Study Result

Dec 16, 2019

Good morning, ladies and gentlemen, and welcome to Axsome Therapeutics Conference Call. Currently, all participants are in a listen only mode. We will be facilitating a question and answer session towards the end of today's call and instructions will follow at that time. As a reminder, today's call is being recorded. I'd now like to turn the conference over to your host, Mr. Mark Jacobsen, Senior Vice President of Operations at 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 GEMINI Phase 3 trial of AXS-five in major depressive disorder. A press release announcing that AXS-five achieved the primary endpoint in the trial crossed the wire a short time ago and is available on our website at axholm.com. During today's call, we will be making certain forward looking statements. These statements may include statements regarding, among other things, the efficacy, safety and intended utilization of our investigational agents, our clinical and non clinical plans, our plans to present or report additional data, the anticipated conduct and the source of future clinical trials, regulatory plans, future research and development 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 Doctor. Herriot Tabuteau, Chief Executive Officer Doctor. Cedric O'Gorman, Senior Vice President of Clinical Development and Medical Affairs Mr. Nick Pizzi, Chief Financial Officer and Mr. Dave Merrick, 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 GEMINI clinical trial. Following Cedric's presentation, we will open the line for Q and A. Following Q and A, Herriot will provide 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 are extremely pleased to announce that AXS-five, Axsome's novel oral NMDA receptor antagonist with multimodal activity met the primary endpoint and rapidly, durably and substantially improved symptoms of depression in the GEMINI Phase 3 trial in major depressive disorder or MDD. These results confirm and extend the positive findings from our previously completed ASCEND trial of AXS-five in MDD. As a reminder, AXS-five has been granted FDA breakthrough therapy designation for the treatment of MDD. The positive results of the GEMINI trial are potentially transformative for many of the patients who are seeking a new effective treatment option and for Axsome since these data along with the ASCEND trial are sufficient to support an NDA filing for AXS-five for the treatment of MDD. We look forward to filing this NDA next year. The goal of making this therapy available to patients as quickly as possible. The GEMINI study was a Phase 3 randomized double blind placebo controlled U. S. Trial in which 327 patients with a confirmed diagnosis of moderate to severe depression were treated with either AXS-five or placebo for 6 weeks. On the primary endpoint of a change in modus at week 6, AXS-five resulted in a substantial and highly statistically significant improvement as compared to placebo with a P value of 0.002. The antidepressant effects of AXS-five were rapid demonstrating high statistical significance on the MADRIS at week 1, the earliest time point measured with a p value of 0.007. These effects translated to important improvement in quality of life and reduction in functional impairment for the patients treated with AXS-five that were also highly statistically significant. We are encouraged by the high degree of internal consistency of the results. Specifically, AXS-five met all pre specified secondary endpoints at week 6 with statistical significance and the vast majority of these endpoints with statistical significance at week 1. AXS-five was well tolerated and was not associated with psychromimetic effects. Now the GEMINI results are especially important in light of the seriousness and high prevalence of MDD. An estimated 17,000,000 adults in the U. S. Experience a major episode each year. And MDD is the leading cause of disability in adults during their most productive years. Up to 70% of patients with MDD failed to respond adequately to treatment with currently marketed antidepressants. In addition, currently approved antidepressants for MDD can take up to 6 to 8 weeks to provide clinically meaningful response and are thought to act primarily through monoaminergic mechanisms. The late onset of antidepressant efficacy has been associated with poor long term outcomes and increased risk of suicide. The potentially fatal consequences of depression highlight the importance of rapidly and effectively controlling depressive symptoms. There is therefore an urgent need for new treatments with novel mechanisms of action and faster onset of action that are orally administered. AXS-five is potentially the first and only oral NMDA receptor antagonist also known as a glutamate receptor modulator, a new mechanism of action for the treatment of MDD. AXS-five is also a sigma-one receptor agonist and an inhibitor of the reuptake of monoamines. These mechanisms of action may be synergistic resulting in the observed clinical effects of AXS-five in patients with MDD. If approved, AXS-five would represent the 1st mechanistically novel oral pharmacotherapy for depression in over 30 years. AXS-five is covered by 41 issued U. S. And international patents providing protection out to 2,034 and Axsome maintains worldwide rights. I would now like to turn the call over to Cedric, who will review the Gemini top line results in greater detail. Thank you, Herriot. The GEMINI or glutamatergic and monomeric modulation and depression study was a Phase 3 double blind randomized placebo controlled multicenter 6 week trial conducted entirely in the United States. A total of 327 subjects with a confirmed diagnosis of moderate and severe major depressive disorder were randomized in a 1:one ratio to receive treatment with either AXS-five or placebo twice daily for 6 weeks. The total dextromethorphan bupropion daily dose of AXS-five was 90 milligrams, 210 milligrams in 2 divided doses. The primary endpoint of the study was the change from baseline in the Montgomery Osberg Depression Rating Scale or MADRS total score at week 6. Secondary endpoints included clinical response, remission, physician and patient reported global assessments, functional and quality of life measures. During the course of the study, extensive quality control measures were employed. The key entry criteria included adult outpatients fulfilling DSM-five criteria for current major depressive disorder without psychotic features, who had a MADRIS total score of 25 or more and a CGIS score of 4 or more. There were no meaningful differences between the two treatment groups in terms of demographics and baseline clinical characteristics. The mean MADRS total scores at baseline were comparable between groups, 33.6 for AXS-five and 33.2 for placebo. These scores reflect clinically depressed subjects with moderate and severe illness. Study completion rates were high in this study at more than 75% for both treatment groups. Turning now to the efficacy results. AXS-five met the pre specified primary endpoint by demonstrating a highly statistically significant reduction in the average MADRS total score at 6 weeks as compared to placebo with a p value of 0.002. The treatment effect was evidenced by a 16.6 point improvement in the MADRS for AXS-five compared to 11.9 point improvement for placebo for a placebo corrected difference of approximately 5 points. The antidepressant effect of AXS-five was rapid with a clinically meaningful and highly statistically significant reduction in the MADRIS total score compared to placebo at week 1, the earliest time point measured. Statistical significance was maintained at all time points thereafter, reflecting both the rapid and durable antidepressant effect of AXS-five. A statistically significantly greater proportion of patients achieved clinical response on the MADRS defined as at least a 50% improvement with AXS-five as compared to placebo at week 1 and at every time point thereafter. At every time point, the proportion of AXS-five patients achieving clinical response was nearly twice that of placebo with more than half of AXS-five treated patients demonstrating a clinical response at week 6 with a p value of less than 0.001. Now turning to the results for clinical remission. Remission refers to the near complete absence of clinically significant symptoms of depression and as such represents an even higher threshold of clinical response. It is defined as a MADRS total score of 10 or less. Remembering that the mean MADRIS total score for all patients was approximately 34 at baseline, getting to a MADRS score of 10 points or less would represent on average a 70% or greater reduction in depressive symptoms for the subjects in this study. The proportion of AXS-five treated patients achieving remission was more than twice that of placebo treated patients at week 2 and at every time point thereafter. And these differences were highly statistically significant. At week 6, 40% of AXS-five patients achieved remission compared to 17% of placebo patients with a p value of less than 0.001. This slide highlights the rapid onset of action of AXS-five as evidenced by early and highly statistically significant separation from placebo on numerous secondary endpoints. As can be seen, AXS-five was statistically significantly superior to placebo on nearly every measure 1 week after the start of treatment, the earliest time point assessed. Furthermore, this rapid therapeutic effect was durable and was maintained out to 6 weeks with statistically significant effects on all endpoints at this last time point. Rapid and statistically significant improvements were seen for AXS-five on the MADRIS total score, MADRIS response, clinical remission, MADRIS 6 subscale, the patient reported quiz scale, the clinical global impression of improvement, the clinical global impression of severity and the patient's global impression of improvement scale. Importantly, these antidepressant effects translated into statistically significant improvements in both daily functioning as measured by the Sheehan Disability Scale and statistically significant improvements in quality of life as measured by the quality of life, enjoyment and satisfaction questionnaire, reflecting tangible real world functional benefits with AXS-five. Overall, multiple secondary endpoints pertaining to efficacy, quality of life and daily functioning in the GEMINI study statistically favored AXS-five as compared to placebo at week 1 and these rapid and robust improvements were maintained over the entire treatment period. Now turning to safety and tolerability. AXS-five was safe and well tolerated in this trial. The most commonly reported adverse events in the AXS-five arm were dizziness, nausea, headache, diarrhea, somnolence and dry mouth. There was only one serious adverse event, which was not drug related. The rates of discontinuation due to adverse events were low in both treatment groups, 6% for AXS-five and 1% for placebo. Importantly, treatment with AXS-five was not associated with psychotomimetic effects or dissociative side effects. In summary, in the GEMINI study treatment with AXS-five resulted in rapid, durable, substantial and statistically significant improvements in depressive symptomatology across multiple efficacy endpoints with AXS-five as compared to placebo in patients with MDD. Furthermore, these symptomatic benefits translated into statistically significant improvements on validated measures of daily functioning and quality of life. AXS-five was safe and well tolerated with a safety profile consistent with prior trial experience. Overall completion rates were high in this study and discontinuations due to adverse events were low. These positive Phase 3 GEMINI study results replicate the early and statistically significant efficacy results previously demonstrated versus the active comparator bupropion, a well established antidepressant in the Phase 2 ASCEND study. With today's results, AXS-five has now demonstrated rapid, clinically meaningful and statistically significant efficacy with well tolerated safety profile across two trials in major depressive disorder. We would like to thank all the patients who participated in this important clinical trial. We would also like to thank the qualified and conscientious clinical site staff who collaborated with us in the execution of this important clinical study. 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. Certainly. Mark Goodman, your line is open. Yatin Suneja with Guggenheim Partners. Your line is open. Hey, guys. Congrats on the results. Maybe just a couple of questions for me. Can you maybe put these in perspective in terms of the effect size, what the effect size are? I mean, we know that currently approved agents have shown somewhere around 0.3, 0.35. Can you just maybe put that perspective? Can you just help us understand what you achieved? And then I have a couple of follow ups. Thanks, Jan, for the question. With regards to the effect sizes, we haven't calculated those exact numbers, although you can probably extrapolate them from the data that we presented. However, what we will say is that the placebo corrected differences are very significant, much larger than what has been reported with currently marketed antidepressants. If you look at the results during the 1st week, the placebo corrected difference there is along the lines of what you see with standard antidepressants out to 6 weeks. And then the results that we showed at week 6 at the end of treatment were about 5 points. So clearly significantly greater than the currently marketed antidepressant drugs. Got it. And then with regard to the discontinuation rate, can you maybe help us understand what the reasons were for Were they earlier in the study or towards the like when on the treatment curve they occur? Yes. Thanks for the question. So we're really happy that the discontinuation rates due to AEs were very low. It was only 6% in the AXS-five arm. And the most common reasons for discontinuation due to AEs were anxiety, insomnia and nausea. And these discontinuations occurred really early in the study right after randomization. Okay. And then just final questions. Can you maybe talk about the durability of these effects after week 6? Are we going to get that information at some point? Were you evaluating patients a or leads to a permanent change in how a patient would react? So what we've seen thus far in the GEMINI trial and also in our previous experience with AXS-five in MDD is that the results are durable. So not only do you not only have we observed a very rapid antidepressant response at week 1, which is actually only 4 days after the start of BID dosing. But it's been shown to persist and actually increase over time out to week 6. And that's the last time point that we measured. We do have an open label safety extension trial, and the majority of patients are rolling over into the open label safety extension trial, which is encouraging and that will give us longer term data. And right now we don't have that data. But there's no reason that we would expect given the experience thus far during the 1st 6 weeks to expect that this would not be a continued treatment effect. Great. Thank you for taking my question and congrats on great results. Mark Goodman with SVB Leerink. Your line is open. Hi, this is Rhona Ruiz on the line for Mark. Thanks for taking the question. Just 2 for you. I was I know you listed the top adverse events as dizziness, nausea, etcetera. I was wondering if you could put that in context to other antidepressants and how that compares? Is it better? Is it worse, etcetera? And then my second question is just kind of thinking ahead like how is the safety database enrollment going in context of this trial reading out? Thanks. Thanks for the question. Actually the rates for adverse events are lower than you tend to see in other antidepressant trials. So to put the dizziness in context, it's much lower. We've seen some rates of up to 30% in the literature with other antidepressants. And so given that the overall discontinuation rates to due to AEs are also low, it speaks to the ability for patients to stay in the study and receive treatment benefits. And in terms of the ongoing safety extension study that will allow us to capture more over a longer period of time, how this drug is being tolerated and those results will be forthcoming in the future. Great. Thanks. Joon Lee with SunTrust. Your line is open. Hi, thanks for taking my question and congrats on the great data. So just looking at the results today, your drug guard in the GEMINI behaved very similarly to what the drug did in the ASCEND study, where you saw about 17 point reduction from baseline. And regarding the placebo in the GEMINI, you saw about 11.9 point reduction, which is just 2 points shy of what bupropion did in the ASCEND trial. So is that 2 point numerical superiority where you expect for bupropion? And is that something that you will still expect in the upcoming STRIDE-one study in early next year? And if so, does that increase your conviction on the positive outcomes for the PRD study, assuming that the bupropion is just 2 points better than the placebo and you see consistent effect in your AXS-five? And then the second question is, has the safety data monitoring board reviewed the safety in the STRIDE-one study at any point? Thank you. Thank you for the questions. With regards to the expectations of a treatment benefit with bupropion and we would agree, so it's about a 2 point difference that's what's been reported in the literature. So our data are consistent. One thing that we would point out in the GEMINI trial is there was a very high placebo response. So as you mentioned, it was 11 point 9 points in terms of reduction on the MADRS. And this is this would be expected given that we had announced the positive results with the ASCEND trial, which clearly would have influenced expectation bias in subsequent studies. Having said that, the XS-five performed really well and was able to handily overcome that. And if you look at the XS-five arm, the way that it performed in Gemini and Ascend, it performed very similarly. So we're encouraged by that. As it relates to STRIDE, certainly now having demonstrated efficacy in 2 separate trials in MDD with AXS-five that was robust. It definitely speaks well of the mechanism of action of the drug and its potential to have an antidepressant effect. So it's clearly relevant to STRIDE, but we would caution that of course STRIDE is enrolling a a different patient population. It is enrolling patients with treatment resistant depression, which by definition means that those patients are a lot harder to treat. Has the Data Safety Monitoring Board reviewed the safety of STRIDE-one thus far at any point? Yes. So there was one interim analysis that was conducted in the STRIDE-one trial. It was an interim analysis for futility. And so it did pass futility, interim analysis for futility. The primary reason is, of course to look at efficacy. However, the independent data monitoring companies always look at safety. And so yes, so they did look at safety on an unblinded basis. And obviously, the company is blinded and there were no observations from that interim analysis. Thank you so much. Charles Duncan with Cantor Fitzgerald. Your line is open. Yes. Hey, good morning, Herriot and team. All I can say is, wow, congratulations on a very well conducted study and the results this morning. I had a couple of questions. Thanks for taking our questions. First is, relative to the patient characteristics for the enrolled sample, how do you think those patients read on the broad potential use of AXS-five in MDD. Do you anticipate the results to have positive predictive value for effect sizes in a more heterogeneous patient population? Thanks for the question Charles. I'll let Cedric what these results might mean in the broader MDD population. I'll just start off by saying that this was MDD and but Cedric will talk to the severity of these patients at baseline and what he thinks that that might mean for clinical practice. Sure. Thanks Charles. And yes, so these patients with a confirmed diagnosed major depressive disorder had on average a moderate score baseline of 34. It's often regarded that a score above 32 and into the 30s above that would represent a severely depressed population. So with a mean of 34, you're getting a very good representative sample of depressed patients in the moderate and severe range. So these patients were clearly ill. And also they were coming in with scores on the measures of daily functional impairment on the SHEIN disability scale and also measures of quality of life and enjoyment of life on the what's called the Q Less Q validated measures of quality of life and satisfaction that suggested significant impairment from their depressive symptomatology. So we're confident that in the GEMINI trial and indeed the ASCEND trial before that, we have captured a truly representative sample of MDD patients who are significantly impacted by their illness. So and of course this is different from the ongoing treatment resistant population in STRIDE. So in terms of the broad applicability and potential for AXS-five as a treatment, we're very encouraged by the fact that not only we demonstrate efficacy in 2 trials now, but also the tolerability and safety profile characterize a drug that has very low discontinuation rates, is very tolerable and results in rapid substantial and durable anti depressant effects. So when you put that all together, I definitely can see no reason why this treatment wouldn't be chosen as a first line treatment for a broad MDD population should it get approved. Yes, for sure. Very impressive results. Let me ask you a couple of questions regarding the future and kind of next steps. One is NDA timing and really the dating activities to that. Any additional clinical studies? How do you feel about the CMC section readiness and inability to manufacture AXS-five? Would you need to do anything else beyond the clinical trial supply that you have? Thanks Charles for that additional question. In terms of the NDA filing, we're in a very fortunate position that we now have 2 positive studies. And based on our breakthrough therapy meeting with the FDA, this puts us on track to file an NDA, which we're targeting for the second half of next year. One of the gating factors and I think the key gating factor is the safety database. We do need a safety database of 300 patients who've been treated for 6 months and 100 patients who've been treated for 1 year. And as you know, we did launch an open label safety extension trial to capture both patients with MDD and TRD back in July. And so we're capturing those patients and we will have the 1 year anniversary hopefully of the 100th patient in the second half of this year putting us on track to file the NDA in that timeline. With regards to CMC, we're in excellent shape. With regards to CMC. The study drug that was used in our and that is being used in our pivotal trials are in fact being manufactured at commercial supplies. Okay. That's very helpful. Last question regarding commercial strategy. I imagine these results really get you to think very intently on that. So probably a little half baked at this point. But if you had to guess, would this be a drug that you would market in house completely or would you do so with a co promote or would you out license it for use in MBB and other potential indications? Thanks for the question Charles. As we stated, we do intend to market AXS-five ourselves in the U. S. So we would look to partner outside of the U. S. But we're fully committed to marketing the product in the U. S. We think that that can be done by a company of our size. And to that point, as you know, we did start recently in Q3 to build our commercial leadership. So in fact, Dave Marrick, our Chief Commercial Officer is sitting with us in the room. Yes. Thank you, Charles. So that certainly would be our intent and what we are planning in terms of moving forward is to look to commercialize it from Axsome in the U. S. Of course, we always keep option open to see how we can do that most effectively to get AXS-five to the right patients who would benefit. But right now, we see the ability to do that within Axsome today. Okay, great. Thanks for the added color taking my questions. Great way to start the week. Ram Selvaraju with H. C. Wainwright, your line is open. Thanks for taking my questions and really congrats on this data. It's very, very clean and I must say that the GEMINI name was quite apropos because this looks so close to the Ascend data. Congratulations. I wanted to ask about the timeline to presentation or publication of the GEMINI data and also if you could clarify the time elapsed between first line treatment during a major depressive episode and treatment with study medication for that 23% of patients who were specifically noted in the press release? So with regards to our presentation, we do intend to present the data at upcoming scientific conferences this year. So we just got the data very recently and we're sharing it with you now. And but we and once we have confirmation from these scientific conferences, We'll let you know exactly at which of these scientific conferences that are coming and you can probably guess which ones we're going to submit the data to, we'll make that known. And in terms of publication, same thing. We are also launching publication planning with regards to the study, especially in light of the fact that we're very close relatively speaking to NND filing. And then for your question on the patients who were being treated during the current major depressive episode prior to enrolling in the study. I think the 23% number that you mentioned was from our ASCENDIT trial. And we're still tabulating the exact percentage of those patients who appeared in the GEMINI trial. But in terms of the timing of when they were on those prior antidepressants. They were on the prior antidepressants during the current major depressive episode. And then they were clearly washed out of any antidepressants that they were on prior to being randomized into Gemini. So just wanted to clarify what that washout period was? The washout period was long enough to assure that there was absolutely no drug on board. So there was at least 5 half lives of the drug or 1 week. So the longer of. Okay, great. Can you comment on what other recent comparator controlled data sets exist in MDD and what the comparators were that were utilized there. And it's my impression and I think the impression of KOLs that bupropion is a very effective active comparator. And therefore, you chose a very high hurdle here, but just wanted to see sort of what the lay of the land is? So thanks for the question, Ram. So in terms of the putting the data in context and as we mentioned earlier, these results in terms of the treatment effect and the treatment difference are demonstrably larger than what has been seen with currently marketed antidepressants. In the ASCEND trial, we did use reprogram as the active comparator and that performed similarly to the way that bupropion has performed in other trials with also a nice benefit from baseline and AXS-five was able to again show superiority to that active comparator and here in Gemini versus placebo. Okay. And then just very quickly to clarify, regardless of what the STRIDE-one outcome is, you are clear with the ASCEND and GEMINI datasets to file an NDA for AXS-five in MDD, correct? That is correct. Thank you very much. Congratulations once again. Robert Hazlett with BTIG. Your line is open. Yes, congratulations on an extremely well conducted study. Congratulations to Cedric and the crew. The TRD and my question is with regard to how timing of that study result will impact at all the filing in MDD. How do you assuming success in STRIDE-one, how do you think about how that will be handled with regard to an NDA application for 5? So the timing of an NDA for XS-five and MDD will not be affected. The gating factor is not STRIDE. The gating factor is the open label safety extension trial. And so we are targeting the second half of next year for that NDA filing and then we are on track to report top line results from the STRIDE-one trial in the Q1. So assuming success in STRIDE-one then those data would be very easily incorporated into an NDA filing. Okay. And then just a couple of quick ones. There was one SAE in the AXS-fifty that was not deemed to be study drug related. Maybe you mentioned that. Could you just mention what that was? And then could you remind us of the IP, the state of AXS-five and is it evolving? And if so, what should we expect in terms of that evolution? Thanks, Bert. Cedric here. The SAE the one SAE was pancreatitis and it was not related to study drug. It didn't occur while the patient was on drug and in fact the subject completed the study. And then with regards to the IP estate, we currently have 41 issued U. S. And international patents covering XS-five. They go out to 2,034. The patents in terms of patent families fall into a couple of categories. 1 is pharmacokinetic patents, which cover the exact PK profile, which is achieved with AXS-five and those are agnostic to any indication. So we're pretty happy about those patents. We also have claims covering the specific doses that are used with AXS-five and then also some of the claims cover the formulation which is used. The patent portfolio is evolving with the availability of efficacy data from now three trials, really if you count smoking patient that allows us to now prosecute more indication specific claims. Those would be a new family of patents. And so we're looking forward to continuing to prosecute those and to having some of those issues. Okay. And just a quick follow-up. Given that you have a comparator data with previous trials, does that again provide a rapid opportunity for the EU either in terms of your filing or licensing or other business related opportunities there? It definitely advantages us with regards to European filing. One of the differences in regulations typically between the U. S. And well, the FDA and then the EMAs is that in Europe, as you alluded to, clinical trials using active comparators are sometimes required. And so we're in a good position that many of our trials, including the ASCEND trial, have used an active comparator. Okay. Congratulations again. Look forward to the filing and to the publication of the data. Thank you. Thank you. Myles Minter with William Blair. Your line is open. Hi, guys. My first question is just related to the demographics of patients enrolled. Did you enroll any patients that were comorbid with agitation? Did you capture that data from an efficacy perspective? And would that be data that we could expect to be presented at Scientific Congress, maybe in advance of your ongoing trial your advanced trial in AD agitation? Thanks for the question. Yes, anxiety is often comorbid with depression and as a symptom of depression. So it's interesting to look at a whole range of symptoms that occur in depression. If the patient's primary diagnosis was an anxiety disorder, they would not have been included in this study because this was a study in patients with MDD diagnosis. But you're absolutely right there's an opportunity to look at a variety of comorbid symptoms and anxiety is one that occurs frequently in depression. So we'll look further into the data as we do additional analysis and look forward to presenting the data at future conference. Okay. Thanks for that. Just on the side effect profile as well, the dizziness, Was the prevalence of that increase in more older patients out of that population? I'm just thinking about in an elderly population dextromethorphan's being sort of attuned to falls in that population? Not saying that you had that here, but interested to see whether there was an age related prevalence in those? Well, the population in the MDD study were adults up to the age of 65. So not an elderly population here. Also the rates of dizziness were low comparative to other antidepressant trials and discontinuations were also low. And now, I think that's it. Yes. And thus far, I mean, first of all, the rates were relatively low and there is no correlation with age. Yes. And no signal for falling in the trial there. Cool. That's helpful. And then just assuming that STRIDE-one is positive next year, correct me if I'm wrong, but it's an patients. But could you potentially file with the STRIDE-one data and incorporate that data set assuming it's positive into the MDD label, so docs would have access to that when potentially prescribing this product? Thanks. That's it. Yes. So the so assuming that STRIDE-one is positive then our expectation would be that it would be included in the package insert and the product label for AXS-five. So even though the overall indication would be MDD, the experience in patients with TRD and the TRD trial would be included in the clinical study section of the package insert. So that's and then with regards to getting a formal indication for TRD, our working assumption is that we would need one additional study in TRD. Okay, great. Thanks for the clarification. Cheers, guys. Congrats on the data. Matt Catlin with Ladenburg Thalmann. Your line is open. Hi, good morning guys and congrats on the very impressive data in the study. Wanted to dig in a little bit more in terms of the onset of action, in terms of the rapid onset of action that you're seeing in this and how specifically how that compares with other drugs in MDD? And then how to think about that with respect to any read through to STRIDE-one as well based on, I guess, this differentiated mechanism action and the onset the rapid onset of action that you're seeing in the GEMINI study? Thanks, Matt. So we were very encouraged by the fact that at the 1st week, we had like a 2.4 difference from placebo. And these are the kind of magnitude of changes from placebo that often at 6 weeks for antidepressant trials results in statistical significance. So we're seeing it at week 1. And the rapid onset that we saw in Gemini replicated what we saw in Ascend, which is really encouraging against an active comparator. So that maybe puts in context a little bit how other trials or how other currently available antidepressants would look with regard to that. And of course, then there's the important clinical parameters of getting to remission. So looking at response and remission and seeing those early achievements of really high thresholds for what's viewed as clinically meaningful. So I think that we stack up superior to what's available when one has to acknowledge that existing medications based on monomerangic pathways often have to be taken for 6 to 8 weeks before being able to truly assess whether a clinical benefit has been attained by patients. So we're very encouraged by what we're seeing in terms of early onset. Great. Thank you. And then one question in terms of the dose adjustment that you made in terms of initial dosing at QD dosing for the first few days and then to BID. Is that something you're replicating in the STRIDE-one study as well? Yes. So that we are replicating that in the STRIDE-one trial and actually in all of our studies essentially that that's how AXS-five is dosed. So once daily for the 1st 3 days and then starting at day 4 getting the full dose, so BID dosing. Great. Thanks. And then last question in terms of can you update us on the status of the AD agitation study? And when we should potentially expect a readout on those results? So with regards to the EEG agitation study, so that study continues to enroll well. I believe that the last study that we gave, the study was approximately 70% enrolled. And then that puts us on track for a readout in the first half of twenty twenty, so towards the end of the first half of twenty twenty. Well, congrats again on the results and thanks for taking the questions. Great. Thank you. There are no further questions at this time. I would now like to turn the call back over to Axsome for final remarks. Well, thank you for joining us on the call again today. We're very pleased with the GEMINI data readout, given its potential implications for the care of patients with MDD, which is a devastating disease. We look forward to an NDA filing for AXS-five in this indication in the second half of twenty twenty. AXS-five is currently also being studied in a comprehensive program of CNS trials including our STRIDE-one trial in TRD. We still expect that readout in the Q1 and also in our ADVANCE-one trial in ED agitation with a readout expected in the first half of twenty twenty. Earlier this month, we did announce positive Phase 2 results of our AXS-twelve product candidate for the treatment of narcolepsy. We anticipate launching Phase 3 trials with AXS-twelve next year. We're also excited about AXS-seven, our product candidate for the acute treatment of migraine. The Phase 3 momentum trial of AXS-seven in migraine is on track for readout of top line results by year end. So I'd like to thank the Axsome team for their hard work and dedication during especially during the month of December. And their hard work is allowing us to advance our CNS pipeline with a goal of providing new treatments for the millions of patients who are failed by current therapies. Thank you again and we look forward to speaking with you again before the end of the year. This concludes the Axsome Therapeutics conference call. We thank you for your participation. You may now disconnect.