Study Result

Dec 3, 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 conference call is being recorded. I would now like to turn the conference over to your host, Mr. Mark Jacobson, 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 CONCERT Phase 2 trial of AXS-twelve in patients with narcolepsy. A press release announcing that AXS-twelve 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 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 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 Axoam'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. On today's call, Herriot will provide 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 CONCERT clinical trial. Following Cedric's presentation, we will open the line for Q and A. Following the Q and A session, 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 today on today's call. Earlier this morning, we announced that AXS-twelve, Axsome's novel oral investigational medicine for the treatment of narcolepsy met the pre specified primary endpoint and rapidly reduced the frequency of cataplexy attacks in patients with narcolepsy as compared to placebo in the CONCERT Phase II trial. The effect was highly statistically significant with a p value of less than 0.001. CONCERT was a Phase 2 randomized double blind placebo controlled crossover multicenter U. S. Trial in which 21 patients with a diagnosis of narcolepsy with cataplexy were all treated with AXS-twelve for 2 weeks and with placebo for 2 weeks. With the treatment period separated by 1 week of down titration and washout. In addition to its effects on the frequency of cataplexy symptoms, AXS-twelve in this study also significantly reduced excessive daytime sleepiness assessed by the Epworth Sleepiness Scale and by the frequency of inadvertent naps or sleep attacks as compared to placebo. AXS-twelve also resulted in statistically significant improvements in cognitive function. The improvement in the ability to concentrate with AXS-twelve is especially relevant because the cognitive impairment associated with narcolepsy is one of the most distressing aspects of the disease for patients as highlighted in the FDA's The Voice of the Patient report on narcolepsy. Finally, AXS-twelve treatment resulted in improvements in sleep quality and sleep related symptoms as compared to placebo. The beneficial effects of AXS-twelve were rapid being observed as early as week 1. Overall, AXS-twelve produced substantial improvements as compared to placebo on all symptoms of narcolepsy assessed in the CONCERT trial reaching statistical significance on most. AXS-twelve was safe and well tolerated with no reported serious adverse events and no discontinuations due to adverse events. These positive results support initiation of Phase 3 trials for AXS-twelve in narcolepsy, which we anticipate in 2020. Based on the clinical profile observed in this trial, we believe that AXS-twelve could be a candidate as foundational therapy to meaningfully improve the lives of many people with narcolepsy. Narcolepsy is a chronic debilitating neurological condition characterized by excessive daytime sleepiness or EDS and cataplexy. Cataplexy is a sudden reduction or loss of muscle tone while a patient is awake triggered by strong emotions. Cataplexy is seen in about 70% of narcoleptics. Other symptoms of narcolepsy include disrupted nighttime sleep, sleep paralysis and hypnagogic hallucinations. Narcolepsy is an orphan condition that affects nearly 200,000 patients in the U. S. Existing treatment options are limited, do not address all symptoms, provide variable efficacy, have significant side effects and are mostly controlled substances. Only one agent is currently approved to treat both cataplexy and EDS. There is therefore an urgent need for new treatments for patients, which address the unmet needs of patients and the limitations of current agents. Narcolepsy is caused by a loss of hypocretin neurons in the brain. Hypocretin neurons normally excite norepinephrine neurons, which promote wakefulness and help maintain muscle tone. Hypocretin loss leads to dysregulation of norepinephrine neurons, resulting in excessive daytime sleepiness and loss of muscle tone or cataplexy. AXS-twelve improves norepinephrine regulation of signaling to affect the symptoms of narcolepsy. AXS-twelve consists of reboxetine, a potent and highly selective norepinephrine reuptake inhibitor. It is orally administered, dosed during the day, has a well characterized safety and tolerability profile and is not expected to be scheduled. AXS-twelve has been granted U. S. FDA orphan drug designation for the treatment of narcolepsy. I would now like to turn the call over to Cedric, who will review the Concert top line results in greater detail. Thank you, Herriot. The CONCERT or clinical outcomes in narcolepsy and cataplexy and evaluation of reboxetine treatment study was a Phase 2 double blind, randomized, placebo controlled, crossover, multicenter trial of AXS-twelve in patients with narcolepsy. A total of 21 patients with a diagnosis of narcolepsy and exhibiting clinically significant symptoms of both cataplexy and excessive daytime sleepiness were treated for 2 weeks with AXS-twelve or with placebo, followed by a crossover to the other treatment after a 1 week down titration and washout period. Patients were dosed twice daily with a total daily dose of 8 milligrams in the 1st week, which was escalated to 10 milligrams for the 2nd week. Patients are randomized in a 1:one ratio to either receive treatment with AXS-twelve followed by placebo sequence 1 or to treatment with placebo followed by AXS-twelve sequence 2. Specified primary endpoint was the change in the weekly number of cataplexy attacks averaged over the 2 week treatment period for overall treatment effect. Secondary endpoints included changes in excessive daytime sleepiness or EDS as measured by the Epworth Sleepiness Scale and the number of inadvertent naps or sleep attacks, cognitive function is assessed by the ability to concentrate item on the patient reported narcolepsy symptom assessment questionnaire or NSAQ and other important symptoms of narcolepsy, including sleep quality and sleep related symptoms as measured by the NSAQ. Assessments were recorded daily using an electronic diary. Because of the crossover design, this study was effectively powered like an approximately 40 patient trial since approximately 20 patients were treated with AXS-twelve and the same number was treated with placebo. Here are the baseline demographics and clinical characteristics for the study population. The mean age was 32.6 years. The mean time since narcolepsy diagnosis was 3.8 years. The average number of weekly cataplexy attacks at baseline was 30 or more than 4 attacks per day on average, reflecting a narcolepsy population with significantly impactful rates of cataplexy. And the mean baseline score on the Epworth Sleepiness Scale was 18, reflecting moderate and severe EDS. With regards to cognitive function, all patients rated their ability to concentrate as very poor, poor or average. Taken in totality, the measures of cataplexy, sleepiness and the ability to concentrate describe a narcolepsy patient population with significant disease burden. On the pre specified primary outcome measure, AXS-twelve demonstrated a statistically significant reduction from baseline in the mean weekly number of cataplexy attacks averaged for the 2 week treatment period for overall treatment effect for a reduction of 13 attacks for AXS-twelve as compared to 0.3 attacks for placebo with a p value of less than 0.001. The mean reduction in cataplexy attacks with AXS-twelve was statistically significant versus placebo as early as week 1, the first time point analyzed and maintained at week 2. This highlights the rapid and significant reduction of cataplexy with AXS-twelve. When we look at response rates who experienced a 50% or greater improvement in the weekly number of cataplexy attacks, at week 2, 76 percent of patients were responders when treated with AXS-twelve versus 30% of patients with placebo, with a p value of 0.003. Then looking at an even higher threshold for response, namely a 75% or more reduction in the weekly number of cataplexy attacks. At week 2, 42.9% of patients were responders with AXS-twelve versus 10% with placebo, which was statistically significant with a p value of 0.018. Assessing the effect on excessive daytime sleepiness as measured by the Epworth Sleepiness Scale, from a baseline score of 18.1, reflecting moderate and severe daytime sleepiness, treatment with AXS-twelve resulted in a clinically meaningful and statistically greater improvement as compared to placebo in excessive daytime sleepiness, with a reduction of 6 points as compared to a reduction of 3.1 points with placebo after 2 weeks of treatment with a p value of 0.003. When we assessed effect on excessive daytime sleepiness in terms of the reduction in the number of inadvertent naps or sleep attacks, AXS-twelve treatment resulted in a statistically significantly greater reduction in the number of inadvertent naps and sleep attacks as compared to to placebo with a 31.8 percent reduction with AXS-twelve versus a 5.3% reduction with placebo at week 2 with a p value of less than 0.001. And now looking at 0 in the number of inadvertent naps or sleep attacks. At week 2, a significantly greater proportion of of patients treated with AXS-twelve as compared to placebo, 38.1% versus 10% had achieved a response with a p value of 0.036. In the CONCERT trial, we assess cognitive function using the ability to concentrate item of the narcolepsy symptom assessment questionnaire, which was assessed daily. For this assessment, patients raised their ability to concentrate on a 5 point scale ranging from 1 for very good to 5 for very poor. 0%, that is none of the patients in our study rated their ability to concentrate as good or better at study entry. Treatment with AXS-twelve resulted in a statistically significantly greater improvement in the ability to concentrate compared to placebo as early as week 1 with a p value of 0.007 and this improvement increased at week 2 with a p value of 0.002. Furthermore, at the end of the 1st week of treatment, 38% of patients had a weekly average ability to concentrate that was good to very good with AXS-twelve treatment compared to 15% of patients with placebo and 0% of patients at baseline. At week 2, these percentages increased to 43% for AXS-twelve and 25% for placebo. Moving now to sleep quality and other sleep related outcome measures, AXS-twelve demonstrated important benefits on these core symptoms of narcolepsy as measured using the narcolepsy symptom assessment questionnaire. 45% of patients reported improved sleep quality with 30% of patients reported a reduction in the number of awakenings at night with AXS-twelve treatment versus only 5% of patients with placebo with a p value equal to 0.044. AXS-twelve treatment also resulted in greater proportions of patients with reductions in sleep paralysis episodes and in hypnagogic hallucinations as compared to placebo. In this study, AXS-twelve was safe and well tolerated. There were no serious adverse events and there were no discontinuations due to adverse events. The most commonly reported adverse events in the AXS-twelve treatment arm were anxiety, constipation and insomnia. In summary, in the CONCERT trial, AXS-twelve met the pre specified primary endpoint demonstrating a statistically significantly greater reduction from baseline in the frequency of cataplexy attacks and demonstrated statistically significant reductions in excessive daytime sleepiness. Beyond the improvements in cataplexy and excessive daytime sleepiness, AXS-twelve also demonstrated meaningful improvements in the ability to concentrate in sleep quality and other sleep related symptoms. AXS-twelve was safe and well tolerated in this study with no serious adverse events and no discontinuations due to adverse events. We would like to thank the patients, the investigators and the clinical site staff who collaborated with Axsome in the completion of this study as we strive to further the clinical development of AXS-twelve in the hopes of bringing to patients a novel, well tolerated therapeutic agent with the potential to effectively address several symptoms of narcolepsy. With that, I will 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. Thank you. And your first question here comes from the line of Mark Goodman with SVB Leerink. Please go ahead. Your line is now open. Yes, good morning. A couple of things. First of all, so the plan for Phase 3 is to do multiple studies at first or are you going to do one study, just so we're clear? And are you going to be going after both endpoints, cataplexy and EDS? Remind us also of the IP around this product and how we should be thinking about that. And then maybe you could just give us a sense of how you think about the data relative to the products that are on the market right now? Thanks. Thank you, Mark, for the questions. So with regards to Phase 3, we do intend to move as quickly as possible into Phase 3 trials. With AXS-twelve, We would anticipate 2 studies, 2 registration trials. This is typical to get a product approved and we would anticipate launching those 2 studies simultaneously. And with regards to the intellectual property, as a reminder, we do have we have been granted orphan drug designation, the boy excess 12 for the treatment of narcolepsy. So that's a minimum 70 years of protection. There's also MCE protection for AXS-twelve. And then in addition to that, we have filed patent applications. And obviously, should those patents issue, then that would significantly expand the runway for the product. And you're pursuing both EDX and Cataplexy endpoints? Yes, we are. I mean, one of the things that we really like about the data is that it shows that the AXS-twelve in this trial addressed both of the key symptoms of narcolepsy. So that is both cataplexy and EDS. And then related to that, you mentioned the other part of your question had to do with how we view ASX12 with regards to the treatment landscape. And what's nice about these data is that they do show that the effects on cataplexy and on EDS are very strong. And the drug is also very well tolerated. As a reminder, there is currently only one product that is approved to treat both Cataplexy and EDS. And so we also like the fact that the data indicate that in addition to cataplexy and EDS that sleep quality is improved and we're also very glad to see that the drug also has a positive cognitive effect. So therefore, we think that there's no reason why if AXS is positive in Phase 3 trials and that they are replicated that it could not be a candidate for foundational therapy in narcolepsy. And the dosing in the Phase 3, what are you planning? We would anticipate similar dosing in terms of total daily dose. So the way that the trial was this trial was designed during the 1st week patients were dosed at 8 milligrams even with that dose there was a significant effect. And then in the second, they were escalated to 10 milligrams. So we would expect similar dosing in the Phase III trials. Thanks. Your next question comes from the line of Charles Duncan with Cantor. Please go ahead. Your line is now open. Good morning, Herriot and Cedric. Congratulations on the data. Lots of data that you shared, really appreciate that. Wanted to ask you a little bit about the patient population and the treatment duration in this study, especially as it relates to the next steps or Phase 3. How would you characterize this particular patient population? You mentioned them as being fairly highly burdened, but do you think that the sample is a representative of the overall population of patients with narcolepsy? Thanks, Charles. I'll let Cedric answer that. Thanks, Charles. So absolutely, the patient population, both in terms of their baseline sleepiness scale as measured by the average Sleepiness Scale of a mean of 18 points is very much in keeping with the baseline level of severity for patient populations for which narcolepsy treatments have been tested. And that also applies then in terms of the cataplexy rates at baseline. In fact, in our study, the cataplexy rates, when we look at some of the trials have been run with other agents are on the higher side. So we've definitely looked at a population that is burdened by catapults. In addition to that, given that they also had cognitive deficits with the fact that no patients at baseline were reporting anything better than average ability to concentrate and we also improved that. So one interesting difference is that our trial was over a shorter period of time, 2 week treatment period. So it's also nice to have seen the effects demonstrated in that short period of time on all important core symptoms, narcolepsy, namely excessive daytime sleepiness, rates of cataplexy, cognitive ability is measured by the ability to concentrate and then other key symptoms of narcolepsy, sleep quality and sleep related symptoms like the hypnagogic hallucinations and sleep paralysis episodes and number of awakenings at night. And as a follow-up to that question and the previous set of questions by Mark, for Phase 3, excuse me, what would you anticipate the treatment duration to be? Could you lay out a little bit of a little bit more details on anticipated design of that study? So it's still we're still digesting the data. And obviously, one of the things that we like to do is to look at the data from prior trials very carefully, in this case our Phase 2 trial to inform the design of the Phase III trial. But just to give you a sense and we have not finalized any of this yet. We so registration trials in this disorder have been on the order of about 4 weeks in duration. So that should help you think about the duration of the trial, so 4 week trial or 5 week trial. And then in terms of the sizing of the study. Slightly bigger. Yes. I mean it's Centric is saying slightly bigger, but look, we're when we run our registration trial, we'll make sure that it is very well powered. And what's nice is we're seeing definitely a large effect here with a small number of patients. And so that I think gives us a lot of room with regards to a powering of the trial, such that it is manageable, but still yields the results and the data that we would hope to generate for registration package. Yes. The effect sizes are pretty notable here and should be capital efficient. Last question is, could you anticipate fully starting both trials in 2020? Is that would that be your goal? That is our anticipation. Okay. Good deal. Thanks for taking my questions this morning. Your next question comes from the line of Joon Lee with SunTrust. Please go ahead. Your line is now open. Hi. Thanks for taking my questions and congrats on the results. Could you remind us what the dose of araboxetine, what the doses that's used in Europe for depression and what you use as compared to what you use in the Phase 2 CONCERT trial? And I have follow ups. So the doses that are used in Europe for depression are in the range of what we studied in the CONCERT trial. Okay. And then you said that the safety was clean, so you expect the scheduling to be not an issue. But would you just ask to say that the mechanism of action are sufficiently differentiated from modafinil and Xyrem to warrant it not being scheduled? Yes. There is I mean, right now our anticipation is that AXS-twelve would not be scheduled. As you know, as you pointed out, it is approved in Europe and it's not scheduled there. And so far in the data and based on the mechanism of action, we would not expect it to be scheduled. Great. And the last question is, could you remind us what the baseline was for cataplexy and for excessive daytime sleepiness? Absolutely. So the mean baseline weekly cataplexy attacks were 30, that's on average more than 4 cataplexy attacks a day. And in terms of the excessive daytime sleepiness, the baseline score was 18.1, which again reflects a moderate to severely afflicted population with excessive daytime sleepiness. Great. Thank you. Your next question comes from the line of Yatin Sunja with Guggenheim Partners. Please go ahead. Your line is now open. Good morning, everyone, and congrats on the results. Just a few questions on the baseline. Can you just comment on or help us understand the baseline scores a little bit better? It seems like the average cataplexy attacks at baseline was 30 for you. And for Xyrem it is about 20 to 24. So does that mean these patients are really truly refractory harder to treat or the higher baseline gives you a better chance to show a larger delta? Well, first of all, thanks for the question. You want to make sure that patients have a level of cataplexy attacks, which demonstrates that they are impacted by their symptoms and that they would need treatment for their symptoms. So certainly the numbers you cited sound about right. We certainly wanted to make sure that we had a population of patients who had complex C attacks that had also been studied for agents that have shown efficacy. And as we mentioned before, there's only one agent that has the approval for both cataplexy and excessive daytime sleepiness. So in terms of baseline, we want to make sure that we were recruiting a population of patients that were moderate to severely afflicted by both of these key symptoms of narcolepsy, the cataplexy and we got that as demonstrated by the baseline level of 30 on average cataplexy attacks per week. And also in terms of a mean baseline score of 18 on the Epworth Sleep in scale, again, right there on the cusp of moderate to severe excessive daytime sleepiness. Got it. And just two more follow-up. Then with regard to the Phase 3 program, is it fair to assume this is the type of patient population you would like to recruit? That's one part of it. And then the other part is that most likely it's going to be a little bit more extended or more longer in duration. Any potential safety issues that you could think of? And with more extended use, do you anticipate the efficacy to sort of improve a little bit more? And then just finally, if you can also talk about the market opportunity, I mean the pricing in narcolepsy is a little bit different, more orphan type pricing than some of the other programs that you are running. Just help us frame the market opportunity also. Thank you. Sure. So thanks for the question. It's a question. So I'll let Cedric respond to the question around the Phase 3 design in the population that we're looking for. And with regards to the safety, what's nice about AXS-twelve is that reboxetine is a very well characterized agent and has been used for long periods of time. So we don't expect any safety issues, any new safety concerns, the drug was incredibly well tolerated in our trial. We had 0 discontinuations due to adverse events. So we're pretty proud of that. So I'll let Cedric answer the Phase III modulation question and then Dave Marek will talk about the market opportunity. And I think the answer is pretty short really just to say, yes, exactly same population, the same degree of severity we will pursue in Phase III. As you know, only one agent has an approval for cataplexy and the population that we're pursuing both in the Phase 2 and in the planned Phase 3 are comparable. And that's the answer to that part. Yes, Flan. And thank you for joining us this morning. Regarding the market opportunity, in short, we believe that this could be very significant. The first way we typically look at the market potential is to look at the impact on patients' lives. And given the very strong efficacy findings for both cataplexy, EDS symptoms and the other endpoints Cedric mentioned earlier, if the Phase III replicates what we see in concert, we believe that this could have a tremendous benefit to a high number of patients with narcolepsy, both with and without cataplexy. So given there's about 200,000 people with narcolepsy in the U. S, we believe, as Herriot mentioned earlier, that this could be foundational therapy for a good number of patients. So as we progress through the development program, of course, we'll fine tune the commercial strategies to assess the likely patient and revenue forecasts. And you asked a question regarding pricing, it's premature for us to really specify where our price would be. However, we would certainly consider the clinical benefit and the corresponding economic value of AXS-twelve, while we also look at the marketplace environment. But what we would do is engage payers ahead of time to ensure that we find a price that we believe would provide fair and timely access for patients while rewarding innovation with what we believe would be a potentially superior profile to other market options. Got it. Thank you very much. Your next question comes from the line of Raim Salvekaraju with H. C. Wainwright. Please go ahead. Your line is now open. Thanks very much for taking my questions. Just a few quick ones. Firstly, can you comment on what you expect the timing to be of a formal end of Phase 2 meeting with the FDA for this product candidate? And in relation to that, also whether or not you would specifically seek to obtain a special protocol assessment from the FDA for the Phase 3 program? Also wanted to ask about the duration of treatment effect that would likely be viewed as clinically meaningful by regulators in the Phase 3 context, if you had any initial indications from them on what their opinion might be on that front? And then 2 other questions that are market related. One is with respect to the scheduling. Let's assume that the boxy team winds up not being scheduled. Do you foresee that the only potential rival in the narcolepsy indication would potentially be et alison? And if so, what specifically do you anticipate are likely to be the edges that rivoxetine might hold over Pitalissant? And then finally, from a market standpoint, could you give us a sense of how you draw the distinction between narcolepsy and excessive daytime fruitiness? Or if you view those as basically being the same thing? And also if you view reboxetine as potentially having a commercial opportunity at all in jet lag? Thank you. Okay. Thank you for the multipart question. With regards to the timing of an end of Phase 2 meeting, we would be looking to meet with the FDA as soon as practicable. As you know, we've got a lot going on. We have a we're fortunate to have a broad pipeline. And there's a lot remaining between now and the end of the year, as I'm sure you're aware. So we have a lot to do. But having said that, we are planning ahead and we will not be specific as to the exact timing of a meeting. We first have to request a meeting. But you can imagine that we'd want to do that expeditiously. With regards to NSPA or our Phase III trials, We will consider the benefits of an SPA. We don't think that it's necessary in every instance, but that's something that we will consider, obviously, especially after we meet with the FDA during an end of Phase 2 meeting. In terms of the duration of effect, which would be needed or required by regulators, We do know that registration trials for some of the currently approved products were in were of a duration of treatment similar to what we are contemplating for our planned Phase III trials. So I don't think that there are any surprises there. And the other thing too is we did announce last year when we announced the excess blood product candidate that we had met with the FDA. And during that meeting, we did get pretty specific guidance and feedback on the planned duration of our trial. And so we feel pretty comfortable with the time frame that we're looking at for dosing. Your next question had to do with how we would compare ourselves, I guess, to pettolizant, assuming that our product is not scheduled. So what I think what we can say is what we see in the product label for betelasan. And so betelasan is approved only to treat excessive daytime sleepiness. And what we saw though in the CONCERT trial with AXS-twelve is that we saw an effect that was robust not only on excessive daytime sleepiness, but also on cataplexy, 2 of the core symptoms. And I would also point out that while we're focused on those 2 endpoints in the questioning so far that what's exciting about AXS-twelve is that it also showed a benefit on numerous other symptoms. In fact, every single symptom of narcolepsy that we assessed, there was a clear benefit. For example, in terms of improvements in the quality of sleep, only about 5% of placebo treated patients reported an improvement compared to about 45% of AXS-twelve patients. So it's still early days for us in terms of really looking at the data and delving into it. We try to provide as much as we could in a very short period of time when we had 48 hours really to look through the data. But so far, what we're seeing would point to a very favorable profile versus currently approved drugs. Then with respect to the distinction between narcolepsy and daytime sleepiness from a market perspective as well as the potential opportunity in jet lag, I was hoping that maybe you could comment on that also specifically within the context of potential pricing paradigms that you might employ. So if I understand the question correctly, I think you're pointing out that excessive daytime sleepiness is seen not just in the narcolepsy population, but in other broader populations, which is true. I mean, and so we right now we are focused on the narcolepsy opportunity. That is the condition that we study the XS-twelve in. And so we're looking to move forward with that indication. Certainly, drugs which improve wakefulness may have a role also in jet lag or other medical conditions. Right now, we're focusing on the data that we have in hand in the indication that we studied in. And with regards to pricing power, as Dave mentioned, certainly we would look to the price the product based on the value that the product provides while ensuring access to the product for patients. And so it's still early days on that front. What we'd look to do is just to try and replicate the findings of the Phase 2 trial in Phase 3 as we think about pricing. But certainly, as you are aware, the current pricing for products that are approved for this indication would leave significant opportunity. And then just curious about one aspect of the safety profile. The press release mentioned constipation. Was this known to be a potential side effect with reboxetine in the European real world usage setting? And if so, I mean, it didn't seem to be particularly severe. Doubtless was well controlled, but I wanted to know what you believe the mechanism is underlying that? Thanks. This is Cedric here. What are the nice things about AXS-twelve by roboxytein in terms of its selectivity for norepinephrine receptors is that it tends not to hit off target receptors and therefore actually has a reduction, has less side effect profile. Now constipation does occur and it has been characterized in terms of use of reboxetine. So that's well characterized previously. Yes. And the other thing that we would add to that is we reported obviously the most common adverse events, but the overall rate was relatively low and very similar to placebo. And importantly, the rate of discontinuation in this trial was virtually nil. I think only one person discontinued and that was not due to an adverse event. So we're pretty pleased with the product profile. Okay. One last item is whether or not at this juncture you expect to need a distinct sales force to market this drug or if you feel that a specialty neurology focused sales force would easily and societally be equipped to market this drug alongside your other drug candidates? Thank you. Hi, it's Dave, and thanks for the question regarding the sales force. I think we have a little bit of time here to understand not only what the ultimate profile would be for AXS-twelve, but the rest of the portfolio. So we would ensure that we have a sales force that would maximize the opportunity for AXS-twelve in this indication. We would also do it with an eye towards driving efficiencies across our entire commercial portfolio. So as we see other programs advance, we would look at any synergies that we could glean across the portfolio to make sure that we're both highly effective but also highly efficient in our promotional efforts, not only with sales force but with non personal promotion as well. Our next question here comes from the line of Bert Hazlett with BTIG. Please go ahead. Your line is now open. Thanks. I have a couple. Just could you remind us congratulations on the data first and foremost, but could you remind us are there delivery technologies embedded in XS-twelve, anything to modify the PK? Thanks for the question, Bert. So part of the patent applications that we have filed would be around the delivery. Okay. And that moves right into the other comments on patents that I had the questions. Could you just discuss the status? Do you have notice of allowance? And are these used patents? Just a little bit more on the general patenting strategy would be helpful. So thanks for the question Bert. So we have filed several patent applications and those patent applications would cover various aspects of AXS-twelve. So as I mentioned, one set of patents that we are looking at to prosecute would be around the formulation, but other patents would also be around the method of use. Okay. And then just one or two quick ones. I think you mentioned 8 milligrams and 10 milligrams. Have you decided on one of those doses to move into Phase 3? And as you see kind of a longer use in Phase 3, would you expect any CV AEs like Tachy tachycardia or anything to manifest themselves in a Phase 3 study? Thanks. That's all for me. So with regards to the VAE profile, roxene is very well characterized. It is very, very safe. We do not anticipate any cardiovascular signals, but that remains to be seen. That's why you do clinical trials. What's nice is we know that the drug is incredibly safe with long term use. Yes, and with regards to the dosing in our planned Phase III trials, it's still early days with regards to looking at the data. So we wanted to look at the data and really understand it. But certainly, I think we've identified an effective dosing range. And what we'd like to tease out is the lower dose, which we gained during the 1st week and it was titrated to the higher dose during the 2nd week, how effective that is. But what's nice is that both doses were very well tolerated. And so that gives us a lot of leeway to maximize efficacy. That's great. Congratulations on the data again. Thank you. Thank you. Your next question comes from the line of Myles Minter with William Blair. Please go ahead. Your line is now open. Hi, guys. Congrats on the data. It looks great. I was just wondering whether you can help with the repetitive effect in the context relative to currently approved therapies. I know you only measured 1 week out after treatment commencement, but did you hear any anecdotal evidence from the patients when they came in for a visit that efficacy may have been bought forward from that time point? Then just curious on, I think it's one patient that dropped out of sequence 1 in your trial. Just wondering whether that was due to adverse effects that was in the dose titration portion or whether they switch back to placebo and just dropped out for efficacy reasons? And then maybe one for Dave, just curious as to whether there's any broader sort of off label usage of the SNRI class in maybe patients that have failed Xyrem efficacy and whether there's any learnings from that from the clinical side? Thanks guys. That's it for me. So thanks, Myles. With regards to the onset of action, we will look through our data to see how fast the onset of action was. We are able to look at that information. But certainly, the onset of action was very rapid. And certainly at least at 1 week, there was a measurable effect. And with regards to the onset of action of other agents that are in the market, I don't know if there are data at less than 1 week for some of the other currently marketed agents. So we don't want to give you an inaccurate answer right now. And the patient did drop out, so that patient was just lost to follow-up. So that was not a discontinuation due to any adverse event. And with regards to SNRIs that are used off label, what's nice about AXS-twelve is that it addresses numerous symptoms. So some of the SNRIs and the SSRIs that are used off label may be used for one symptom of narcolepsy. And that leads to polypharmacy, of course. And with AXS-twelve, we have shown that for every symptom of narcolepsy that we assessed, there was a significant effect. And your last question here comes from the line of Matt Kaplan with Ladenburg Thalmann. Please go ahead. Your line is now open. Hey, guys. Thanks for taking the questions and congrats on the results. I guess one question, narcolepsy, what percentage of patients suffer from both EDS and cataplexy? Well, if you look across narcolepsy, we see that up to 70% of patients that have narcolepsy also have cataplexy associated. Okay. That's helpful. And then I guess given the current treatment landscape, I guess specifically Xyrem being the only drug approved to treat both symptoms and the cumbersome miss associated with using that drug, you have to dose it in the middle of the night once before you go to bed and once in the middle of the night. It seems to me with respect to the data that you gave us that only 25% of patients of the 50% diagnosed or receiving treatment, it seems to me that there remains a significant unmet need in this patient population. Have you done any market analysis with respect to how you think this product with this product profile, if approved, will be used given the current treatment landscape? Well, I think with just receiving the data, many times what we would do is put the data in front in terms of a product profile to get a more specific kind of willingness to prescribe and willingness to use. So we don't have those kind of results, given the fact that we're just analyzing the clinical data now. However, the way you characterize it, I think, is accurate that we look at narcolepsy with the significant disability, it's an incurable neurological disorder. And when you look at the current treatment options, we know that there is still significant unmet treatment need in the marketplace today. So we would certainly anticipate, as Herriot said earlier, if we can replicate the Phase 3 data consistent with Concert, there's really no reason we can see at this point why this wouldn't be considered as a first line or foundational therapy for a sizable portion of those patients. Thanks, Dave. Congrats again, guys. Thank you. And there are no further questions. I will now turn the call back over to Mr. Mark Jacobson for closing remarks. So this is Arius Heavyuto. Thank you all for joining us on the call. We're excited by the results of the CONCERT trial and we're especially excited by what they potentially mean for narcolepsy patients who are living with this debilitating disease. I would also like to thank again the patients and the investigators and especially our Axsome team. Our team has worked very hard to generate these important data And we're looking forward to continuing to update you on our progress with the ExcessFlow program. Now we also look forward to the remainder of the year, which will continue to be a busy time for us, as we're still expecting top line results from our Phase III trials with AXS-five in major depressive disorder and with AXS-seven in the acute treatment of migraines. Thank you and we look forward to speaking with you again throughout the month of December.