Sage Therapeutics, Inc. (SAGE) Earnings Call Transcript & Summary

Good morning. Welcome to Sage Therapeutics conference call. [Operator Instructions] This call is being webcast live on the Investors and Media section of Sage's website at sagerx.com. This call is the property of Sage Therapeutics, and recording, reproduction or transmission of this call without the express written consent of Sage Therapeutics is strictly prohibited. Please note that this call is being recorded. I would now like to introduce Helen Rubinstein, Investor Relations at Sage.

Good morning, and thank you for joining Sage Therapeutics' conference call on data presented at the European College of Neuropsychopharmacology, or ECNP, Congress. Before we begin, I encourage everyone to go to the Investors and Media section of our website at sagerx.com where you can find the press release and slides related to today's call. I'd like to point out that we will be making forward-looking statements, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. Please consult the risk factors discussed in today's presentation and in our SEC filings for additional details. On today's call, we will be joined by Barry Greene, our Chief Executive Officer; and Dr. Anita Clayton, Chair of Psychiatry and Neuro Behavioral Sciences at the University of Virginia School of Medicine, who will review the data presented yesterday. Steve Kanes, our Chief Medical Officer; and Jim Doherty, our Chief Research Officer, will join us for Q&A. With that, I'll now turn the call over to Barry.

Thanks, Helen. And thank you, everyone, for joining us this morning. Obviously, we'd all like to be together in Portugal, but that certainly isn't possible. So I am pleased to be here today to review the zuranolone data presented at ECNP and the totality of the data from the LANDSCAPE and NEST programs to date. At Sage, our vision is to deliver medicines that matter so people can get better sooner and stay longer -- stay better longer. And we believe that we have the potential to transform the lives of millions of people with brain help disorders who are need of innovative new therapies. With zuranolone, we're rethinking how depression is thought about and treated. This is a paradigm shift that will require understanding and education on the totality of data we've generated in the program. Importantly, to date, these data show a very consistent differentiated profile for zuranolone. On this morning's call, we'll be joined by Dr. Anita Clayton, who has participated as an investigator in the zuranolone clinical development program. Dr. Clayton will review the data we've seen with zuranolone to date. This is an important review, and Dr. Clayton's presentation will help with the data generated to date in context. With that, let me turn the call over to Anita who will discuss the data presented. Anita, off to you.

Thanks, Barry. It's my pleasure to join you all this morning. For background, I'm Professor and Chair of Psychiatry and Neuro Behavioral Sciences at the University of Virginia School of Medicine. I've been a clinician and researcher in major depressive disorder, MDD; and reproductive psychiatry, including postpartum depression, or PPD, for 30 years. I continue to be impressed with the emerging profile of zuranolone, which has consistently shown rapid improvement in depressive symptoms across clinical studies in PPD and MDD. In clinical trials conducted to date, zuranolone, a short course, 14-day treatment, has led to a rapid, robust and sustained improvement in depressive symptoms and has shown a differentiated and well-tolerated safety profile, the type of profile I believe would be welcomed by patients suffering from depression who are seeking additional treatment options. I'll now review the data with zuranolone to date. We'll start with Slide 3. As a reminder, zuranolone is a novel positive allosteric modulator, or PAM, of the GABAA receptor. And it has a truly novel mechanism of action and is in development as a treatment for both MDD and PPD. Benzodiazepines bind to a synaptic site on the GABAA receptor, affects are short-lived and help with anxiety but not depressive symptoms. Importantly, zuranolone not only interacts with the synaptic GABAA receptor but binds extrasynaptic GABAA receptors. This is the mechanism of action that really intrigues me, potentially explaining the rapid and persistent effect on MDD by restoring adaptive signaling in the brain. Interacting with both synaptic and extrasynaptic receptors may be important to the clinical profile of zuranolone. Slide 4 shows a summary of the zuranolone clinical development program. The LANDSCAPE and NEST programs are comprised of multiple trials that were each designed to generate complementary information to provide a complete understanding of how zuranolone may benefit patients. Importantly, you can see that the program has been designed to evaluate zuranolone in 3 different use cases, including postpartum depression, monotherapy for MDD and co-initiation with the current standard-of-care antidepressant. These trials include a range of measures of efficacy that are widely accepted as valid measures of depressive symptoms or of the functional impact of these symptoms. For example, social, occupational or physical functioning. This includes both investigator-reported and patient-reported outcomes. The MDD-201B, ROBIN, MOUNTAIN and WATERFALL studies evaluated the efficacy of a short course of zuranolone consisting of 14 days of treatment. So the primary endpoint in each of these studies is day 15 after the course is completed. Also part of the development program is a Phase II study with similar design by Shionogi, comparing 20 milligrams and 30 milligrams of zuranolone to placebo in patients with MDD in Japan. The SHORELINE study evaluates what would classically be referred to as maintenance: how long do patients with zuranolone sustain improvements in their depressive symptoms and when, if ever, do they require a repeat dose within the 1-year period of evaluation. The CORAL study is evaluating zuranolone started together with a newly initiated standard-of-care antidepressant therapy. On Slide 5, you can see that zuranolone has consistently demonstrated rapid improvements in depressive symptoms across studies completed to date in the LANDSCAPE and NEST programs. The chart on the left of the slide shows the reduction at the first measured time point in each trial: day 2 after 1 dose and day 3 after 2 doses. As you can see from the slide, zuranolone treatment resulted in a significant change from baseline in the Hamilton Depression Rating Scale 17-item version, or HAMD-17, at the first measured time point: day 2 or 3 in each completed trial. On the right, you can see the robust reduction in HAMD-17 scores compared to baseline in each trial at day 15, with a reduction from baseline HAMD-17 scores ranging from 12.5 to 17.8. As a reminder, zuranolone met the primary endpoint, a statistically significant reduction in HAM-D scores at day 15 compared to placebo in 4 of the 5 completed trials in the LANDSCAPE and NEST programs as well as the Phase II trial run by Shionogi. That compares to a typical success rate of less than 50% across trials in the depression space. On Slide 6, we can review the secondary endpoint. This is an overview of these endpoints in the WATERFALL study, all favoring zuranolone 50 milligrams with the majority being nominally significant. Nominally significant because the secondary endpoints were powered and analyzed in a hierarchical manner, requiring statistical significance in the prior endpoint at the top of this slide to claim statistical significance to subsequent endpoints. The CGI comparison was not statistically significant, so subsequent analyses are noted as nominally significant. Patients treated with zuranolone demonstrated rapid and sustained improvements in depressive symptoms as assessed by the HAMD-17 and the MADRS and an improvement in symptoms of anxiety as assessed by the HAM-A total score. Slide 7 provides data on CGI improvement, measuring the clinician perspective on the proportion of patients that were much or very much improved. This is a key endpoint that speaks to the clinical meaningfulness of results. You can think of it as a gestalt measure that takes into account a fuller picture, potentially including psychosocial circumstances, symptoms, behavior and the impact of symptoms on the patient's ability to function. The X-axis on this chart is time, and the Y-axis is the percent of patients who are deemed much or very much improved by the clinician. You can see improvement and significant separation favoring zuranolone at all-time points from day 3 through day 21. Slide 8 showcases response and remission rates at day 15 across the completed studies from the LANDSCAPE and NEST clinical programs. Response is defined as a reduction from baseline in HAMD-17 score of greater than or equal to 50%. This is a significant measure in clinical trial. Remission is defined as a HAMD-17 total score of less than or equal to 7. As you can see, response and remission rates at day 15 are higher than placebo across each completed study. It's also important to note these rates are -- we are seeing are through 2 weeks, day 15 after 14 days of treatment, not 8 or 12 weeks, demonstrating the rapidity of response. The X-axis on this chart is time, and the Y-axis is the percent of patients who are deemed much or very much improved by the clinician. You can see the improvement in significant separation favoring zuranolone from day 3 through day 21. Slide 9. This shows the SHORELINE study in MDD, which sustained efficacy or maintenance of effect zuranolone as being characterized. The study initially enrolled patients using zuranolone 30 milligrams. The protocol was amended to allow enroll patients to receive treatment with zuranolone 50 milligrams, and a new cohort was initiated with zuranolone 50 milligrams as an initial and retreatment dosing. Nonresponders to the initial 14-day course of zuranolone exited the study. In the completed 30-day milligram zuranolone cohort, nearly 45% of patients with positive responses to the initial 2-week treatment required only that initial treatment course. And approximately 70% of participants required at most 1 additional zuranolone treatment during the 12-month follow-up of the study. The chart on the left of the slide provides detail on the total number of treatments in the 30-milligram cohort of the SHORELINE study. Patients who respond to oral standard-of-care antidepressants are followed every 3 months once on a stable dose in clinical practice. So follow-up every 2 months is much like the current clinical practice. Of course, patients are also instructed to come earlier with changes in symptoms or tolerability problems. Since major depressive episodes are generally thought to last about a year, the 12-month duration of the SHORELINE study is a reasonable follow-up period. I followed patients as described above for 25 years. Now of course, they have recurrent MDD. But I see them approximately every 3 months on schedule. We look forward to the next data cut from the SHORELINE study in patients who received 50 milligrams for a full year expected later in 2021. Now on Slide 10, you see information about the Short Form 36, or SF-36, patient-reported outcome measure. While evaluating zuranolone's ability to reduce depressive symptoms, it's important to understand how treatment impacts patient well-being and functioning. Patients often prioritize returning to their usual level of functioning over reduction in depressive symptoms, and functional recovery has been associated with better prognosis of depression. Also, patients are frequently slow to recognize improvement in depressive symptoms with standard-of-care antidepressants as functional improvement often occurs later in the treatment. The SF-36 is the patient-reported quality-of-life measure that is used to evaluate how a person perceives the impact of a disease on their well-being and functioning and how that evolves with treatment. This is a widely recognized tool as being among the leading patient-reported outcome, or PRO, measures and capture scores across 4 physical and 4 mental health concepts of general health. The SF-36 has been used as an efficacy endpoint in clinical trials across a wide range of therapeutic areas, such as rheumatology, respiratory conditions and cardiovascular disease. Slide 11 shows the risks from integrated patient-reported data in the program that demonstrates the impact of zuranolone treatment on patient well-being and functioning as captured by SF-36 data collected during the double-blind phase of each trial. As you can see, there were statistically significant improvements from baseline across assessments of well-being and functioning at both day 15 and day 42. What this means is that after the 2-week treatment, 6 of 8 components measured were significantly improved. And through follow-up to day 42, patients across studies reported significant improvements in overall quality of life. In fact, at day 42, the integrated analysis showed that patients continue to improve, reporting increasing and sustained statistical improvement from baseline across every domain of quality of life measures. Why is this so important? The other measures I shared are physician evaluations. These are data patients are reporting that they are better and having differentiation at day 15 and 42, 4 weeks after completing their course of therapy. This is really striking. If you think about the symptoms of depression that patients are particularly bothered by: fatigue, low energy and amotivation, these often manifest as not getting up, not getting out of bed, not getting off the couch, not getting dressed, not eating and not going to work or taking care of their family. Slow thoughts or movements and trouble concentrating or indecisiveness may lead to decreased productivity at work or school or difficulty, for example, driving their children to activities. This results in fears of educational failure, losing their job or losing or hurting their children. Rapid improvement in less than 2 weeks is noticeable to patients, their families, their employers or teachers and their doctors and is reflected in these ratings of change in function. Slide 12 shows data from the Phase II study of zuranolone in MDD recently completed by Shionogi in Japan. As you can see, the profile of zuranolone seen in clinical trials to date was further confirmed in this study. At days 8 and 15, zuranolone 20 milligrams and 30 milligrams demonstrated a statistically significant improvement in depressive symptoms. Additionally, in the study, all adverse events were mild or moderate. Patients treated with zuranolone 20 milligrams or 30 milligrams experienced the HAMD-17 reduction from baseline of at least 8 points. That was compared to at least a 6-point reduction from baseline for placebo. Notably, this was a relatively small data set, about 82 patients per arm, so it's particularly impressive to see these separate from placebo. That said, these findings represent the fourth positive study of 5 completed studies of zuranolone and reinforce the profile of Zuranolone demonstrated in the LANDSCAPE and NEST development programs to date, where we've seen rapid improvements in depressive symptoms and a well-tolerated safety profile. On Slide 13, you can see that the tolerability profile for zuranolone has been consistent across clinical trials to date. Adverse events have largely been associated with the mechanism of action, somnolence, dizziness, sedation, but rates across the program have generally been tolerable with rates of steady discontinuation of less than 5% in MDD trials. However, the AEs frequently associated with current antidepressant therapies, such as weight gain, sexual dysfunction, euphoria and sleep disruption have not been seen to date with zuranolone. These are the adverse effects I have to deal with to help my patients be able to continue to take their standard-of-care antidepressants, and they affect a significant percentage of patients. These symptoms also are typically the cause of treatment discontinuation with standard-of-care antidepressant drugs. Additionally, there have been no signals for increased suicidal ideation or behavior or withdrawal symptoms after completion of the 14-day course of treatment in the zuranolone trial. Slide 14 highlights the tolerability profile of zuranolone from the completed pivotal studies in our LANDSCAPE and NEST programs. Specifically, we analyzed the discontinuation due to side effects using an analysis called Number Needed to Harm, or NNH. In MDD, discontinuation due to side effects is often used for this calculation as it may represent patient ability to remain compliant to medication treatment, which has notable implications for clinical practice and patient outcomes. Starting on the left, you see discontinuation rates across studies in the programs, which are quite low and generally comparable to placebo rates of discontinuation. On the right is a meta-analysis of standard antidepressants with an NNH of between 7 and 43. But with zuranolone, you see a score of 98, which speaks to the fact that zuranolone has been generally well tolerated in the clinical trials to date. That means 98 patients would need to be treated with zuranolone to see 1 additional patient discontinue due to adverse events. Also, a 2-week course of treatment is much easier for a patient to complete even with mild AEs than a 6- to 12-month course of their standard-of-care antidepressant. Slide 15 is a little bit complicated, so I'm going to explain this in a little more detail. Although there have been 35 treatments for depression approved in the last 30 years, the benefit risk profile of antidepressant therapy remains fairly unchanged. On this slide, we're shown side-by-side assessment of zuranolone and standard-of-care antidepressants to provide context of the product profile by utilizing metrics with implications for real-world clinical practice. The graphic on this slide shows MDD response rates plotted on the X-axis, higher rates moving right; and discontinuation rates due to adverse events, increasing on the Y-axis. You can see that a representative basket of standard-of-care treatment at 8 weeks and Citalopram, the first-line treatment in the naturalistic STAR*D trial, have similar levels of efficacy, less than 50%, and rates of discontinuation due to these adverse events of between 8% and 16% with placebo rates in standard-of-care randomized controlled trials of 5%. In contrast, the integrated response and discontinuation data generated with zuranolone studies to date shows a higher response rate of about 60% and much lower discontinuation rates between 2% and 4%. On Slide 16, based on the totality of data, zuranolone has the potential to address significant unmet needs for patients with depression. As you can see from today's presentation, the data on zuranolone today demonstrate a profile that has been consistent across trials and, if approved, may be useful for a variety of patients with MDD and PPD. Zuranolone has a novel mechanism of action and is intended as a 2-week as-needed course of treatment. This is an innovative approach as current antidepressant therapies are typically prescribed for at least 6 months following a first depressive episode and chronically following subsequent episodes. Further, the onset of efficacy seen in clinical trials has been consistently rapid, and the safety profile has been generally well tolerated to date. With that, I'll turn the call over to Helen to handle Q&A with the operator. Helen?

Thanks, Dr. Clayton. [Operator Instructions] Now I'll turn it over to the operator. Operator?

[Operator Instructions] Our first question comes from Salveen Richter with Goldman Sachs.

This is Andrea on for Salveen. Our question is for Steve or Dr. Clayton. Just wondering if you performed any analysis to correlate individual HAM-D scores and improvement in depressive symptoms with the SF-36 score.

Thanks, Andrea. I appreciate the question. So what you're looking to do are -- is understanding the correlation between HAM-D and patient-reported outcomes, which I think are fairly well-validated. Steve, do you want to start and then Anita, add some color?

Sure. Obviously, we're looking at the data in its totality now. And if you're looking for something like a scatter plot, we haven't done that yet. It's an interesting question. But what you can derive from the data pretty clearly is that those patients are getting better, and similar rates are also showing the same benefits in things like the CGI-I. So physicians are seeing their improvement as well as Barry and Anita said, the patient-reported outcome is SF-36. And that's actually been true across the board. In our earliest trials, we've released them as individual study by study. But now we have the totality of the data, we see a very clear picture. Anita, do you have any other comments to make about how the SF-36 pertains to our understanding of patient benefit?

Yes. So if you look at that slide, which I think is 11, that 4 -- as domains at the left are really physical components and the 4 domains on the right are mental or emotional components. And you can see, this is major depression. So you're going to see much higher scores -- well, much lower scores at baseline and much high -- greater improvements because those scores are so low. People with major depression have some physical symptoms, but generally, many unstable physical symptoms are excluded from clinical trials. So to see statistical improvements even in physical health is really pretty critical. I think the other one for me to point out is vitality, which is really energy, motivation, being able to move forward and accomplish tasks, and this is a critical area with patients. People with depression often don't have any energy. This is one of the biggest complaints. They can't get things done. They can't even motivate themselves to do regular activities of daily living. And this is a significant improvement. At day 15, so you're talking about a really early improvement, in fact, statistically significant improvement very early in the course of the depression, and that's critical for patients. And then I think you continue to see further improvements a month out from completion of the treatment. And so early impact on functioning, both physical and mental, and then continued improvement, this is critical for patients. It happens fast. They notice it. [ I've seen ] this in the trials in which I was an investigator. So hopefully, that answers your question.

Our next question comes from Ritu Baral with Cowen.

I wanted to ask about the response/remission rates at day 15. Barry, have you done any analysis on how sustained both the response and remission rates were at day 42 versus what you have on the slide, which is day 15? And for Dr. Clayton, any thoughts on sort of the placebo rates of both of these measures? There's -- response is sort of going up. Remission is going up over time over the course of the program. How should we be thinking about those changes and the differences?

Yes. Ritu, thanks for the question. And I'll have Steve answer the first part of that question, and then Anita can add some color there. What I will say is when we look at the integrated set of response and remission, the consistency across all studies, it's the kind of response/remission when coupled with all the other data that gives us tremendous confidence in how zuranolone is performing for patients. Steve, do you want to take the next part?

Sure. I mean due to limitations on all our time, maybe not presenting every last data point here. But Ritu, we've shown this before for all of our other trials, and the results remain essentially consistent just as the HAM-D scores have been over time. And so that's been an overall, a very consistent story. Once patients get better, they remain well. And we'll be presenting additional materials later this year, which sort of continue to demonstrate what those response and remission rates in our naturalistic SHORELINE study, which show what treatment with 2 weeks -- 2-week courses of therapy, what benefit patients have over the course of a year. So overall, a very consistent story for both response and remission for longer duration.

So I want to respond to then about placebo rates. So I want you to realize that patients were seen at day 0, which is the day they were randomized to their treatment, day 3, day 8, day 12 and day 15. So we've got 5 visits in 15 days. And that is certainly going to provide some difference than just taking a pill and going home and coming back at the end of a week and the end of week 2. And that may, in fact, impact on the placebo response rate. So I think this is not a shock in terms of a response with placebo, but it's significantly more with the zuranolone. And I think it's important to recognize that when patients notice this in the first 14 days -- and in fact, for -- most of the patients, that I -- that responded in my trials, in the first 2 days of after treatment, so day 3, this is just something really quite striking to patients and providers.

Our next question comes from Paul Matteis with Stifel.

This is Katie on for Paul. Thinking about this data ahead of the CORAL readout, is there a specific threshold that you guys are hoping to see? And I guess, how should we think about the bar for success and what you would want to see from CORAL in the context of the data generated to date?

Yes. Thanks, Katie, and our best to Paul. So let me step back and put this in context. As we said in January, with several studies behind us on zuranolone that we've designed the LANDSCAPE and NEST program, 2 studies in MDD, 1 study in PPD, any 1 of which if positive, gave us the package to file. So with the WATERFALL being positive, and you can see how impressive the totality of data here are, we do believe that we've got the package to file. Certainly, CORAL, which is aimed to be completed at the end of the year, will enhance the safety database. But that's really today how we're looking at the totality of data.

Our next question comes from Yasmeen Rahimi with Piper Sandler.

Thank you for the thoughtful integrated analysis. I guess the first question I had for you is the integrated analysis concludes -- includes NEST and LANDSCAPE. But I assume that your filing will be mostly on MDD. So will there be an opportunity that NEST is included from an efficacy perspective? And then the second question is, when you look at the integrated safety analysis across all studies, can you maybe comment on the severity of somnolence and sedation when you put all the studies together as you have done in -- for this presentation?

Yes. Thanks for the questions. I'll answer the first part because that has to do with sort of NDA filing strategy. And maybe Anita can talk about, because she's treated some of these folks, the safety aspect of the integrated data. So yes, just to repeat again, when we set out the year, we designed 2 studies in MDD and 1 additional study in PPD to sit on top of the data we had to date, which included an MDD study and a PPD study. And obviously, the fact that we can now include the Shionogi work gives us 4 or 5 clinical studies, all depression studies, whether it's PPD or MDD, it does speak to zuranolone, the profile. And I'll remind you that now in each and every study, and as Anita has highlighted, we've seen a rapidly durable response with a benefit risk profile that is very different than standard of care today. So we're pretty excited by what we have here and our ability to help patients. And what -- and I'm sure Anita will talk about this a little bit more, what patients want is they want improvement in the depressive mood, they want reductions in anxiety, and they want to sleep better, which gives them vitality, social function, the ability to get out of bed, work and go to school. So we believe that we've got evidence to date on the totality of zuranolone that can really help this group. Anita, do you want to talk specifically about the safety side and what you're seeing, both personally and with the integrated data set?

Yes. So overall, looking at the tolerability profile, somnolence and sedation are maybe not all that different and not unexpected for a drug that acts at synaptic GABAA receptors. Benzodiazepines, for example, make people sleepy in general. So that's not necessarily a surprise. This is dosed at night, though. So it's not a significant problem, and it seems to be positive for patients to help them sleep. I think also, these adverse effects are only mild to moderate, and people are taking the drug for only 2 weeks. So this is not an issue in terms of safety or complaints or concerns. I will tell you, the 2 most common adverse effects that people tell me in advance of prescribing an antidepressant that they don't want to have to happen are weight gain and sexual dysfunction. And sexual dysfunction is also one of my areas of expertise. And they will do anything to avoid these problems. And sometimes we add additional [ medications ] to manage these problems or we have to change their antidepressant because of weight gain, in particular. So we're not seeing that. We also don't see any loss of consciousness. That's a concern if people get sedated or somnolent. But none of that happened. And my patients generally felt improved partially because they recognized that they were sleeping better. A number of the questions on the HAM-D are about sleep. And this was readily evident to them even at day 3. So I find the safety profile very attractive. It helps patients remain adherent to treatment. And that's what's really critical because we know lots of patients discontinue their standard-of-care antidepressant therapy mostly because of adverse effects.

Our next question comes from Vamil Divan with Mizuho Securities.

So maybe just, again, going back to CORAL, which obviously is coming up soon here. I've gotten some questions from investors, just curious about if there's any learnings from these prior trials that you could implement. I guess a couple of questions that come up. The trial is a little bit smaller than the number of patients in WATERFALL's. Any thoughts on potentially increasing enrollment? And then also, you tend to get a bigger sort of separation or placebo at day 3 as opposed to day 15. Any thoughts on potentially sort of changing that to be the primary? And if not, why not?

Great. Yes. To answer the question, and again, with -- I think you can tell from this integrated data set and now the fourth, the fifth positive trial with Shionogi, we believe that we have the efficacy, the integrated safety to file. CORAL, at the end of the year, is a different question. It's concomitant prescription with -- concomitant in taking with standard-of-care antidepressant along with zuranolone. We haven't really studied that yet. We've studied monotherapy or patients that have been on a stable antidepressant. So it is a new question. What I will highlight is, while in WATERFALL, the numbers demonstrated that those on an antidepressant did a little less well than those on monotherapy. The Phase II study that we published in New England Journal was quite opposite. And Shionogi study was a monotherapy alone. So we're excited for the CORAL readout. I think, certainly, if in looking at the integrated data set or understanding anything from CORAL there were things to change, we certainly would take those actions.

Our next question comes from Laura Chico with Wedbush Securities.

Dr. Clayton, I have 1 for you. I guess I'm kind of curious, how would you envision monitoring patients on zuranolone in your practice compared to other agents that you put patients on? And I guess, I'm thinking about not only in the beginning of treatment, but I guess, post the course of therapy, how would you have to modify your current practice?

Laura, thanks for the question. Appreciate it. And Dr. Clayton, do you want to take that?

Sure. So when the FDA issued a warning about standard-of-care antidepressants increasing suicidal ideation and behavior in patients under 25 years old, we actually increased monitoring initially in order to try to catch that. So it would not be common, though, for us to necessarily monitor people at a week, but we might monitor people at 2 weeks. And that might be particularly true for people who have anxiety symptoms as part of their symptom of depression or if they have a comorbidity anxiety disorder because those people tend to be more sensitive to side effects of medications. But patients are going to be done with the treatment with zuranolone at the end of 2 weeks. So we also have added where patients can contact us through the electronic medical record. And that's a fairly easy way, especially people are much more facile with that kind of method of communication. And so they can send us concerns or complaints or problems or even how well they're doing in advance of that visit at 2 weeks. Beyond that, if they're responders to zuranolone, I probably would follow based on the SHORELINE data and follow them up maybe in a month after the first 2-week visit and then follow them up every 2 months or 3 months beyond there. If they're nonresponders to zuranolone, then obviously, we're going to try a different treatment. And given that there was not a difference in management in response to patients who were taking antidepressants, oral antidepressants or patients who are not taking oral antidepressants in these studies, I might, at least in a first depression, not initiate an antidepressant that standard-of-care oral medication. In patients with recurrent episodes, we might think about that going forward, but again, trying to avoid the adverse effects over the long term. I think I'd wait to see if they did not respond to zuranolone. And with a 60% response rate, I think that's an appropriate consideration.

Our next question comes from Brian Abrahams with RBC Capital Markets.

So in general, you've shown pretty good consistency with respect to zuranolone's profile across your studies. When you look at the day 15 and 42 response and remission rates presented at ECNP for WATERFALL, it looks like you showed a similar near-term benefit on response to what you showed in MOUNTAIN but lower remission rates in WATERFALL despite the higher dosing in that study. And so I'm curious if you had any explanations for why this was a different study to study, whether it may be patient baselines or running the study during COVID. And I guess, how important is remission at day 15 and 42 from any individual study from a regulatory and clinical practice standpoint? Or would you expect a greater focus on response or -- and/or on the totality of data you're seeing across the studies?

Yes, Brian. Thanks for the question. It's important. And I'll start, and then maybe Steve can comment, and if Anita has some color to add. So I think you answered the question -- you answered it for yourself at the end, Brian. When we submit in the NDA, the clinical section will be a clinical section highlighting the totality of data. We've got 4 or 5 positive studies here. And when we look at the integrated data set, as we've already highlighted on this call, it's pretty impressive and offers a new approach to treat depression for many, many patients. And as we talked about -- or talk to on SHORELINE, those patients that respond, if they have another depressive event, respond again. So when we think about the regulatory filing, it's the totality of data and what zuranolone does in studies over time in the overall population. Steve, any other things to add?

Yes. The way that I think about this, and this is sort of the way that the FDA looks at these kind of data as well, is, first and foremost, does the drug work? That's the primary endpoint. Then we look across secondary endpoints and -- including response and remission. And across the board, whether it's response, whether it's remission, whether they were statistically significantly better or numerically significantly better, literally in every secondary endpoint that we look at. So when I -- when we talk about totality of the evidence and consistency of profile, that's what we're looking for. And so any individual trial may have some variability, and that happens in these studies. Dr. Clayton pointed out that about half of trials in the field are not successful. And so we're talking about 4 out of 5 trials that are showing the exact same profile, rapid onset, sustained benefit. And most importantly, for us, in SHORELINE, we really understand what those benefits will look like in real life with between 50% and 60% response and remissions over the course of a year for each individual treatment. It tells a very consistent story about what the drug is doing. And that's the way that the FDA looks at these programs and certainly the way that we think about it and will represent benefit for patients.

Oh, I was going to say -- I do have something to say. We realize these are the mean response. These are the means, okay? So it includes people who had no response at all and people who had a robust response. And I can tell you the first patient that we entered and treated in the MOUNTAIN study responded at day 3. When she came in, her HAM-D had dropped to 9. It's only 2 above remission. And she sustained that, and she sustained that at 42. And then we had a naturalistic follow-up out 6 months, and she sustained that through all kinds of stressors like nursing school, having back surgery, et cetera. So those are the people who are going to get to remission because she was in remission nearly at day 3. So I think that -- now that's an anecdotal study -- I mean, story, but I think that you just have to keep in mind that some of these people are responding dramatically, and other people are not responding at all.

Our next question comes from Marc Goodman with SVB Leerink.

This is Madhu on for Marc. Just 1 question that has come up in our conversations with physicians is the individual items from the HAM-D and if you've started to look at that. And if so, if you could provide any details on that or when we might see that data.

Yes. Thank you, Madhu. As I think Steve said earlier on the call, we have looked at the individual items on HAM-D. We'll be presenting those individual items either in a presentation or publication. But importantly, they're consistent. All the items point to a favorable drug profile across depressive symptoms and other aspects of the HAM-D.

Our next question comes from Sumant Kulkarni with Canaccord.

This is for Dr. Clayton. What are some of the key parameters that you think will be important for clinicians to gauge in new patients who you might start on zuranolone as an episodic monotherapy? And for continuing patients, is it your preference to switch to an episodic monotherapy or add as an adjunctive?

Thanks, Sumant. Just so I understand your question, so that Anita can answer. You're asking, as the patient comes in, what's Dr. Clayton looking for to make her treatment decision? Anita, you want to take that?

Exactly.

Sure. So I don't know who wouldn't want to get better fast. I mean that's been one of the issues with regard to antidepressants. And then sustaining that is the thing that I think would make a difference in terms of whether we augment it essentially or added a treatment or we repeated this treatment. And frankly, with me and my family, I would want to get this treatment. I would want it repeated if I fell in that 70% -- well, in this 55% who required more than 1 treatment. Although 3% of people only required 1 additional treatment. This is really different than, say, other rapidly acting medications available where they have to be repeated very often, weekly or biweekly. Or, for example, transcranial magnetic stimulation, we're finding we have to repeat those treatments, which are 6 weeks of 5-days-a-week treatment. So I think as those are in treatment-resistant depression now, so that is a slightly different population. But that would be on my mind, too. We've not studied it in treatment-resistant depression but for people who are struggling with effects who potentially have had previous episodes of depression, I think they're going to want to get this treatment. And then we would make a decision about adding in an antidepressant, if we had to, or some other augmenting strategy.

Our next question comes from Joon Lee with Truist Securities.

The Shionogi study in Japan was [ synaptic ] even with the 20 milligrams. Is that purely a demographic difference? Or is there a difference in the sort of the metabolism of the drug in Japanese subjects and/or were there some trial conduct differences? And did you say that the study from Japan will be included in the FDA NDA? And would that be supportive even though that study did not include any U.S. population? And lastly, is Shionogi conducting a Phase III trial in Japan? And if so, when can we expect that data?

Yes. Thanks, Joon. Let me take a kind of in reverse order and then kick it to Steve to talk about the results and to Jim to talk about the pharmacology. So yes, the -- they are planning a Phase III. They're meeting with the Japanese agency to map that out. They have not given guidance yet, so we'll look for their guidance. But I can tell you, in talking to them, they're incredibly excited to move forward for Phase III. For all the same reasons you heard from Dr. Clayton, the Japanese population is looking to get better faster as well. Steve, do you want to talk about the results a bit? And then Jim, do you want to talk about kind of the pharmacology?

Yes. So thanks, Barry. So first and foremost, we view this as a replication of the data. I mean what did they see? Early onset, day 3, day 8, day 15 and yes, in this case, 20 and 30 milligrams. This was a monotherapy study. Patients were washed off of their prior antidepressants. So that's terrific. We've already demonstrated the 30 milligrams of dose. It was really nice to see the 20 milligrams working here. And we'll be looking to understand how best to use that data and integrate it. The most important piece for me as the Chief Medical Officer, seeing a replication of those data in an entirely different population run by Shionogi, a really great development partner. It was just wonderful to see the profile. It looks exactly the same, and we're really excited to think about the plans together moving forward. Jim, do you want to comment on the pharmacology and how we can understand that?

Yes. I think -- Steve, I think the comment I'd make is that what we've seen again and again is pharmacology is quite consistent, whether we're talking about efficacy measures or whether we're talking about things like biomarker. So I think from our perspective, this is around achieving the appropriate levels in plasma to have the biological effect. So it's good to have the data from the Shionogi trial. We'll have a look at things like PK as we go forward. But I think the main point is very consistent.

Yes. One other point I'd make, Joon, and is that the profile, the safety profile that we've seen in Japan, which is really important for success in the Asia Pacific region, is important elsewhere as well, is exactly the same, perhaps even a better profile in that population. So no surprises there and, in fact, just additional data that supports our overall findings. So yes, we'll look to find ways to integrate that into a filing because it's yet another trial that demonstrates the benefit of the drug.

There are no further questions. I'd like to turn the call back over to Barry Greene for closing remarks.

Thanks, operator, and thanks, everyone, for joining us today. Special thank you to Dr. Anita Clayton for taking time out of her busy day. Thank you so much. As you can see from the totality of the data we presented today, zuranolone continues to show consistent, impressive efficacy and safety data in MDD and PPD clinical trials with positive results seen in 4 of 5 completed clinical trials. The data presented at ECNP add to the growing body of clinical evidence supporting our belief in zuranolone's differentiated product profile and supports our vision for zuranolone to change the way depression is thought about and treated. Our goal for zuranolone is to be able to provide better tools for health care providers to offer patients with depression and have the potential for a rapid response, a well-tolerated response without, as you heard, weight gain, sexual dysfunction and a response that's long, durable and sustained. We look forward to continuing to provide updates on next steps with zuranolone over the coming months. Thank you, and everyone, have a great day.

This does conclude the conference. You may now disconnect.