Good morning. Welcome to the Axsome Therapeutics Conference Call. Currently, all participants are in a listen-only mode. Later, there will be a question-and-answer session, and instructions will follow at that time. If anyone should require operator assistance, please press star zero on your telephone keypad. As a reminder, today's conference call is being recorded. I would now like to turn the conference over to your host, Mark Jacobson, Chief Operating Officer at Axsome Therapeutics. Please go ahead. Thank you, operator. Good morning. Thank you all for joining us on today's conference call to discuss the approval of AUVELITY for the treatment of agitation associated with dementia due to Alzheimer's disease. During today's call, we will be making certain forward-looking statements. These statements may include statements regarding, among other things, the efficacy, safety, and intended utilization of our agents, our clinical and non-clinical plans, our plans to present or report additional data, the anticipated conduct and the source of future clinical trials, regulatory plans, future research and development plans, commercial plans, and possible intended use of cash and investments. These forward-looking statements are based on current information, assumptions, and expectations that are subject to change and involve risks and uncertainties that may cause actual results to differ materially from those contained in the forward-looking statements. These and other risks are described in our periodic filings made with the Securities and Exchange Commission, including our quarterly and annual reports. You are cautioned not to place undue reliance on these forward-looking statements, which are only made as of today's date, and the company disclaims any obligation to update such statements. Joining me on the call today from the Axsome team are Dr. Herriot Tabuteau, Chief Executive Officer, Ari Maizel, Chief Commercial Officer, Nick Pizzie, Chief Financial Officer, and Hunter Murdock, General Counsel. Also joining me on the call today is one of the leading experts on agitation in Alzheimer's disease dementia, Dr. Jeffrey Cummings, the Chambers-Grundy Professor of Brain Sciences at the UNLV Kirk Kerkorian School of Medicine. Herriot will start with opening remarks, followed by Ari, who will provide an overview of our commercial plans. Dr. Cummings will then provide an overview of Alzheimer's disease agitation treatment needs and will then discuss the profile of AUVELITY and the indication. We will then open the line for questions. Questions will be taken in the order they are received. With that, I am pleased to turn the call over to Herriot. Thank you, Mark. Good morning, everyone. Since Axsome's founding, we have been on a mission to deliver and develop transformative medicines to improve brain health. Today, we are very pleased to share that the FDA has approved AUVELITY for the treatment of agitation associated with dementia due to Alzheimer's disease. Agitation is one of the most common and challenging aspects of care in Alzheimer's disease, and to date, treatment options have been limited. AUVELITY is a first-in-class medicine with a distinct mechanism of action that provides an important new treatment option for this debilitating and critically underserved condition. This approval therefore marks an important milestone for the millions of patients living with Alzheimer's disease, their families, and their caregivers. Alzheimer's disease agitation is the second indication for which AUVELITY has received FDA Breakthrough Therapy designation and has been granted FDA Priority Review and approval. This underscores Axsome's pioneering work in neuroscience and our dedication to people living with serious brain health conditions. Next slide. In Alzheimer's disease, a cascade of cellular events leads to synaptic loss and neuronal cell death. These events are thought to result in reductions in certain neurotransmitter systems, which in turn contribute to the cognitive and behavioral symptoms of Alzheimer's disease, including agitation. AUVELITY targets the mGluR and sigma-1 receptors, which are believed to modulate neurotransmitter systems implicated in Alzheimer's disease. The exact mechanism of action of AUVELITY in the treatment of agitation associated with dementia is unclear. Next slide. AUVELITY has a differentiated efficacy and safety profile. It is the only approved treatment for agitation associated with dementia due to Alzheimer's disease that has demonstrated substantial symptom improvement, which was shown to be sustained in a long-term trial over up to six months. In clinical trials with Alzheimer's disease patients, it was well-tolerated, with a low discontinuation rate that was identical to placebo. Next slide. We are pleased with the labeling for AUVELITY in this new indication. Highlighted in yellow are the updates to the AUVELITY label for the new indication of agitation associated with dementia due to Alzheimer's disease. Importantly, with this new indication, there is no new box warning. Next slide. Turning now to the key efficacy data, the efficacy of AUVELITY in the treatment of agitation associated with Alzheimer's disease was demonstrated in the ADVANCE-1 and ACCORD-2 trials. ADVANCE-1 was a five-week parallel group study. In ADVANCE-1, AUVELITY met the primary endpoint by demonstrating statistically significantly greater improvement in agitation symptoms as measured by the Cohen-Mansfield Agitation Inventory, or CMAI, total score compared to placebo at week five. Patients who received AUVELITY experienced a 14.9 point reduction in the CMAI total score compared to an 11.6 point reduction for placebo. The improvement with AUVELITY was numerically greater versus placebo starting at week two, demonstrating early separation. Additionally, a statistically significantly greater proportion of AUVELITY patients were rated by clinicians as improved compared to placebo as assessed using a modified Alzheimer's Disease Cooperative Study- Clinical Global Impression of Change for agitation, a key secondary endpoint in the study. Next slide. ACCORD-2 was a long-term, double-blind, randomized withdrawal trial in which patients who were known responders to AUVELITY were randomized in an up to six-month double-blind phase to either continue treatment with AUVELITY or switch to placebo. In ACCORD-2, the patients who continued treatment with AUVELITY experienced a statistically significantly greater time to relapse of agitation symptoms measured by the CMAI than the patients who switched to placebo. In the study, treatment with AUVELITY reduced the risk of re-relapse by 72% compared to placebo. Overall, the study showed that 28.6% of patients on placebo relapsed compared to 8.4% of patients who received AUVELITY. Taken together, these data demonstrate rapid and durable improvement in agitation symptoms in Alzheimer's disease dementia, supporting AUVELITY's potential for timely and long-term symptom management. With that, I'd like to turn the call over to Ari, who will review the commercial opportunity for AUVELITY in Alzheimer's disease agitation and discuss our launch plans. Next slide. Thank you, Herriot, and good morning, everyone. Agitation in Alzheimer's disease dementia has represented a significant unmet medical need. Today, more than 5 million people in the U.S. have Alzheimer's disease agitation, a number which is projected to double in the coming decades. Approximately half of these patients are currently treated with pharmacotherapies, reflecting a significant unmet treatment need that has existed for decades, with only one previously approved treatment that reached the market in 2023. The treatment landscape is defined by variability in patient disease severity and access to specialists in certain geographic markets, which influences where patients are treated and what provider specialty is responsible for clinical decision-making. The majority of Alzheimer's disease agitation patients live with loved ones in the community and are generally considered to have more mild to moderate agitation symptoms. Conversely, nearly four out of 10 patients reside in long-term care facilities and are generally considered to have more moderate to severe agitation symptoms. Treatment decisions are overwhelmingly made by primary care providers across the U.S., with psychiatry, neurology, and geriatric specialists playing an important role in managing symptoms for many patients. Next slide. Last year, Axsome conducted a survey in partnership with a leading polling and research survey firm, receiving critical insight from 751 care partners, including spouses, children, grandchildren, family members, and friends of Alzheimer's disease agitation patients. The goal of the survey was to learn more about the challenges of living with and managing agitation symptoms. An overwhelming majority of 97% of care partner respondents stated that Alzheimer's disease agitation symptoms have a negative impact on their loved one's quality of life. Further, 96% of care partner respondents agree that their loved ones seem more like themselves when agitation is under control. Although non-pharmacologic interventions such as environmental changes are recommended as first-line treatment, their success is highly context-dependent. This variability, combined with the burden, risk, and quality-of-life impact associated with agitation symptoms, underscores the urgent need for safe and effective treatment options to preserve quality of life for patients and care partners. Next slide. Our comprehensive launch strategy is designed to reflect current prescribing patterns, addressing points of care across treatment settings and key prescriber segments. Our expanded sales team of approximately 630 representatives will engage a broad group of clinicians aligned with where these patients are treated today, including primary care providers, psychiatrists, neurologists, and geriatric specialists who treat patients in both the community and long-term care settings. Our target list includes approximately 68,000 healthcare professionals with substantial overlap from our existing AUVELITY prescriber base in major depressive disorder, which we anticipate will further support adoption. We've spent the past year working closely with payers and PBMs to ensure access to AUVELITY for Alzheimer's agitation patients, and we've enhanced our comprehensive patient services program, AUVELITY OnMySide, to facilitate education and support for patients and the caregiver community. Payer coverage for AUVELITY is strong at approximately 100% of lives covered in Medicare and Medicaid, which together represent nearly 90% of the expected payer mix in Alzheimer's disease agitation. In addition, approximately 78% of commercially insured lives have coverage for AUVELITY. Overall, our commercial infrastructure positions us well to execute a strong and coordinated launch of AUVELITY in Alzheimer's disease agitation. Next slide. In summary, Axsome has taken a disciplined approach to launch readiness to support AUVELITY's entry into the Alzheimer's disease agitation markets. Our expanded sales team is well-positioned to effectively educate across key prescriber segments and patient settings of care. Our strong foundation of insurance coverage and patient support services will facilitate patient access to AUVELITY and support ongoing treatment experience. We expect our launch preparations to be completed in approximately one month with a full commercial launch planned in June. We're excited to bring this important new treatment option to the Alzheimer's disease dementia community, and we look forward to updating you on our progress in the weeks and months ahead. I'd now like to hand the call over to Dr. Cummings. Thank you. Thank you very much, Ari. It's great to be on the call today. This is a very rare event to be participating in the announcement of a successful drug development program in Alzheimer's disease. I just couldn't be more pleased than I am today and to share some information about agitation. If I could have the next slide. This just is a definition of agitation to make sure that we're all understanding what agitation encompasses. There are generally three areas: excessive motor activity, verbal aggression, and physical aggression. These have been used in the IPA, the International Psychogeriatric Association definition of agitation in cognitive impairment. You can see that excessive motor activity is things like pacing and rocking. Verbal aggression, yelling and shouting. Physical aggression, things like resisting and pushing and kicking and scratching. You can imagine what family members go through when these are the behaviors that their loved one exhibits. Agitation is present across the spectrum of Alzheimer's disease severity. You see in the, in the bottom part of the slide, 56% of mild patients, that would be a Mini-Mental of above 20. 75% of moderate to severe patients, this is the real target population. 75% of them exhibit periods of agitation. 68% of patients with severe dementia, that is Mini-Mental of less than 10, exhibit agitation. Let's go on to the next slide, which is the CMAI. This is the Cohen-Mansfield Agitation Inventory. It is the approved regulatory instrument for measurement of agitation in clinical trials. You see how well it maps onto the IPA definition. There's the physically aggressive domain, you see spitting, physical aggression, scratching. Physically non-aggressive things, these are like pacing, repetitious mannerisms. Verbally aggressive, like cursing and screaming. Verbally non-aggressive, like complaining and negativism. You can see on the right there that the scale is scored from never, one, to several times per hour. You can imagine what those patients are like at a score of seven. Giving the range of scores of 29, which is the lowest score one can have, because there is no zero on this scale. There is only a one as the lowest or never rating on the 29 items. And it can go as high as 203 if one had a maximum score on all of the items. Next slide. Agitation is among the most prevalent and distressing of neuropsychiatric symptoms of Alzheimer's disease. Ari emphasized this as well. It accelerates disease progression and a really great question is going to be, does AUVELITY slow this, the accelerated decline? That'll be an important research question. It agitation exaggerates functional decline. It leads to increased, earlier institutionalization, and increased fall and mortality risk. There are very many negative consequences of agitation, leading to the importance of treating this and controlling it as well as we can. It's certainly a significant burden to caregivers. Next slide. This is an unmet need for Alzheimer's disease. Historically, there's the usage for typical and atypical antipsychotics, antidepressants, benzodiazepines, and antiepileptics. Most of them have not been rigorously shown to be efficacious. There is one approved atypical antipsychotic, brexpiprazole, for the treatment of agitation in dementia due to Alzheimer's disease. About half of the treated patients are on more than one class of anti-agitation medication, suggesting the low rate of response. Limitations to these off-label medications include sedation, extrapyramidal effects, falls, the worsening of cognition, cardiovascular and cerebrovascular events. These are mainly associated with the atypical antipsychotics. There is a black box warning for increased mortality risk among elderly patients with dementia treated with atypicals. They have modest efficacy, with it being rigorously shown only for brexpiprazole. If I could go on to the next slide. I would just say this is my last slide, that this is a huge unmet need. Highly prevalent and very disabling in terms of the course of Alzheimer's disease and its impact on patients and caregivers. AUVELITY has a unique mechanism of action. It is not an antipsychotic. It targets the NMDA and sigma-1 receptors that modulate glutamatergic pathways that are affected in Alzheimer's disease agitation. The clinical results then support the use of AUVELITY in agitation in Alzheimer's disease. There was a significant reduction in agitation. You saw that in the material that Herriot presented. It was safe and well-tolerated. One of the things I like about this data set is the convergence from the CMAI and the global scale that was used, the ADCS Clinical Global Impression of Change, 'cause we have two perspectives, and they give you the same information, increasing the validity and credibility of that result. The onset of action is rapid and sustained. I'll stop there, Ari, and turn it back or Mark, and turn it back to you. Great. Thank you. Thank you, Dr. Cummings. What we'd like to do now is open the line for questions, and I'll pass it to the operator, who will provide the instructions for how to get in the question queue if that's of interest. Thank you. Thank you so much. We will now be conducting a question and answer session. If you would like to ask a question, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two to remove your question from the queue. For participants that are using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. We ask that you please limit yourself to one question and one follow-up question. One moment, please, while we poll for your questions. Our first questions come from the line of Leonid Timashev with RBC Capital Markets. Please proceed with your questions. Hey, guys. thanks for taking my question, and first of all, congratulations on the approval here. I wanna ask on sort of how patients are actually treated in the real world. I guess, is treatment intermittent or as needed, or do patients typically select the drug and then stay on a drug for multiple months or years? I guess ultimately, how should we think about how many prescriptions each patient's going to be getting per year and what the compliance might be like? Thanks. Maybe I can start with that. Dr. Cummings? Yeah, please. Great. Great. Great. Yeah, okay. Great. Thank you. Yes, that's a really good question. This is not a PRN medication. I think that's very important. This is a medication that when patients become agitated, they tend to remain agitation-prone over a period of about three years. Patients will not be treated for the entire course of their illness, but they will be treated for relatively long periods during the course of the illness. Compliance is high because these patients are pretty impaired cognitively, the caregiver is administering the medication, and the caregiver is experiencing, of course, very great distress from these symptoms, so they're motivated to keep the medication going. When the threshold for treatment is passed, then the patients, you know, will be treated with a pharmacologic medication. Families try not to use medication. We respect that. Most patients have intolerable levels of agitation. Most patients that we would define as agitation have intolerable levels. They're treated with medications. Compliance will be good. It will be for a period of roughly three years. Thank you. Our next question has come from the line of Ami Fadia with Needham. Please proceed with your questions. Good morning. Congratulations on the approval, and thanks for taking my question. Maybe, I can sort of ask about just the payer coverage here. Now, you know, MDD, which was the prior indication for AUVELITY, it benefited from being a protected class status, you know, which had sort of 100% support in the government channel. AD agitation does not enjoy the same protected class designation. What is your expectation with regards to the prior authorization requirements in AD agitation, particularly given that, you know, the high volume of antipsychotics that are used off-label and, you know, they're obviously a lower cost. Maybe, you know, kind of just from a clinician standpoint, what is going to be the approach, and maybe from Axsome standpoint, what type of step edits do you anticipate there? Thank you. Yeah. Thank you, Ami, for the question. As you mentioned, for the MDD indication, Abilify was considered part of the protected class. Over the past year, we've been working closely with payers and PBMs to ensure that our access extends to the Alzheimer's disease agitation indication. We are confident, based on those discussions and the terms of our contract, that the coverage I referenced in my opening comments, 100% coverage across Medicare and Medicaid, is applicable to both indications. As it relates to utilization management, that's an area we've been very focused on in terms of launch preparation. Approximately 75% of agitation patients will not require prior authorization in order to receive Abilify once prescribed. That is, you know, currently active, so that is not something that is coming down the road. That is effective, you know, in January 2026. That is sort of the state of coverage, going into the launch. Thank you. Our next questions come from the line of Andrew Tsai with Jefferies. Please proceed with your questions. Hey, guys. This is John on for Andrew. Congrats on the approval. What a great achievement. In our doctor work, it seems like psychiatrists who treat depression also treat Alzheimer's agitation patients. They're very aware of AUVELITY given their experience with MDD. Given that AUVELITY is so penetrated in the PCP community, who generally tend to avoid antipsychotics, then now with the FDA posting about it being a non-antipsychotic, with all this awareness already, maybe just speak to why wouldn't this launch be fast, and just kind of your expectations on the pace and speed that the launch can grow. Yeah. Thank you so much for the question, John. To your point, there's significant overlap in prescribers as it relates to MDD and Alzheimer's disease agitation. That is part of the primary focus of our sales team is calling on those clinicians that see a high volume of both sets of patients. We're very optimistic. I think the awareness of AUVELITY in MDD certainly will support uptake in prescribers who have written over the past couple years. There will be some clinicians who either don't have experience or are more predominantly Alzheimer's agitation treaters, for which education and awareness will be really important in the coming months. You know, we're excited about the potential here and, you know, we'll keep everyone updated on our progress as we get through the launch. Maybe one quick follow-up if I can. I'm curious on the overall messaging for your sales reps of maybe why AUVELITY should be used over other treatments and how they'll be positioning AUVELITY specifically. Will it be like a first-line drug for Alz agitation? Maybe remind us if AUVELITY is being used ahead of REXULTI in MDD in the first place. Thanks. Sure. Maybe Dr. Cummings, could you offer your perspective on, you know, AUVELITY's potential place and for potential prescribers or patients? Absolutely. I'll just say that this will evolve as we come to understand AUVELITY better. The way I think it will be positioned is as a first-line therapy for many patients with agitation and Alzheimer's disease because the box warning is a discouraging factor for the use of REXULTI. REXULTI has a strong data set. I think it's an effective medication, but the box warning is important in terms of discouraging prescribers. I think that AUVELITY is likely to be the first choice for prescribers. There's no medication which is going to work for every patient, and so there'll be room for other drugs in the market. I think AUVELITY will do very well within the therapeutic landscape of this very large problem. John, the only thing I'd add is our insurance coverage and the contract that we've negotiated will support first-line use for the majority of patients. I think that is in line with Dr. Cummings' view on potential place of treatment. Great. Thank you so much. Thank you. Our next questions come from the line of Ash Verma with UBS. Please proceed with your questions. Oh, hey. Yeah, thanks for taking our questions, and congrats on the approval. This is great. I know it's early days, but what do you expect the average duration of therapy in Alzheimer's agitation as opposed to what it has been in MDD? Just trying to understand if AUVELITY in Alzheimer's agitation would more likely be kind of like a first-line pass-through treatment before patients ultimately start to go to some of the other off-label D2 blockers like Seroquel, Zyprexa, or REXULTI for that matter. If you can comment on that would be great. Thanks. Dr. Cummings, I know you touched on this briefly. Is there anything you would add to your prior comments? Then maybe we can offer something to round it out. Absolutely. I appreciate the fact that you brought up the off-label prescribing, because I think this represents a liability for physicians, and it represents a liability for healthcare systems where most physicians are currently employed. The presence of now two on-label treatments, I think, is going to increasingly move doctors and the systems away from the off-label use of risperidone and quetiapine that have been the standards for such a long period of time. I think we will see the market migrating towards approved medications, which I think is absolutely an appropriate thing. These are the drugs that we know about safety and efficacy. AUVELITY is gonna be very, very well positioned within that migration to on-label prescribing as I say because I think the box warning has been a factor in terms of use of REXULTI. Ash, you know, the only thing I would add is obviously we're gonna have to wait and see as the market develops with AUVELITY in market. you know, there's never been a product like AUVELITY for this patient population. As Dr. Cummings suggested, compliance generally is very high if the drug is successful at treating these symptoms. we'll share more updates as it relates to duration of therapy, you know, as we get some experience in the marketplace. Thank you. Our next question has come from the line of David Amsellem with Piper Sandler. Please proceed with your questions. Thanks. This is one for Dr. Cummings. A number of your peers talk about off-label use of reuptake inhibitors, be it, selective serotonin reuptake inhibitors or dual reuptake inhibitors of serotonin and norepinephrine. We hear a lot about off-label use there. Really two questions. Do you think there's still going to continue to be off-label use of the reuptake inhibitors, particularly upfront? And then what can you say about the portion of patients who don't respond adequately to reuptake inhibitors, just given that it seems to be there's a lot of off-label uses of those in addition to the off-label uses of the atypicals that you cited? Thank you. Yes, really great question and an informed question. There is a lot of use of the SSRIs in particular because of the citalopram in AD study. That showed that there was a statistically significant reduction in agitation associated with the use of citalopram or prescribing of citalopram. That was a very well conducted and influential study. However, it also used a dose of citalopram, which the FDA believed is too high, and there was a cardiac warning associated with the dose that was used in the citalopram study. It hasn't enjoyed as the kind of widespread use that it might have if we had greater confidence in the safety of the agent. Again, I think there will be a migration towards drugs that are approved and where the efficacy has been established to the comfort level of the FDA. The other thing I would say about the SSRIs is not surprisingly, they tend to do best in patients who have concomitant mood symptoms, and they also have performed best in patients with lower levels of agitation as compared to higher levels of agitation as seen in the current trial. I think people absolutely will continue to use those drugs. They're comfortable with their use because of their widespread prescribing in depression. I think we will see the market migrating towards drugs that are shown to be efficacious for this indication and safe and approved. I think the approval is of tremendous importance to docs. Thank you. Our next question has come from the line of Ram Selvaraju with H.C. Wainwright. Please proceed with your questions. Thanks so much. So the first one is probably for both Dr. Cummings and Ari. If you look at REXULTI experience in the elderly Alzheimer's population, you know, maybe comment on how long patients who get put on REXULTI for agitation stay on that drug and the principal reasons for discontinuation. Also what you anticipate are likely to be the principal advantages for AUVELITY in prompting a physician decision in favor of that medication versus REXULTI. Then I was just wondering if, Ari, you could provide us with some additional details on something you said in your prepared remarks about the target prescriber base and what percentage of that approximately is currently covered by the sales team of, you know, effectively promoting AUVELITY based on the original MDD label. Thank you. Dr. Cummings, would you like to start with the REXULTI experience question? I will. I have to say that I don't know the answer to that question. I'm not sure how long the patients have remained on the agent. I'm not sure of why it was stopped when it was not renewed. I'll just say one thing about the AUVELITY development program that I particularly like is the combination of the parallel double-blind design followed by the withdrawal, the randomized discontinuation design. The randomized discontinuation shows this very high rate of relapse in the patients who are randomized to placebo compared to those who continue treatment with AUVELITY. I think that's a powerful piece of information and useful both in the question you're asking, what is the persistence? If people see the relapse, they're going to renew the prescription if they didn't do it automatically. Then there are some rules that nursing homes have to abide by, including periodic efforts to try to get patients off of psychotropic medications. Again, that's a provocation that I really don't like because you see in the data that patients will relapse when you do that. I think this is a more comprehensive data set that allows us to think more about the use of AUVELITY in the market because we both have the acute effect in the parallel design, and we have the enduring effect in the randomized discontinuation design. I think it's a very useful complementary set of observations. Yeah, I would build on that and just say one of the unique aspects of our messaging is related to that clinical trial plan, our development program. What's unique is we're able to communicate the impact of AUVELITY in both short- and long-term studies, with strong, rapid onset of action, durable efficacy out to six months for many patients, and a highly safe and tolerable profile. You know, no box warning associated with elderly patients. Overall, the feedback we've received is this is a very, very compelling clinical profile that we feel very good about. Ram, your question about target HCPs. As I mentioned in my opening remarks, we'll be calling on approximately 68,000 healthcare providers across the community and long-term settings. Today, we call on roughly 80% of those targets for the MDD indication. There is high overlap with the folks that we've been calling on over the past few years. Obviously, that provides some advantage in terms of awareness and relationships. There is a group, about 20% of that group, 13,000, that are primarily high volume Alzheimer's disease agitation providers, who will be new for Axsome, but who we expect to engage with early in the launch. Thanks. Congrats again on this landmark approval. Thank you. Our next questions come from the line of Ben Burnett with Wells Fargo. Please proceed with your questions. Hey, thank you, and I'll say congrats as well. I had two questions. Just one, I wanted to go back to the question around sort of the payers. What are your expectations for gross net as you add AD agitation patients to the mix long term? Sure, yeah. Hey, this is Nick, Ben. We would anticipate that GTN for this year will look similar to 2025, similar how we shared previously. Looking at the phasing that we had in 2025, very similar in 2026. Reminder that we were in the mid-50s for the first half of the year and the high 40s for the back half of the year. With this approval in ADA, we don't anticipate to see much change in GTN this year. Longer term, what we've shared before and continue to share is that we will likely level out in the 50s range from a GTN from a longer-term perspective. Okay. That's helpful. Thank you. I just wanted to ask just regarding the label, there was some description about hyponatremia, and I think there's maybe some guidance about concomitant use of other serotonergic antidepressants. Just wonder if you could maybe offer some color on that? Sure. That was one addition to the label. It was based on one case of hyponatremia in our entire clinical development program. The FDA wanted to make sure that we think the FDA wanted to make sure that clinicians are aware of hyponatremia in the elderly patient population because even any kind of clinical setting with elderly patients, you do tend to see higher rates of hyponatremia. I guess, would a patient who's on a serotonergic antidepressant have to come off that? I guess, how relevant is that to this population? Our clinical studies did not include concomitant dosing with other agents. Okay. Okay. Thanks so much. Thank you. Our next questions come from the line of Jason Gerberry with Bank of America. Please proceed with your questions. Hey, guys. Congrats on the approval. My question is for Medicare Part D patients who are not low income subsidy, what is your expectation for average out-of-pocket costs? Do you see that as a barrier for that group of patients? Do you think there's a differential level of uptake in non-low-income subsidy Part D versus low-income subsidy Part D? Given that Part D is such a big part of the ADA population, I wanted to hone in on this out-of-pocket cost issue just because it's come up with REXULTI as a barrier to uptake because the sponsor can't deflect those out-of-pocket costs. Thanks. Yeah. Thanks for the question. I think it's important to note that the overwhelming majority of Alzheimer's disease agitation patients do qualify for low income subsidies. In terms of predicting out-of-pocket, if it's not an LIS patient, yeah, it's difficult to forecast until we see what the patient mix is during the launch itself. We'll likely have more to share as we get into the launch. We've been very mindful of our contracts with Part D plans to try to minimize out-of-pocket as much as possible. Obviously, it won't be a perfect solution, but given the high proportion of LIS patients in this marketplace, and the contracts that we've been able to secure, we feel optimistic that out-of-pocket will not be a tremendous barrier to use. If I could just follow up on that, 'cause my understanding was LIS was, like, 30% of Part D. Is what you're saying in that that's wrong, it's a much bigger proportion of Part D? It really depends on setting of care. I would say in the long-term care setting, it's likely a higher, much higher proportion of lives. In the community setting, it may be closer to what you're referring to. However, you also do see commercial coverage being stronger in the community setting, so there are some different dynamics at play. Ultimately, our view is that out-of-pocket expenses will not be a significant barrier to initial trial. All right. Great. Thanks. Thank you. Our next question has come from the line of Joseph Thome with TD Cowen. Please proceed with your questions. Hi there. Good morning. Congrats, and thank you for taking my questions. Maybe the first one for Dr. Cummings. What proportion of your patients, under your care or at your center with Alzheimer's disease associated agitation are actually on pharmacological treatment, to manage their agitation? Do you expect this would expand with the availability of AUVELITY, or will patients be switching at all? Then maybe second for the company, how will you be reporting information on how the launch is progressing? Is it gonna be clear which scripts are coming from MDD versus Alzheimer's agitation? Just sort of how are you gonna relay that information to the street? Thank you. I'll jump into the first part of that question. In terms of my own practice, I tend to see earlier patients who have less agitation, maybe only about 20%, 25% of patients with very early disease have periods of agitation, and only about half of them are actually treated pharmacologically. Because in the early part of the disease, the agitation tends not to be prolonged. Families just, you know, figure out ways to adjust to it. On the other hand, I consult in long-term care facilities, and there 60% or 70% of patients will have agitation, and most of it, over 50%, would require pharmacologic management because the non-pharmacologic strategies simply don't work in that population. You can't do music therapy and make that work or aromatherapy and make that work in severely impaired nursing home patients, in my own experience. I would say the prevalence of use is going to depend on the kind of practice that an individual has. In patients in that moderate to severe stage of the illness, it is very common. Most of it, 2/3 of it will require pharmacologic management, just as a kind of a rule of thumb. Joe, this is Ari. I'll start with your question about reporting. Yeah, as we're evaluating launch performance, clearly NBRx growth, new patient start growth will be one of the most important aspects. We will also be looking at activation of new prescribers, particularly the prescribers that we'll be adding who are specifically treating high volumes of Alzheimer's disease agitation patients. As it relates to looking at the proportion coming from either indication, as you know, with IQVIA and Symphony, they don't split out by indication. We will be looking at claims data retroactively to estimate the proportion of lives that are coming, you know, from one indication or the other. Last thing I'd mention is just our entry into the long-term care setting. Although we expect there to be demand for both Alzheimer's agitation and MDD in long-term care, we suspect that Alzheimer's agitation will be sort of the primary source of initial trial. Monitoring uptake in the long-term care setting will provide a helpful view on how the launch is progressing. Yeah. Joe, from a net sales and GTN perspective, we'll obviously just be providing one number for AUVELITY in totality. Great. Thank you. Thank you. Our next question has come from the line of David Huang with Deutsche Bank. Please proceed with your questions. Hi there. Congrats on the approval. Just a couple questions here. Maybe first, could you talk a little bit about the threshold to initiate a patient on AUVELITY? What would you be looking for? Would it be cases, number of cases of agitation, a particularly severe agitation episode? Just anything of that nature. Then in terms of other drugs being developed for adjacent indications like Alzheimer's disease psychosis, there are a few there, such as COBENFY. Would you view those drugs as competitors, or are they, do you view them as operating in a different patient segment that has psychosis? Thank you. Well, maybe I'll jump in on that, and others can fill in. The threshold is really dependent on the family to such a great extent, because, some families just, you know, the last thing they want to use is a drug, and they'll just go way out of their way to accommodate the agitation. Other families have very low thresholds. The discussion that you have with the family is to what extent is this impacting the life of the patient and your life and the life of the family, and what are the activities that can still be done, and are there still enjoyable things that the patient can embrace? So it's a negotiation with every patient. This is, this is truly personalized care. Most families are going to want treatment. Most families do not want to have to adjust their own lifestyles to accommodate a very agitated patient. You can just imagine if your wife or your, or your mom or dad had any of the behaviors on that list of behaviors that we went over. Most patients who have agitation, which is occurring several times per week, and reaches a modest level of severity, are going to be treated pharmacologically. That's sort of the threshold that you're working with, is how frequent is it and how severe is it. There's a relationship between those two, so that the patients who are agitation-prone have it more often, and they have it more severely. That's the kind of discussion that you have. In terms of adjacent medications, I think that's a really interesting question. The COBENFY program is proceeding, and I think we'll read out this year. Psychosis does overlap with agitation. There are psychosis patients who become agitated. I think there'll be a very interesting learning period here that we're all coming into as to whether or not the prescriber would say, "Well, I think I should try to treat the psychosis," or, "I should try to treat the agitation." I would say, at this point, we haven't figured that out. It's going to take professional guidelines to give some guidance to clinicians around those kinds of issues if COBENFY is approved. I think it's gonna be a really interesting evolution as we get more drugs that bear on this kind of issue. Thank you. Our next question has come from the line of Rudy Li with Wolfe Research. Please proceed with your questions. Congrats on approval. Thanks for taking my question. Main question for Dr. Cummings. Can you actually talk about the overlap of agitation and psychosis in Alzheimer's in your patients? Just wondering how that will impact the treatment sequencing, maybe medication selection while managing behavior symptoms. Just a quick question for Ari. You can talk about REXULTI dynamics since has been on the market for three years, also approved for MDD plus ADA. What are the key learnings that you can apply for AUVELITY? Thanks. I'll pick up the psychosis question. We touched on that a little bit. One of the things that we need to do with the current AUVELITY data set is to look at psychosis. I understand that it was either excluded or occurred at a very low level at baseline. We can look at whether there was greater evolution of, or emergence of psychosis in the treated patients, or in the placebo group patients to see whether there are any benefits of the use of AUVELITY in this population in terms of psychotic symptomatology. I think there might be because this glutamatergic pathway is implicated in psychosis. Again, in terms of sequencing, I don't think we know that yet. I think the prominence of the symptom complex will be very important. If the patient is very paranoid, very disturbed by the thought that people are stealing from them, that patient is likely to be treated first with an antipsychotic. On the other hand, if the major problem is the list of problems that we saw on the CMAI or in the IPA definition, those patients are going to be treated with an anti-agitation agent, the safest one available. I think there will continue to be a very important role for AUVELITY, regardless of what happens in the antipsychotic space. Rudy, regarding your question around REXULTI dynamics and learnings, you know, obviously, we think the REXULTI team has done a nice job in building awareness and trial of REXULTI over the past few years. You know, we've been students of their approach. Obviously, the adopters of REXULTI are likely adopters of AUVELITY. You know, their choices in terms of engagement with healthcare providers and the caregiver community have been things that we've evaluated to inform our launch strategy. Without getting into too many specifics, I would just say that they've done a nice job and has given us a lot of confidence in the market opportunity for AUVELITY as we enter the space. Got it. Very helpful. Thank you. Thank you. Our next question has come from the line of Sean Laaman with Morgan Stanley. Please proceed with your questions. Good morning. Hope everyone's well, and thank you for taking my question. My first question is more macro. You know, obviously, Alzheimer's a significant economic burden, but I'm wondering, you know, if you have a sense of, you know, how much, this indication, you know, contributes. If you have a number around that. We think about the alleviation of that burden, you know, what would be the economic benefit is kinda where I'm going. Then maybe a question for Dr. Cummings. You know, just in terms of looking at the, you know, clinical practice, I mean, how much does this move the debate along? How much does AUVELITY, you know, adoption of AUVELITY move the debate along? Are these patients really going to be, you know, significantly more manageable in a practical sense? Thank you. Yeah. Sean, thanks so much for the question. you know, obviously, the economic burden of Alzheimer's disease is significant, when you take into consideration the amount of healthcare required to support these patients, the institutionalization, you know, our estimates and their variety of estimates based on existing literature, you're talking in the hundreds of billions of dollars annually within the U.S. alone. The ability to treat these symptoms effectively, to potentially prevent or delay institutionalization for patients can have massive benefits from an economic perspective on the healthcare system. Maybe I could just add to that. I think if you look at just the mean differences between the placebo and the treatment group and take the most conservative view, there was at least a 25% reduction in the mean levels of agitation. That's seen as an important threshold in terms of meaningfulness of the response. Importantly, one of the trials used the patient or really in this case, caregiver impression of change, which means that the caregiver was able to see the same change that the clinician saw on that CMAI. I think these are changes that are appreciable to the caregiver. They're not minor. They're at least 25% in the mean, which means that some patients do very well. Some patients probably continue to have substantial agitation. We're gonna have to work that out. I think we need responder analyses. We, we're gonna need more studies. We're gonna have to understand this in much more detail than we currently do. On average, the change it was so it would be the most conservative view, and it was still accepted as, or will be accepted as within the range of meaningful. Perfect. Thank you so much. Thank you. Our next question has come from the line of Graig Suvannavejh with Mizuho. Please proceed with your questions. Great. Thanks so much for taking my question. Congrats to the team on the approval. I just wanted to get another perspective on how to think about launch trajectory. Given the knowledge that you've got basically two prescriber segments, whether it's PCP oriented or long-term channel, based segments, how should we think about the launch trajectory in each of those segments? Can you remind us whether prescriptions in long-term care get incorporated into the prescription data services? A question for Dr. Cummings. Just given your experience with treating Alzheimer's patients, what's your estimation of the awareness of AUVELITY as a potential treatment for agitation amongst the broader Alzheimer's prescriber community? Thanks. Yeah, thanks for the question. In terms of launch trajectory, you know, as you mentioned, primary care is a large segment of this treatment population, followed by specialists in psychiatry, neurology, and geriatrics. You know, we expect there to be adoption across specialties. I think it really comes down to the volume of patients that exist in any one practice. Not necessarily specialty specific, but practice specific. Our expectations just from a national perspective is, you know, we anticipate growth acceleration to begin in Q3 and build throughout the second half of 2026. As it relates to the data sources, you know, as you mentioned, long-term care, which is sort of a new wrinkle for AUVELITY sales. IQVIA Symphony do capture portions of long-term care, but there are some unique dynamics and certain facilities that may not report directly through IQVIA Symphony. We'll, we're working on ensuring that we have a transparent view of data, across both community and long-term care settings. I can take part of that question also. In terms of the prescribing and the long-term care question, which is part of this discussion, it's important to remember that the medical directors of long-term care are docs that have other jobs. They're PCPs or they're geriatricians that are familiar in general with caring for older patients and patients with Alzheimer's disease. In terms of how aware is the medical community of this program, of course, it's been called AXS-05 in the development program, in the clinical trials. I think it is not well known by the medical community. I think it's gonna be very interesting because as soon as they realize that AXS-05 is AUVELITY, I think they'll say, "Oh, I know that drug." They'll be comfortable with it. I think once that educational gap about these two names being the same drug is bridged, then I think it will be a relatively easy transition for prescribers. Okay. Thank you. Thank you. Our next questions come from the line of Myles Minter with William Blair. Please proceed with your questions. Hi, team. This is John on for Myles. Thanks so much for taking our question, and also would like to echo our congratulations. Maybe a follow-up to the question on psychosis for Dr. Cummings. Wondering if you can give us an idea of the proportion of patients that have overlapping agitation and psychosis, which would conflict with REXULTI's prescribing, giving the black box warning there. Then for the company, are these patients with overlapping agitation and psychosis readily identifiable? Could they be leveraged as an initial pool to drive early uptake? I'll jump into the first question. Psychosis occurs in about 25% of Alzheimer patients, and agitation, as you've seen, in about 75%. You would say that roughly 1/3 of agitation patients have symptoms of psychosis. Some of that psychosis is relatively minor, and some of that agitation is relatively minor. I would just say that it's certainly far from all patients with agitation being psychotic, but it's a non-trivial number, which also have psychotic symptoms. It's one of the things we're going to have to look at more closely. In the REXULTI studies, they limited the amount of psychosis to 30% of the population, but it did represent roughly, again, about a third of the patients with agitation. John, your question about could this be a specific segment of patients that we target? I would say our focus is on all agitation patients, not just specifically patients that might have overlapping psychosis symptoms. The reason for that is, you know, based on the label, the totality of data, this is a first-line option for any patient suffering from agitation associated with Alzheimer's disease. That's our orientation as we enter the launch. Thank you. Our next questions come from the line of Brian Skorney with Baird. Please proceed with your questions. Hey, good morning, everyone. Thanks for taking the question. Let me offer my congratulations on the approval as well. We've all watched the Rexulti launch in Alzheimer's agitation and, you know, we spent a lot of time kind of talking about some of the nuances and differences between AUVELITY and REXULTI. Maybe, Ari, if you could kind of just give us a synopsis in terms of compare and contrast, where you think AUVELITY's positioned in terms of coverage, physician enthusiasm, just the operational aspects of the launch versus REXULTI. Do you think that the REXULTI Rx curve, is that a reasonable hurdle to hold you to? What do you see as the primary reasons why this launch could outperform or underperform REXULTI 's initial launch in Alzheimer's agitation? Yeah, thanks. Thanks for the question, Brian. Obviously, we're very enthusiastic about this launch, and the enthusiasm we're receiving from healthcare professionals, caregivers, advocacy organizations is equally as high. I think you saw some of that in just the press release announcements coming from the Alzheimer's Association yesterday. You know, our expectation relative to REXULTI is not necessarily to compare ourselves to REXULTI. Obviously, it's the only analog in this space because it's the only other approved agent. I do think it's helpful from a directional standpoint. Our expectation is that, you know, based on the totality of evidence and the strong clinical profile, there's a really good chance AUVELITY will be considered a first-line treatment for these patients. That's how we plan to approach the market. We think our insurance coverage will support that in the early days. We're optimistic about the potential for impact. We'll have more to share as we get into the marketplace. Okay. Fair enough. Thanks, Ari. Thank you. Our next questions come from the line of Madison El-Saadi with B. Riley. Please proceed with your questions. Hi. Congrats on the approval, and thanks for taking our question. AUVELITY and MDD, it took a few quarters to really inflect. Of course, you were building access from zero. You know, this is a very different story now. Just wondering how we should think about the shape of the ADA ramp relative to, say, MDD, for example. You know, what the right analog is here? Relatedly, what are the key drivers that would support AUVELITY in agitation becoming a larger overall contributor? Thanks. Thanks, Madison. I do think your comment around AUVELITY and MDD, the uptake, you know, from our perspective, you know, the best analogs to look at for the launch are either REXULTI or AUVELITY and MDD. Obviously, there are differences that are noteworthy, which you shared a little bit of. We obviously have a larger base of insurance coverage than we did at the MDD launch. Our sales team is larger. There's awareness in the marketplace. Those are reasons for optimism. The Alzheimer's agitation market is a little smaller than the MDD market. In terms of overall patient opportunity, it is more limited from that perspective. There's only one other approved treatment, from a competitive standpoint, you know, there's less competitors to think about. There are lots of factors that go into it. Our expectation is that we're focused on execution with the 60,000 HCPs we're calling on to maximize uptake in the early days. You know, in terms of, you know, reasons, drivers of use, I think the fact that there's rapid onset of action, durable response and our short and long-term safe trials, as well as non-antipsychotic option, no box warning for elderly patients. I think one factor that we haven't spoken about today, but in long-term care facilities in particular, star ratings are of importance, meaning delivering quality care to maximize reimbursement from CMS. Having a non-antipsychotic for these patients will facilitate those star ratings. There are lots of reasons for optimism, but ultimately, predicting the exact uptake is very difficult. Understood. Thank you. Thank you. Our final questions will come from the line of Yatin Suneja with Guggenheim. Please proceed with your questions. Hey, good morning. This is Eddie on for Yatun. Congrats on the approval and thanks for sneaking us in here at the end. I appreciate all the color so far. You've talking about the differences between the two channels. Can you sort of put a pin on it and talk about how the company is thinking about how the earliest adoption patient mix between long-term care and community settings? What you might think the longer term revenue split overall would be between these channels. Thank you. Yeah, thanks for the question, Eddie. You know, we expect there, largely because we're currently in community-based settings, that there may be earlier uptake in the community setting just by nature of, you know, experience with MDDs and the existing relationships of our sales colleagues with those practices. With long-term care, we, you know, we expect there, as I mentioned earlier, you know, growth acceleration to begin in Q3 and build throughout the second half of 2026. I think in terms of proportion of business over the long term, it's hard to predict exactly. I would just say that today when you look at prescription volume, you know, roughly 60% coming from community settings, 40% from long-term care settings for agitation specifically. Thank you. Thank you. We've reached the end of our question and answer session. I would like to turn the call back over to Herriot Tabuteau for closing comments. Thank you. Thank you, Dr. Cummings, for your time this morning and your valuable insights. We also want to thank the patients, healthcare professionals, and our Axsome team for all their contributions that led to this approval. The approval of AUVELITY for the treatment of agitation associated with dementia due to Alzheimer's disease exemplifies our mission to deliver innovative new treatment options to clinicians and patients living with serious CNS conditions. Axsome today represents a singular CNS platform with now three commercial products approved across four highly prevalent conditions and a broad pipeline, including six novel product candidates that target 10 serious areas of unmet medical need across psychiatry and neurology. The continued performance of our marketed medicines, driven by the accelerating growth of AUVELITY and potentially first-in-class and best-in-class treatments in our pipeline, promise to deliver substantial long-term value as we further our mission to advance the frontiers of brain health. Have a great day. Ladies and gentlemen, thank you so much. This does conclude today's teleconference. We appreciate your participation. You may disconnect your lines at this time. Enjoy the rest of your day.