SAGE Therapeutics Inc (SAGE) 2020 Q2 法說會逐字稿

Ladies and gentlemen, thank you for standing by, and welcome to the Sage Therapeutics Second Quarter 2020 Financial Results Conference Call. Please be advised that today's conference is being recorded. (Operator Instruction]. I would now like to hand the conference over to your speaker today, Jeff Boyle, Senior Director, Investor Relations. Thank you. Please go ahead, Sir.

Good morning, and thank you for joining Sage Therapeutics' Second Quarter 2020 Financial Results Conference Call. Before we begin, I encourage everyone to go to the investor and Media section of our website at sagerx.com, where you can find the press release related to today's call as well as the slides that contain supplemental details.

I would 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 press release and in our SEC filings for additional details.

We will begin the call with prepared remarks by Dr. Jeff Jonas, our Chief Executive Officer; Mike Cloonan, our Chief Business Officer; and Kimi Iguchi, our Chief Financial Officer. We will then be joined for the Q&A session of the call by Dr. Steve Kanes, our Chief Medical Officer; and Jim Doherty, our Chief Research Officer. I will now turn the call over to Jeff.

Thanks, Jeff, and thanks, everyone, for joining us this morning. We're pleased to update you today on our second quarter with progress across our development programs. Today, I'll provide an overview of our second quarter activity and discuss our depression, neuropsych and neurology franchises. Then Mike will provide a more detailed business update. And lastly, Kimi will provide an update on financials. As all of you are aware, we're operating in a new environment with the challenges of the global COVID-19 pandemic. However, even in the face of these challenges, I'm pleased to report that execution of our clinical programs remains on track.

We're aware that some companies made the decision to stop a pause recruiting or enrollment in clinical trials. But I'm pleased that the teams at Sage were proactive in their planning and management of our trials. As you know, our lead clinical asset is zuranolone in studies for major depressive disorder and postpartum depression. Additionally, we have SAGE-324 in development for essential tremor and SAGE-718 which we are exploring based on early study findings, we believe are compelling for its potential in areas where executive function is impaired. Based on our progress in the last 6 months, we expect to have numerous catalysts coming over the next 18 months. We've been able to advance several programs and have had strong enrollment to date in our zuranolone WATERFALL Study. We have been dosing subjects with 50 milligrams in our SHORELINE Study as well and have advanced the anticipated top line readout for our SAGE-324 tremor study to the latter part of 2020 or the first quarter of 2021. So we are running on or ahead of schedule across our development programs.

In sum, during the second quarter, we initiated 4 new clinical trials across 2 franchises. I'd like to comment further on our depression franchise. We set out to develop a therapy that we believe, if successfully developed and approved, will be an important and unique option for people with major depressive disorder, or MDD. Our clinical programs are designed to answer very specific questions to achieve this goal. And we are executing in a step-wise progression. We believe that patients want to get well quickly and stay well, and many would prefer not to undergo chronic pharmacotherapy. In this light, we believe both ZULRESSO in postpartum depression and Zuranolone in MDD and PPD, have pharmacological characteristics consistent with this type of approach. As a reminder, Zuranolone program has been designed to achieve a first NDA as efficiently as possible. With 3 ongoing studies where each with a positive outcome, supports a unique potential filing pathway. For each pathway, we believe just one additional positive acute study is needed to show efficacy.

As noted earlier, we made significant progress towards this goal by initiating dosing with 50 milligrams in our Phase III WATERFALL Study in patients with MDD. Based on our enrollment, which has now surpassed 50%, we have updated our anticipated completion date for the WATERFALL Study to the first half of 2021. We've also initiated dosing in our postpartum study, our Phase III SKYLARK program. Top line data from the SKYLARK Study is anticipated in 2021. And finally, as noted earlier, we initiated dosing in the 50-milligram cohort of our Phase III open-label SHORELINE Study. Top line data from the SHORELINE Study, 30-milligrams, is expected by the end of this year, and it is also possible we will have preliminary data from patients who receive 50 milligrams in this study by year-end as well. We're also on track to commence dosing in the Phase III CORAL Study later this year. Recall the CORAL Study is looking at Zuranolone 50 milligrams as an acute rapid response therapy in MDD when co-initiated with a newly administered standard antidepressant. Mike will talk about the utility of this potential indication later in the call. But what I can say is that we now have 3 shots on goal to bring zuranolone to market.

Today, we're also reporting results from the 6-month follow-up arm from the MOUNTAIN Study. As we set out to understand more about the durability of zuranolone, we asked what happens to treatment responders in 6 months. This has been an important question and an area of speculation, as clinicians need to understand the treatment path for patients who respond to zuranolone. As part of the MOUNTAIN Study, subjects will offered the opportunity to participate in a 6-month blinded follow-up to assess durability of response in those patients who responded after 14 days of treatment. As a reminder, the study was not powered to detect statistical significance from placebo beyond day 15. About half of the study participants elected to participate in the follow-up, and we were pleased to see that more than 80% of those completed the 6-month follow-up period. There were no drug-related adverse events, changes in labs, EKG measures, vital signs or suicidality ratings seen following exposure to zuranolone. And there were no signals of withdrawal or rebound after treatment with the zuranolone was completed at day 14. We were also pleased to see that approximately 75% of the patients who responded to Zuranolone 30 milligrams at day 15, maintained their response rate at the last follow-up on day 182. This was true of the overall population regardless of treatment arm, but more importantly, for those who saw a significant benefit from zuranolone 30 milligrams, that is the population with a HAM-D, greater than or equal to, 24 at baseline.

The improvement over placebo seen at day 15 was sustained over the full 6-month period and at no time during the follow-up period, did the change from baseline in HAM-D in the placebo arm, surpassed that in zuranolone 30-milligram arm. This suggests that persistence of benefit following the initial 2 weeks zuranolone course. This benefit was seen regardless of whether or not the patient was treated with SSRIs. We believe these data support our vision for a unique treatment profile for zuranolone for people with MDD. We understand development of an as-needed therapy in MDD runs entirely counter to the status quo of assuming all patients require chronic drug treatment, and we understand 2 decades of one approach will require data to effect change. We believe these data are another step along that path. We're looking forward to the top line data readout for the zuranolone 30-milligram cohort in the SHORELINE Study, which we expect will be reported by the end of the year.

Before I move on, I want to reemphasize that our goal of MDD is nothing less than to offer a disruptive, distinct and novel treatment approach for patients. There are already several things we've observed in clinical trials with zuranolone to date, which we believe, along with our Six-month data, suggest the potential for zuranolone to be uniquely situated for this approach. First, we've observed rapidity of response within days that has been consistently observed across our studies. Second, the drug has been well tolerated in these studies with more than 2,500 subjects. There have been no adverse events of loss of cautiousness, including up to doses of 90 milligrams evaluated in our clinical pharmacology studies. And third, there have been no signals of rebound or withdrawal after the drug is stopped.

I'm sometimes asked why we are looking to treat depression like a medical condition rather than a chronic disease that labels a person as a mental health patient. It's long been recognized that the preference or reliance on chronic pharmacotherapy is a problem in psychiatry, and the numbers bear this out. 17 million new diagnoses a year for major depression, but nearly twice that many people remain on treatment for 2 years or more. We see this as an area of substantial unmet medical and societal need. If we are successful, zuranolone has the potential to allow patients to get treated, get better quickly and not require another treatment until when or if, he or she has another depressive episode, as you might expect when treating any other medical condition.

Now turning to a new development with Brexanolone. We are pleased to announce that under the FDA's coronavirus-treatment acceleration program, or CTAP, brexanolone stand-alone has been cleared for a Phase III study in people with advanced COVID-19 related Acute Respiratory Distress Syndrome, or ARDS. This announcement comes after several months of analysis of brexanolone clinical and preclinical data. As many of you know, we already have extensive ICU experience and generated significant critical care data with brexanolone in our SRSE trials. Sage also has extensive chemical equity and medical chemistry experience. And we've been looking at other ways our compounds may impact peripheral receptor systems. The brexanolone trial and COVID-19 related ARDS will involve several leading academic centers. Sage has undertaken this initiative, believing there's a sound rationale to test whether brexanolone may be able to mitigate the morbidity and mortality associated with COVID-related ARDS. It's also, we believe, the right thing to do. We look forward to answering further questions about this trial during our upcoming Investor Day planned for September.

Turning now to our neurology franchise. We have begun dosing in our Phase II double-blind study which we are calling KINETIC with SAGE-324 at 60 milligrams in essential tremor. As a reminder, essential tremor is the most common movement disorder in the U.S., affecting an estimated 6 million people in our country. Earlier open-label data with SAGE-324 demonstrated it is a compound with the pharmacologic characteristics, we believe are well suited for development opportunities, not only in essential tremor, but also in epilepsy and Parkinson's disease. We anticipate reporting top line data from the essential tremor trial in the fourth quarter of this year or the first quarter of 2021.

We're also on track to initiate our Phase II-A open-label study with SAGE-718 in the second half of 2020, the lead asset in our neuropsych franchise and our most advanced NMDA PAM, in patients with Parkinson's disease cognitive dysfunction. Results from this study, which we are calling the PARADIGM Study will inform the potential advancement of SAGE-718 in various disorders as cognitive dysfunction. As a reminder, in early studies, SAGE-718 was well tolerated and patients as well as healthy volunteers demonstrated improved performance compared to baseline on assessment of executive functioning. We believe the data we generated in our Phase I program support our hypothesis that SAGE-718 maybe relevant to multiple disorders with impaired cognitive dysfunction, including Huntington's, Alzheimer's and Parkinson's disease.

Before I turn it over to Mike, I want to share my appreciation for the team at Sage. The team is executing well across all franchises to advance our therapies as quickly as possible for the benefit of patients and families. We believe we've created a novel drug company successfully able to convert our chemical equity library into a rich pipeline of clinical assets that are new chemical entities and not just re-purpose molecules. So with that, I'll turn the call over to Mike.

Thanks, Jeff, and good morning, everyone. As Jeff mentioned, we made significant progress over the last quarter with the initiation of 4 new clinical trials. We've built upon the rigorous prioritization and resource allocation we began in the first quarter as we continue advancing programs across our depression, neurology and neuropsych franchises.

Let me add a bit of perspective on how we're thinking about positioning the differentiated profile of zuranolone in our depression franchise is successfully developed and approved. We have consistently observed rapid response within days and good tolerability of zuranolone in our landscape clinical program to date, rapid action and depression if also seen in our ongoing and planned trials would be an important profile for zuranolone, whether used episodically or treat as needed or as a rapid response for RRT therapy when co-initiated with a new antidepressant. Physicians, patients and payers have consistently viewed the many unique characteristics of this target profile positively. As you know, we initiated dosing in the WATERFALL Study and updated our guidance on an anticipated data readout to first half of 2021. We also initiated dosing in our PPD Study SKYLARK as well as the 50-milligram cohort in the ongoing SHORELINE Study. We are on track to begin dosing in the CORAL Study, the acute rapid response with a newly administered antidepressant study.

During the second half of the year, as we think about the endgame for zuranolone, if we're successful, changing the paradigm by moving towards a treatment as needed or episodic option. There are going to be physicians who will want to use zuranolone, at least initially, in combination with traditional antidepressants, until they get comfortable with zuranolone as a stand-alone agent. This is consistent with the CORAL Study design, which we are on track to initiate this year. If the CORAL Study is positive, we expect to first seek regulatory approval for use of zuranolone when co-initiated with a new antidepressant in the treatment of MDD. If we receive approval in this indication, it would give us an opportunity to leverage the profile for physicians, patients and payers to gain real-world experience with zuranolone and better understand the rapid-acting profile. And if WATERFALL and the longer-term safety data are positive, we think the combination of the RRT experience and the retreatment data from SHORELINE and REDWOOD will expand the labeling and use, making the transition to episodic treat as needed, much more efficient.

This means that physicians would be able to take a phased approach in changing the treatment paradigm, building on their own experiences along the way, from using zuranolone in conjunction with a newly administered antidepressant to prevent relapse to the use of zuranolone as needed or episodically to treat subsequent episodes. The receptivity to a unique target profile is there. We have heard the questions on durability including what happens after day 15 and day 42. With a 6-month MOUNTAIN data we just announced and with the SHORELINE data anticipated by the end of the year, we continue to build our data sets to help answer some of the questions we anticipate receiving from key stakeholders. We want to give patients and physicians another option in the treatment of MDD. And if we are successful, we believe zuranolone can offer, not only a clinically differentiated treatment option, but also a commercially differentiated approach. This is another example of our overall strategy. We leverage learnings and quickly adapt all with the mission of bringing medicines that matter to people with brain health disorders.

With ZULRESSO, we are executing as expected. Revenue during the quarter was $1.1 million, and as anticipated, was impacted by COVID-19 as multiple hospitals continue to prioritize their bed capacity, reducing elective admissions like ZULRESSO. Through Sage Central, we remain close to all the treating sites of care to understand their ability to treat PPD patients and any shifts in their approach. We will continue to support geographies with active existing treating sites and support PPD patients through the process. Given the ongoing surge in the number of cases of COVID-19 in the U.S. and continuing concerns about the pandemic across the country. The company expects the significant adverse impact of the pandemic on ZULRESSO revenues to continue.

Jeff provided a thorough update on the clinical progress we've made with SAGE-324 in essential tremor and our plans with SAGE-718 in indications involving cognitive dysfunction. I'll spend just a few minutes discussing the tremendous unmet need for patients suffering from these disorders. With ET, we're talking about the most common movement disorder, affecting the estimated 6-million plus people in the U.S. despite its high prevalence, only about 20% of people with ET seek treatment. And for cognitive dysfunction associated with diseases like Huntington's, where we've already seen an early signal pointing toward the potential for improvement in executive function and other neurodegenerative conditions that manifest with executive functioning deficits like Alzheimer's and Parkinson's, we're talking about the potential to improve cognitive dysfunction symptoms that track closely with functioning in the real world. By improving these symptoms, our goal is to provide patients with the opportunity to remain more cognitively intact and potentially retain the ability to live and thrive independently. And so we believe SAGE-324 and SAGE-718, if successfully developed and approved, have the potential to become truly innovative treatment options with the potential to help millions of people and their families.

Before I turn it over to Kimi, I also want to take a minute to express my appreciation for the team at Sage. They have worked tirelessly in executing with precision during these challenging times and supporting our mission to bring medicines that matter to people with brain health disorders. I feel as confident as ever that our execution against the well-thought out strategies will enable us to get medicines that matter to patients as quickly as possible. And now I'll turn the call over to Kimi to review our financials.

Thanks, Mike. This is a year of execution for Sage, with cash on hand anticipated to support operations into 2022. We have a clearly defined path forward designed to advance programs across 3 green health franchises. Our experienced team is working to create value by converting our extensive chemical equity into a rich pipeline of clinical assets in areas of unmet medical need. We remain true to our mission.

As a reminder, we started the quarter with a difficult but prudent decision to restructure the organization. But we ended the quarter with the extensive list of accomplishments and progress that you heard from Jeff and Mike. As we move into the second half of the year, we do that with a solid financial position to continue to build on those achievements. As you've heard me say many times before. At Sage, we take a portfolio approach to how we think about resource allocation with the goal to maximize the value of our opportunities. By reprioritizing our activities and rethinking how to deploy our resources, we anticipate annualized cost savings as a result of the restructuring of approximately $170 million. These savings are intended to help Sage advance our mission to deliver medicines that matter to people with serious brain house disorders.

I'll now walk you through the highlights of our second quarter 2020 financial results. Revenues were $1.1 million in the second quarter from sales of ZULRESSO compared to $0.5 million of collaboration revenues from the Shionogi collaboration for the same period in 2019. As Mike noted earlier, ZULRESSO revenues have been significantly affected by COVID-19 in the U.S. and we expect a significant adverse impact of the pandemic on ZULRESSO revenues to continue. Selling, General and Administrative expenses were $38.2 million in the second quarter compared to $88.2 million in the first quarter of 2020. Our reduction in commercial support for ZULRESSO was the primary driver of the decrease in the SG&A in the second quarter. And as part of the restructuring, we recorded a charge of $28 million in the second quarter. Research and development expenses were $73.3 million in the second quarter compared to $89.1 million in the second quarter of 2019. The decrease was primarily related to the completion of the MOUNTAIN Study and a decrease in the noncash stock-based compensation expense.

Finally, we reported a net loss of $136.3 million for the second quarter of 2020 compared to $168.2 million for the first quarter of this year. We ended the quarter with $757 million in cash, cash equivalents, restricted cash and marketable securities. As previously stated, we anticipate ending the year with approximately $550 million in cash which we expect will provide runway for us into 2022. We're looking forward to the second half of the year, we anticipate continued savings from our restructuring and resource reallocation.

In closing, we expect the second half of 2020 will be highlighted with proof points to illustrate our ability to execute, showcase the progression of the pipeline and show the value of our chemical equity. This will be accomplished in part by the strength of our balance sheet, and I'm confident that we have the right team in place at Sage to execute on all the opportunities. We look forward to sharing our ongoing updates I'll now turn it over to Jeff for closing comments.

Thanks, Kimi, and thanks, everybody, and good morning, everyone. I just want to make a few more comments prior to our going to question and answer. I think as you've heard today, that the execution of our clinical programs remains either on track or ahead of schedule. And that's no small part of the efforts of the folks at Sage working through these programs. Our goal remains constant with respect to zuranolone. We are looking to disrupt the treatment model in depression. We understand that is something that may be hard to do, but it's something that we think meets an important unmet medical need in the treatment of psychiatric disorders. As you've heard today, with our Phase III initiation for brexanolone in to COVID-related ARDS, we have a distinct and active discovery group and medicinal chemistry group, and we're looking to leverage that expertise as we move forward. We have clearly defined pathways to advance all of our programs across all of our franchises. And as you can hear today, we have a catalyst-rich 1.5 years upcoming, where we hope to report on this progress over time.

So with that, let me open the call to questions.

[Operator Instruction]. Our first question comes from Akash Tewari with Wolfe Research.

I have a few, if I may. So I wanted to dig into what the 50-mg dose can and cannot help with. So #1, will the 50-mg dose ensure that patients who take 217 without a proper meal would still maybe get into a therapeutic drug concentration or would that just not be possible if you don't take it with food? #2, were the patients in the MOUNTAIN study generally heavier than the Robin study? And will the 50-mg dose allow for a greater percentage of those patients to hit a therapeutic thresholds? And then lastly, can you give some color on how your PK curves evolve over time as you go from a single ascending dose to multiple ascending dose for 217? Like visually, how does that PK look like? And how would you define someone who would be low exposure versus high exposure?

It's Jeff. I'm going to start, and then I'm going to turn this over to Jim. Just some broad commentary. One of the goals of any drug development program is fixing the proper dose. And the metrics and the biomarkers and the analysis required are not necessarily straightforward. I know people like to look at it that way, but they're not, and as a company, I just have to say that, as I think you're alluding to, picking the right dose can be challenging. And in fact, we think that the 50 mg is a good dose, as we've mentioned earlier, we've now dosed up to 90 mg. It's very well tolerated. And so we're comfortable about the 50-milligram dose. But that analysis that has led us to 50 mg in some part remains proprietary. We realized that this could be a competitive advantage for the company. We know we have a lot of fast followers looking at these mechanisms. So a lot of this, we just have not disclosed and will not disclose. With that said though, the performance of the 50 mg to date, I think, as we've mentioned earlier, has been quite satisfactory. We've now gone up to 90 milligrams. And so we're very pleased with that. I'm going to turn the rest of this over to Jim Doherty.

Yes. To answer a couple of your questions in a little bit more detail. So first, around the 50-milligram and PK. As Jeff said, we are quite confident in the performance of the 50-milligram dose from the data that we've seen so far. And so yes, we are confident that by dosing at 50 milligrams, we are moving the population into range of exposures that we think is going to be consistent with efficacy. I think, obviously, each individual person responds a little bit differently, but we do think that this does gives us the right balance that puts folks into an efficacious range. Yes. To your question around body mass, I would say that all of our trials, we see a pretty consistent picture of body mass for individuals, pretty consistent with most of U.S. population.

And then to your point around PK profiles, yes, we think that the PK profile for zuranolone, which recall, is designed to have once-a-day kinetics in human, gives us really a very good opportunity to sort of keep the exposure levels where we think they need to be to see efficacy in our studies across a population.

[Operator Instruction]. Our next question comes from Paul Matteis with Stifel.

Great. I just have a quick follow-up on MOUNTAIN 6-month data. Can you just quantitatively speak to how you define responder or maintenance of response at 6 months I guess, in the Phase II MDD Study, we saw a couple of point up creep in HAM-D from day 15 to 42. Would kind of something in that margin of error constitute maintain response? And then I was wondering if you could just comment on the proportion of patients that initiated an SSRI during follow-up and how this kind of all informs your expectations for SHORELINE?

Yes. I'll take this. I think, and then I'll turn it over to Jim. A couple of points I want to make. First is, one of the interesting findings that all the 6-month data has shown runs counter to the current mythology around depression that you have to stay on a drug. And that's the sort of most striking finding to me. And I think to us, as we move forward to this notion that if you have depression, you don't have to be on an antidepressant for the rest of your life. And so that's number one. And I think what really came home, and if you look at the population that had a response, and I think that's the 24 and above, what you see there is actually a constant -- or very constant separation, pretty steady between drug and placebo.

And what that indicated initially and what suggests is that if you respond to the drug, you continue to respond to the drug, even after the drug is stopped. And we think that is a unique finding. With respect to antidepressants, this was also what made us -- what encourages us about these data, and which we also gives us a lot of optimism about SHORELINE. And that is only a very small number of patients actually started new antidepressants. And overall, I'd say it was only a handful, and overall, it's only about 30% of the patients were on SSRIs during the study.

So this really does run counter to the dogma, the dogma about depression that you have to be on a drug and that you're -- you must be chronically treated. And for us, it's very -- it has been very encouraging. When you see that almost 75% of the patients maintain their response and with the 24 and above, which, of course, is the relevant population where we had a positive end point, that response is maintained out to 182 days. The study was not powered for significance, but even then, the p-value there was 0.06. So this was a very strong finding. And when I think that -- I have to say, exceeded our expectations. Jim, do you want to add anything else to that?

I think I just would reiterate, Jeff, that when you look at the data, I think the key message is that patients who are seeing a benefit, patients who are getting better at that day 15 time point are staying better. So Paul, we'll put the detailed data together from the MOUNTAIN study for a presentation later. But the answer to your question is the scores are pretty similar to what they were in those early days out of the 6-month time point.

Our next question comes from Tazeen Ahmad with Bank of America.

I wanted to focus on essential tremor, if I could. Can you give us a little bit of color on why you think it will be important to look at the primary endpoint at [day 29]? And then as it relates to upper limb tremor score, can you walk us through the importance of that and how physicians view that particular score in general as it relates to ET?

Yes. Tazeen, this is Jim. I'll take that one, and then I'll ask Steve Kanes in a couple of minutes around your question around how physicians perceive upper limb score. So of course, the study that we're talking about that was initiated for SAGE-324, the kinetic study is building on what we've already learned, both from our earlier programs, but importantly, from the work we did last year in the 324 program, where we confirmed that a neuroactive steroid like 324 has a significant ability to reduce tremor in essential tumor patients. Those studies were done with acute dosing. And so we are at an important stage of progression for the program. Essential tremor is a chronic disorder. And so that 28-day time point is our next step in showing the sustainability of the response to 324 that we've seen earlier. And I'll mention around upper limb scores. That is one of the most sensitive measures for essential tremor patients and also one of the most troubling when you think about daily life and what people are trying to do. But Steve, let me have you jump in at that point.

Sure. We've been looking at this quite a bit, Tazeen. As you know, we've been working in essential tremor since early days with -- initially with ZULRESSO than 217. And as Jim said, we've seen very consistent results across the board. We consult with experts in the field, and they have told us that the upper limb tremor is the most debilitating part of the symptom complex, but you can have tremor anywhere. The inability to do things like write or drink or -- and it's an intention tremor. So the more you try to do something that worse the tremor gets. Those are the things that really get in patients way on a day-to-day basis. So there's a few things that we've really been focusing on. One, the upper limb score, we have to make sure that's improved across the board, and that's something that we've seen consistently. The other is, given the level of use of accelerometers and other wearables, it's something that we're able to track throughout the day. So there are real advantages in understanding the signal, understanding the effects on patients as well as the ability to understand what impact our development program may have on these patients throughout the day.

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

This is David Szeto on for Brian. Just 2 quick questions. First, looking ahead, how are you thinking about the landscape of depression evolving ahead of any potential launch? And maybe just related thoughts on how the pandemic might have affected mental health. And telemedicine and how you see that potentially evolving ahead of the next couple of years. And then the second question, just on -- going back to WATERFALL trial and the enrollment that you're seeing. I know that there's definitely synergies from the MOUNTAIN trial. But I'm just wondering if you see any extrinsic reason for why enrollment might be better as possible read through to the other MDD trials, including CORAL and RRT?

This is Jeff. Thanks for the question. In general, I think we're seeing an increased incidence of reporting of people with mood disorders. But psychiatry and depression has always been a major area of unmet medical need. And so I think what we're seeing in the MOUNTAIN Study, there are a couple of things that we're seeing in the MOUNTAIN study. And I'll do your second question first. One is there is increasing interest among people who are doing depression studies looking at novel therapies. And if you think about all the therapies that are currently in development, they all have -- they all really are of a kind, except for zuranolone. They are 2 to 6 to 8 weeks and then chronic pharmacotherapy for as long as the physician requires it. We just think that patients deserve another option, and we're seeing tremendous interest in our studies because the zuranolone data really, so far, I have with the 6-month data, I think it's even more so suggest that there may be a different and unique way to treat depression. So we view that as an area of interest and an area of uptake that has really spurred interest in our trials. Also, the team has done a great job. I mean, I think the -- I think, as I said at the start, a lot of people have stopped their studies or thought they couldn't do studies, and our teams really have done a nice job proactively preparing for this environment. And the reality is there are a lot of people who are depressed.

Now the second point is that as you -- if you think about the face of depression, I think that's really something that we are really interested in changing. And with COVID, I think what you're seeing is a greater recognition of the importance of mental health, the importance of -- and the morbidity associated with depression in terms of lack of function and a lack of engagement. And it's brought home as people are not distracted by work and have more time with their families where people can be -- where the depression can be diagnosed. We don't think the diagnosis has changed, obviously. We think that using rigorous criteria, we can find people who have made real depression versus reactive depression, which is what we're distinctly not treating. But we do think the face of depression is treating. And we believe very firmly, in fact, probably more now than we have in the past, that there is a real need for not putting everyone who gets depressed on a drug therapy for years and years and years. We think that zuranolone with its profile, with its ability to show rapid response with its tolerability profile really can offer disruptive and unique approach in treating depression, especially as the treatment of depression becomes ever more recognized as something that's an area of unmet medical need.

Yes. Maybe just let me -- this is Mike. Let me just add on to that, Jeff. I think you said it well. And I also think just if you think about our 2 shots on goal that Jeff alluded to before, right, we have the RRT option for patients. And then we also have the end game for us is getting into [episodic] or treat as needed. And as Jeff said, like there has not been a molecule like zuranolone that is given -- that will give the physicians and patients this opportunity to treat as rapidly within days and see that effect if we successfully get either RRT or the episodic treatments over the line.

And the way we see this playing out is we'll be able to move this paradigm in time, right? So we will evolve the paradigm, but we can start with the RRT indication, allow patients and physicians to get comfortable with the rapid-acting nature of zuranolone while they're using in combination with the antidepressant, standard antidepressants, as they get that real world experience, and we can publish REDWOOD data and the SHORELINE data and they get more comfortable with their treatment data, that will give us the opportunity to expand the label and to evolve that paradigm to that treatment as needed approach that we think is really important for patients. And that's what we hear back from patients and physicians. This is what's important to them. And it's giving them multiple approaches as to how to treat MDD, it allow us a chance to evolve that paradigm over time.

[Operator Instruction]. Our next question comes from Ritu Baral with Cowen.

This is Lyla on for Ritu. Congrats on the progress so far. I was wondering if you could maybe speak to the dropout rates or maybe patients lost a follow-up that you're seeing with SHORELINE. Did COVID have any impact on your ability to follow-up with patients? And can you remind us if patients need to come in for retreatment or they can initiate via telemedicine and have it delivered to their home?

This is Jeff. We've not seen much of an issue with that. And I think we've always used various maneuvers to assure compliance in terms of follow-up. And if you take a look at our 6-month data, compared to most psychiatric trials, we have an astonishing amount of follow-up, and I think it was almost 80%. That's really -- I mean, I've done this a long time, and that's a very good follow-up number. And part of this is due to the diligence of the teams. And the nature of the trial designs that we've instituted to encourage patients to maintain the blind. And if you look at what we did with Mountain, in particular, I'd argue that I can't -- I don't think we can find another 6-month blinded follow-up of any drug after the drug has been discontinued and just watch these patients naturalistically. So we haven't seen really this much as an issue. As I mentioned, we've done a number of internal maneuvers to ensure compliance and the team has done a great job at that. But one of the things about COVID is that I think people are depressed. They do need treatment and depression is a serious medical disorder, and it has not discouraged patients from either participating in trials or in their follow up.

Our next question comes from Salveen Richter with Goldman Sachs.

With regard to the 6-month follow-up cohort in the MOUNTAIN Study, could you just help us understand how the placebo in 20-milligram arms compared to the 30 milligram at 6 months?

Actually, I'll start, and I'm going to turn it over to Jim. So remember, in the overall trial, we did not achieve significance so -- but the interesting finding in the overall population as regardless of treatment in the overall population, that the patients who got better tended to stay better. So we were interested. And again, that runs counter to the current dogma about depression, which was we were fascinated by because it's not what you would -- what people have been taught. But we've seen this in most of our studies. And at 6 months, we've seen the same thing regardless of treatment.

The problem with, of course, in the overall population is that what you see is like with any medical disorder, when people -- whoever people are when they get better, they get better, that would be true of a community-acquired pneumonia study where people get better versus penicillin. But the interesting finding in the MOUNTAIN study was in the relevant population where we saw a treatment effect 24 and above, and that's why we looked at it. There, we saw a continued separation from placebo. And that persisted whether or not the patient was on an SSRI. And it's important to note that the minority of the patients, only 30% were on SSRIs. So this is a really unique finding for us and one that we think continues to -- in a stepwise fashion, derisks our thesis that there is a way to treat patients with depression with a drug that acts rapidly and can get people better without the necessity for maintenance therapy.

Just so you know, we think this is a pretty unique finding. And we are going to publish this and prepare for presentation because we think some of the science is important. And it's likely we'll wait for the SHORELINE data because we think that there's a lot we've learned now about the natural history of depression in the modern world that is really runs counter to all the dogma that I think people accept that if you're depressed, you are a chronic mental patient. And we've been very encouraged by the 6-month data, and we think it's unique. And we're looking forward that we will be publishing it and presenting it.

Our next question comes from Andrew Tsai with Jefferies.

Maybe just to follow-up on Salveen's question, of course, and press release noted a large majority of patients maintain response regardless of arm. So I'm just wondering for the placebo arm conceptually could a durable response that you saw be attributed to background SSRIs kicking in after 6 to 8 weeks or what could be the explanation of that.

Well, this is Jeff. I mean you have to pretend that if you look at this like a regular disease. So in the original study, obviously, we didn't have significant separation, so it's hard to interpret those data. What you're seeing in the large -- in the -- and again, just imagine if you have anyone spontaneously remitting from any disease, they spontaneously remit. So if you have one patient, that remission curve will look the same as 100 patients. So it's hard to make much of the overall population, except to say, yes, you're right, they -- everyone was a lot on antidepressants, they could have rescue therapy. So that's why when the study -- we turned to the 24 and above, where the study showed difference. And that's why -- which is, of course, the relevant population. And that's the majority of the patients in the study. And there, you don't see any drift at all. You just simply see the patients -- 75% of the patients maintain their response out to 6 months.

The other point to make and remember is that the relevant question, and we're not really dealing with it today because I don't want to -- we don't want to be -- we don't want to sort of cherry-pick the data. If you look at responders, the majority, almost the large majority maintain their response and even without intervention. And when you go back to the early days, and I think someone mentioned this earlier, when you look at curves in the original study, you sort of see those curves creep up. Sometimes they creep down. You got to remember, those curves represent combinations of nonresponders and responders. So here, we did a blinded study out to 6 months, and we just observed stability. I understand for everyone it's counterintuitive, but it looks as though the natural history of depression, remembering, 2/3 of these patients were on an SSRI, it actually looks like a medical disorder. We know depression waxes and wanes. And it looks as though that it looks just like any other medical disorder. If you get better and you have a successful treatment, you stay better. The difference is in all of these approaches, even in the MOUNTAIN, the original study, the patients on drug get -- show separation from placebo much more -- very rapidly within days. So you do see benefit within the first 2 weeks, even though in MOUNTAIN, you didn't see -- didn't quite a treat in significance. And for us, plus the 6 month data, that really supports the utility and the rapid RRT approach, where you do see early separation as well as our overall thesis that one can treat depression very differently.

Our next question comes from Yatin Suneja with Guggenheim Partners.

Congrats on the faster-than-expected enrollment in all of the trials. Just a question, a quick one on MOUNTAIN, have you looked at the data in terms of its consistency between men and women? Given that this neurosteroid is more implicated in -- inflicted in women and any differences you saw in sort of the responses? And then the second part of the question is, I think, Jeff, you did mention a p-value of 0.6. I missed it. Could you just tell me -- or just confirm what you were referring to in the MOUNTAIN follow up?

I'll answer the quick one and then I'll turn it over to Jim. We had -- wasn't -- we looked at the difference that whether it was maintained on the 24 and above, right? So if you're looking at -- see if there's a difference, you got to start with the population where there was a difference. And that was -- but the majority of the population was 24 and above. And even though it wasn't powerful significant, after 6 months on the blinded analysis, the p-value between placebo and drug was about 0.06. So it almost maintained its significance out the 6 months, which was, we thought, a very remarkable finding considering that this was a long-term study. It wasn't powered for that.

I'll turn the rest over to Jim.

Yes. And then to your other question, we -- yes, of course, we have looked for whether or not there are differences between men and women as well as a number of other demographic factors in the study. And the short answer is we don't see any difference between genders in the study.

Our next question comes from Thomas Lavery with Morgan Stanley.

I have a question about SAGE-718. The top line data in Parkinson's disease is expected later this year. What kind of data do you need to see -- to move this program ahead next year?

Yes. So this is Jim Doherty. I'll take that one. So the study that we're talking about is looking at the effects of SAGE-718 with relatively short-term dosing in Parkinson's patients with cognitive impairment. And what we're doing is building off the results that we had talked to you all about to the end of last year, showing that in Huntington's patients, we're able to see acutely an improvement in executive function and other aspects of cognitive function. And so because this is such a novel space and because it's such a novel approach and because we were so happy to see the results that we saw from the Huntington's patients, rather than move forward with the very first patient population that we saw into a more detailed placebo-controlled study, we decided to pause and go through the activity of looking at various patient populations. So that's what this study is now. We're going to essentially run a similar short duration study in an open-label format in Parkinson's patients, similar to what we did in Huntington's patients to see if that's another patient population that can benefit.

We'll also look at other neurodegenerative disorders. And really, this is all built on the role of the NMDA receptor in cognitive functions. There's reason to believe that you can see a broad improvement in cognitive function across more than one patient population. And so that's what we'll do with the next study in PD patients is really look to see if we can expand the results that we've seen to date in HD rations.

Our next question comes from Neena Bitritto with Citi.

So I just wanted to ask a quick one on kind of the regulatory strategy. I know you talked a little bit about kind of next steps once you have some initial data in MDD and some of these upcoming studies. But once you get data from WATERFALL, I guess, what's kind of the plan for REDWOOD? Are you going to wait until you have data from WATERFALL? Or do you anticipate maybe reinitiating that study a little bit earlier?

Thanks for the question. I think, obviously, it will depend on the data from WATERFALL and the data from SHORELINE. Right now, we still think we have to have some larger study or some study like the longer-term analysis. But when we see waterfall, 1 of the things we're going to have to take a hard look at is based on the 6-month data, we're not seeing a lot of relapses. If you think about patients getting the drug treatment. And you're thinking about 75% of patients maintaining their effect regardless of background therapy or no background therapy, that's something we'll have -- we'll need to take up with the agency. Because initially, we had looked at -- we had only had follow-up data out to day 42, and we had assumed that people would need sort of recur a treatment. I think that assumption so far is being challenged by the 6-month data. And we'll have to take a look hard or look at SHORELINE. And SHORELINE, which we're optimistic about now based on the 6-month data, gives us something like that, we'll revisit what long-term data we might need if WATERFALL reports out positively. Steve or Jim, you want to add anything to that?

Yes. Yes. I would just say a few things. I mean, first of all, just to remind everyone, this is a program that's proceeding under breakthrough therapy designation, which gives us an opportunity to have interactions across the board. And so as we -- as the data unfolds, we're able to interact with the FDA and talk about what the potential pathways forward are as breakthrough because we share our understanding of the urgency for developing an entirely new therapy, and that's what this whole program has been designed to do. So yes, when we have data, we'll do -- we obviously -- we just go back to the agency. Remember, it's not just the clinical efficacy data. It's also [clinpharm] data and everything else that we've been consistently showing across the board. And now with more than 2,500 patients that have been exposed to the drug, we have a very clear idea on the-- what the overall adverse event profile, safety profile is. So a lot of information comes through all of which will lead to the most efficient regulatory strategy forward. So that's a lot of words to say as the data unfolds, we'll have those discussions and identify the most efficient path forward for patients.

Our next question comes from Cory Kasimov for JPMorgan.

So for the RRT study that's untapped to begin in the second half, do you plan to piggyback on top of your existing MDD sites? Or will they be separate? I guess I'm just curious how fast this can go since it sounds like this would represent the initial MDD filing.

Yes. So there will be a combination of sites. I mean WATERFALL is moving quickly. We have a lot of really well-performing sites. I think for water -- so I think that we'll continue to try to execute quickly. I think that one of the lessons of WATERFALL and the lessons of this whole of this year has been that our ability to leverage our infrastructure that we've developed over time and the team's ability to move quickly from protocol to protocol. So we'll be doing that as well. We do think the design of these studies, we do design the studies to be, want a better word, palatable to the investigators and sites. And one of the advantages of zuranolone in general has been that 2-week course of therapy patient -- potential patient benefit quickly, has been very -- has been greeted with a lot of enthusiasm by treating clinicians. So we're -- that's one of the encouraging things that we've seen throughout all of this. Jim, I don't know if you want to add anything to that.

Yes. I would just add, Jeff, that we have a pretty large network of sites. And so we're confident that we're going to be able to run all of the studies and keep ourselves on track for all of them.

Our next question comes from Laura Chico with Wedbush Securities.

This is Kenneth on for Laura. So on SKYLARK, ZULRESSO's results were clearly impacted by COVID. And while the extent of disruptions appear to have stabilized since the spring. What are your expectations around recruitment base? And with data in 2021, how should we be thinking about the number of sites that will be necessary for recruitment? And will this be fully outpatient?

Sure. Thanks for the question. This is Jim. Yes, I think the important thing to remember for SKYLARK is that with zuranolone, what we're talking about is an outpatient therapy. And so that's just a different opportunity than with ZULRESSO. But certainly from a recruiting perspective, we're anticipating that we're going to be able to recruit for the SKYLARK Study. We have in a comparable way to what we're seeing in our other studies with zuranolone. It's a smaller patient population. And so, of course, there'll be an impact there. But I think the -- probably the most important thing is that with an oral drug in an outpatient setting, it's just a slightly different situation. Steve, did you want to add anything?

Yes. I would just say, with COVID, Mike referred to that as impacting patients sort of being able to be admitted to the hospital for treatment. On the other side of that, of course, is that there's enormous unmet need and that's only growing. With increased isolation of women in the face of being delivering without significant others in the delivery room and having to go without the support of family members and so forth. The rates and potential interest in postpartum depression is only growing. So as Jim said, the trial itself is an outpatient trial, gets around some of those logistical challenges. And just based on our experience with execution, we anticipate being able to enroll that in a very similar way as we have with waterfall. It's an important issue. It's an important disorder and one that we've been committed to for a long time.

Yes. And I'll just come in, this is Mike, as well. I think it's important for a couple of points. One is, as we said, we have those distinct paths now for zuranolone. We have the PPD path with SKYLARK, right, one study, and we'll be able to seek approval there. Have the 2 paths with MDD, both the RRT indication and the episodic. And the one point I'll also make in combination with what's saying very different profiles, right, on the PPD side between ZULRESSO and zuranolone, right? The rapid-acting nature is still there, but an oral therapy that patients aren't going to have to go into a hospital to receive the 60-hour infusion, right? We're still very excited about the PPD market and what we think zuranolone can do there.

And our last question is from Jay Olson with Oppenheimer.

Were you surprised by the durability of zuranolone in the 6-months MOUNTAIN follow-up? And how do you plan to leverage that finding with regards to your filing strategy and ultimately, your target product profile for zuranolone?

This is Jeff. Thanks for that question. I don't want to use the word surprise. I guess I'd say we were gratified that the data that we've acquired to date over all of our studies can now be extended out to 6 months. We're aware, and as I said in my opening remarks, this is really counter to the narrative about depression that you enlist -- that patients enlist themselves as chronic mental health patients for the rest of their lives that they're so delicate that they have to stay on treatment for years and years. And those of us who are treated these patients, we've always wanted something better. And we wanted something different. And so I think we've been gratified by it. I do think that the data really do -- I wouldn't say surprised, but the data don't run counter like -- I think Steve and I are both (inaudible) don't run counter to our personal experiences and how we used to treat patients. But it really does -- it is surprisingly inconsistent with the pharmacomethology about how to treat depression.

And so we do think that data, we continue to -- this is just another step and we do think that these data though do inform what might come from SHORELINE. And if we can sustain this, we think the profile of the drug will be unique. We think that the ability to get patients better more rapidly to have a tolerable side effect profile and to eliminate the necessity for automatic chronic pharmacotherapy will be in a really important treatment option for patients that otherwise are looking at years -- potentially years of SSRI therapy. So we're very encouraged by it. And we would -- we intend to think about how we could disrupt the treatment paradigm. And that will be, of course, Mike's job once we have the data. But we do think these data are an important next step, where you're not seeing rebound, you're not seeing withdrawal. You're seeing very good -- you're not seeing any sign. You're seeing really good durability.

Now the other thing I'd point out, though, as we've said early on that the thesis behind these drugs and the mechanism behind some of the neuro stories is the ability to alter post synaptic receptor trafficking. And we've always thought about restoring normal homeostatic mechanisms in the brain. And in that respect, we've always believed that zuranolone is a distinct model. It's not really what other people call an antidepressant. It's something different. It's something that normalizes mood, potentially normalizes neural circuitry and potentially offers a reset of mood function. So we think the 6-month data really represent this sort of paradigm shift and how one can think about major depressive disorder. So we do think we're on the way to doing it. We think that this will be an important treatment option for patients, and it's one we intend to continue to pursue.

Thank you. I'd now like to turn the call back over to Jeff Jonas for closing remarks.

Well, again, thanks, everyone, for joining us this morning. I know you're all busy, and I hope everyone is healthy and your families are healthy.

To close, I just want to reiterate 3 important points. The team at Sage has done a great job executing on our clinical programs, all of which remain on track or ahead of schedule. As you've heard today, we have numerous catalysts over the next 18 months. And Sage is really proud of our discovery medicinal chemistry group are developing this really -- what makes us unique, a rich pipeline of novel and internally develop clinical assets, which we believe have the potential to help literally millions of people.

So with that, I'm looking forward to updating all of you in the future with all of our milestones, and hope all of you stay well, and have a great day.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.