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

Good morning, ladies and gentlemen, and welcome to the Axsome Therapeutics Conference Call. [Operator Instructions] 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-1 Phase III trial of AXS-05 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 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 our investigational agents, our clinical and nonclinical plans, and our plans to present or report additional data, the anticipated conduct and the source of future clinical trials, regulatory plans, future research and development plans and possible intended use of cash and investments. These forward-looking statements are based on current information, assumptions and expectations that are subject to change and involve the risks and uncertainties that may cause actual results to differ materially from those contained in the forward-looking statements. These and other risks are described in our periodic filings made with the Securities and Exchange Commission, including our quarterly and annual reports. You are cautioned not to place undue reliance on these forward-looking statements, which are only made as of today's date, and the company disclaims any obligation to update such statements. Joining me on the call today from Axsome's management team are Dr. Herriot Tabuteau, Chief Executive Officer; Dr. Cedric O'Gorman, Senior Vice President of Clinical Development and Medical Affairs; Mr. Nick Pizzie, Chief Financial Officer; and Mr. Dave Marek, Chief Commercial Officer. We will also be joined on today's call by Dr. 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 of the topline results of the STRIDE-1 clinical trial. Following Cedric's presentation, we will open the line for Q&A with the Axsome management team and Dr. Fava. Following the Q&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 Dr. Maurizio Fava, Psychiatrist-in-Chief at the Massachusetts General Hospital, Director of the Division of Clinical Research at the MGH Research Institute and Associate Dean for Clinical and Translational Research at Harvard Medical School. Dr. 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-1 results in detail. Dr. Fava will then provide his clinical perspective on treatment-resistant depression, STRIDE-1 results and their implications. Dr. Fava will also be available for the Q&A session. Today, we announced the top line results of the STRIDE-1 trial of AXS-05, Axsome's novel, oral NMDA receptor antagonist with multimodal activity in patients with treatment-resistant depression. STRIDE-1 randomized 312 patients with confirmed treatment-resistant depression with failed 2 or 3 prior lines of treatment, the treatment with either AXS-05, consisting of 45 milligrams of Dextromethorphan and 105 milligrams of bupropion or with 150 milligrams of bupropion twice daily for 6 weeks. AXS-05 met the key secondary endpoints in the STRIDE-1 trial by rapidly and statistically significantly improving symptoms of depression on the Montgomery-Åsberg Depression Rating Scale, or MADRS, at weeks one and two 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-05 was numerically greater than the active comparator, but did not reach statistical significance. Importantly, treatment with AXS-05 was associated with a rapid and highly statically significant induction of remission, defined as a score of 5 or less on the QIDS-SR-16 scale as compared to the active comparator, starting at week 1, with a p-value of 0.001. Statistical significance was maintained at every time point thereafter. Remission on the QIDS 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-05 also improved cognition on the Massachusetts General Hospital cognitive function subscale with a p-value of 0.011, and it reduced the anxiety symptoms on the HAM-A a with a p-value of 0.009. AXS-05 was well tolerated and was not associated with psychotomimetic effects, weight gain or sexual dysfunction. These STRIDE-1 results provide the first evidence of activity of AXS-05 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-05 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-05. The data indicate a differentiated profile for AXS-05 and support its continued development in treatment-resistant depression, with initiation of a second Phase III trial of AXS-05 in this indication anticipated in the third quarter. Note that this new study is already included in our recently provided financial guidance. With regards to the development of AXS-05 for our lead indication of major depressive disorder, or MDD, we remain on track to file our planned NDA for AXS-05 and MDD in the fourth quarter of this year. The NDA filing is supported by our 2 completed positive pivotal efficacy trials in MDD, the ASCEND active-controlled trial and the GEMINI placebo-controlled trial, as previously disclosed. Our long-term open-label trial of AXS-05 in patients with MDD and TRD to build the safety database required for an NDA filing is on track with nearly 900 patients dosed. To date, more than 1,300 patients with major depressive disorder have been or are being evaluated in our completed and ongoing trials. As a reminder, AXS-05 has been granted FDA Breakthrough Therapy designation for the treatment of MDD. We look forward to filing an NDA in the fourth quarter of this year with the goal of making this therapy available to patients as quickly as possible. We're also developing AXS-05 for the treatment of Alzheimer's disease agitation. We recently announced completion of dosing in our pivotal Phase II/III ADVANCE-1 trial of AXS-05 in this indication and remain on track to report top line results in early 2Q. We have also completed our Phase III INTERCEPT trial of AXS-07 in the acute treatment of migraine. We expect to announce top line results for the study imminently. Related to AXS-07, we remain on track to file an NDA for this product candidate in the acute treatment of migraine in the fourth quarter. Now a few words on depression before turning it over to Cedric. Of the estimated 17 million adults in the U.S. who experience a major depressive episode each year, about 1/3 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 dosing 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 fast onset of action that are orally administered. AXS-05 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 depression. AXS-05 is also a sigma-1 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-05 in patients with depression. If approved, AXS-05 would represent the first mechanistically novel, oral pharmacotherapy for depression in over 30 years. AXS-05 is covered by 44 issued U.S. and international patents, providing protection out to 2034, and Axsome maintains worldwide rights. I would now like to turn the call over to Cedric, who will review the STRIDE-1 top line results in greater detail.

Thank you, Herriot. The STRIDE-1, or Symptom Treatment in Resistant Depression 1 study, was a Phase III 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 fail to respond to bupropion during this lead-in period, a total of 312 patients, were randomized in a 1:1 ratio to continue treatment with bupropion at this same total daily dose or to treatment with AXS-05 for 6 weeks. The total dextromethorphan bupropion daily dose of AXS-05 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-Åsberg Depression Rating Scale, or MADRS, and the Quick Inventory of Depressive Symptomatology-Self-Rated, or QIDS SR-16. The primary endpoint was a change from baseline in the MADRS after 6 weeks of treatment. The key secondary endpoints were the change from baseline in the MADRS 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 dosing duration in their current depressive episode. Patients who fail 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 2 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-05 and 33.2 for bupropion, reflecting moderate to severely depressed subjects. Study completion rates were high with 89% and 94% completion rate for patients treated with AXS-05 and bupropion, respectively. Turning now to the efficacy results. AXS-05 met the key secondary endpoints in the study, demonstrating a rapid, statistically significant reduction in the MADRS 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-05 was consistently greater than that of bupropion, and the treatment difference increased over the course of 6 weeks of treatment. AXS-05 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-05 versus 6.9 for bupropion with a p-value equal to 0.031. The antidepressant effect of AXS-05 was rapid. At week 1, treatment with AXS-05 resulted in a 5.2 point improvement on the MADRS total score compared to a 3.6 point improvement with bupropion with a p-value of 0.02. At week 2, the treatment effect and treatment difference increased in favor of AXS-05, as evidenced by an 8-point improvement on the MADRS total score for AXS-05 compared with a 6.1 point improvement with bupropion with a p-value of 0.031. At week 6, the primary endpoint, AXS-05 demonstrated a numerically greater improvement in the MADRS with mean reductions of 11.6 for AXS-05 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-SR-16, 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 HAMD-17. It may provide a more sensitive measure of change with reduced variability in studies of longer duration. AXS-05 demonstrated a statistically significant improvement versus bupropion on the QIDS 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 QIDS. Remission refers to the near-complete absence of clinically significant symptoms of depression and was defined as a QIDS 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-05 resulted in a statistically significantly greater proportion of patients who were in clinical remission as compared to bupropion. As early as 1 week, 6.5% of AXS-05 treated patients were in clinical remission compared to no patients on bupropion with a p-value of 0.001. At week 6, 18.2% of AXS-05 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 CPFQ, 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 CPFQ assesses sharpness, mental acuity and the ability to focus or maintain attention, to remember or recall information and to find words. AXS-05 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-05 was rapid as compared to bupropion, reaching statistical significance as early as week 2 with a p-value equal to 0.001 and at every time point thereafter. Statistical significance for the superiority of AXS-05 versus bupropion was also achieved for the entire CPFQ p-value equal to 0.014, and the full scale also assesses physical functioning. Now turning to safety and tolerability. AXS-05 was safe and well tolerated in this trial. The most commonly reported adverse events in the AXS-05 arm were dizziness and nausea, which were low on incidence. Rates of discontinuation due to adverse events were also low in both double-blind treatment groups, 2.6% for AXS-05 and 1.3% for bupropion. There were 3 serious adverse events in the AXS-05 group: migraine; suicidal ideation, which occurred more than 1-week after the subject of finished treatment; and an overdose in a subject who is undergoing significant personal stresses. In summary, in the STRIDE-1 study, treatment with AXS-05 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 QIDS scale were statistically significantly greater for AXS-05 at all-time points, emphasizing the clinical meaningfulness of the treatment effect for AXS-05 in TRD. Furthermore, AXS-05 also resulted in statistically significant improvements in cognitive functions and in anxiety as compared to bupropion. AXS-05 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&A, Dr. Maurizio Fava will provide his perspective on treatment-resistant depression, STRIDE-1 results and their clinical relevance. Dr. Fava?

Thank you. Thank you, Herriot. 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 have shown in the STAR*D study, the largest clinical trial ever conducted in depression. The patients that, for example, entered the study failing 2 to 3 trials of antidepressants. The STAR*D have a response rate of 8% to 10% with monotherapies of antidepressants, showing 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 no limitations and prohibitive issues of those treatments. So there's clear importance in finding oral treatments that work for patients who don't respond to standard therapies. AXS-05, although not meeting the primary outcome criteria, still had I consider kind of clinically meaningful changes throughout the study. While in regular depression, and when we consider a clinically meaningful difference from placebo is a 2.5 to 3-point difference during the study. In treatment-resistant 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 AXS-05 had a reduction in the dose of bupropion from 300 to 210. Now of course, in AXS-05, there was also Dextromethorphan, 45 milligrams, twice a day. So the - so it is normal to expect some changes just by continuing the bupropion, the same dose. In fact, in STAR*D, half of the patients remitted in the second half of the 12-week study of STAR*D. So for that reason, it's not unexpected if you wish that we have some benefit from continuing the bupropion 300 milligrams. But despite that, there was a clinically meaningful difference favoring of the AXS-05 over bupropion that was statistically significant at week 1 and 2 and overall. The other thing that kind of clearly speaks of the clinical meaningfulness is that, like in STAR*D, we had shown 8% to 10% remission rates at 6 weeks at level 3 or 4. That's what we see bupropion, plus placebo, 8.2% at week 6. Whereas AXS-05 increases our definition of we call less than 5. Hence, the remission rate of 18% with the difference of basically 10% and a number needed to treat of 10. So again, statistically significant p=0.012, but also clinically meaningful. Because you're more than doubling your odds of remission by adding -- by using AXS-05 versus continuing the bupropion. And the additional benefit that was detected was on the MGH-CPFQ, the cognitive dimension, which was statistically significant at week 6 and showing that advantage in mental sharpness/mental acuity, attention and 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-1 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 AXS-05 in this population or treatment-resistant depression on patients. Thank you.

Thank you, Dr. 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 at from different locations, some of us, so please bear with us if there are some technical difficulties. The Axsome management team as well as Dr. Fava are available for questions, and I'd like to hand over to the operator to open the line up for the questions.

[Operator Instructions] Charles Duncan with Cantor Fitzgerald.

Herriot and team, interesting results, so appreciate you holding this call this morning. Had a quick question for Dr. Fava. He just really addressed many of my questions in terms of clinically meaningfulness, but, Dr. Fava, I'm wondering if you could tell us which of, call it, 3 measures of efficacy you're most interested in. Is it MADRS, the QIDS or the cognitive function measures that you saw with AXS-05? And then also, second question is, do you think that the activity seen in the earlier weeks was -- in terms of the 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?

So let me start with your last question. Can you hear me? I don't know if you can hear me, but --

Yes, yes.

The -- yes. The people have argued that more rapid effect is an artifact of greater efficacy. That said, though, the mechanism of Dextromethorphan, 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 a greater efficacy, in this case, paradoxically, at end point, the statistical significance was not achieved. So one could not, in theory, argue for that because the statistical significance was obtained 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 treat patients. They failed 2 to 3 treatment trials, including 1 prospective. So 6 weeks is 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 and antidepressants in addressing cognition, 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 MADRS, in QIDS are clearly -- are 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 then for Herriot, and then I'll hop back in the queue, 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 February and March, 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 III 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 third quarter. 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 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 would be filing an sNDA for TRD assuming further success.

Marc Goodman with SVB Leerink.

Yes. There's another company, Sage, is talking about this rapid onset indication. Dr. Fava, 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 sNDA afterwards? You mentioned that you were considering placebo-controlled, Herriot. 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 Dr. Fava, maybe you can just talk about, what's your hypothesis on why we missed at 6 weeks? I mean, it should have worked. Why didn't it?

So I'll let Dr. Fava first answer your 2 questions.

Sure. So let me start with your second question. Why did we miss the -- it's very simple. If you -- it's a function of 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 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 and in week 6 in terms of absolute numbers. But yet, actually, week 2 is 2.1 and then week 6 is 2.2. The difference, and the reason why you're losing significance, is the standard deviation. The -- that's why, for example, trials that are very short give you an advantage, because you have 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 the significance because of 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 STAR*D, half the patients who remitted, remitted in the second half of the 12-week trial. So between week 6 and 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 AXS-05 actually have a drop in dose of bupropion from 300 to 210. So these are factors, if you wish, that may account for the lack of significance. But again, they lack 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 have a positive Phase II trial and a negative Phase III trial that they disclosed to the public.

So just, Marc, 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 III trial in MDD, we -- so our 2 key secondary endpoints were the change in MADRS 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 MADRS at week 1 and week 2 were also the key secondary -- were also 2 of the key secondary endpoints in the STRIDE-1 trial. So we think it is an important aspect of AXS-05, and we think it is clinically important, as I'm sure Dr. Fava 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 want to confirm that feedback, especially now that we've gotten the results from the STRIDE-1 trial, and we will incorporate that feedback prior to initiating the second study.

Yatin Suneja with Guggenheim Partners.

I have a couple. Maybe if I'll start with Dr. Fava. Dr. Fava, 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 -- the more rapid antidepressant effect is something that is very appealing to clinicians. Whenever I start the patient on an antidepressant, and I tell them, "By the way, it's going to take between 4 and 8 weeks for you to start feeling better," there's often a sense of disappointment from patients. "What do you mean at 4 to 8 weeks?" So the greater rapidity of the treatment, we'll make it very appealing to clinicians just for depression alone. Any data that then suggested this -- the AXS-05 would 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, one, if you wish to get more rapidly better for standard treatment of depression and to get greater efficacy from the onset, if you wish; and two 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 already 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 1 line failure versus the 2 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, Yatin. 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 only done those types of subset analysis, 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, first 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 nonresponse, if they have failed to get 30% or more improvement in their symptomatology in that open-label phase, they were deemed to be nonresponders. And that's a very stringent and a strict definition because if they had 30% or more, they were deemed to be responders. So we're 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 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 checked with the FDA. Can you just comment on that?

So we -- just as a reminder, this is not the first active control trial that we've conducted with AXS-05. We did conduct that -- the first active -- 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-05. So it's an even higher bar for establishing component contribution. So it was 210 milligrams of bupropion is incorporated in AXS-05. That's a daily dose versus 300 milligrams in the -- of a daily dose in the control arm. And the data, as Cedric and Dr. Fava reviewed, did separate statistically during the first 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 in all the data, is that for every single efficacy measure that was assessed, AXS-05 was numerically superior. And sometimes we're superior. So just in the -- just in the interest of time, we want to be mindful of Dr. Fava's time. So he has a strict cutoff at 9., so we'll just take one last question.

Your final question comes from the line of Ram Selvaraju with H.C. Wainwright.

I think, Dr. Fava, if you could perhaps give us a bit more color on what you see as the 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-05's potential applicability in areas beyond TRD.

Yes. That's a great question. So the antianxiety effects detected with HAM-A at week 6, which was statistically significant, do suggest an antianxiety effect. So on the other hand, many antidepressants also have antianxiety effects. So we don't know how differentiating that element is. On the other hand, the pro-cognitive effect, that, to me, is very exciting because we know that antidepressants typically don't necessarily process pro-cognitive effects. As I mentioned, response 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 self-ratings compared to bupropion versus placebo and a higher dose, by the way, of bupropion and the 210 of AXS-05, 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 AXS-05 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 I can think of.

Okay. Well, thank you all so much for the call. Dr. 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-05 and 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, 1 for AXS-05 in MDD and 1 for AXS-07 in migraine. We look forward to reporting top line results from our INTERCEPT Phase III trial in migraine imminently and also for our pivotal advanced Phase II/III trial in Alzheimer's disease agitation in early second quarter. 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.