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

Good morning, everyone, and welcome to the Sage Therapeutics conference call to discuss topline results from the CORAL Study. [Operator Instructions] This call is being webcast live on Investors and Media section of Sage 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, Director of Investor Relations at Sage.

Good morning, and thank you for joining Sage Therapeutics conference call to discuss topline results from the CORAL Study of zuranolone in major depressive disorder. 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'll 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 press release and in our SEC filings for additional details. We'll begin the call with prepared remarks by Barry Greene, our Chief Executive Officer, who will provide an overview of this morning's announcement. Barry will be joined by Jim Doherty, our Chief Development Officer, who will review the findings in more detail. Kimi Iguchi, our Chief Financial Officer; and Chris Benecchi, our Chief Commercial Officer, will join for the Q&A portion of the call. I would now like to turn the call over to Barry.

Thanks, Helen, and thank you, everyone, for joining us this morning. I'm pleased to be with you today to review the positive results from the Phase III CORAL Study in major depressive disorder or MDD. I'll start by sharing highlights from the study, and I'll set some context for these results. Jim will then walk through the topline data in more detail. As you may have already seen from our press release with our collaborators of Biogen, we have a very successful study. We're happy to report that zuranolone co-initiated with standard-of-care antidepressants or ADTs met the primary endpoint in the CORAL Study, demonstrating a statistically significant reduction in HAMD-17 scores at day 3, the first measured time point compared to standard-of-care antidepression co-initiated with placebo. Additionally, zuranolone co-initiated with ADT met the key secondary endpoint in the CORAL Study, demonstrating a statistically significant improvement in depressive symptoms compared to ADT co-initiated with placebo over the 2-week treatment period, or in other words, zuranolone showed continuous benefit over the treatment period. Equally as important, zuranolone co-initiated with ADT was well tolerated with no new safety signals attributable to zuranolone identified. We believe the CORAL Study is clinically meaningful. And with the addition of this data, the LANDSCAPE program now demonstrates zuranolone has 3 potential real-world uses for the treatment of MDD. Each study in the LANDSCAPE clinical development program was designed to answer a different question on how zuranolone might be used in the real world. In the case of the CORAL Study, we executed an active comparator trial comparing the combination of zuranolone 50-milligram and an active standard-of-care ADT with standard-of-care ADT co-initiated with placebo. The CORAL Study was designed to evaluate the benefits of zuranolone co-initiated with ADT including rapid onset of effect. I'd like to take a step back to reflect on how we got here. After our successful WATERFALL study and following our pre-NDA meeting with FDA in late 2021, we confirmed our belief that we had the data needed to submit an NDA for MDD for zuranolone. Given our confidence in the data package to support the filing, we announced that the primary endpoint in the CORAL Study will be measured at day 3 because we believe that demonstrating rapid reduction in depressive symptoms at day 3 is an important differentiator and informs potential real-world use of zuranolone. The CORAL Study met its predefined objectives. And we believe these results support the potential of zuranolone when co-initiated with standard of care to accelerate the benefit of depressive symptoms compared to the treatment with ADTs alone. With today's results, we now have 6 positive studies with zuranolone. The other big win for the study, and this is really important, was the very positive effects we saw on the prospectively defined subgroup of MDT with elevated anxiety. These results are very important because this is a patient population where today's standard of care is well documented not to work well, and we have very big effects in MDD with elevating anxiety. It's very exciting to know where your drug works very well. The data from the CORAL Study adds to the unique and differentiated profile zuranolone has demonstrated to date in clinical trials. Collectively, clinical trials with zuranolone suggest broad potential use as a monotherapy, adjunctive use on a stable antidepressant or in the case of CORAL when co-initiated with a standard antidepressant. This profile includes rapid and sustained reductions in depressive symptoms; improvements in quality of life and overall health across domains of feeling, functioning and well-being that patients report continued after completion of treatment; a short course treatment that can be taken as needed with a novel mechanism of action that may help rebalance neuronal networks; and a well-tolerated safety profile that's been consistent across the LANDSCAPE program, now including the CORAL data. You've heard us say that mental health is perhaps the most neglected of all health concerns with many patients not receiving the treatment and care they deserve or the outcomes they seek. It's clear that new treatment approaches are needed. Today's results represent a meaningful step toward meeting unmet needs for people with MDD. We're committed to putting people with MDD and PPD first in our zuranolone development efforts with a goal of delivering a treatment option that provides the attribute patients tell us they care most about: getting better faster, short course of treatment instead of daily medication for sometimes years or their entire lives and sustained benefit, so they can get back to their life. We look forward to continuing to provide updates on zuranolone as we pursue the initial NDA filing submission for MDD. We remain on track to start the rolling submission for an NDA early this year, and we plan to complete the NDA in the second half of 2022. Before I turn the call over to Jim, I want to thank the participants in the CORAL Study, their families, the trial investigators, everyone at the clinical sites and importantly, all Sage employees who contributed to this program. They've all been invaluable. With that, I'll turn the call over to Jim to discuss the results in more detail. Jim?

Thanks, Barry, and good morning, everyone. I'd also like to extend my thanks to the study participants, their families, the trial investigators, everyone at the clinical sites and certainly Sage employees for their contributions to the CORAL Study. I'll now walk through the data we shared this morning. Starting on Slide 4, I'd like to start with the CORAL Study design, which was distinct from other studies included in the LANDSCAPE program investigating zuranolone for the treatment of MDD. Zuranolone is a next-generation positive allosteric modulator of GABA A receptors that is in development as a potential first-in-class treatment for MDD and also is in development for PPD. We believe zuranolone has the potential to be a novel treatment paradigm in depression. The CORAL Study was a Phase III randomized double-blind study comparing the efficacy and safety of zuranolone 50 milligrams when co-initiated with an open-label ADT compared to open-label ADT co-initiated with placebo in adults 18 to 64 with MDD. The open-label antidepressants or ADTs included in the study were sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine, so 3 SSRIs and 2 SNRIs. These represent a spectrum of the most commonly used standard-of-care ADTs, which reassures us the results are generalizable to help clinicians treat their patients in the real world. The study design allowed HCPs and patients to decide which ADT to co-initiate in combination with either zuranolone or placebo. As you can see, patients received a 2-week blinded course of either zuranolone 50 milligrams or ADT co-initiated. They followed -- then they were followed for 4 weeks, during which they continued their ADTs. In thinking about the CORAL Study, it's important to recall that patients in both study arms were given a drug that was expected to improve their depression. The study enrolled 440 patients with HAMD-17 total score of 24 or above at entry. The mean HAMD-17 score at baseline was 26.8 for patients in the zuranolone co-initiated with ADT group and 26.6 for patients in the ADT co-initiated placebo group. Turning to the efficacy results from the CORAL Study. As you can see on Slide 5, the primary endpoint of the study was changed from baseline in the HAMD-17 total score at day 3. As Barry mentioned, we are pleased that the study hit its primary endpoint at day 3 with zuranolone 50 milligrams co-initiated with ADT, demonstrating a statistically significant reduction in depressive symptoms compared to ADT co-initiated with placebo with a p-value of 0.0004. Slide 6 shows that we also saw statistical significance on the key secondary endpoint, which measured the treatment effect over the full 2-week treatment period. The average treatment effect over the treatment period for patients who received zuranolone 50 milligrams co-initiated with an ADT was 11.7 points compared with 10.1 points for patients who received ADT co-initiated with placebo. The p-value for the key secondary endpoint was 0.0054. This is important because it demonstrates the benefit of zuranolone throughout the treatment period. HAMD-17 total score changed from baseline at other time points are shown on Slide 7. We saw a statistically significant reduction in HAMD-17 scores in the zuranolone co-initiated with ADT arm compared with ADT co-initiated with placebo arm at day 8 and 12, while day 15 demonstrated numerical superiority and day 42 showed equivalents. Importantly, we did not see a mean increase in depressive symptoms during the follow-up period in the zuranolone co-initiated with ADT arm. Turning to Slide 8. Based on the consistent findings suggesting a benefit of zuranolone in people with MDD with elevated anxiety across the LANDSCAPE program, the CORAL Study prospectively examined this population. The population was defined here as patients with HAM-A scores at or above 20 at baseline and was about half of the patient population in this study. In the CORAL Study subgroup, zuranolone co-initiated with the ADT was nominally statistically significant compared to ADT co-initiated with placebo in reducing depressive symptoms as measured by the primary endpoint and the key secondary endpoint, demonstrating the potential to address the unmet need for this population, which has been historically less responsive to chronically administered ADTs. Slide 9 covers the promising safety results seen in the CORAL Study. The study showed that zuranolone 50 milligrams co-initiated with an ADT was generally well tolerated with no new safety signals attributable to zuranolone identified. The most common adverse events occurring in 10% or greater of the patients in the zuranolone co-initiated with ADT arm were somnolence, dizziness and headache. In the ADT co-initiated with placebo arm, the AEs occurring in 10% or greater of the patient population were headache and nausea. Additionally, it was an interesting observation that while ADT was given in both arms, the ADT co-initiated with placebo arm had a higher incidence of nausea. That's something we'll be digging into further to examine if the addition of zuranolone may have had an ameliorating effect on nausea. These findings support the known safety profile of zuranolone. The majority of treatment-emergent adverse events reported in the study were mild or moderate in severity, consistent with previous data in the LANDSCAPE program. Additionally and importantly, there were no signals for increased suicidality or withdrawal symptoms in the study. On Slide 10, we believe the data from the CORAL Study support the potential efficacy and safety of zuranolone when co-initiated with ADT. The LANDSCAPE program was designed to evaluate how zuranolone might be used in different real-world settings. And across the program, we've now seen positive efficacy and safety data from our clinical trials in MDD when zuranolone is used as a monotherapy, adjunctive therapy or co-initiated with a standard-of-care ADT. Given the heterogeneity of MDD, our goal is to provide options to prescribers and to patients. In addition to the traditional use of ADT monotherapy studies in the LANDSCAPE program, we have subpopulation data from our WATERFALL and SHORELINE studies showing that adding zuranolone to a stable ADT improves outcomes. The CORAL Study progresses this concept even further, evaluating a new additional option of co-initiating zuranolone with a standard of care simultaneously. This is important because we believe that if approved, zuranolone may provide optionality to HCPs and be a unique treatment option for people suffering with MDD, offering the potential to achieve a rapid and robust response as early as day 3 in contrast to the standard-of-care ADTs that often take 6 to 8 weeks to show efficacy. Turning to Slide 11. With the CORAL data reinforcing the existing evidence we already have from our clinical development program, we're highly confident that zuranolone, if approved, has the potential to offer patients, physicians and payers an important therapy that will help raise the standard of care for those living with both MDD and PPD. We believe that the potential for rapid and sustained efficacy that we've seen in clinical trials with zuranolone after a short course of therapy could, if approved, provide a treatment option for people with MDD that may enable them to effectively and safely manage their depression. What we're hearing from potential treaters is a focus on several key patient types in MDD. Those patients include the treatment-naive young adult, who may be a university student or someone just starting their first job; the person already on an ADT but still suffering; person who is having breakthrough symptoms of depression, perhaps due to the death of a loved one or the loss of a job; the older adults who have depression perhaps associated with another medical condition and doesn't want to be on ADT in perpetuity due to polypharmacy concerns; or the person who has issues with adherence, who stops taking their therapy because they don't think the ADT will work. All the patients I've mentioned can't afford to have their lives derailed by poorly managed depression and would, therefore, potentially benefit from the attributes of zuranolone to effectively manage their disease. We believe the data across the LANDSCAPE program will be of interest to clinicians treating patients with MDD. We look forward to updating you in the coming months as we begin the planned NDA submission in MDD. With that, I will now turn the call over to Helen to handle Q&A with the operator. Helen?

Thanks, Jim. [Operator Instructions] Now I'll turn it over to handle -- now I'll turn it over to the operator to handle Q&A. Operator?

[Operator Instructions] And our first question coming from the line of Paul Matteis with Stifel.

This is Alex on for Paul. I just want to talk a little bit about day 42. I know it's been a lot of controversies here. But in this particular context, wondering if you could comment on the fact that patients are on a concomitant antidepressant and how that might make it more challenging to interpret durability at this time point?

Yes, Alex. Thanks for the question. So again, I will remind you that the objective of the CORAL Study was to obtain data that we had not yet gotten from the LANDSCAPE and NEST programs. And that is to understand what happens when zuranolone is co-initiated with standard antidepressants. So we are thrilled to see the rapidity of effect and particularly in that group of MDD with elevated anxiety, a real differentiator, as you saw on the slides, between ADTs and ADT plus zuranolone. We think that's a huge benefit. Keep in mind that every treating physician and every patient knew they were getting an active drug. So the expectation bias is pretty significant. And we frankly did not expect to see much separation in any out of day 42. That's when in the real-world antidepressants actually do start kicking in. The other thing I'd highlight is that this is a study where, unlike in the real world, patients are getting basically perfect care. They're getting an antidepressant that they know they're getting. They're seeing a white coat, if you will, at day 0, 3, 8, 12, 15 and then many time points in between. That's really not what happens in the real world. So again, seeing separation out of day 42 is not something we expected. And we're pretty pleased with the rapidity of effect and the duration, the continuous benefit over the treatment period. Jim, anything to add?

No. I think that really covers it, Barry. It really is with this active comparative study design, we know that all the subjects in the study are receiving treatment for depression. And as you said, the day 42 time point, you're really starting to see contributions from the ADT. So we are not surprised to see equivalents out at that time point.

Our next question coming from the line of Salveen Richter with Goldman Sachs.

This is Andrea on for Salveen. I'm just curious, Jim, maybe if you could speculate here on why the additional benefit of zuranolone appears to be lessening over the treatment period? Is that something that you would expect? Or just curious how you're thinking about that profile.

Yes. Thanks, Andrea. Let me start, and then I'll turn it to Jim, as you suggested. So we are seeing the treatment effect of zuranolone on top of an antidepressant consistent with all the data we've seen to date. So the drug is doing what the drug does. We, at day 15, are seeing a 12- to 15-point drop. What you're seeing here is really an added placebo effect or an antidepressive effect because of the kind of the white-coat effects, particularly during COVID. So the drug is doing what we expect it to do. Jim, do you want to add?

Yes. I would just add, Andrea, as we have been talking about this with you guys leading up to the study, what we're really concerned about not seeing is any loss of response or rebound after the end of the treatment period, which, of course, we're not seeing. So what we're actually seeing is a sustained improvement in depressive score. So as the study is progressing, patients are maintaining the benefit that they're achieving very early with the combination of zuranolone and ADT.

And I'd add, without any additional safety issues, in fact, potentially some safety benefits.

Our next question coming from the line of Tazeen Ahmad with Bank of America.

So with this study now in hand, can you give us some color on what type of label you would ask for when you have your discussion with FDA? And how important is the difference of being set [ say at ] 12 days but not at 15 days do you think in the mind of the agency?

Yes, Tazeen, thanks for the question. So it's really too early to talk about the totality of label. But as we talked about before, we set out with the LANDSCAPE and NEST program to treat MDD and PPD. So we'd hope for an indication statement similar for the treatment of MDD and PPD. This adds the richest of data that we have with monotherapy on top of a standard antidepressant now co-initiated with antidepressant. So it should be a very rich data package. I'll also highlight that the subgroup predefined here, MDD with elevated anxiety, which we know through the STAR*D publications, standard of care does not work very well in this publication -- in this population. In fact, standard of care antidepressant often increases anxiety and inability to sleep. So we think the overall data set is very strong. As we confirmed with the FDA in the fall with a positive WATERFALL, we had a fileable package. So we're able to really position CORAL to demonstrate rapidity effect and continuous benefit over the treatment period. So we think we've got a pretty good data set here. I'm very happy with what we've seen.

Our next question coming from the line of Cory Kasimov with JPMorgan.

I'm also going to ask about something that's probably a little too early to talk about, but still important question I get quite a bit. So clearly, a key point of debate around these results like others are that you have statistical significance at earlier time points yet again, but not later. So given that, can you just take a step back and talk about the value proposition here for zuranolone and how results like this impact or further inform how you broadly think about potentially pricing this type of product?

Thanks for the question, Cory. As you said, it's early to talk about pricing. So we think the value proposition here is extremely beneficial. The debate that you hear from patients and providers is that with the tools they have today, it takes 6 to 8 weeks for people to see benefit. Often, patients drop off the drug because of side effects before that 6 to 8 weeks, never achieving the benefit. We know that the data suggests that the average course of treatment is 7 weeks per year and that 80% of patients are on 2 or more antidepressants in the course of the year if they go back on antidepressant. So we have a population, 6.8 million people per year, that just are not getting benefit from the current drugs and are a significant health economic burden on society besides themselves and their families. So having a drug that gets people better faster is extremely valuable. We know through the SHORELINE data, which is the largest naturalistic study run, that 80% of people studied in the 50-milligram dose only require 2 to 4 weeks of drug in the course of the year. So that's the rest of the year off drug. So again, we think the benefit there is extreme. Now we'll think about this as a branded product, not in a special tier and not in the kind of the lower tiers to give you kind of a range. But we'll work through that. Importantly, we've agreed with our partners, Biogen, that we're going to approach payers with a proactive value-based agreement. So we're willing to share some of the risk in case there's any hesitancy on a branded product. And those discussions are going well.

Our next question coming from the line of Ami Fadia with Needham.

Barry, could you help us think about where in the real world this product is likely to be used more? Is it in first-line patients when they're starting treatment? Or do you see it more as patients who haven't responded to other standard antidepressant therapy and are looking for something else and then go on SAGE-217?

Yes, Ami, great question. So I'll start and then kick it to Chris to talk a bit more. So look, we have data right now on over 3,500 patients with zuranolone as a monotherapy on top of a stable antidepressant and in the case of CORAL, which we're talking about today, co-initiated with an antidepressant. So the data are supportive if a patient and a physician believe they should use it frontline or on top of a stable antidepressant or co-initiated. We studied MDD, not TRD. So these are not patients who have failed antidepressant. They're just not being well served by the current antidepressants. But let me ask Chris to talk about the feedback we're getting from potential prescribing physicians on where they think they're going to use the drug.

Yes. Thanks, Barry. First, let me say that clinicians and patients alike are excited about the opportunity to use zuranolone in their patient population because it really represents a fundamentally different way of treating depression than what they've had historically over the last 30 years. Now in conversations that we've had in prior sessions, we talked a lot about there are more than 7 million patients in a given year who are initiating therapy for the first time or switching therapy. So you have the treatment-naive patients, you have patients that are add-on, you have the switch patients, and you have the reinitiation patients. And what CORAL has done for us is it's given us a different lens into how physicians may actually treat patients differently than they have in the past. So if you think about the patients that are new to therapy for the first time or perhaps reinitiation patients then you're drilling specifically into what their journeys have looked like as patients. You may have, as Jim mentioned, a young adult in college right out of school, who's initiating therapy for the first time. You want to get that patient's depression under control really quickly, and you maybe want to sustain it over the course of time in pairing zuranolone with another ADT, maybe a particularly interesting way or novel way for clinicians to treat depression that they haven't actually had the opportunity to treat before. Also, when you think about the adherence-challenged patient, this may be somebody who has never really been able to experience the benefit of an ADT because they've given up on their therapy long in advance of experiencing efficacy. Pairing zuranolone with another standard ADT for an adherence-challenged patient, giving them the opportunity to experience that efficacy by day 3 and to experience a sustained or durable effect over time with, frankly, a safety profile with zuranolone that is really remarkable with regard to what we've seen. And in some senses, as Barry mentioned, has the ability through what we see in this co-initiation study to potentially ameliorate some of the symptoms, the GI symptoms like nausea. It's a game-changer for physicians when you think about the opportunity here. So we're really excited about having continued conversations with clinicians and the patient populations that we can use this in. And I'd be remiss if I didn't mention the MDD with elevated anxiety, again, offers a particularly difficult-to-treat patient population with a novel treatment option that they've never had before.

Our next question coming from the line of Laura Chico with Wedbush Securities.

You made comments, Barry, on the subgroup with concomitant anxiety at study entry. And I'm just wondering, did subjects see improvements on their underlying anxiety in addition to the depression improvement? And I guess the reason I'm asking is there was a pretty wide range of concomitant ADT that could be administered here. So not sure if anxiety change is dependent somewhat on what was co-administered with zuranolone.

Yes, Laura. Great question. So I'll start, and I'll ask Jim to make some comments. So I'll remind you that in a post-hoc analysis across the data we've seen to date, WATERFALL and others, we saw that zuranolone worked particularly well in patients with MDD with elevated anxiety as a symptom of their depression. So it improves their depressive symptoms, their anxiety symptoms and without any impact to sleep. So we believe that this is generalizable across all antidepressants used, not specific to any particular antidepressant. And if you look at the slides we shared, the rapid effect on the depressive symptoms and the anxiety symptoms really separates incredibly well from standard care antidepressants, where we know in the real world, it takes 4 to 8 weeks to work if ever. But Jim, do you want to comment further?

Yes, I think what I would add, and you can see this on the curves that we presented is, in our study, what we're seeing, again, is very similar to what has been reported in STAR*D and other places that not only are we seeing an additional benefit of zuranolone in this patient population. But if you just look at the placebo responses across the 2 groups, these folks are actually not responding as well to the standard-of-care antidepressants. So what we're seeing here is a patient population, and in this study, it's about 50% of the total, that is not only more sensitive and responsive to zuranolone, they're actually performing or responding less well to standard-of-care antidepressants. And that very much matches what we're hearing from health care providers and with the literature, such as STAR*D is saying.

Our next question coming from the line of Yasmeen Rahimi with Piper Sandler.

Maybe the first one is a quick clarification one. So the blended endpoint of looking at HAMD-17 at day 3, 8, 12 and 15, was that a prespecified endpoint and signed off by the FDA, question one. And then question two is, I did not see rates of sedation or serious AEs in the topline release or in this presentation. And I would greatly appreciate it if you could comment on it.

Let me take the first question and then ask Jim to ask -- answer the second question. So the answer is yes. We -- the primary endpoint was reduction at day 3 and the kind of area under the curve day 0 to 15 was a prespecified secondary endpoint and the stat -- discussion with the agency, then Biogen's stats plan was sent in SAP. So those are all prespecified. Jim, do you want to take the second one?

Yes. I'm just going to add something to the first point. I think it's important to understand that this key secondary endpoint, as Barry said, absolutely prespecified and part of the statistical analysis plan. But probably more importantly, often we think in terms of individual point values, right? So day 15, day X. What we're doing with this key secondary endpoint is measuring the response of the patient population across the entire treatment period, right? So it is a very sensitive measure, but also a measure that really describes the response over time, right? So that's why we say it's a measure of continuous benefit. So we think it's an important measure. And speaking to the safety profile, as I think I mentioned in my remarks, what we saw in AEs 10% or higher would -- somnolence, dizziness, headache. So again, that's pretty consistent with what we have seen previously from our other studies. And I would say more broadly, we see the safety profile in the CORAL study as very much in line with the overall safety profile for zuranolone across the LANDSCAPE and NEST program, which, of course, is really great to see.

Our next question coming from the line of Jay Olson with Oppenheimer.

Do you believe there are synergistic effects between the mechanism of zuranolone and the SSRI-SNRI mechanism? So what we're seeing in CORAL is a potentiation of efficacy? Or are we basically seeing the monotherapy activity of zuranolone through day 15 because the SSRI-SNRI mechanism has such a slow onset?

Yes. Thanks, Jay. Let me ask Jim to talk about that.

Yes, Jay, I think what we're seeing and, of course, what CORAL was designed to show was that the rapid benefit that we see with zuranolone consistency across the LANDSCAPE and NEST program is also a feature when you co-initiate with a standard-of-care antidepressant. And as you say, that's what you would expect is that with the ADTs in both arms of the study, as time goes by, you start to see the document and benefit of a standard-of-care ADT. But what we're seeing is as early as day 3, the rapid response to zuranolone. So what we believe we're seeing in the CORAL Study is a combination of efficacy for both the agents. Of course, that's why you would expect to see equivalents out at later time points like day 42. So not unexpected at all. More mechanistically, of course, zuranolone acting at the GABA system; SSRIs, SNRIs acting presumably through serotonin and the serotonergic mono means. It's -- they are distinct mechanisms, whether -- and I think that we would assume additivity rather than synergy.

Our next question coming from the line of Sumant Kulkarni with Canaccord.

Could you remind us if there were any appreciable differences between average or median retreatment with zuranolone during the SHORELINE study for patients that are on preexisting antidepressants versus patients that were not? I'll ask this slightly different way, I guess, roughly what percentage of MDD patients do you think might need rapid-acting rescue therapy and how many times per year?

Yes, Sumant, thanks for the question. Let me start and ask Jim to add and then maybe Chris can add on also. So with -- in the SHORELINE study, this large naturalistic study where patients were given zuranolone either as monotherapy on top of a stable antidepressant, about 1/3 of the patients were on a stable antidepressant. They were given zuranolone for 2 weeks and then followed every 2 weeks. So they are proactively asked how they're doing every 2 weeks. And they stayed in a normative state, which is really a strong statement because they knew they were on drug. It's sort of a nocebo study. And every 2 weeks, they were asked how they were doing. And if they weren't doing well, they were brought back in for examination and then evaluated to see if they could get zuranolone. As I mentioned already, about 80% of patients required only 1 or 2 2-week treatments in the course of the year, which is really strong. There was a 75% response rate. So we believe that's how zuranolone will work in the real world. And what's remarkable here is that unlike other antidepressants or things like benzos, when patients stop drug, they need to get back on drug because they experience withdrawal effects or other safety concerns getting them back on drug. We don't see that at all, which is another added benefit of zuranolone. Jim, do you want to add?

Yes. I would just add that -- recall that we extended the option for patients participating in the CORAL Study to potentially roll over to the SHORELINE Study as a cohort. What we saw is about around roughly 75% or so of patients from the CORAL Study have taken that option, and so we'll be rolling into CORAL. And that will give us another look at the durability of response, specifically from this CORAL patient population. So that is the data still to come.

Yes. And I think in addition from the perspective of clinicians that we've spoken to, zuranolone's approval will give them the opportunity when they see one of those 7 million patients that come into their office that are initiating a therapy for the first time or adding on or switching therapy or reinitiating the opportunity to experience efficacy as early as day 3. And that's not in and of itself rescue therapy. That's about providing patients with what they need to really reduce the symptoms of their depression and continue to progress with lives that could be derailed if that rapid onset of action and then durable effect over time wasn't experienced with zuranolone. The piece to CORAL that I think is really interesting is that when you pair it with what we saw in the SHORELINE, you see that patients get rapid effect as early as day 3. And that with just 2 courses of therapy, 80% of patients maintain that effect out to a year. That's a different way of treating depression that they've never had before, and it's a really unique opportunity for us as an organization to have a profound impact on patients that are suffering with MDD.

Our next question coming from the line of Akash Tewari with Jefferies.

This is [ Leo ] for Akash. In the WATERFALL study, we saw 86% efficacy retention at day 42. So what's the efficacy retention here for CORAL? And how does that affect regulatory approval? And if I could just squeeze another one. And so if we don't see too much additive benefit in patients without anxiety, how that will affect the doctors' prescribing behavior or payer coverage?

[ Leo ], thanks for the 2 questions. So let me take the second one. So we are, in fact, seeing effect with patients with MDD. What we're highlighting, however, is that in patients with MDD with elevated anxiety where standard of care does not work very well, it's well documented, we work particularly well. So in the course of drug development, learning from each study and understanding where the drug works particularly well will help us in educating and guiding treating physicians on the best patients to use. And any company wants their drug used where the drug works best. So we think that's what we're seeing. We're seeing effects across MDD. We're seeing particularly strong effects with MDD with elevating anxiety. I'd also add, and both Jim and Chris mentioned this earlier, very often a patient will get prescribed an antidepressant and be told keep taking this. You might experience side effects like nausea, vomiting, diarrhea and stay on your drug. If you experience that, call me, I'll give you something else. We potentially ameliorate all those GI effects. So it's an added benefit to also change the safety profile and co -- when co-initiated. So again, the profile here will really allow us to help guide potential treating physicians on where to best use the drug, which patient types to use them in. Jim, you want to take the first one?

Yes. And so to the question of response retention, you're referring to the analysis that we have conducted for studies like the WATERFALL Study or other parts of the LANDSCAPE program, where with zuranolone being delivered as a monotherapy, either alone or given on top of a stable antidepressant, we calculated response retention. And as we are -- as you mentioned, it was approximately 85%. So although we didn't calculate it in this study, recall it's a different study design. So with an active comparator design, subjects are receiving treatment throughout the study period. And as you would expect, therefore, what you're seeing in both arms is that patients continue to improve. So we talked about equivalents at day 42. But in fact, when you look at absolute scores, those scores have continued to improve over the duration of the study. So our response retention would actually be over 100%.

[Operator Instructions] Our next question coming from the line of Yatin Suneja with Guggenheim.

Question is on the retreatment. So this treatment, I think the CORAL treatment setting is a little bit different than what you have evaluated in the past. So is SHORELINE enough to answer the retreatment question? And can you maybe just talk one more time like at what interval we should think about retreating these patients? And then quickly, what are the gating factors to the NDA submission?

Yes, Yatin, thanks for the question. So let me take you back to January, a couple of years ago. So when we described the LANDSCAPE and NEST program, we highlighted there was another Phase III study called REDWOOD. REDWOOD was the study that we set down design with the agency along with WATERFALL and CORAL and ROBIN that would treat patients on a specific basis every 6 weeks. And before we had the SHORELINE data, we and the FDA believe that we should run a study that treated patients on a specific time course. So we had that retreatment data, and we landed on every 6 weeks. We highlighted way back then that we believe that the emerging SHORELINE data would allow us not to run that study as a requirement for approval because of the SHORELINE data. And in fact, when we announced the SHORELINE 50-milligram interim data, we met with the agency and announced to all of you guys that we, in fact, weren't going to run REDWOOD. So that's a long way to say yes. We think the SHORELINE data are the data required that helps us with retreatment. Again, I'll remind you that in the real world, physician's office is likely to check in the patients with some basis. But in this study, we checked in with patients every 2 weeks, and patients confirmed that they were still well. So we're not exactly sure in the real world how many 2-week course of treatment, but that sort of 1.5-ish to 2-ish at 50 milligrams seems like how this drug might perform in the real world.

Our next question coming from the line of Douglas Tsao with H.C. Wainwright.

Just when you look at the sort of data in its totality and not just this -- not just the CORAL data, I mean, obviously, the rapid onset is [ rarely ] manifesting and the durability seems to be a little bit more mixed. I'm just curious, what do you think is the sort of like an ideal treatment sort of duration? And what would you push back on a physician who said, yes, I want to use zuranolone for a week to 10 days or 15 days and then have them continue on with the traditional antidepressant because presumably, you would argue that there should be a longer-term treatment. But I guess, what evidence would you point to right now that if that is warranted.

Yes, Doug, thanks for the question. So let me start with the durability. So we see a durable effect. We see a durable effect in SHORELINE. These are MDD patients that are either on a stable antidepressant or not that get zuranolone get better. 50 -- over 50% require only 2 weeks of treatment in the course of the year. We think the 2-week treatment course would be as prescribed. Now like with many medicines, there may be, hey, here's a refill. And if you feel your mood darken, you get more anxious, you can't sleep, take this other 2-week course and then call us afterwards. So we might see that use. Now if a physician believes that their patient requires a concomitant zuranolone with antidepression, there is no argument from us. We now have the data that supports that you can do that, and you can do that safely. Very often, the hesitancy for polypharmacy is the question about additional safety or adherence. And we are seeing tremendous adherence and tremendous safety. So we now have the data for a physician that they decide to use as monotherapy in that young adult, for example, or concomitantly with an adherence-challenged person who may suffer GI effect and want to ameliorate that or in an older person where you don't want polypharmacy. We have the data to support all of that. And we'll be educating in scientific exchange the potential treaters to where best to use the drug. And it's really good to know where your drug works best.

And so, Barry, to clarify, so it sounds like SHORELINE is going to be the sort of key study that you're going to really focus attention on for prescribers?

We'll focus on the totality of the data and all the clinical data because I think all of them are instructive.

Our next question coming from the line of Marc Goodman with SVB Leerink.

This is Rudy on the line for Mark. So for the regulatory pathway, you mentioned that CORAL is not required for filing. But now since we have the data report, I assume CORAL will still be included in your filing package. So given that zuranolone meet the day 5 endpoint and the magnitude of effect was slightly lower than prior data, how would this additional data impact the totality of the efficacy for both 30-milligram and 50-milligram dose as this seems to be a concern for some investors regarding regulatory approval and the clinical meaningful needs?

Yes, Rudy, thanks for the question. So as we have communicated in the fall of last year after our pre-NDA meeting, after that -- we had -- with a positive WATERFALL, we had the fileable package to move forward with. We confirm that with the agency. We then decided, along with Biogen, the agency to have CORAL, the design work as we originally intended, which is to show the rapidity of effect when co-initiated with an antidepressant. So what we said back then was a positive CORAL Study was not necessary for filing, but would be included in the filing. And I'll remind you that after we met with -- when we met with the agency, they were very helpful in guiding us, suggesting that, look, we've got 2 outstanding Phase IIIs, one in MDD, one in PPD. Let's complete the MDD study, include that in the filing and file for MDD. And then once you complete the PPD study, file for PPD. And the window there is such that we might be able to kind of launch both indications at the same time. So what we're doing going forward is consistent with what we've already communicated. Now the fact that we have a positive study here, both in terms of rapidity of effect and continuous benefit over the treatment course. And as Jim said, out of day 42, patients continue to get better as we expected because they are on an active drug, and the compliance rate was pretty high. So that's what we're doing. Now I will remind you again that CORAL was a very different design. This is the first time that we had a design that was co-initiated with the antidepressant. So we now have data for monotherapy on top of a stable antidepressant and when co-initiated and are continuing our march to file our NDA.

Our next question coming from the line of Brian Abrahams with RBC Capital.

Can you talk about the response rate at the end of the 2-week treatment course? And maybe how that compares to the roughly 8% improvement you saw in MOUNTAIN and WATERFALL? And I'm also curious if you could comment then on any predictors of response you're seeing that might provide some information on the optimal population the drug could ultimately be used in.

Yes. Brian, let me start and ask Chris to describe the patient types, and then Jim can take the first part of the question. So as we've now said a dozen times on the call, zuranolone has demonstrated the ability of rapid effect across all of MDD. We're particularly excited by MDD with elevated anxiety because the drug works particularly well there where standard of care does not work well. So that will be a major point of emphasis as we educate the treating physicians rather than have patients suffer for years trying to figure out how to get their anxiety and depression under control or their anxiety as a symptom of depression, you can use zuranolone for that patient population.

Yes. So Barry, I think as an add, we've talked about 5 different patient types that we think are particularly appropriate for zuranolone based upon the data that we've seen and the feedback that we've gotten from clinicians around where they see appropriate use. And in some cases, there are patients that are monotherapy patients experiencing therapy for the first time, like a young adult or treatment-naive college student who needs therapy, as I said, for the very first time. And it may actually be a patient who has late-onset depression, who has concerns around polypharmacy and want to experience the rapid and durable effects of a product like zuranolone to manage their depression. There's a number of different types that we talked to, but I think the red thread that connects all of these isn't just the depression itself. In many cases, there is MDD with elevated anxiety. And if you go to the literature, it's 54% to 66% of patients cited in studies like STAR*D. But in the real world, as you talk to practicing clinicians, they believe it's actually in excess of 70% of the patients that they see. So our opportunity when we go out and talk about delivering a new therapy into the hands of clinicians isn't just about identifying the potential use cases around those 4 or 5 types that I've discussed. But really giving them an option that, for the first time, gives them the opportunity to treat a patient with MDD with elevated anxiety in a way that provides that rapid and durable effect over time through a short course without the stigmatizing side effects of sexual dysfunction and weight gain that they see with other ADTs. So as I said earlier, we believe that we're delivering a therapy here that profoundly changes the way that they have an opportunity to treat.

Jim, do you want to take the first part?

Yes. I would add to the first part. There are a number of other endpoints in the study that we are in the process of working through. So things like MADRS, HAM-A, CGI, response retention, response to individual ADT. So we're going to continue to work through a very rich data set. And through the course of scientific exchange, we'll be continuing to put numbers out associated with the study.

And our next question coming from the line of Gary Nachman with BMO Capital.

This is Evan Hua filling in for Gary. So in clinical practice, how do you expect the combination will be used? Do you think it will just be used for the first 3 days and then taper off for patients?

Yes, Evan, thanks for the question. So the treatment regimen of zuranolone is QD for 14 days. So we believe that that's the right way to use it as a monotherapy on top of a stable antidepressant or in co-initiated with an antidepressant. So -- and then if the patient were to suffer some months later from another depressive episode, it'd be QD for 2 weeks.

Our next question coming from the line of Neena Bitritto-Garg with Citi.

I was just wondering if you could elaborate a little bit more on the baseline profile of the patients, just given that these are patients, I guess, that were not on SSRIs or other ADTs at baseline. Were there any significant differences or anything notable that you would highlight versus some of the previous studies with zuranolone?

Neena, thank you for the question. Jim, do you want to take that?

Yes, Neena. So the patient population is quite similar in most respects to the other populations we've studied in the LANDSCAPE program. And that's by design. We're looking for consistency across the program, and you can see that in things like the elevated anxiety cohort where we saw about a little under 50% of the subjects in this study were HAM-A above 20%. To your point, one thing that is different is that since we're co-initiating ADTs in the study, 100% of the subjects were asked to be ADT free for a period of at least 60 days before the beginning of the study. But most of the demographics of the study are quite similar to what we've seen across the other components of the LANDSCAPE program.

Yes. I'll remind you, Neena, in WATERFALL, about 1/3 of the patients were on a stable antidepressant. So 2/3 weren't. So many of those same patients would be enrolled in CORAL. And those that were on an antidepressant, as Jim mentioned, were asked to wash out for a couple of months before they could come into the study. So we saw some of that as well.

Our next question coming from the line of Vamil Divan with Mizuho Securities.

Great. I know there's some discussion earlier around price, and you're mentioning obviously with branded pricing, not a low-tier price. But can you talk a little bit about how you're thinking about pricing just given the sort of 2-week duration? So is this sort of traditional oral chronic antidepressant pricing you think about on the branded side? Or is it more, say, something like a SPRAVATO or something that's used more acutely for short-term -- time period? Is that maybe more of the pricing you're thinking since again, it's like -- many patients will only get it for 2 weeks and then not get it at all during the year? So any sort of early insights you can give on that would be helpful.

Yes, Vamil, thank you again. Again, it's too early to talk about the specifics of pricing. We've got a lot of work to do talking about payers. And as I mentioned, we're leaning in with a proactive value-based agreements. We're sharing with patients that we're willing to take risks. So if we explain to them, for example, that we believe that their patient population that is depressed might require 4 weeks of drug in the course of the year and therefore, here's the price, but they require more, we can protect them against that. So too early to tell. Again, we're thinking about this is a per patient per year kind of a branded drug.

Our next question coming from the line of Tim Lugo with William Blair.

Suicidal ideation is usually in the single digits as a percentage in MDD patients. If you look at kind of the total adverse events, was there any imbalance between the zuranolone ADT arm versus ADT alone arm? And do you expect the typical black-box warning around the suicidal ideation for zuranolone?

Yes. Tim, thanks for the question. Jim, do you want to take that?

No signal for increased suicidal ideation in the study across either arm. So in that sense, balanced across arms. And I think it's a little early to speculate on the label. I think black-box warnings are a feature for many antidepressants. I think we have a novel mechanism of action and a novel approach, but we'll have to see how those discussions go as part of the NDA submission and label discussions.

Yes. And what I think is on our side for the discussions is, over 3,500 patients' worth of data, including over 1,000 patients in the SHORELINE Study. So we've got really good well-controlled Phase III studies and a really well-run naturalistic study to have the robust discussion with the agency.

I'm not showing any further questions. I would now like to turn the call back over to Mr. Barry Greene for any closing remarks.

Thank you. Thanks, everyone, for joining us this morning. We believe the CORAL Study reaffirms the potential for zuranolone to meet substantial unmet needs for millions of people living with MDD, so they can return to their normal lives and doing what matters most to them, living a whole life with them and their families. So thanks again. I hope everyone has a great day. Appreciate it.

Ladies and gentlemen, that does conclude the conference for today. Thank you for your participation. You may now disconnect.