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

Good morning, ladies and gentlemen, and welcome to Axsome Therapeutics' conference call. [Operator Instructions] As a reminder, today's conference call is being recorded. I would now like to turn the conference over to your host, Mr. Mark Jacobson, Chief Operating Officer, Axsome Therapeutics. Please go ahead.

Thank you, operator. Good morning, everyone, and thank you for joining us on today's conference call to discuss the positive top line results from the ADVANCE-1 Phase II/III trial of AXS-05 in Alzheimer's disease agitation. A press release announcing that AXS-05 achieved the primary endpoint in the trial crossed the wire a short time ago and is available on our website at axsome.com. During today's conference 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 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; 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 Axsome's management team are Dr. Herriot Tabuteau, Chief Executive Officer; Dr. Cedric O'Gorman, Senior Vice President of Clinical Development and Medical Affairs; Mr. Nick Pizzie, Chief Financial Officer; and Mr. Dave Marek, Chief Commercial Officer. Herriot will start by providing an overview of today's announcement before turning the call over to Cedric, who will review in greater detail the top line results of the ADVANCE-1 clinical trial. Following Cedric's presentation, we will open the line for Q&A. To close off the call, Herriot will make some concluding remarks. I shall now turn the call over to Herriot.

Thank you, Mark. Good morning, everyone, and thank you for joining us on the call today. We hope that you and your loved ones are staying safe. We are extremely pleased to announce that AXS-05, Axsome's novel, oral, NMDA receptor antagonist with multimodal activity, met the primary endpoint in the pivotal ADVANCE-1 Phase II/III trial by significantly reducing agitation symptoms in patients with Alzheimer's disease. The ADVANCE-1 trial randomized 366 Alzheimer's disease patients with clinically significant agitation to treatment with AXS-05, bupropion or placebo. This trial is one of the largest randomized controlled trials in this condition. AXS-05 met the primary endpoint by demonstrating a rapid, substantial and statistically significant mean reduction in the Cohen Mansfield Agitation Inventory, or CMAI score, as compared to placebo at week 5, with a P value of 0.010. The benefit of AXS-05 was seen as early as the second week of treatment. Furthermore, AXS-05 was superior to bupropion on the CMAI total score, with a P value of less than 0.001, establishing component contribution as required by the FDA's combination product rule. These results were clinically meaningful, with AXS-05 treatment resulting in an almost 50% reduction from baseline in agitation symptoms. In addition, a statistically significantly greater percentage of patients showed improvement on the modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change for Agitation as compared to placebo. Similarly, a significantly greater percentage of AXS-05 patients experienced a clinical response, defined as a 30%-or-greater reduction in agitation on the CMAI, with a P value of 0.005. We are also pleased with the favorable safety and tolerability profile of AXS-05 in this elderly patient population. Importantly, treatment with AXS-05 was not associated with cognitive impairment or sedation. The results of the ADVANCE-1 trial represent an important milestone potentially for patients and for the clinical and scientific community, given the lack of approved treatment for Alzheimer's disease agitation and a serious and distressing nature of this disease. We look forward to discussing these data with the FDA. As a reminder, AXS-05 has been granted FDA Fast Track designation for the treatment of Alzheimer's disease agitation. The ADVANCE-1 trial exemplifies Axsome's commitment to developing new, effective treatments that address the needs of patients living with difficult-to-treat CNS diseases. AXS-05 is an oral NMDA receptor antagonist with multimodal activity, including sigma-1 receptor agonism and in addition of the reuptake of serotonin, norepinephrine and dopamine. AXS-05 uses a metabolic inhibition to increase the plasma concentrations of its dextromethorphan component into a therapeutic range. We have now generated positive efficacy data across 4 different indications with AXS-05, which highlights a potentially broad applicability, the unique pharmacology of this novel, oral investigational medicine. These indications include major depressive disorder or MDD; treatment resistant depression or TRD; smoking cessation; and now Alzheimer's disease agitation. We remain on track to file our planned NDA for AXS-05 in MDD in the fourth quarter. As a reminder, AXS-05 has been granted FDA Breakthrough Therapy designation for the treatment of MDD. We also remain on track to file an NDA for our AXS-07 product candidate with the acute treatment of migraine in the fourth quarter of this year. Now Alzheimer's disease is the most common form of dementia, and it is characterized by cognitive decline and behavioral and psychological symptoms, including agitation. Agitation is reported in up to 70% of the approximately 6 million Americans with Alzheimer's disease, translating to an estimated 4 million patients in the U.S. currently living with Alzheimer's disease agitation. Agitation is characterized by emotional distress, aggressive behaviors, disruptive irritability and disinhibition. Its management is a major medical priority, as it is associated with decreased functioning, increased caregiver burden, accelerated cognitive decline, earlier nursing home placement and increased mortality. Because there are no approved medications for the treatment of Alzheimer's disease agitation, physicians must resort to off-label treatments, typically antipsychotics. These agents have modest or uncertain efficacy, and because of well-known and documented safety concerns, carry FDA black box warning, specifically against their use in elderly patients with dementia. There is, therefore, an urgent need for safe and effective treatments for Alzheimer's disease agitation. The production and accumulation of insoluble beta-amyloid protein is thought to be central for the pathophysiology of Alzheimer's disease. This accumulation triggers a number of secondary steps that result in synaptic loss, neuronal cell death and a decrease in specific neurotransmitters. The neurotransmitter alterations are thought to contribute to the cognitive and behavioral symptoms associated with Alzheimer's disease, including agitation. AXS-05 modulates the function of serotonin, glutamate, sigma-1, norepinephrine and dopamine, which are neurotransmitter systems implicated in Alzheimer's disease. AXS-05 may therefore enhance synaptic transmission and improve the functioning of cortical circuits in patients with Alzheimer's disease and agitation. I would now like to turn the call over to Cedric, who will review the ADVANCE-1 top line results in greater detail.

Thank you, Herriot. The ADVANCE, or Addressing Dementia via Agitation-Centered Evaluation, study was a pivotal Phase II/III randomized, double-blind, controlled, multicenter, 5-week trial conducted entirely in the United States. A total of 366 Alzheimer's disease patients with clinically significant agitation were randomized initially in a 1:1:1 ratio to receive treatment with AXS-05, bupropion or placebo for 5 weeks. After an interim futility analysis, further randomization to the bupropion arm was stopped. And subsequently, patients were randomized in a 1:1 ratio to receive AXS-05 or placebo. A total of 159 patients were randomized to receive AXS-05, 49 to receive bupropion and 158 to receive placebo. Dosing was titrated, with patients receiving an AXS-05 dose of 30 milligrams dextromethorphan and 105 milligrams bupropion once daily during the first week; twice daily during the second week; and at the target AXS-05 dose of 45 milligrams dextromethorphan and 105 milligrams bupropion twice daily thereafter. The primary endpoint of the study was the change from baseline in the Cohen Mansfield Agitation Inventory, or CMAI, total score at week 5. The CMAI is a 29-item scale that assesses the frequency of agitation-related behavior, including excessive motor activity such as pacing and restlessness, verbal aggression, such as screaming and shouting and physical aggression, such as grabbing, pushing and hitting in patients with dementia. Eligible patients were between 65 and 90 years of age, had a diagnosis of probable Alzheimer's disease according to the 2011 National Institute on Aging Alzheimer (sic) [ National Institute on Aging and Alzheimer's Association ] criteria and a diagnosis of clinically significant agitation according to the International Psychogeriatric Association provisional definition of agitation. Patients were required to be community dwelling, with Mini-Mental State Examination scores of between 10 and 24, indicating mild to moderate cognitive impairment. Clinically significant agitation of study entry was documented by a score of 4 or more on the Neuropsychiatric Inventory, or NPI, agitation/aggression domain. Baseline demographics and clinical characteristics were broadly similar across treatment groups. The mean age of patients was approximately 75 years. The mean CMAI total scores at baseline were 60.7, 59.4 and 66.1, respectively, for the AXS-05, placebo and bupropion groups. The CMAI does not have a natural 0 point. Therefore, the minimum score on the CMAI is 29, indicating no agitation, with higher scores corresponding to greater agitation. Study completion rates were high in this study, with 86% of patients in the AXS-05 and placebo treatment arms completing the study. Approximately 24 randomized were discontinued early from the study, solely out of precaution relating to the COVID-19 pandemic. Adjusting for these patients, the study completion rate would have been approximately 94%. Now to the efficacy results. AXS-05 met the primary endpoint, demonstrating a rapid, substantial, clinically meaningful and statistically significant mean reduction from baseline on the CMAI. At week 5, AXS-05 had a statistically significant reduction in CMAI total score of 15.4 points compared to 11.5 points for placebo, with a P value of 0.010. Component contribution was demonstrated, as AXS-05 was also superior to the bupropion arm, which performed similarly to the placebo arm with a P value of less than 0.001. Importantly, the benefit of AXS-05 on agitation as compared to placebo was observed as early as week 2, reaching statistical significance at week 3 or only 1 week after receiving the full dose of AXS-05, with a P value of 0.007. This rapid onset of effect of AXS-05 has now been observed across multiple indications. These point improvements on the CMAI equates to an almost 50% reduction in agitation symptom frequency with AXS-05, demonstrating a very clinically meaningful effect with the clinical benefit being observed as early as week 2. AXS-05 resulted in a clinical response defined as a 30% or greater reduction in the CMAI total score in the majority of treated patients. A 30% cutoff is widely regarded as clinically meaningful. At the end of treatment, 73% of patients receiving AXS-05 experienced a clinical response compared to 57% receiving placebo, with a P value of 0.005. The results from the CMAI total score were internally consistent with the clinician-rated modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change for Agitation, which demonstrated statistically significantly greater improvements with AXS-05 compared to placebo, with a P value of 0.036. Safety and tolerability is especially important in this elderly patient population. AXS-05 was very well tolerated in this trial. The most common adverse events in the AXS-05 treatment arm were: somnolence, which occurred in 8% of AXS-05 patients compared to 4% and 3% for bupropion and placebo, respectively; dizziness, which occurred in 6% of AXS-05 patients compared to 10% and 3% for bupropion and placebo, respectively; and diarrhea, which occurred in 4% of AXS-05 patients compared to 6% and 4% for bupropion and placebo, respectively. Importantly, the rate of falls in patients receiving AXS-05 was low and comparable to placebo, occurring in about 2% of each group. Discontinuations from study due to adverse events in patients receiving AXS-05 was low and similar to placebo at about 1% in each group. The rate of serious adverse events was lowest in the AXS-05 arm, and none of these were deemed to be drug-related. There were no deaths in the AXS-05 treatment arm. Importantly, there was no evidence of cognitive decline for patients treated with AXS-05 as shown by the Mini-Mental State Examination, and treatment with AXS-05 was not associated with sedation. In summary, in the ADVANCE-1 study, AXS-05 met the primary endpoint by demonstrating a substantial, rapid, clinically meaningful and statistically significant reduction in agitation, measured by the CMAI, as compared to placebo after 5 weeks of treatment. Over 70% of patients receiving AXS-05 reported a clinically meaningful response on the CMAI, defined as an at least 30% reduction from baseline. Statistical superiority was also achieved by AXS-05 on the clinician-reported global measure of change in agitation, as reported on the modified Alzheimer's Disease Cooperative-CGIC (sic) [ modified Alzheimer's Disease Cooperative Study-CGIC ]. AXS-05 was well tolerated with low rates of adverse events and discontinuations due to adverse events. Importantly, for this elderly Alzheimer's disease patient population, AXS-05 was not associated with sedation or with cognitive impairment. Alzheimer's disease exerts a significant toll on patients, their caregivers and loved ones. We would like to thank the patients, their caregivers and investigators for participating in this groundbreaking trial. With that, I would like to hand the call back over to Herriot.

Thank you, Cedric. I would like to hand it back to the operator to open the line for questions.

[Operator Instructions] And our first question today comes from the line of Yatin Suneja from Guggenheim Partners.

Congrats on these results. Very nice positive surprise, I must say. Can you maybe just talk about the -- first, the approval pathway? What needs to be done? Do you need to conduct another trial to get the approval? And then I have a follow-up.

Thank you for the question. The -- so our baseline assumption has always been that we would need 2 positive trials in order to file an NDA for AXS-05 in Alzheimer’s disease agitation. This is a pivotal study. We've designed as such. So this is our one study and so the baseline assumption is that we would need a second trial.

Okay. Very helpful. Then the question is on the severity of the disease in these patients because if you look at the CMAI score, it is somewhere in the 60 range. But if you look at some of the other studies in the space, it was a little bit higher, maybe somewhere in the 70s. So just trying to get a sense of how severe these patients are. You did that trial in community setting. Does that sort of imply that these are maybe not the most severe patient? And then if you also could comment on the rate of fall. It was definitely lower in the drug arm. Can you comment what might be driving it in the bupropion arm? Because it was pretty high there.

Thanks for the question. First of all, as regards to the severity of agitation, no, these CMAI scores are in keeping with the literature that we've seen. They definitely reflect moderate to severe agitation. Also, the inclusion criterion, which we use to identify moderate to severe agitation, is measured by the NPI agitation/aggression score, and that's commonly used to ensure that a sufficient threshold of agitation is present in these patients.

Falls?

Oh, falls. So the rates of falls were low. They were comparable to placebo, slightly more than in the bupropion arm. But still, I think that for a patient population of this age group, the falls rates overall were low. So that was encouraging too.

Good. And just final question, if I may. Like do you have -- given that now that you've shown that there is an anti-agitation properties of the drug, do you sort of plan to move into some other indication like schizophrenia or bipolar? Any readthrough that you see here? Or are there any significant differences in these types of agitation? And I'll get back in the queue.

That's a good question. One of the things that we're looking at is the neurobiology of agitation and the cortical circuits that are involved in agitation. So we've looked at that very closely for Alzheimer’s disease. Some of those same circuits may be involved in other conditions, specifically the interaction between limbic circuitry and funnel circuitry. So we're looking at that, and we'll -- but right now, obviously, we're focused on Alzheimer’s disease agitation. That's where the greatest clinical need is. There currently is no product that is approved to treat this condition. And as we know, it has significant consequences beyond the agitation.

Our next question comes from the line of Marc Goodman from SVP Leerink (sic) [ SVB Leerink ].

Yes, Herriot, maybe you could just talk about the market today and the standard-of-care and what's used and how your product compares to that with respect to the data? And you talked about the CMAI changes that are clinically meaningful. And so what has been shown to be clinically meaningful so far and how you compare to that?

Sure. Sure, Marc. I'll make some initial comments, and I'll let Cedric add to that. So with regards to the current market, there currently is no product that is approved to treat Alzheimer's disease agitation. This is a serious condition. And physicians are in a very difficult position right now because the only products -- the products that are currently used off-label are antipsychotics. And those -- and all antipsychotics carry an FDA black box warning, specifically against their use in elderly patients with dementia, including Alzheimer's disease. And the reason for that is they've been shown to double the risk of mortality and also of cerebrovascular incidents. So basically, stroke. So physicians do not want to use these product candidates. But when you have a patient who is agitated and who cannot be controlled and who is at risk to themselves and to family members potentially, something must be done. So the clinical need here is great. And in all the antipsychotics are used, the randomized data shows that they're not effective. And it is possible obviously to control anybody's agitation by significantly sedating them. But in patients who are elderly, obviously, that is a -- there is a significant risk of inducing falls. So the clinicians do not like to do that. And also, it -- as you can imagine, that also further impairs cognition, which is a hallmark of the disease. So that's the current market. So this is a need -- there is great. And with regards to clinical significance, I'll turn that over to Cedric.

Yes. Thanks, Marc, for the question. So it's generally regarded that a 30% or more improvement in the CMAI is clinically meaningful. And as you can see from these data that practically 3/4 of patients experienced that degree of response. Now on average, however, the patients treated with AXS-05 had an almost 50% reduction in their symptoms of agitation from baseline. So really, a great magnitude of an effect there. So these results are very good. And also, what's particularly encouraging is that you want to treat agitation in the community, so that you reverse the risks or you delay the nursing home placement, the accelerated cognitive decline. That's where you can really make an impact. And then you don't get into that bad cycle of patients being -- people use the expression zonked out or heavily sedated with benzodiazepines or even worse, still using antipsychotics with all the risks associated with them that Herriot mentioned.

And have any of the other companies that have been working on this ever gotten to this point with respect to showing a clinically meaningful benefit in their study?

So Marc, the -- so this has been an area of drug development in general, which has not been kind to drug developers. Alzheimer's disease, as we all know, is a very difficult clinical indication that running these studies are challenging. And most companies that have attempted to develop products in this area have not had success or had very, very mixed results. So we're very pleased. We're very pleased with the results, especially because the high clinical need in terms of what this means potentially for patients. And because of the lack of product candidates and the previous failures, this is obviously also a significant milestone for the clinical as well as scientific community.

Our next question comes from the line of Charles Duncan from Cantor Fitzgerald.

Congratulations on what looks to be another very well-executed clinical program. Had a couple of questions. One is going back to the question regarding next steps and clinical meaningfulness. This is a 5-week treatment period study and then that makes sense to me. But when you think about next steps in terms of the next study, would you anticipate that to be longer duration? Or how would it differ from this particular study? And when would you anticipate being able to articulate the design and start of that study?

Thank you, Charles, for the question. So the ADVANCE-1 study was designed as a pivotal study, and it was designed in consultation with the FDA. And the -- in terms of next steps for registration, we do anticipate that we would need 2 studies. So this is one. The next study, we would not anticipate being of longer duration. Our assumption going into the study design was that 5 weeks was an adequate period of time. This is in keeping with developing other drugs for neuropsychiatry, for example, in depression and schizophrenia, where in order to demonstrate a treatment effect, you conduct studies over a 4- to 8-week period. Now others have had to go longer because it's taken longer for their drugs to actually show an effect. So other studies have not shown separation from placebo until about 12 weeks. And it does not even -- that is statistical separation in the very few that have worked and that have been analyzed through post hoc analyses. So no, I mean, we think that this was the right period of time. And this decision was made in consultation with the regulatory agencies. And with regards to the precise design of the trial, I think what we can say right now is this, the ADVANCE-1 trial, one of the benefits of it is it did demonstrate component contribution very handily. So we would not anticipate that the next study would need to have -- would need to be a [ 3 on ] trial. And so we would anticipate that study to be AXS-05 versus placebo. And we are looking forward to meeting with the FDA to discuss these results. And upon having those discussions, we will update you on the design of the next study.

Okay. That's helpful. I'll assume perhaps in the second half of this year and to hear more. With regard to really the potential for use in AD, you laid out some very nice, call it, mechanistic rationale and use in -- for the use of AXS-05 in AD. But I'm kind of wondering if you think that the drug could work in other dementia settings that have agitation as a component such as Lewy body. It would seem like that would be the case, but what are your thoughts there?

That is certainly a possibility. And one of the benefits of studying a particular disease or particular indication is that you're answering one question at a time. And we -- and that's how we design our study. Now it turns out that Alzheimer’s disease is, of course, the most common form of dementia, accounting for at least 60% of dementia. So this is the bulk of the clinical need. But certainly, we would explore, in the future potentially, other types of dementia, such as Lewy body or vascular dementia.

Okay. And then last question is regarding agitation in Alzheimer's versus psychosis. There's other programs that have worked on dementia-related psychosis. And I'm just kind of wondering if you could provide us your perspective on, call it, agitation versus psychosis in terms of differential diagnosis and what is really the more burdensome kind of symptom complex that you see when you've talked to KOLs about that and whether or not this drug would compete with other drugs that had been evaluated in dementia-related psychosis?

So it's -- both of these symptoms and these complications of Alzheimer’s disease are obviously very serious. And so Alzheimer’s disease patients do have neurobehavioral symptoms, including agitation and including psychosis. While -- so if you look at psychosis, why only antipsychotics do carry the black box warning against their use, at least we know that antipsychotics do work in psychosis. Currently, there is no drug that is approved for agitation. It is widely regarded, agitation that is, as being one of the most difficult symptoms to treat in Alzheimer's disease. And currently, there is no product that is currently approved. Agitation is one of the primary reasons for nursing home placement, meaning the patients get separated from their families. And we know that it is associated with an acceleration or progression to severe dementia and also that it is associated with increased mortality. So we -- there certainly is great clinical need there. But obviously, there's a lot of clinical need for other neurobehavioral symptoms, too.

Our next question comes from the line of Joseph Thome from Cowen and Company.

Congratulations on this morning's news. Great to hear. My first question is maybe just -- I know we touched that the 30% change is what's deemed clinically meaningful. But is there any information just on the numerical changes that are seen in Alzheimer's agitation patients at baseline without treatment? And then second, to the placebo arm performed as you expected in this study. And then my second question is you mentioned the Clinical Global Impression of Change was also significantly beneficial there. How is this viewed in terms of physicians and regulators versus the CMAI?

Sure. So I'll start off and I'll turn it over to Cedric. With regards to the numerical change, so we looked at clinical meaningfulness in a couple of different ways. Obviously, we looked at clinical response, which as Cedric mentioned, is at least a 30% reduction in agitation symptoms from baseline. So -- and there -- and that is widely regarded as being clinically meaningful. I'd say even lower cutoffs, which is 25%, are considered to be clinically meaningful. But what's interesting about the results of the ADVANCE-1 trial is you don't really even have to look at clinical response. You just look at the reduction in -- the average reduction in symptoms. And there was an approximately nearly 50% reduction in agitation symptoms from baseline. So that is obviously clinically meaningful. And with regards to the placebo arm, there was a large placebo response in the study, no doubt. And that is one of the problems or one of the challenges with trials in neuropsychiatry. You see this large placebo response, and this -- the large placebo response is the reason why a lot of studies fail. The fact that we were able to show statistical separation despite the high placebo response, I think, speaks to the drug effect here with AXS-05.

And I might add that also at the beginning, when you have a 3-way arm, a 3-way study, right, 1:1:1, you inject even greater expectation bias, which can contribute to placebo response, which we definitely saw in this study. And your other question referenced the fact that we had also observed statistically significant superiority on the modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change for Agitation score. And this is very important because this reflects how the clinician assesses and observes that the Alzheimer's disease patient who has agitation in their clinic. So we're seeing that not only does the comprehensive, thorough, 29-item CMAI primary endpoint demonstrates a large magnitude of statistically significant improvement in agitation, but that translates over to the clinical impression that the doctor is seeing when he sees this patient in the clinic from week to week. So that's important.

Our next question comes from the line of Joon Lee from SunTrust.

Congrats on the positive data. An NDA inhibition is thought to confer some protection against its cytotoxicity. Do you have any thoughts on giving the drug earlier, maybe even in prodromal AD patients, for potential disease-modifying effects in Alzheimer's disease in general? And the second question is what are your strategies for a second Phase III given the ongoing pandemic and the particularly susceptible demographic, which is the reason you pushed up the data in the first place? And do you expect any laxity from the FDA to facilitate the second Phase III? And if so, what shape or form would that be? And I have a follow-up.

Great. Well, thank you for the multipart question. With regards to the potential use of AXS-05 in earlier stages of disease for Alzheimer's disease or the neurobehavioral symptoms of Alzheimer's disease, what is interesting is this the pharmacology of AXS-05, which is relevant to some of the neuropathological changes that are seen in Alzheimer's disease. And so in other words, they're not just the pathological changes that result in the behavioral abnormalities, but the neuropathological changes that have been observed that are related to cognitive impairment and decline in these patients. So you mentioned glutamatergic cytotoxicity, which is downstream from amyloid beta generation. And we know that the NMDA receptor antagonism of AXS-05 does counter that mechanism. Also, what we don't speak as much about is the fact that the dextromethorphan component of AXS-05 has pretty potent effects on microglial activation. And we know that microglial activation underlies a lot of the inflammation that is seen in Alzheimer's disease, resulting in neuronal cell death. So mechanistically, there are a lot of reasons to study AXS-05 further in this disease. With regards to the impact of the pandemic on the next study. We -- I think we are in a fortunate position whereby we -- whereby by the time that we initiate potentially a second trial, hopefully, there will be some normalization of activity in clinical trial sites and just in the economy in general. So we're monitoring that, of course, and we're keeping that in mind as we think about the design of the next trial. And then with regards to your question about -- in change in receptivity from the FDA to accommodate any issues around the COVID-19 pandemic, we do know that the FDA is watching that very closely. They had issued guidelines for sponsors on ways to amend clinical trial, the clinical trial protocols, recognizing that they may be impacted by COVID-19. So we've studied those guidance documents. And certainly, we'll know more as things progress in general and also after we meet with the FDA to discuss these data.

Great. And last question, can you remind us how you came up with the dose for AXS-05? And would the FDA ask for you to try a lower dose or maybe a different dose? And mainly because one of your competitor, Otsuka, who also has a similar drug, reported one of the dose hitting the endpoint, while not for the other dose. So just curious how you came up with the dose that obviously worked and if the FDA would ask for a different dose?

So we selected the dose of AXS-05 for the study and also for our other trials based on examining the PK of AXS-05 and making sure that we reached with our selected dose platform concentration that resulted in targeting the kinetics, so the KIs and [ NIC 50s ] for the various neurotransmitter systems that we think are implicated in these diseases. So that's how we arrived at the dose and also doing other types of PK/PD modeling and then triangulating that with animal data. So now we ran also a number of doses in our Phase I trials to make sure that we selected the right dose. So that was our approach, which is, I think, a bit unconventional. And -- but what we've seen now with these results in Alzheimer's disease agitation as well as in other disease states is that it appears that we are targeting -- we have managed, with our selected dose, to effectively target these neurotransmitter systems. Now one of the reasons for looking at various doses is if you believe that either you don't have enough efficacy or maybe that there's some toxicity or tolerability issues. What's nice with the ADVANCE-1 results is we've shown definitely very strong efficacy with a very favorable tolerability profile for a lot of the adverse events. They were placebo-like. So we're very encouraged by that. So right now, we think that we have the right dose.

[Operator Instructions] Our final question today will come from the line of Ram Selvaraju from H.C. Wainwright.

I was wondering if you could perhaps comment on differentiation that you see between the acute and chronic agitation populations, specifically within Alzheimer's disease. And to what extent do you think AXS-05 would be applicable to both of those situations?

Yes. Thanks, Ram. I can speak to the nature of agitation over time. So agitation is an acute event, which you need to treat and get under control quickly. But it's chronic in the sense that once it develops in the Alzheimer’s disease patient, it continues. So if you think about sporadic attacks of agitation that occur to a certain degree of frequency, but they continue. It's going to be lifelong once it sets in. It's associated with all the risks we talked about before: cognitive decline, institutionalization, death. And therefore, you need to intervene quickly and try and control it, but it's going to be a lifelong event.

Okay. And then I was just wondering if you could comment on the logistics of what remains to be finalized with the FDA if you need to sort of have a formal interaction with them to discuss the results of the ADVANCE-1 study before you can embark on the next Phase III trial or if that is not necessarily going to have to happen? And then also, if you could maybe comment on a couple of items relating to the commercialization aspect. Would there potentially -- if AXS-05 were to be approved for the agitation indication within Alzheimer's, need to be a separate sales force? Would this potentially be focused on assisted-living facilities specifically? And do you have any thoughts at this juncture about the possibility of pricing considerations and differentiation from the pricing paradigm in the MDD indication, for example?

Sure. Thanks, Ram, for the question. I'll turn it over to Dave to answer the commercialization questions. With regards to interacting with the FDA, we certainly and absolutely want to meet with the agency to discuss these data. And we obviously will do that prior to initiating any new studies, if needed. And then Dave?

Yes. And thank you for the questions. There were 3 items that you mentioned regarding commercialization. The first one was sales force. I think one of the advantages that we have is looking at the specialists who treat Alzheimer's disease agitation largely being around psychiatrists and neurologists to a great degree. And the benefit that we have in building our sales force is having that clarity now, as we start to build out our presence for depression, largely with psychiatrists, and our presence for migraine, of course, largely with neurologists. So we will look at options around what kind of synergies we can get within one sales force. But we'll also look at more dedicated efforts as well. So we won't have the specific sales force size and structure across all 3 indications at this time, but we're certainly -- our spirit of sales force design is to look for efficiencies and synergies across the various specialties. Regarding the setting, you asked if there was -- our focus would be more in the long-term care setting. We certainly have no reason to believe why AXS-05 should be limited to the long-term care setting. Patients who have Alzheimer's disease agitation, of course, reside in the community as well. And I think, as Cedric mentioned earlier, if we can be the -- provide the benefit to enable patients to stay in the community setting with their families and loved ones, we certainly would want to afford that opportunity. So we see applicability in the long-term care setting or the memory care setting as well as in the community setting. And then finally, regarding pricing. Certainly, we will look, as we do in any therapeutic area, as to what the clinical benefit is, the economic benefit. And we will make sure that our pricing is consistent with facilitating fair and timely access while also simultaneously rewarding innovation. So we will certainly look at price range not only for AXS-05 within -- or excuse me, within depression, but also separately within Alzheimer's disease agitation.

Our next question comes from the line of Matt Kaplan from Ladenburg Thalmann. And we'll move on to the next question, we'll take from Myles Minter from William Blair.

Congrats on the data. I know you excluded patients that were on an SSRI and SNRI prior to randomization. Just curious whether you enrolled patients on memantine, just thinking about overlapping mechanisms of action with NMDA receptor antagonist there? And maybe that opens up a broader question. How do you see AXS-05 positioned as adjunctive therapy in an elderly disease population that are on multiple medications, where you have to pull people off and retitrate up and how are you thinking about that? And I have a follow-up if Matt's not on the line.

Sure. Thanks, Myles, for the question. So these -- just as a reminder, all the patients in the study were allowed to remain on their background Alzheimer's disease medications. So -- and obviously, the common ones are acetylcholinesterase inhibitors as well as memantine. So there were no restrictions around that. And so these data do reflect what you're referring to as adjunctive treatment.

Okay. Cool. And then my follow-up is just on the fall rates remarkably lower, I think, compared to the Nuedexta Phase II trial, which was double placebo. Just curious as to thoughts, is that something because DEX is anchored to bupropion in your product? Or is it a function of different patient population? Or is it maybe because you did a partial titration in these patients that made the drug more tolerable? Just curious if you have any color between that discrepancy. Obviously, a good thing for your product.

Yes. So our product, of course, is different and it had different molecules. And so it's hard to do cross-trial comparisons, and it's hard to speak about other agents. But what we did see with AXS-05 in our trial and the comparison that we can make as it relates to the other study, which you mentioned, is that both studies involve titration. So we titrated and they also titrated. So that's just a -- we're not saying that, that may not have had something to do with it, but we just want to point out that there was titration or gradual titration in both cases. And we're very encouraged by the rate of falls and the fact that it is very similar to placebo and that it's low. It was not even one of the top adverse events.

We have no further questions in queue. I'll turn back to the presenters for closing remarks.

Well, thank you all. We are very pleased with the ADVANCE-1 data readout, and we're especially pleased, given the potential implications for the care of patients with Alzheimer's disease agitation, which is a debilitating condition for which currently there is no approved treatment. We're excited by our broad pipeline of differentiated late-stage CNS product candidates, which includes AXS-05 for the treatment of depression, AXS-07 for migraine, AXS-12 for narcolepsy and AXS-14 for fibromyalgia. We are on track to file 2 NDAs, one for AXS-05 in major depressive disorder and the other one for AXS-07 in the acute treatment of migraine by year-end. We also anticipate initiating our Phase III program for AXS-12 in the treatment of narcolepsy by year-end. I'd like to thank the Axsome team for their hard work and dedication, which is allowing us to advance our CNS pipeline with the goal of providing new treatment for the millions of patients failed by current therapies. Thank you, and we look forward to keeping you updated on our progress.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.