Axsome Therapeutics, Inc. (AXSM) Earnings Call Transcript & Summary

Good morning, and welcome to the Axsome Therapeutics Conference Call. [Operator Instructions] Please note that today's call is being recorded. I'll now turn the call over to Darren Opland, Director of Corporate Communications. Please go ahead.

Good morning, everyone, and thank you for joining us today. This call will focus on the top line results from the ACCORD-2 and ADVANCE-2 Phase III trials evaluating AXS-05 in patients with Alzheimer's disease agitation. Today's presentation is being made available via webcast, which is accessible on the Investors section of our website at axsome.com. Those joining via webcast may also advance through the presentation slides at any time during the discussion. Before we begin, please note that this conference call may contain certain forward-looking statements regarding, among other things, the efficacy, safety and intended utilization of our investigational agents, our clinical and nonclinical 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, our commercial plans regarding Sunosi, Auvelity and our pipeline products, revenue projections and other financial forecasts, if any, and possible intended use of cash and investments. These forward-looking statements are based on current information, assumptions and expectations of future events and are subject to certain risks and uncertainties that may cause the company's actual performance and results to differ materially from those projected. Please refer to today's press release, presentation and our SEC filings for additional details on these and other important risk factors. You are cautioned not to rely on these forward-looking statements, which are made only as of today's date and the company disclaims any obligation to update or revise these statements. Our speakers on today's call from Axsome are Dr. Herriot Tabuteau, Founder and Chief Executive Officer; Mark Jacobson, Chief Operating Officer; and Dr. Sue Giordano, Vice President of Medical Affairs. Additionally, we're pleased to be joined by Dr. Jeffrey Cummings, Director of the Chambers-Grundy Center for Transformative Neuroscience and Vice Chair of Research at the University of Nevada, Las Vegas Department of Brain Health. Mark will start by providing an overview of today's announcement before turning the call over to Herriot, who will review the top line results of the ACCORD-2 and ADVANCE-2 clinical trials. Following Herriot's update, Sue will provide an overview of Alzheimer's disease agitation. Dr. Cummings will then offer a clinical perspective on the unmet need in Alzheimer's disease agitation and comment on the trial results. We will then open the line for questions about the results. Questions will be taken in the order they are received. I'd now like to turn the call over to Mark.

Thank you, Darren, and good morning, everyone. Thank you for joining our call. Today, we are very pleased to share with you the top line results from our ADVANCE-2 and ACCORD-2 Phase III trials evaluating AXS-05 in patients with Alzheimer's disease agitation and as a result, the successful completion of our comprehensive suite of 4 pivotal Phase III placebo-controlled efficacy trials, including the previously completed positive ADVANCE-1 and ACCORD-1 trials supporting the efficacy and safety of AXS-05 in AD agitation. AXS-05 met the primary and key secondary endpoints in the ACCORD-2 trial, statistically significantly delaying the time to relapse the agitation symptoms as compared to placebo, the primary endpoint as well as statistically significantly preventing relapse of agitation, the key secondary endpoints. The ADVANCE-2 trial did not achieve statistical significance on the primary endpoint. Results for the primary and nearly all secondary endpoints numerically favored AXS-05 over placebo. In addition, we are pleased to share top line data from our long-term open-label extension study that confirm and extend our findings from the short-term trials. Long-term dosing with AXS-05 led to rapid, robust and sustained improvements in agitation symptoms and was well tolerated, consistent with prior trial with AXS-05 in patients with Alzheimer's disease agitation. The required number of patients treated for 6 months and 12 months to support an NDA filing was also achieved. Finally, AXS-05 was not associated with death, increased risk of falls, cognitive decline or sedation. With that, I'll pass over the call to Herriot, who will provide an overview of the program and review the Phase III trial results in greater detail.

Thank you, Mark. At Axsome, we are committed to advancing the frontiers of neuroscience to develop and deliver transformative medicines for people living with serious neurological and psychiatric disorders, conditions that are often characterized by limited treatment options, difficult-to-treat symptoms and poor patient outcomes. As many of you know, agitation is one of the most distressing and challenging behavioral symptoms in patients with Alzheimer's disease. It's common, persistent, costly and is associated with severe adverse consequences for both patients and caregivers. It is a significant unmet medical need. AXS-05 is a novel oral NMDA receptor antagonist, sigma-1 receptor agonist and aminoketone CYP2D6 inhibitor. By modulating the neurotransmitter systems implicated in the cognitive and behavioral symptoms of Alzheimer's disease, including agitation, AXS-05 may enhance synaptic transmission and improve functioning of cortical circuits in patients with Alzheimer's disease agitation. We are excited to share today's results, which represent an important milestone for Axsome and for physicians, caregivers and patients living with Alzheimer's disease agitation. The ACCORD-2 and ADVANCE-2 trials represent our third and fourth Phase III efficacy trials of AXS-05 in this indication. Starting with ACCORD-2. ACCORD-2 was a double-blind, placebo-controlled, randomized withdrawal trial of AXS-05 in Alzheimer's disease patients with agitation consisting of an open-label AXS-05 treatment period and a randomized double-blind treatment period. A total of 295 patients were treated with open-label AXS-05 and monitored for sustained clinical response, defined as at least a 5-point reduction from baseline in the Cohen-Mansfield Agitation Inventory, or CMAI, total score, an improvement on the Patient Global Impression of Change, or PGIC, that was maintained for at least 4 consecutive weeks. The patients who achieved a sustained clinical response were then randomized into the double-blind treatment period to either continue on AXS-05 or to switch to placebo. A total of 167 patients, 83 in the AXS-05 arm and 84 in the placebo arm were randomized into the double-blind phase. The primary endpoint was the time from randomization to relapse of agitation with relapse defined as a greater than 10-point increase or worsening in the CMAI total score. Demographics and baseline clinical characteristics for the open-label and double-line periods are shown on this slide. Patients had a mean baseline CMAI total score of 73 with AXS-05 treatment, this score decreased to approximately 45 prior to randomization, representing a 28-point or 62% reduction from baseline. Results of the primary endpoints are shown on this slide. The ACCORD-2 trial achieved the primary endpoint with AXS-05 substantially and statistically significantly delaying the time to relapse of Alzheimer's disease agitation as compared to placebo, with a hazard ratio for time to relapse of 0.276 and a p-value of 0.001. This hazard ratio corresponds to a 3.6-fold lower risk of relapse in patients continuing treatment with AXS-05 compared to those switched to placebo. The ACCORD-2 trial also achieved its key secondary endpoint of relapse prevention with 8.4% of AXS-05 patients relapsing versus 28.6% of patients switched to placebo with a p-value of 0.001. Results of the study demonstrated a statistically significant effect of AXS-05 not only when on agitation symptoms, but also on the severity of Alzheimer's disease overall, as assessed by the Clinical Global Impression of Severity, or CGIS, for Alzheimer's disease overall clinical status. AXS-05 substantially and statistically significantly prevented worsening of severity of Alzheimer's’ disease overall as compared to placebo with 13.3% of AXS-05 patients worsening on the CGIS for Alzheimer's disease overall clinical status versus 39.3% of patients switched to placebo with a p-value of less than 0.001. Also shown on this slide is the Kaplan-Meier curve, the time to worsening of severity for Alzheimer’'s disease overall, which was also highly statistically significant in favor of AXS-05 compared to placebo with a p-value of less than 0.001. AXS-05 was well tolerated in the trial with a similar overall rate of adverse events for AXS-05 and placebo, 29.3% and 32.1%, respectively, with no individual adverse events occurring in more than 3.7% of subjects. Two patients in the AXS-05 group experienced falls, only one of which was deemed related to study medication. Discontinuations in the double-blind period due to adverse events were low, 0% for AXS-05 and 1.2% for placebo. There were no deaths in the ACCORD-2 trial and AXS-05 was not associated with sedation or cognitive decline as assessed by the Mini-Mental State Examination, or MMSE. Turning now to the ADVANCE-2 trial. ADVANCE-2 was a double-blind, placebo-controlled parallel group trial of AXS-05 in Alzheimer'’s disease patients with agitation. 408 patients with probable Alzheimer's disease and associated clinically significant agitation were randomized 1:1 to receive AXS-05, which was dose escalated to 45 milligrams, 105 milligrams twice daily or matching placebo for 5 weeks. The primary endpoint of the trial was the change in the CMAI total score from baseline to week 5. Here is a summary of the demographics of the study population as well as some relevant baseline characteristics. Patients had a mean baseline CMAI total score of 71 in the AXS-05 arm and 73.5% in the placebo arm. The results of the primary endpoint are shown on this slide. AXS-05 demonstrated a reduction from baseline in the CMAI total score at week 5 of 13.8 points compared to a reduction of 12.6 points for the placebo group. However, this improvement did not reach statistical significance. Secondary endpoints also numerically favored AXS-05 throughout the trial. A key objective for ADVANCE-2 was to generate controlled safety data for AXS-05 in this patient population. We are pleased with the very positive controlled safety data from this trial. Adverse events were reported in 26% of subjects in the AXS-05 arm and 21.6% in the placebo arm. The only treatment-emergent adverse events that occurred in more than 3% of subjects in the AXS-05 group were dizziness and headache, which occurred in 5.9% and 4.4% of subjects, respectively, as compared to 1.5% and 3.4% of subjects in the placebo group, respectively. Falls were reported in 1 patient, 0.5% in each treatment group, which for the subject proceeding, AXS-05 was deemed unrelated to study medication. No deaths were reported in either treatment group and AXS-05 was not associated with sedation or cognitive decline as measured by the MMSE. The long-term safety of AXS-05 was evaluated in a total of 456 patients with Alzheimer's disease agitation who were treated with AXS-05 for up to 12 months. AXS-05 was well tolerated with long-term dosing. The overall rate of adverse events during the up to 12-month treatment period was 39.9% with headache being the only adverse event occurring in greater than 5% of subjects. The rate of falls for the up to 12-month treatment period was 3.1% with only 0.2% deemed related to study medication. Notably, this rate is similar to that observed in the placebo arms of trials conducted in this patient population. The rate of serious adverse events during the up to 12-month treatment period was 2.6%, none of which were deemed related to study drug. Discontinuations due to adverse events with long-term dosing were low at less than 1%. There were no deaths, and AXS-05 was not associated with sedation or cognitive decline. We are very pleased with these results. As Mark mentioned, AXS-05 has now been evaluated across a comprehensive clinical program that includes 4 pivotal randomized, double-blind, placebo-controlled multicenter trials in nearly 900 patients with Alzheimer's disease agitation. These studies along with a long-term open-label safety database support the efficacy and safety of AXS-05 in Alzheimer's disease agitation. As a reminder, we have engaged with the FDA throughout this program and have received feedback on our overall development plans as well as the design and analysis of these trials. We, therefore, can move expeditiously to file an NDA with the FDA, which we are preliminarily targeting for the second half of 2025. With that, I'd like to turn the call over to Sue Giordano, Axsome's Vice President of Medical Affairs, who will provide a brief overview of the indication. Sue, please go ahead.

Thank you very much, Herriot, and thank you all for joining us today. I would like to provide an overview of Alzheimer's disease agitation and the significant burden it can have on patients and their caregivers. In the U.S., there are currently 7 million people with Alzheimer's disease with the prevalence expected to grow to reach 14 million by 2060. Alzheimer's disease agitation is a common behavioral symptom in patients with Alzheimer's disease. The majority of Alzheimer's patients up to 70% will exhibit this symptom, which can be distressing for patients and their family members with a specific burden on loved ones who care for the patients often at home. Recognizing this as an area of unmet need, the International Psychogeriatric Association, or IPA, has created a standardized, validated diagnostic definition of agitation in individuals with cognitive disorders in order to facilitate research and clinical decision-making. Based on these guidelines, patients identified as having agitation must meet the criteria for cognitive impairment or dementia and must meet the criteria for agitation behavior with defined duration and severity, while ruling out attribution to other factors such as infection or environment. Agitation is often associated with verbal and physical aggression, but may also manifest as excessive motor activity such as pacing that can also impact a patient's ability to function and make caregiving more challenging. Alzheimer'’s disease agitation has a significant negative impact on patient outcomes. Compared to Alzheimer's patients without agitation, those with Alzheimer's disease agitation have a higher risk of mortality, a more rapid Alzheimer's disease progression and are more likely to be institutionalized. Alzheimer's disease agitation patients also have high rates of comorbidities, including psychiatric comorbidities with over 1/3 having anxiety or depression, making clinical management of these patients more difficult than patients without agitation. In addition to negative patient outcomes, there is a significant caregiver burden, which includes high rates of depression and stress. Alzheimer's disease agitation is an area of high unmet need for which effective and safe treatment options are in high demand among clinicians, patients and caregivers. I'd now like to turn the call over to Dr. Jeffrey Cummings, who has joined us today to share his expert perspective on the Alzheimer's disease agitation treatment landscape and his impressions on the results of the trials and overall clinical program. Dr. Cummings is the Director of the Chambers-Grundy Center for Transformative Neuroscience and Vice Chair of Research at the University of Nevada, Las Vegas Department of Brain Health and is a leading expert on Alzheimer's disease agitation. Dr. Cummings, thank you very much for joining us, and please go ahead.

Thank you, Sue. Good morning, everyone. Really great to be with you today. Exciting results to discuss. And I'd like to bring my perspective to bear on it. Just to reiterate about the unmet need that Sue recognized there as she says, there are about 70% of AD patients who have agitation. It's important to note that about 40% of patients with AD have treatable levels of agitation. So if we have -- we're on our way to 14 million people with Alzheimer's disease and 40% of 14 million will have treatable agitation at some point in the course of their illness. Very disturbing to the patient, very disturbing and disruptive to the family. There's one approved agent in the market, brexpiprazole, was approved in 2023. It clarifies the regulatory expectations for the treatment of agitation. I think that's a useful thing. It has a black-box warning. It's one of the challenges to using brexpiprazole. There's a lot of off-label use of drugs for treatment of agitation with risperidone or quetiapine. These drugs don't have FDA approval. They have less safety information. They have less efficacy information. I think we'd like to do alleviate clinicians of the vulnerabilities associated with use of off-label agents. The landscape is interesting. AXS-05 is clearly the leading compound. Other agents that are being developed. There's a lot of interest in cannabinoids, and there are several trials of cannabinoids in agitation. Dexmedetomidine, I think, is pretty interesting. It is a PRN drug only. So it would be a complement to the AXS-05 program, if it is approved. There's been a lot of recent attrition, including [indiscernible] prazosin and escitalopram in the landscape of developing agents. So in terms of our trials that we're discussing today, we have one negative trial, ADVANCE-2 and one positive trial, ACCORD-2. I think it's important to recognize that negative trials in neuropsychiatric symptoms are not uncommon. It's sort of a play because patients respond well to being in clinical trials. So we call these placebo effects, but I think there are clinical trial effects. The family has to get engaged in order to give informed consent. The patient sees a clinician regularly. There are ratings. They have a special status in -- if they're in a nursing home or assisted living. And all of these things tend to relieve the agitation that the patient is having. So this kind of marked placebo response that we saw in the ADVANCE-2 trial is not uncommon. It's also seen in depression, and that's why Maurizio Fava developed a serial -- the sequential parallel comparison design to try to get at these placebo effect to understand them better. We have the ACCORD trial, ACCORD-2 trial, which I think has an innovative design. It was unequivocally positive in terms of the time to relapse and also the percent of relapse with longer time to relapse in those on AXS-05 and a smaller percentage of relapse in those on AXS-05. I think this is pretty important. I like the randomized withdrawal design. I think it gives a clear information. It also gives information on enduring effects, how long disease effects last, which you can't get with a shorter parallel group design. It's also important information in nursing homes where there is a requirement for periodic withdrawal or periodic reduction in dose of antipsychotic medications or anti-agitation medications, both. And here, you have information about what will happen in those circumstances. So I think this is particularly important in long-term care. There's a lot more to understand in both of these studies. One peculiarity of the CMAI, the Cohen-Mansfield Agitation Inventory, is that each of the items, the 29 items has a score of 1 to 5. So if you have repeated questioning, which is one of the items, and it's very frequent, you'll get a score of 4 on that item. And if you have repeated biting, you'll get -- that's frequent, you'll get a score of 4 on that item. So there's -- the way this is managed is by having factors with some factors relating to very severe symptoms and other factors relating to less severe symptoms and we will have to understand that in both ADVANCE-2 and ACCORD-2 in order to give more insight from these clinical trials. So there's still a lot to do in terms of analysis. In terms of safety, there -- I think this is a really good safety profile. The only things that we're seeing were headache at more than 5% of individuals, I think that's good. Both deaths and impairment of cognition we're seeing in the Kd AD trial of multiple antipsychotics, and I think the absence of deaths or any impairment of cognition are important negative observations in terms of these studies. Just considering things more broadly, as we look forward to what could happen with AXS-05, the black-box warning is of interest. It's been applied to all antipsychotics. I think it's a great interest that it was not applied to KarXT, the muscarinic agonist that was recently approved for schizophrenia. And that gives me some hope that it's likely not to be applied to AXS-05 since this is not a typical antipsychotic mechanism that is commonly used in agitation. Finally, I'll stop with meaningfulness. There's about a 30% reduction over placebo, if you look across all these studies. That's very important to patients, very important to caregivers. And the overall global improvement suggests that there might be better function and better cognition when there is less agitation. So I think that's an important observation. So these are meaningful outcomes in terms of the programs that have been seen. I'll just quickly review these slides. I covered the material on Slide 28. Can I go to Slide 29, please? I think someone was going to advance the slides for me. Okay. Yes, thank you. So Slide 29 shows that there are multiple challenges. I mentioned a robust placebo improvement and how we're thinking about that and the benefit of randomized withdrawal designs with the longer-term data. Next slide. So we have a comprehensive Phase III clinical program, 4 programs with great safety and tolerability. Three of them have statistically significant outcomes, one does not. There's global improvement in Alzheimer's disease that was observed. I think that's encouraging, well tolerated in terms of safety and tolerability. Next slide. So I'm very happy to turn this back over to our group, and I'll be happy to participate in question and answers going forward.

Great. Thank you, Dr. Cummings. And operator, if we could turn the line over to questions now, that would be great.

[Operator Instructions] Our first question is coming from Joseph Thome from TD Cowen.

Congrats on the data. Maybe the first one for me, just what remains to be done ahead of the NDA submission, what's going to happen over the next 6 months. And is there any sort of granularity on the decision to do an NDA versus an sNDA? And then maybe one follow-up for the physician. Maybe just how would you use this drug if approved versus brexpiprazole?

Jeff, would you like to take that last question first?

Absolutely. I think we need to understand the profile of responsiveness of most of these drugs better. In general, I think I and other physicians are going to turn from drugs that don't have 2 drugs that do not have a black-box warning. So there is a certain liability associated with drugs that have the black-box warning. And I think AXS-05 is likely to come in without a black-box warning. So I think this would be your first choice and then patients who are unresponsive would certainly go on to some other drug and brexpiprazole as an approved agent would be your follow-up agent. So I think it's the likely order, although we need more information about the profile of response is going to be AXS-05 followed by brexpiprazole.

Great. This is Herriot. Just with regards to your question on time line to NDA filing, I think that, that was what was behind the question. What remains to be done is to prepare the filing. Now that we have all the studies completed successfully, we can move very expeditiously. It does take a while to make sure that things are written up. The other aspect is CMC. There are no manufacturing concerns. However, as you may recall, there is a separate dosage strength for AXS-05, which is used during the titration phase in Alzheimer's disease agitation. So we successfully manufactured those registration batches and that will be the -- one of the gating factors is just waiting for the required 6-month period to get stability data in order to file the NDA. So all in all, we feel very comfortable that we should be able to file an NDA by the second half of 2025.

Next question is coming from Leonid Timashev from RBC Capital Markets.

Happy New Year. Congrats on the data. I just want to ask maybe a bit about the discordance between ADVANCE-1 and ADVANCE-2. I guess any early thoughts on why there may have been a difference between these 2 trials as it relates to AXS-05's efficacy. And then as my follow-up, I guess, can you talk a little bit more about what you saw in the secondaries from ADVANCE-2, maybe things like response rate or responder analysis? And I'll hop back in the queue.

Sure. Thanks for the question. If you look at the patient population for ADVANCE-1 and ADVANCE-2, they were very similar. We just got the data. And as you can see, there was consistent separation between the 2 treatment groups, AXS-05 and placebo, although it did not reach statistical significance. One of the preliminary observations is that there is a greater placebo response in the ADVANCE-2 trial versus ADVANCE-1. The -- with regards to the secondary endpoints, what we saw also was numerical separation favoring AXS-05 as compared to placebo on almost all the secondary endpoints that were examined.

Next question is coming from Joon Lee from Truist Securities.

Congrats on the great data and thanks for taking our questions. So a question for Dr. Cummings. To what percentage of your treatable Alzheimer's patients, i.e., 40% of the 14 million, do you think you'll be offering AXS-05 to once it's approved? And related to that, related drug called AVP-786 with relatively similar mechanism of action as AXS-05 didn't work out exactly in ADA. Any thoughts on why the 2 drugs had different outcomes?

Yes. Thank you. Really great question and an informed question. You know the history of these drugs. The AVP-786 outcomes are mysterious to me. I led the Phase II program. We used the SPCD. It's the only time that, that particular trial design has been used in neurodegenerative disease and it was specifically designed to allow insight into the placebo response because you -- in the second phase of an SPCD, you do not include the placebo responders. And so it's a very unique design and that was a positive trial. It then went on to 2 parallel studies. And no drug placebo effect was seen, but those trials have also not been reported to at least to my knowledge. So I just don't have enough insight into what were those trials like? Where were they recruited? What was the severity of the agitation? What was the distribution of agitation in terms of the CMAI factors. These are the things that we would need to know in order to interpret the discrepancy between the positive Phase II and the negative Phase III study. So the AVP-786 program. So I just don't have enough insight into that. In terms of what percent, again, I think the safety profile here is very good for AXS-05 and the efficacy profile is good, taking into consideration a negative ADVANCE-2 study. So assuming that efficacy is acceptable to the agency, then AXS-05 would be your primary choice, your first choice with brexpiprazole being the second choice because of the black-box labeling and the safety concerns. So would you offer to everybody, all the 40%? You'll have a discussion with the family. These are all very individual decisions. But in general, you're going to give the safest medication. Now if the family has some sort of history of a good response to an antipsychotic in the past or the patient does and maybe you're going to go the other way. There are conditioning factors in every discussion of the family. But I think that in the market, you would place AXS-05 in -- as the first choice for most patients. So there will be exceptions to that rule. For most patients, you would chose a safer agent.

Next question is coming from Charles Duncan from Cantor Fitzgerald.

Herriot and team, thanks for sharing these results, taking our questions. Congratulations on the ACCORD-2 results. I did have a question for Dr. Cummings, and that is Dr. Cummings, what -- which of the 2 trials would you place the greater weight of evidence in terms of efficacy? It does sound like the ACCORD-2 trial gives you a lot of information, but when you compare these 2 results, which one are you more compelled by? And then I do have a follow-up for the company.

Thank you, Charlie. Good to hear from you. I think the ACCORD-2 is better evidence. I really like these randomized withdrawal studies. You have much less of a placebo response. You see that great response in the open-label portion before you randomize. And then you've got these 2 measures of the outcome, which is time to relapse and percent of relapse. So I happen to think that, that is stronger data. Now I think what the regulatory agencies will be thinking is what's more like clinical practice. And I think what's more like clinical practice are the parallel design. So both of these trial designs are going to come into the discussion when -- before the FDA because I think they have -- they appeal to different audiences. I'm interested in efficacy. And I think that information is strongest for withdrawal design. The agency is interested both in efficacy, but also in how does it play out in the real world. And I think they tend to emphasize the parallel designs, I wouldn't want to speak for them, but the parallel designs are very important to the agency.

And the 29% relapse or so in the control arm in ACCORD-2, do you think that's representative of what would occur in the real world? Is that consistent with what you would have anticipated?

Yes. Yes, I think that's right because you're still having a placebo effect. So there are some patients who, of course -- who don't relapse. But I would say that overall, in this length of observation, 21% is about what one would expect. And of course, that's important. That's a lot of people who become symptomatic in a fairly short period of time. So I would say that, that's what I would have expected.

Okay. And then for the company, just quickly back to an earlier question regarding sNDA versus NDA, especially given what Dr. Cummings just said about, call it, the regulators and perspective on the 2 different trial designs. Could you provide a little bit more color on your thinking about this versus an NDA versus an sNDA? Do you -- is the process similar in terms of the feedback? And in your minds, the requirement for, call it, the different trials working out? I know Brex didn't have a universally -- universal success across their trial. So what's your thinking there?

Charles, thank you for the question. Just as a reminder, I know that we are obviously talking about the new data that we released today. But -- let's not forget that we also have another Phase III trial, which is the ADVANCE-1 trial and also another Phase III trial, which is the ACCORD-1 trial. So it's -- we feel very, very comfortable and confident having data using both a parallel design as well as a randomized withdrawal design. And we -- we do agree that those 2 designs and the 2 data sets from those 2 designs will be very, very informative. As it relates to filing pathway, NDA versus sNDA, it doesn't really matter. Right now, what we would need to do in order to be able to file an NDA, whether that flavor is a full NDA or a supplemental NDA is not any different. So based on the 2 pathways. One other consideration that I know folks think about is the length of review. And just as a reminder, we do have breakthrough therapy designation for AXS-05 in Alzheimer’'s disease agitation, and that breakthrough is based on the positive ADVANCE-1 trial, which is a parallel group design. And that does offer us the possibility of a 6-month review, so regardless of whichever regulatory path we take.

Congrats on completing this robust program.

Next question is coming from Vikram Purohit from Morgan Stanley.

Two quick ones from us. One for the company. So on ADVANCE-2, could you remind us on the patient population enrolled, were all of these patients community dwelling similar to Advance-1? And then for Dr. Cummings. Just based on the data you've seen today and then also from ADVANCE-1 and ACCORD-1, would you expect assuming approval to use AXS-05 continuously? Or do you expect it to be more start and stop, especially for patients that are being treated in the nursing home setting?

So the answer to the first question, all of these patients were community dwelling. Dr. Cummings?

Yes. I think the use of the agent will be continuous for a matter of months until the patient has been agitation free for a period such as 3 months. These rules are not firm. But you don't want to be treating patients with drugs if they don't need them. So if the agitation has been adequately controlled for a period of 3 months, at that point, I would start withdrawing the medication to see whether they relapse. Now here, we know the relapse rate is high, but if you're treating a patient for a very long period of time, let's say they've been on the drug for 6 or 9 months and they don't have agitation during that -- or they have less agitation and almost no agitation for 3 months, then you're going to try to get that patient off of medication. And we just don't have that kind of long-term data from the trials. But I think doctors are not going to want to just leave patients on any kind of medication that aren't absolutely indicated. So I think the use will be long term, but not throughout the course of the illness. There will be a decision where the patient is brought off of the medication. And so that's the way we have used off-label medications until now. And that's why we'll be using on-label medications as they become more available.

Next question today is coming from Ash Verma from UBS.

So for ACCORD-2, I wanted to understand, do you think this study on its own is viable? Correct me if I'm wrong, but I think the study included all the previously studied ADVANCE-1 and ACCORD-1 patients. So these are effectively repeats and not unique patients from an NDA perspective. And we've seen this play out before with the Serina Therapeutics. So I just want to make sure this situation is different or not? And then for ADVANCE-2, so just comparing to the prior ADVANCE-1, it seems like your baseline is 10 points higher there. Is that the reason why the drug effect size could be a little bit lower?

Ash, this is Mark. I'll take the first question about feedback we've received from the FDA on ACCORD-2. And so the agency has been aware of the approach we're taking with ACCORD-2 and they've reviewed the protocol and the statistical analysis plan, and they provided feedback. And we've conducted the analysis according to the specific feedback they provided, which would be required for us to use in the study to demonstrate efficacy in this indication.

And as it relates to the second question, there will be differences across studies in terms of baseline. You do try to enroll the same patients in 2 similar studies, but the reality of it is that there will always be variance.

Next question is coming from Cerena Chen from Wells Fargo.

Congrats on the data. I wanted to ask a follow-up on the baseline demographics. If you have the percent of patients in ADVANCE-2 who may have already been on Rexulti? And then a question for the company. Just do you have any expectations for an AdCom given the results of ADVANCE-2?

Just with regards to the baseline question, there were some patients who were on background antipsychotics. We don't have -- it's a lot of data, so we don't yet know which of those background antipsychotics that they were on, but it was the minority of patients in the trial. And as it relates to your AdCom question, that's a decision for the FDA. But it's -- the question as it relates to the potential reason for an AdCom, it's difficult to know and predict when the agency will decide to have an AdCom. If you look at our program, though, we feel very encouraged that we have won an agent which is already approved for another indication. But importantly, we have 3 positive pivotal trials. As you know, the statutory requirement for demonstration of efficacy is 2 positive trials. So we feel very pleased to have 3 positive trials using 2 different treatment paradigms.

Next question is coming from David Amsellem from Piper Sandler.

So I have 2 questions for the featured key opinion leader. Number one, and I apologize if you addressed this earlier, but wanted to further tease this out. Just how do you see the role of Rexulti once Auvelity is available for AD agitation? In other words, in a space that has been so dominated by atypical antipsychotics, even an approved antipsychotic like Rexulti, do you see a diminution of usage of that product in favor of Auvelity? And just how do you see the 2 stacking up in commercial practice? And then secondly, I know that there is a Phase II study ongoing for lumateperone, a deuterated form a lumateperone or CAPLYTA for Alzheimer's agitation. So another next-generation atypical antipsychotic. I'm wondering about your thoughts on that and how that product would have a role in the AD agitation landscape.

So I can't comment on the second because I don't really know about that program. And I simply can't comment on it. The Rexulti question, I think, is an interesting one. If patients are responding well with their agitation, then docs aren't going to change it. You're trying to achieve some degree of harmony in the home for your patients. And if Rexulti has done that, you're going to leave them on Rexulti. I think the question is going to be more about, well, how does the doc make the choice between AXS-05 in Rexulti once both are approved and you're starting a patient for the first time. And there, I think the black box will weigh heavily on the thinking of the prescriber and the prescribing system. Most docs are in systems now and the systems have rules, and those rules are -- often include tolerability and safety as well as efficacy. So I think AXS-05 will be well positioned to compete with Rexulti, but I think there will continue to be robust result to use because docs are familiar with it. So I think my guess and I'm far from this, I'm a guy who likes drug development and don't know about markets, but I would guess that both of these will have important use in the market.

Next question is coming from Ami Fadia from Needham & Company.

Congratulations to Axsome for putting together this robust data set. I have 2 questions. One is for the management team. There have been a few questions along the way around just how the FDA is likely to view the sort of failed ADVANCE-2 on the primary endpoint, but in the context of the 3 additional positive Phase III studies, could you sort of just remind us on any conversations you might have had on FDA's view on the need for 2 parallel design studies or whether -- or how they would sort of accept or view a randomized withdrawal study design? And then a second question for Dr. Cummings. Can you tell us what percent of the 40% treatable Alzheimer'’s disease patients are currently being treated with any antipsychotic and with the availability of AXS-05, do you expect more patients to be brought under treatment given the availability of a potentially safer treatment? Yes, that would be helpful.

Dr. Cummings, do you want to take the question for you first?

Yes, absolutely. Really interesting question. Thank you for it. So how do we get to these data that I quoted? Well, 70% of patients have a score of at least 1 on the neuropsychiatric inventory agitation domain. So you say, well, they're agitated and they definitely have agitation. On the other hand, the patient with a score of only 1 is having infrequent or not very severe agitation and, therefore, many docs, including me, would not treat that patient. But 40% of patients with Alzheimer's disease dementia have NPI scores of greater than 3. And that's enough agitation to be very distressing to the patient. They're obviously upset about something and very disturbing to the family. So those -- that's how we think quantitatively about these 2 states. So most of those patients, I don't have a number for you, but I would guess that 70% or 80% of those patients are currently being treated with something with quetiapine being the most commonly used agent for agitation and risperidone being the second most commonly used agent for agitation. So there's a huge amount of off-label use that I think will be switched -- is being switched to brexpiprazole now and will be switched to AXS-05 in a substantial number of patients as it comes on to the market. And I think there is just too much liability to continue to use off-label agents when there will -- at that point, be too, on on-label -- not patients, but on-label medications for use with patients. And so I think we will see a migration from the off-label use, which is very common now in a lot of patients to on-label use as we get more familiar with these drugs.

Sorry, just a very quick follow-up there. So could you give us a sense of what percent of patients get used -- get treated with either quetiapine or risperidone versus Rexulti?

Rexulti hasn't had, I think, a large uptick. I don't know these numbers. I haven't seen them reported somewhere. But I would guess at this point that maybe Rexulti has acquired 20% of the previous market, something like that. I think it takes a while to have docs understand the availability of new medications and what the advantages of drugs that are approved by the FDA and have a safety and efficacy profile that has been rigorously reviewed. So it takes a while to change prescribing habits, and I would say that, that's happened probably even 20% in that market at this point.

Great. And this is Mark. So with respect to our engagement with the FDA, we've received feedback from the FDA on an ongoing basis throughout the entire program. And we have feedback from them that we need 2 adequate and well-controlled trials, which aligns with the statutory requirements. We have feedback that ADVANCE-1 will serve to review component contribution and demonstrate component contribution. We have feedback that we needed one additional trial in addition to ADVANCE-1 and that we need a stand-alone long-term exposure, safety database. We have those numbers now, as we mentioned earlier today, and that we also needed parallel group controlled safety data, which we now have from ADVANCE-1 and ADVANCE-2. And again, with respect to ACCORD-2, we conducted the statistical analysis plan and the analysis of the study according to the specific feedback that we received from the FDA, which we would need to do in order to use the study to demonstrate efficacy in this indication.

Next question is coming from Marc Goodman from Leerink Partners.

This is Basma on for Marc Goodman. We have a follow-up question on the difference between the baseline characteristics between ADVANCE-1 and ADVANCE-2. As it was mentioned before, ADVANCE-1 seems to be severe than the ADVANCE-2 by 10 points. So we had a score of 60 for CMAI versus 70 for ADVANCE-2. Does it mean that Auvelity maybe more effective in the less severe patient population? And along the same line, could you please share the NPIA score for baseline for ADVANCE-2 and ACCORD-2?

Thank you for the question. There's a lot of data and these are top line results, so we'll need to go through the data in greater detail. But looking at the data for ADVANCE-1 and by CMAI scores, what we did see was consistent responses, both for higher scores as well as for lower scores.

What about the NPI AA score? Was it -- can you please share those scores or not?

So the NPI AA scores were definitely similar between the 2 studies because that was a requirement for entry into the study.

Next question today is coming from Graig Suvannavejh from Mizuho Securities.

Calling from Turkey. First of all, congrats on the data. Just a few questions, maybe for Dr. Cummings. Thanks for sharing your comments. Doctor, you had mentioned that the use of Rexulti is relatively low right now in relation to perhaps quetiapine and risperidone. And I'm wondering if you feel that reflects perhaps more of a payer reimbursement dynamic relative to perhaps lack of awareness that there is a label drug or perhaps it reflects maybe a certain lack of satisfaction by prescribing physicians given whether it's a black-box warning or given lack of efficacy in this patient population. So if you could comment on that. And then I guess a follow-up for you, Dr. Cummings, would be if AXS-05 were approved and given that the assumption would be it would not perhaps have a black-box warning, do you think brand pricing relative to the availability of alternative cheaper generics that are already used, how much of a hurdle do you think that might be?

Yes. Thank you. Hope you're enjoying Turkey. These are marketing questions and I'm a clinical and trial guy. I'll give you my answers, but please take them with a note of caution. So I think it's highly likely that systems are, of course, paying attention to differences in price and we've got generic agents versus branded agents. Nevertheless, I think the importance of FDA approval is very great in terms of the liability of the doc and the system. So I think we'll -- even though there is price sensitivity regarding this and that probably translates sometimes into the patient's price sensitivity if they're bearing the price, then -- and those patients aren't going to be moved on to a branded agent because they just can't afford it. So I think there is price sensitivity in the market, but I think there's also counter portions with regard to approval and liability issues that will move the market gradually towards brexpiprazole and eventually AXS-05. The other thing that amazes me is that if you look at nearly all of the studies of agitation in Alzheimer's disease with quetiapine, they're negative. You don't see a positive study until you get above 200 milligrams and almost no patients are treated with 200-milligram of quetiapine. So these are mostly very robust placebo responses that you see in ACCORD-2 are also what people are seeing in the market and they're satisfied with that. It's a little bit crazy. So I think there are odd forces at play here. I think the major one is prescribing conservatism. And then with regard to price sensitivity in AXS-05, of course, I'll let the company comment on that, but this is a competitive market and there will be an important aspect of pricing.

And Dr. Cummings, I would like to just follow-up just quickly. Your perception of awareness amongst the Alzheimer's clinician community of AXS-05 for Alzheimer's agitation, would you just describe that as high or modest or low?

I think it's low right now. These drugs don't become into the doc's mind unless you're clinical trialists. Until they get into the market, they begin to see advertisements. They begin to see publication, primary and secondary publications. So I just -- and the other dextromethorphan drugs have not had very much of a market presence. AVP-786 didn't make it. The new dextro compound had very little use. And so in general, this passive agent is not well known in Axsome among them.

[Operator Instructions] Our next question is coming from Jason Gerberry from Bank of America.

Just to follow up on the question or the comment about the 6-month stability. Is that work just starting and I would have assumed that, that would have been parallel processed with these previous studies that they should be ready to file? Or was that a late FDA request to generate that stability data? I'm just sort of a little bit confused with the sequencing there.

Jason, there's nothing new there. And as Herriot mentioned, those batches are produced. So -- but recall that those data have to be incorporated into the NDA. And so that lines up with just building the NDA with the clinical study reports, et cetera. I think the question was just being thorough in the response.

Okay. So you have the 6-month stability data already then?

I don't know exactly how many months of data we have, but a reminder, I believe the current shelf life for Auvelity is over 24 months and the products are -- the formulations are very, very similar. So I don't have a comment on the potential shelf life at this time, but we don't expect any issues with it.

Next question is coming from Joel Beatty from Baird.

A follow-up question for the company on FDA's feedback. What feedback have you gotten from the agency with regards to ACCORD-1 and whether that accounts as a pivotal trial given that it was stopped early?

Joel, that's a key consideration. So we know there -- we have -- with respect to ACCORD-1 and just in general, with respect to the 2 studies that we need, they can be different trial designs. And as a reminder, the statutes actually indicate that different trial designs are advantageous for controlling type 1 error. So keep that in mind, you did raise one of the key considerations with ACCORD-1, which is that it was stopped early. But the design itself, again, we have specific feedback from the agency on that as well as how that design should be analyzed.

One of the other points to add is the concordance of the results between ACCORD-1 and ACCORD-2, which were almost identical. So if you look at the hazard ratios for ACCORD-1, it was 0.275 and for ACCORD-2, it was 0.276 as well as the percentage of patients who relapsed. So the studies really do complement each other and are very consistent.

Next question is coming from Myles Minter from William Blair.

Maybe one for Dr. Cummings. You did mention that the CMAI measures a variety of agitation symptoms, some of which are, at least for my look, they're much more severe than others and different levels of subjectivity. So I'm just wondering whether or not AXS-05 had any sort of differential efficacy on much more physical symptoms like pushing, shoving things, biting, scratching versus a more subjective endpoints like the being negative, complaining that sort of thing and whether or not that could explain why we saw a higher placebo effect here in ADVANCE-2?

Yes. Very good question, and you're obviously very familiar with the CMAI. I can't wait to get that answer as a matter of fact, but we just haven't had the data long enough to be able to look at the factor scores of the CMAI in terms of both the placebo response and in terms of the active therapy response is because more severe symptoms tend to require medication compared to the response to placebo. It would be very interesting to know whether those patents -- whether the physically aggressive items that you're mentioning, pushing, shoving, hitting, biting are more affected by AXS-05 than placebo, we just don't have that information right now and that's one of the things we've discussed as a priority in terms of the analysis.

Our final question today is coming from Matt Kaplan from Ladenburg Thalmann.

I guess for Dr. Cummings, with respect to the long-term safety data that we now have out with patients greater than 12 months for AXS-05, can you comment a little bit more on your perspective with respect to its safety profile with respect to impact on cognition and morbidity and mortality versus the atypical antipsychotics that are being used and approved or approved?

Yes. These drugs are approved on relatively short trials and short exposures and used long term, and that's true of all of these drugs. It's great that we have this longer-term data that you saw today on AXS-05 because the safety profile looks like it holds up over enduring use. So I'm pretty happy with that. The Rexulti data and all atypical antipsychotics at this point have the black-box warning based on excess mortality and some of the atypical antipsychotics have a bolded warning on excess stroke. So we haven't seen that in the AXS-05 program. It's also true that we have much more data on the atypical antipsychotics than we do on AXS-05. So although there's no reason to expect to see either the mortality signal or the stroke signal with AXS-05, we had to be cautious about how much more data we have with the extensive use of atypical antipsychotics than we do with AXS-05, but at this point, I would say that the differential safety concerns are very much in favor of the AXS-05 being the safer agent.

We've reached the end of our question-and-answer session. I'd like to turn the floor back over for any further or closing comments.

Thank you all for joining us for today's call focusing on the top line results from the ACCORD-2 and ADVANCE-2 Phase III trials. Also, a special thank you to Dr. Cummings for his perspective. So we are pleased to share the news about the successful completion of our clinical trial program, evaluating AXS-05 in patients with Alzheimer's disease agitation, where we now have robust efficacy demonstrated in a third pivotal placebo-controlled trial to go along with the favorable safety and tolerability profile, reinforced by data from a long-term open-label extension trial. I want to take the time to thank everyone who helped to make this happen, including the Axsome team and the dedicated health care professionals, patients and their caregivers who took time to participate in the study. Thank you again, and have a great new year.

Thank you. That does conclude today's teleconference and webcast. You may disconnect your line at this time, and have a wonderful day. We thank you for your participation today.