Study Result

Mar 30, 2020

Good morning, ladies and gentlemen, and welcome to the 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'd now like to turn the call over to your host, Mr. Mark Jacobson, Chief Operating Officer 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 top line results of the STRIDE-one Phase 3 trial of AXS-five in treatment resistant depression. A press release announcing the results of the trial crossed the wire a short time ago and is available on our website at axon.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, anticipated conduct and the source of future clinical trials, regulatory plans, future research and development plans and possible intended use of and investments. These forward looking statements are based on current information, assumptions and expectations that are subject 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 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. We will also be joined on today's call by Doctor. Maurizio Fava from Massachusetts General Hospital and Harvard Medical School. 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 STRIDE-one clinical trial. Following Cedric's presentation, we will open the line for Q and A with the Axsome management team and Doctor. Fava. Following the Q and A, 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 are pleased to have with us on the call Doctor. Mauricio Fava, Psychiatrist and Chief at the Massachusetts General Hospital, Director of the Division of Clinical Research at the MTH Research Institute and Associate Dean for Clinical and Translational Research at Harvard Medical School. Doctor. Fava is one of the world's leading experts on treatment resistant depression and clinical trial designs in psychiatry. After my brief comments, Cedric will review the STRIDE-one results in detail. Doctor. Fava will then provide his clinical perspective on treatment resistant depression, the STRIDE-one results and their implications. Doctor. Fava will also be available for the Q and A session. Today, we announced the top line results of the STRIDE-one trial of AXS-five, Axsome's novel oral NMDA receptor antagonist with multimodal activity in patients with treatment resistant depression. STRIDE-one randomized 312 patients with confirmed treatment resistant depression who had failed 2 or 3 prior lines of treatment. The treatment with either AXS-five consisting of 45 milligrams of dextromethorphan and 105 milligrams of bupropion or with 150 milligrams of bupropion twice daily for 6 weeks. AXS-five met the key secondary endpoints in the STRIDE-one trial by rapidly and statistically significantly improving symptoms of depression on the Montgomery Depression Rating Scale or MADRIS at weeks 12 and averaged over the entire 6 week treatment period as compared to the active comparator bupropion in patients with treatment resistant depression. On the primary endpoint of MADRS change at week 6, the improvement with AXS-five was numerically greater than the active comparator, but did not reach statistical significance. Importantly, treatment with AXS-five was associated with a rapid and highly statistically significant induction of remission, defined as a score of 5 or less on the quiz SR16 scale as compared to the active comparator starting at week 1 with a p value of 0.001. Physical significance was maintained at every time point thereafter. Remission on the QUIDS scale is especially important for measuring clinical effect in the treatment resistant depression population as it was the instrument used in the STAR*D trial, the landmark NIH funded depression trial examining treatment outcomes after multiple lines of therapy. AXS-five also improved cognition on the Massachusetts General Hospital cognitive function subscale with a p value of 0.011 and it reduced anxiety symptoms on the HAM A with a p value of 0.00 9. AXS-five was well tolerated and was not associated with psychomimetic effects, late gain or sexual dysfunction. These STRIDE-one results provide the first evidence of activity of AXS-five in treatment resistant depression, an area of high unmet medical need. While not achieving statistical significance on the week 6 primary endpoint is disappointing, we are pleased with the overall results as we continue to demonstrate that AXS-five has a rapid onset of action, which in this study has translated through even the hardest to treat population, despite the use of a higher dose of bupropion than that incorporated in AXS-five. The data indicate a differentiated profile for AXS-five and support its continued development in treatment resistant depression initiation of a second Phase 3 trial of AXS-five in this indication anticipated in the 3rd quarter. Note that this new study is already included in our recently provided financial guidance. With regards to the development of AXS-five for our lead indication of major depressive disorder or MDD, we remain on track to file our planned NDA for AXS-five and MDD in the Q4 of this year. The NDA filing is supported by our 2 completed positive pivotal efficacy trials in NDD, the ASCEND active control trial and the GEMINI placebo controlled trial as previously disclosed. Our long term open label trial of AXS-five in patients with MDD and TRD to build the safety database required for an MDD filing is on track with nearly 900 patients dosed. To date, more than 1300 patients with major depressive disorder have been or are being evaluated in our completed and ongoing trials. As a reminder, AXS-five has been granted FDA Breakthrough Therapy Designation for the treatment of NVD. We look forward to filing an NDA in the Q4 of this year with the goal of making this therapy available to patients as quickly as possible. We are also developing AXS-five for the treatment of Alzheimer's disease agitation. We recently announced completion of dosing in our pivotal Phase twothree ADVANCE-one trial of AXS-five in this indication and remain on track to report top line results in early 2Q. We have also completed our Phase 3 INTERCEPT trial of AXS-seven in the acute treatment of migraine. We expect to announce top line results for the study imminently. Related to AXS-seven, we remain on track to file an NDA for this product candidate in the acute treatment of migraine in the Q4. Now a few words on depression before turning it over to Cedric. Of the estimated 17,000,000 adults in the U. S. Who experience a major depressive episode each year, about 1 third of them are considered treatment resistant. A patient is defined as treatment resistant if they have not responded to at least 2 different antidepressants of adequate dose and duration within the current major depressive episode. In addition to having a low likelihood of responding to treatment, patients with TRD have a significantly reduced quality of life, various comorbidities and the disease carries a high economic burden. Only 2 agents are currently approved to treat TRD in the U. S. There is therefore an urgent need for new treatments for TRD with novel mechanisms of action and a faster onset of action that are orally administered. AXS-five is potentially the 1st and only oral NMDA receptor antagonist also known as a glutamate receptor modulator, a new mechanism of action for the treatment of depression. 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 depression. If approved, AXS-five would represent the 1st mechanistically novel oral pharmacotherapy for depression in over 30 years. AXS-five is covered by 44 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 STRIDE-one top line results in greater detail. Thank you, Herriot. The STRIDE-one or symptom treatment in resistant depression 1 study was a Phase 3 double blind randomized active controlled, multicenter trial conducted entirely in the United States. A total of 799 subjects with a confirmed diagnosis of moderate and severe major depressive disorder who had previously failed 1 or 2 antidepressant treatments in their current depressive episode were treated in an open label fashion with 150 milligrams bupropion twice daily for a 300 milligram total daily dose during a 6 week lead in period. Patients who failed to respond to bupropion during this lead in period, a total of 312 patients were randomized in a 1:one ratio to continue treatment with bupropion at this same total daily dose or to treatment with AXS-five for 6 weeks. The total dextromethorphan bupropion daily dose of AXS-five was 90 milligrams, 210 milligrams compared to a total daily bupropion dose of 300 milligrams in the comparator arm. The change in depressive symptoms over time was measured using the Montgomery Asberg Depression Rating Scale or MADRS and the quick inventory of depressive symptomatology self rated or CRIDS SR16. The primary endpoint was the change from baseline in the MADRS after 6 weeks of treatment. The key secondary endpoints were the change from baseline in the MADRIS after 1 week of treatment, after 2 weeks of treatment and the average change over the entire 6 week double blind treatment period and the change from baseline in the Sheehan disability scale. During the course of this study, extensive quality control measures were employed. Key eligibility criteria for entry into the open label lead in period included adult outpatients with a diagnosis of moderate or severe major depressive disorder who had inadequate response to 1 or 2 prior antidepressant treatments of adequate dose and duration in their current depressive episode. Patients who failed to respond to treatment with bupropion in the open label period were then confirmed to have treatment resistant depression having failed a total of 2 or 3 antidepressant treatments and were randomized to the double blind phase. 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, 33.4 for AXS-five and 33.2 for bupropion, reflecting moderate to severely depressed subjects. Study completion rates were high with 89% 94% completion rates for patients treated with AXS-five and bupropion respectively. Turning now to the efficacy results. AXS-five met the key secondary endpoints in the study, demonstrating a rapid statistically significant reduction in the MADRIS total score at weeks 1, 2 and overall across 6 weeks of treatment as compared to bupropion. Statistical significance was not reached on the primary endpoint at week 6. The treatment effect of AXS-five was consistently greater than that of bupropion and the treatment difference increased over the course of 6 weeks of treatment. AXS-five rapidly and significantly improved symptoms in patients with TRD as measured by the MADRS over the entire 6 week treatment period, a key secondary endpoint with mean reductions of 8.5 for AXS-five versus 6.9 for bupropion with a p value equal to 0.031. The antidepressant effect of AXS-five was rapid. At week 1 treatment with AXS-five resulted in a 5.2. Improvement on the MADRIS total score compared to a 3.6. Improvement with bupropion with a p value of 0.02. At week 2, the treatment effect and treatment difference increased in favor of AXS-five as evidenced by an 8 point improvement on the MADRS total score for AXS-five compared with a 6.1. Improvement with bupropion with a p value of 0.031. At week 6, the primary endpoint AXS-five demonstrated a numerically greater improvement in the MADRS with mean reductions of 11.6 for AXS-five versus 9.4 for bupropion for a treatment difference of 2.2 points and a p value of 0.117. Now let us consider the improvement observed on the QIDS. The QIDS SR16 or the Quick Inventory of Depressive Symptomatology is a well established self reported depression scale that correlates well with clinician rated scales such as the MADRS and the HAM D17. It may provide a more sensitive measure of change with reduced variability in studies of longer duration. AXS-five demonstrated a statistically significant improvement versus bupropion on the quids over 6 weeks averaged for overall treatment effect with a p value of 0.013. Now turning to the results for clinical remission as defined by the quiz. Remission refers to the near complete absence of clinically significant symptoms of depression and was defined as a quiz score of 5 or less, the same cutoff utilized in the STAR*D study. The STAR*D or sequence treatment alternatives to relieve depression study was funded by the NIMH and conducted to determine the effectiveness of sequential treatments for patients with major depression who have not responded to initial treatment with an antidepressant. As you can see at each time point, AXS-five resulted in a As early as 1 week, 6.5 percent of AXS-five treated patients were in clinical remission compared to no patients on bupropion with a p value of 0.001. At week 6, 18.2 percent of AXS-five treated patients achieved remission compared to 8.2% of bupropion patients with a p value of 0.012. Turning now to the treatment effect on cognition. We know that patients with depression can suffer from significant cognitive impairment. The Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire or CPSQ was developed to assess clinically relevant cognitive and physical symptoms associated with depression, which are not adequately assessed by traditional measures. The cognitive subscale of the CPSQ assesses sharpness, mental acuity and the ability to focus or maintain attention to remember or recall information and to find words. AXS-five significantly improved cognitive function in patients with TRD as compared to bupropion with a p value equal to 0.011. The improvement in cognitive function with AXS-five was rapid as compared to bupropion reaching statistical significance as early as week 2 with a p value equal to 0.01 and at every time point thereafter. Statistical significance for the superiority of AXS-five versus bupropion was also achieved for the entire CPSQ, p value equal to 0.014 and the full scale also assesses physical functioning. Now turning to safety and tolerability. AXS-five was safe and when tolerated in this trial. The most commonly reported adverse events in the AXS-five arm were dizziness and nausea, which were low in incidence. Rates of discontinuation due to adverse events were also low in both double blind treatment groups, 2.6% for AXS-five and 1.3% for bupropion. There were 3 serious adverse events in the AXS-five group, migraine, suicidal ideation, which occurred more than 1 week after the subject had finished treatment and an overdose in a subject who is undergoing significant personal stressors. In summary, in the STRIDE-one study, treatment with AXS-five resulted in rapid and statistically significant improvements in depressive symptoms in a TRD population as compared to bupropion. While the primary efficacy endpoint at 6 weeks was not met, statistical significance was observed as early as week 1, the earliest time point measured at week 2 and averaged over the entire 6 week treatment period. Rates of remission on the QUIDS scale were statistically significantly greater for AXS-five at all time points, emphasizing the clinical meaningfulness of the treatment effect for AXS-five in TRD. Furthermore, AXS-five also resulted in statistically significant improvements in cognitive function and in anxiety as compared to bupropion. AXS-five was safe and well tolerated with a safety profile consistent with prior trial experience. Overall, completion rates were high in the study and discontinuations due to adverse events were low. With that, I would like to hand the call back over to Herriot. Thank you, Cedric. Before we open up the line for Q and A, Doctor. Mauricio Fava will provide his perspective on treatment resistant depression, STRIDE-one results and their clinical relevance. Doctor. Fava? Thank you. Thank you, Harriet. Yes, treatment resistant depression is a big clinical challenge for clinicians. As many as 50% of the patients that we see in our clinics don't respond adequately to 1 or more antidepressant treatments. As we've shown in the Study, the largest clinical trial ever conducted in depression, the patients that, for example, entered the study failing 2 to 3 trials of antidepressants, InstaD had a response rate of 8% to 10% with monotherapies of antidepressants, knowing that your odds of remitting only 1 in 10 in this population. We only have a handful of treatments approved, either adjunctive treatment or treatment resistant depression that are oral. And they're all atypical antipsychotics with the known limitations and probability issues of those treatments. So there's clear importance in finding oral treatments that work for patients who don't respond to standard therapies. AKS-five, although not meeting the primary outcome criteria, so what I consider kind of clinically meaningful changes throughout the study. While in regular depression, what we consider a clinically meaningful difference from placebo is a 2.5 to 3 point difference during the study. In treatment of zeta and depression, we consider clinically meaningful changes compared to placebo, changes of 1.5 to 2 points on the MADRS. And as you can see from Slide 13 of STRIDE 1, the from week 2 on, there was always a greater than 2 point difference from the placebo augmentation of bupropion. In addition, I'd like to point out a methodological aspect. Bupropion was all the patients were treated prospectively with bupropion for 6 weeks with 300 milligrams. And then were maintained on the same dose for the remaining 6 weeks of double blind treatment. Whereas those assigned to AKS-five had a reduction in the dose of bupropion from 300 to 210. Now of course, in ACTS-five, it was also bactromethorphan, 45 milligrams twice a day. So it is normal to expect some changes just by continuing the bupropion the same dose. In fact, in Study, half of the patients remitted in the second half of the 12 week study of Study. So for that reason, it's not unexpected, if you wish, that we had some benefit from continuing the bupropion to 100 Milligants. But despite that, there was a clinically meaningful difference favoring the Actimel 5 over bupropion. That was statistically significant in week 12 and overall. The other thing that kind of clearly speaks of the clinical meaningfulness is that like in STAR D, we have shown 8% to 10% remission rates at 6 weeks and level 3 or 4, that's what we see with bupropion plus placebo, 8.2% with 6%, whereas axiomo5, which is our the SAR definition of equal less than 5 has a remission rate of 18% with a difference of basically 10% and a number needed to treat the 10%. So again, statistically significant 0.012, but also clinically meaningful, because you're more than doubling your odds of remission by adding by using axial 5 versus continuing the bupropion. And the additional benefit that was detected was on the MGH CpfQ, the cognitive dimension, which was statistically significant and week 6 and showing an advantage in mental sharpness, mental acuity, attention, ability to remember things. So again, clinically and statistically meaningful, though as I mentioned, the primary outcome was not met. So overall, my interpretation of the results of STRIDE-one is that they do confirm the antidepressant properties combination that have been demonstrated in the MDD studies. And I feel like it's really important to continue to study this actual 5 in this population or treatment resistant depression patients? Thank you. Thank you, Doctor. Fava. So with that, I'd like to hand it back over to the operator to open the line for questions. Just as a reminder to folks, we are all operating from different locations, some of us. So please bear with us if there are some technical difficulties. The Axle management team as well as Doctor. Favre are available for questions. And I'd like to hand it over to the operator to open the line up for those questions. Certainly. Charles Duncan with Cantor Fitzgerald, your line is open. Okay. Thank you very much for taking our questions. Herriot and team. Interesting results. So appreciate you holding this call this morning. Had a quick question for Doctor. Fava. He just really addressed many of my questions in terms of clinically meaningfulness. But Doctor. Fava, I'm wondering if you could tell us which of, call it, 3 measures of efficacy you're most interested in? Is it the Modris, the quiz or the cognitive function measures that you saw with AXS-five? And then also second question is, do you think that the activity seen in the earlier weeks was, in terms of efficacy, was an artifact of the efficacy measure? Or is there a mechanistic rationale that clearly supports the differences that we're seeing between arms? Thank you. So let me start with your last question. Can you hear me? I don't know if you can hear me, but Yes. The yes, the people have argued that more rapid effect is an artifact of greater efficacy. That said though, the mechanism of vector metorpha, the NMDA receptor antagonism is something that we know leads to more rapid effects as we've seen with Ketamine and esketamine and so forth. So, although one cannot rule out the possibility that, that greater efficacy is simply a reflection of greater efficacy. In this case, paradoxically, at endpoint, the statistical significance was not achieved. So one could not in theory argue for that because the statistical significance will obtain early, but not later. But I understand your point. The things that in my mind are most clinically meaningful, The remission data are very impressive. I mean, these are tough to 3 patients that failed 2 to 3 treatment trials, including one prospective. So 6 weeks, it's very unlikely that you get anything more than what we've seen, so an 8% remission rate with antidepressant monotherapy. So going from 8% to 18% and more than doubling the odds of remission is very, in my mind, is very clinically meaningful. It happens to be statistically significant at week 6, but it's clinically meaningful. The cognitive dimension, what we know is that antidepressants, about 30% to 40% of patients who respond to antidepressants continue to have cognitive impairment, whether attention, concentration. So having a treatment that actually is more effective than monotherapy under the presence in addressing condition, that's very kind of clinically meaningful and it happens to be statistically significant too at week 6. So that and that also again is consistent with a kind of a glutamatergic effect. So in my mind, yes, the changes in matters include are clearly clinically meaningful, but the most impressive in my mind are the remission data and the cognitive the pro cognitive effect. It's very helpful. Makes sense to me. One quick question And that is regarding regulatory strategy, Herriot, I think you clearly outlined that you will move forward with MDD later on this year. Can I just clarify whether or not then the subsequent TRD data or TRD study would result in, say, an sNDA type regulatory strategy assuming MDD is approved? So thanks for the question Charles. With regards to our regulatory strategy for the MDD indication, as you know and as we mentioned in the prepared remarks, we're on track and very excited about that. With regards to the TRD specific indication, we are encouraged by the results of this trial. We think it definitely merits running a second Phase 3 trial and we're on track to do that. So the preparations have been underway and are underway and we'll launch that study in the Q3. Importantly, this new trial would be streamlined, so we think that it would enroll in a much more efficient way. The feedback that we had previously gotten from the agency, which we've disclosed is that this next study could potentially be also a placebo controlled trial. But we need to confirm the further details of that study after meeting with the agency. So we look forward to doing that. With regards to whether or not this could be an sNDA strategy, the answer is yes. Assuming that we are successful with our NDA review for MDD and the product is approved for that indication, then we will be filing an sNDA for TRD assuming further success. Okay, very good. Thank you for taking my questions. Interesting results. Mark Goodman with SVB Leerink. Your line is open. Yes. There's another company Sage, that is talking about this rapid onset indication. Doctor. Fab, I was curious about your thoughts on this indication in general. And is that the type of thing, Herriot, that you're considering maybe using here as you launch into TRD as an SND afterwards? You mentioned that you were considering placebo controlled hair, you just mentioned that. I'm curious that has not come from FDA at all. So you have no guidance with respect to whether you can push through a TRD in one versus the other. And then Doctor. Faba, maybe you can just talk about what's your hypothesis of why we missed it 6 weeks? I mean, it should have worked, why didn't it? Thanks. So I'll let Doctor. Favre first answer your two questions. Sure. So let me start with your second question. Why did we miss the it's very simple. If you it's a functional standard deviation. The longer you give a drag, remember the placebo here is not just placebo, it's placebo plus continuing bupropion. And so those who, let's say, were starting to improve on bupropion, on bupropion alone continue to improve on augmenting the spread of scores and that will increase your standard deviation. And so if you look at Slide 12, the separation exactly the same in week 2 week 6 in terms of absolute numbers. But yet, actually week 2 is 2.1 and week 6 is 2.2. The difference and the reason why you're losing significance is the standard deviation. That's why, for example, trials that are very short give you an advantage, right, because you have a more restricted standard deviation, the shorter the better if you wish. Now I'm not saying that we should have had a 4 week trial, but I'm just saying that the with over 6 weeks, that's the reason. So the extent of the clinical difference was the same. It lost its significance because of the standard deviation. The other factor that contributed to it is that bupropion stayed the bupropion arm stayed on the same dose throughout. And in STAR D, so bupropion alone was basically a 12 week trial of bupropion 300 milligrams. In Stand G, half of the patients who remitted, remitted in the second half of the 12 week trial, so between week 6 12. So you have a kind of a delayed effect of keeping the patients on the same dose of bupropion. Whereas if you remember, the people assigned to XL5 actually have a drop in dose of bupropion from 300 to 10. So these are factors, if you wish, that may account for the lack of significance. But again, the lack of statistical significance, now we could have addressed that greater standard deviation by increasing the sample size. A 2.2 difference with a larger standard deviation could have become statistically significant with a larger sample size. But the point is that that's not what we did. Your first question I thought was about Sage. Yes, Sage is also trying to develop an oral treatment. So that is the same space. And as you know, they had a positive Phase II trial and a negative Phase III trial that they disclosed to the public? So just Mark with regard to your question around the rapid onset strategy and pursuing that as an indication itself and how does that pertain to Axsome. Just as a reminder, we in our GEMINI Phase 3 trial in MGD, we our 2 key secondary endpoints were the change in MADRIS at weeks 1 and at weeks 2. And the point of a key secondary endpoint is to potentially be included in product labeling. So you can actually get a claim for that in the product label if it is replicated. So in a way, we have replicated the early onset. So the change in modulus at week 1 and at week 2 were also the key secondary we're also 2 of the key secondary endpoints in the STRIDE-one trial. So we think it is an important aspect of AXS-five. We think it is clinically important as I'm sure that Doctor. Faber will agree in this patient population and in MDD in general. And so we would look to discuss with the agency the strategy for getting the early onset in the label. And then with regards to the design of the second TRD trial, which we plan to conduct, we have gotten feedback from the FDA already on some of the aspects of that study. Clearly, we'll want to confirm that feedback, especially now that we've gotten the results from the STRIDE-one trial. And we will incorporate that feedback prior to initiating the second study. Yatin Suneja with Guggenheim Partners. Your line is open. I have a couple. Maybe if I'll start with Doctor. Fawa. Doctor. Fawa, so Axsome is developing this drug for 2 indications, right? They have successful MDD data readout and then the TRD data that we saw today. So maybe can you just help us understand how you might be using this drug in the MDD indication if it were to get approved based on ASCEND and GEMINI data? And how would the treatment paradigm and the use of drug will change if and when the company gets a TRD indication on the label? And then I have a few questions for the company. So let me start, how would I use it clinically? Well, I think that the more rapid antidepressant effect is something that is very appealing to clinicians. Whenever I start the patients on an antidepressant and I tell them, by the way, it's going to take between 4 8 weeks for you to start feeling better, there's often a sense of disappointment from patients, what do you mean 4 to 8 weeks? So the greater rapidity of the treatment will make it very appealing to clinicians, just for depression alone. Any data that then suggested this the actual five will also work in resistant depression would then argue that this could also be used when patients don't respond to standard therapies. And that so it would be kind of a second use of the drug. 1, if you wish to get more rapidly better for standard female depression and to get greater efficacy from the outset, if you wish. And 2 is, when patients don't respond to standard therapies, as in the case of this study where they failed 2 to 3 trials. What was your other question? I apologize. So I think you addressed the question. I have a few for the company. Herriot and team, like if you could maybe talk about the severity of the disease in these patients, how many were one line failure versus the two line failure when they entered the study? And any differences in how the drug might have worked in these respective patient population? And I don't know if you disclosed that on the call, but can you also talk about how you define inadequate responder in the placebo or in the open label arm? Thanks, John. So I'll turn it over to Cedric to answer the question on inadequate response and also on the severity of disease. In terms of the differences between the patients who had failed 2 versus 3 lines of treatment. We've just got the data. It's a lot of data that we've been working through. So we have not formally done those types of subset analyses, but those will be forthcoming. Cedric? Yes. We use very stringent criteria to define treatment resistance. So again, patients who are coming into the trial had to have demonstrated, 1st of all, that they had failed 1 or 2 antidepressants in their current depressive episode. So in addition to being acutely depressed, they were stringently defined in terms of having received an antidepressant at an adequate dose and duration of time. This needed to be documented. So if they failed 1 or 2 antidepressants, they would then enter the open label period and then prospectively defined if they failed on a total daily dose for 6 weeks of 300 milligrams of bupropion, then they were essentially treatment resistant in terms of having failed 2 or 3 antidepressants. And in terms of the actual your question around the non response, if they have failed to get 30% or more improvement in their symptomatology in that open label phase, they were deemed to be non responders. And that's a very stringent and a strict definition because if they had 30% or more, they were deemed to be responders who are really getting the toughest and most difficult to treat patients who were then randomized into the double blind phase. Got it. Very helpful. Just final quick question and I'll get the back in the queue. And with this trial, can you maybe comment, have you established a component contribution with this study or that needs to be sort of validated or reminder, this is not the 1st active control trial that we've conducted with AXS-five. We did conduct that the first study that we reported results out for in depression was the ASCEND trial, which was active controlled and we did establish component contribution in that study. So we have established component contribution. And with regards to this trial, we were clearly also better than bupropion. And as a reminder, the dose of bupropion in this trial and the comparator was a higher dose than in AXS-five. So it's an even higher bar for establishing component contribution. So it was 2 10 milligrams of bupropion is incorporated in AXS-five that's a daily dose versus 300 milligrams in the of a daily dose in the control arm. And the data as Cedric and Doctor. Rafava reviewed did separate statistically during the 1st 2 weeks. And as a reminder, those were key secondary endpoints. It also did separate on average over the entire 6 week treatment period. And as a reminder, that is also a key secondary endpoint. And then on numerous other measures, one thing that we should point out, although we have not shown all the data is that for every single efficacy measure that was assessed, AXS-five was numerically superior and sometimes it's superior. Got it. Thank you very much. So just in the interest of time, we want to be mindful of Doctor. Fava's time, so he has a strict cutoff at 9. So we'll just take one last question. Certainly. Your final question comes from the line of Ram Selvaraju with H. C. Wainwright. Your line is open. I think Doctor. Fava, if you could perhaps give us a bit more color on what you see as clinical meaningfulness of the impact seen in this study on cognitive dysfunction and anxiety, whether you would place greater weight on one versus the other, if this has additional implications broadly speaking for the TRD population as a whole? And if you think it might potentially say more about AXS-five's potential applicability in areas beyond TRD? That's a great question. The anti anxiety effects detected with the hemA at week 6, which were statistically significant, do suggest an anti anxiety effect. On the other hand, many antidepressants also have anti anxiety effects. So we don't know how differentiating that element is. On the other hand, the procognitive effect, that to me is very exciting because we know that antidepressants typically don't necessarily possess pro cognitive effects. As I mentioned, responders to antidepressant typically continue to have residual difficulties with attention, concentration and memory in 30% to 40% of the patients. And so having an effect there that is statistically significant, those those health ratings compared to bupropion versus placebo and a higher dose by the way of bupropion than the 210 of Axon 5, that's very impressive. So could it lead to other indications? Possibly. One could, in theory, take patients who have responded to antidepressants and continue to have cognitive impairment and randomize them to either placebo or XL5 as an augmentation, if you wish, to the antidepressant. That could be a very interesting study and potentially provide a new indication for the compound. But anyway, so there are many other things that one could think of. Okay. Well, thank you all so much for the call. Doctor. Fava, thank you for being so generous with your time. And so we and all the other participants, thank you also for getting on the call early this morning. We are very encouraged by the demonstration of antidepressant activity of AXS-five in now this third efficacy trial and which was conducted in a difficult to treat patient population with high unmet medical need. We remain on track to file 2 NDAs by year end, one for AXS-five in MDD and one for AXS-seven in migraine. We look forward to reporting top line results from our INTERCEPT Phase 3 trial in migraine imminently and also for our pivotal ADVANCE Phase twothree trial in Alzheimer's disease agitation in early Q2. Again, thank you and we look forward to speaking with you very shortly. This concludes today's conference call. We thank you for your participation. You may now disconnect.