. Yeah, you know, I think practice is something that emerges over time, but what I would say is that it it's for the average depressed patient. I mean, anhedonia is a very common symptom. It would be something that I would look for in patients that I would be considering prescribing navacaprant to. Let me just highlight this about how a new treatment changes practice. I think that too many clinicians and mental health practitioners have ignored anhedonia in their patients. And may have ignored patients and not treated patients who had primary anhedonia if their depression overall wasn't so severe, even if that anhedonia was really compromising their quality of life. What a drug like navacaprant can do is really heighten our focus on anhedonia as a dimension of depression and the unmet need related to inadequately treated anhedonia. And I think once you look, you'll find that a lot of patients are gonna benefit from a drug like this. Absolutely. Dr. Mathew, anything to add? Yeah. No, I agree that it really allows an opportunity to identify patients who have anhedonic depression and are struggling with standard of care. So I see it being used certainly in these SSRI non-responsive patients after the first-line treatment, perhaps as a second-line agent, as a monotherapy option. Sure. I mean, in an ideal world, if payers were on board, there's no reason not to consider it as a first-line agent. Absolutely. A question for Rob, in the context of this discussion: could you remind folks how the COASTAL studies are powered? Sure. So, we've powered all three of the studies at approximately 90% for the primary outcome measure, which is the MADRS change from baseline to week six, so quite robust power across all three of the studies. Thanks, Rob. Okay, Josh, a question for you, or actually, excuse me, Rob, a question for you also on the bipolar signal finding study. Could you just share a little bit more about the patient population that we're focused on? Yeah. So this is gonna be the initial study, which is a signal-seeking study, is gonna be in a population that is experiencing a depressive episode as part of their bipolar diagnosis. We're gonna focus specifically on Bipolar II in this instance, and in part, that allows us to run a monotherapy study to have clarity on the signal seeking and the estimate of what that treatment effect will be, as well as being a bit more straightforward in terms of understanding what the safety tolerability profile is in the population. So that'll be the focus for this initial signal-seeking study. And then, you know, depending on what we see, assuming we see positive results, that really could broaden the aperture out to continue full development, not only in Bipolar II, but also, you know, continue development into a Bipolar I broader patient population. Sure. Thanks, Rob. Turning back to MDD, we've received a question for Dr. Mathew: how confident can we be that kappa is the primary driver of a antidepressant, anti-anhedonic effect within this class? And beyond the navacaprant data themselves, is there anything else that we can point to to derive confidence? That the kappa antagonism is the primary driver of effects? Yes. I think, I mean, given the selectivity of the drug on kappa and no evidence for off-target effects, given the well-described pathway, in terms of what's going on in brain reward circuitry, I think we're confident that the mechanism is subserving those circuits and that the kappa selectivity is what's driving that. Sure. Just scrolling through the questions here. Rob- Mm-hmm. Could you speak a little bit to our ability to use the ongoing monitoring that we've spoken about during today's presentation to, you know, make adjustments to the COASTAL studies as they proceed? Sure. So we've implemented a really rigorous and comprehensive oversight that I think it's important to contextualize, goes well above and beyond what would be typical for a phase III study, even in a depression study. And this includes oversight at the site level, it includes oversight at the patient level, and it includes oversight at the rater level, across all the sites in the study. And really what we do is we look at the blinded instances efficacy data to look for evidence of, say, inconsistency within a subject, either at a given time point or inconsistencies within a subject across multiple time points. And there's a variety of methodologies we can employ to do that, including some advanced statistical approaches. And what that allows us to do, in that instance, is intervene in really quickly at the rater level and potentially remediate or retrain that rater to ensure that there's consistency of rating. We also use central raters who specifically focus on the MADRS. And they looked for consistency of administrations and to ensure that there aren't errors being conducted, you know, that happen as part of the rating at the site. And that allows them to intervene very, very quickly and potentially, you know, in some instances, correct that score. And then one other one that I think we haven't mentioned yet is we actually monitor for medication compliance and adherence during the study. It's not something that's discussed a lot, but we know from objective pharmacokinetic data from these types of studies that the non-compliance can be quite high. And so we've implemented some approaches, including this video sort of confirmation, where patients have to basically take a video in each administration when they take the study medication. And we know that that can drive increased adherence and compliance during the clinical trial. So those are just a couple examples, and there are several more that we're doing, that really allow us this sort of real-time ability to assess the integrity of the study and then to intervene as quickly as possible. One additional question we received, Rob. Of course, we're not providing guidance on blinded data, but could you speak in general to your level of confidence in the study execution? Yeah. I mean, again, all the measures that we're putting in place, we have, you know, a dedicated team that we've built out internally of both clinicians and statisticians to look at this and sort of triangulate in a number of ways. And so I'd say, based on the totality of these measures that were put in place, you know, we've got a high degree of confidence that we're doing essentially everything we can to help ensure a successful trial. Absolutely. And, our next question is, again, for Dr. Mathew and Dr. Krystal: How do you view, KORAs relative to some of the other, emerging mechanisms and developments, such as, Kv7s? Dr. Mathew, I'll ask you to comment first. Yeah. I mean, the Kv7 program in many ways is targeting similar symptom dimensions. There's been an interest in anhedonia for that class of drugs as well. I mean, the data for the Kv7 programs there is still quite early on. But it'll be interesting to see what emerges there. They have different, certainly different mechanistic profiles as well as different safety tolerability profiles. Sure. And we have time for about one more question. So I think, just in terms of the last question, we've received several inbounds here, really just focusing on the overall benefit-risk profile. And, you know, if you could each maybe close it out one last time on what you'd like to see from the navacaprant studies. Maybe Dr. Krystal, you go first, and then Dr. Mathew. So, you know, as I said earlier, I think we're looking for overall statistical significance and good safety profile, overall risk-benefit. And, you know, I think we'll all be watching the SHAPS data carefully because we have a lot of hope that these medications will have additional benefit with regards to anhedonia. You know, I think that having more options is better, and having kappa-opioid receptor in the KORAs in your armamentarium will be really important for clinicians. And I think that even having multiple kappa-opioid receptor antagonists will be a good thing for psychiatrists as they treat depression, which you'd think is something that is easy to treat but is actually a major public health challenge. Absolutely. Dr. Mathew, anything to add? No, I agree with all, all of that, and I'd be looking for, I mean, not only the effects on the MADRS, but some of these secondary measures that we were looking at to really confirm the robustness of the efficacy across many different sort of symptom domains. And then ultimately, how is the patient thinking that... How does the patient believe they're doing? And looking at some of these patient-reported outcome measures will be of high interest. Great. Well, thank you both for joining us today. With that, this concludes our Q&A session, and I will turn the call over to Henry Gosebruch for closing remarks. Great. Well, thanks, Helen, and thank you, Dr. Mathew and Dr. Krystal, for participating in this event. Your expertise is invaluable as we seek to reshape the treatment of neuropsychiatric disorders. As you've heard, it's an exciting time in Neumora as we move forward. Our goal remains steadfast: to redefine neuroscience drug development by bringing forward the next generation of novel therapies that offer improved treatment outcomes and quality of life for people suffering from brain diseases. We're looking forward to the first of our three phase III data readouts from the COASTAL Program investigating navacaprant for the treatment of MDD, which is on track for the fourth quarter. While navacaprant, of course, was the focus of today's discussion, I'd also like to mention again that beyond navacaprant, Neumora is advancing a deep pipeline of additional novel clinical and preclinical opportunities, addressing such conditions as Alzheimer's, agitation, schizophrenia, Parkinson's, and ALS. We believe we are well on our way to bring forward the next generation of novel therapies that offer improved treatment outcomes and quality of life for patients suffering from brain diseases. So thank you for joining us this morning, and have a great day.