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

All right. Good morning, everyone, from the virtual JPMorgan Healthcare Conference. My name is Cory Kasimov. I'm the senior large-cap biotech analyst, and it's my pleasure to introduce our next company, Sage Pharmaceuticals and CEO, Barry Greene. [Operator Instructions] So with that, Barry, thanks for being here today, and let me hand things over to you.

Thanks, Cory, and thanks to the organizers of JPMorgan for having us here at the first ever virtual JPMorgan meeting. You guys have done a good job. It's certainly been very efficient. Before I begin, I will be making forward-looking statements. So as Cory said, I'm Barry Greene, CEO of Sage Therapeutics, and it's my pleasure to provide an update on the extraordinary progress that Sage has made on brain health over the last decade, and importantly, provide my thoughts on what I believe our next chapter will be. At Sage, it's our belief that we have the potential to transform the lives of millions of people with brain health disorders, and we see possibilities where others don't. If we look at Slide 3, we believe that people suffering from brain health disorders actually deserve better. Now I recently joined Sage because I see CNS as the next frontier of innovation. And I was excited by the team and the work that the team has done over the last decade. I mean to me, CNS feels like oncology was 10 or 15 years ago, lots of information, lots of knowledge of the pathways and it's really necessary and ready for big time innovation. I also saw the potential for Sage to become a leader in brain health with the possibility to help millions of patients worldwide. And that's incredibly exciting. Now importantly, what I saw when I started talking to the folks at Sage, the deep scientific progress in understanding brain circuitry by focusing on the GABAA and NMDA pathways and applying unique chemical innovation to neuroactive steroids, also several chemistries also. The team has created potential innovative therapeutics through allosteric modulation, and they built it from knowledge of endogenous starting points to target receptors that dial in very specific properties to engage these pathways and I've seen very highly tailored approaches. And very importantly, as we've seen, it's an approach that's worked. As you guys know, Sage developed the first ever treatment specifically approved for women with postpartum depression. And has built behind that a rich pipeline of potential treatments focused on brain health. And if these are successfully developed, we believe they'll give patients the opportunity, frankly, to get their lives back. We're advancing our leadership in brain health and intend to become a top-tier biopharmaceutical company in the next 5 years. And we're doing that starting with an incredibly catalyst-rich 2021. Today, we have 2 programs in late-stage development with 4 ongoing Phase III programs, 3 actually due to read out this year, we have 5 additional mid and early stage programs, and we've committed to the goal of developing 2 or more high-quality IND-enabling investigational products by 2023. We're well positioned to progress this pipeline with a strong IP strategy and more than $2 billion of capital that we plan to utilize in a very disciplined way to expand and accelerate our pipeline in order to advance our mission of making medicines that matter. Now if you look at Slide 4, when Sage launched 10 years ago, they were largely focused on the U.S. market with early neuroscience research leading directly to late-stage efforts in major depression and PPD. With that focus, we had the opportunity to reach approximately 18 million patients with the goal of bringing them innovation that we believe then and still believe is desperately needed. Now with the Shionogi collaboration in 2018, we expanded our geographic reach to Asia, increasing the patient potential to about $22 million. On Slide 6, we can see that now, just 10 years and through the strategic use of collaborations recently adding Biogen, with the opportunity to accelerate development of innovative treatments on a global level with the potential patient impact of over 450 million people around the world, incredibly exciting place to be. Now let me turn to Slide 7, and we can see why our planned expansion and acceleration is just so critical. Many of you are well aware that patients have been told for too long, this is as good as it gets, just deal with it. With limited innovation or truly transformative medicines, people living with brain health disorders are not getting the help they need, whether it's a women suffering from PPD or people dealing with essential tremor, they're losing vibrancy, they're losing their quality of life and the thing we all treasure the most, many are losing independents. They're losing the opportunity to reach their full potential and possibly even losing their lives. Families are suffering, too. And in many cases, there's a lasting generational impact. We're consistently hearing from the advocacy community that the current system just doesn't work, and caregivers are burning out. This really is an urgent concern. Now on Slide 8, we can see that over the last decade, the devastating impact due to brain health diseases and the frank absence of innovation have resulted in significant cost to individuals, families, communities, society and governments at large. In the 20 years illustrated in these graphics, the U.S. economy experienced a nearly 100% increase in economic impact for many of these disorders, things like depression, anxiety, bipolar disorder, ET and Alzheimer's disease. And now, unfortunately, with the impact of the COVID-19 pandemic, people are suffering around 3x the previous rate of depression, and that's in the U.S. alone. All this comes as the world economies are being devastated by the pandemic and doing nothing about this could be catastrophic. Now while CNS and brain health are not considered infectious diseases, I believe we are indeed in a brain health pandemic. You can see on Slide 9, that our pipeline and innovative product engine are designed to create a consistent and sustainable organic flow of Sage inventive products with the potential for big effects on brain health disorders for millions of people. Imagine a world where the status quo isn't good enough. At Sage, we're imagining the future where brain health disorders are treated with therapies that are matched to patient need, destigmatized and demystified and finally, treated with the urgency and made a priority as serious diseases. These are not the patients' fault. Sage's focus is on expanding and accelerating our brain health franchises to address critical unmet need. Now we made great progress against all of our franchises. And you can see on Slide 10, initiating multiple new clinical trials and progressing the pipeline. With this progress, we're anticipating 10 data readouts this year alone. Let me now turn to Slide 11. We have a rich pipeline of Sage-created therapeutics in development with multiple opportunities to make medicines that matter. And we're focused on efforts to expand and accelerate this pipeline. Let's take zuranolone. With zuranolone, we plan on working with Biogen to evaluate additional indications in parallel to PPD and MDD, and we're going to follow the data to make rapid decisions about new indications. Also with SAGE-324, we're starting with essential tremor, we also intend to follow the data to evaluate additional indications there as well. Now in addition to SAGE-904 and SAGE-689, you can also see we've expanded the pipeline and reported advancing SAGE-421, SAGE-319 to preclinical studies. Now importantly, all of these programs have unique differentiated characteristics. With Slide 12, and as we turn to depression and other mood disorders, there's a significant need for new approaches. There's never been a more urgent need than now. We can highlight the fact that there's currently nearly 800 million people globally suffering for mental health disorders. Now if you look only at people experiencing a major depressive episode, the numbers are still staggering. Nearly 200 million people a year experience an episode, and that number is increasing every year. We need new approaches. At Sage, we believe depressive episodes can be treated as needed, and the data we've seen to date with zuranolone gives us confidence in the potential of a new treatment approach. We believe that whether the depressive event is caused by genetics, having a baby or COVID actually, that we may be able to help. Now if we take a look at current therapies, there has been more than 35 treatments approved for depression in the last 30 years, but -- and this is really important, the benefit risk profile of antidepressant therapy has remained unchanged. The graphic on Slide 13 demonstrates the point. And let me just set up the graph because this is important. MDD remission rates are plotted on the x-axis and discontinuation rates to adverse events on the y-axis. Of the 11 most prescribed treatments including this validated and soon to be published actually analysis, the cluster in the upper left corner have similar levels of efficacy and rates of discontinuation due to adverse events. Now in contrast, importantly, the integrated remission and discontinuation data generated with zuranolone, and this comes specifically from the 201B and MOUNTAIN studies with patients HAM-D over 24, these data are quite unique. We see higher rates of remission and much lower discontinuations. Importantly, zuranolone achieved this effect with 2 week course of therapy. And that compares favorably to the 8 or more weeks for these typically chronically used antidepressants, shown in the upper left cluster. In clinical trials to date, including 2 positive pivotal trials, one in PPD and one in MDD the data have been consistent and support our hypothesis that depression can be treated as needed. The data thus far with zuranolone give us a reason to believe. In fact, the clinical studies we've done in approximately 3,000 subjects we've seen consistent data, and that is a rapid onset of activity, it can come as early as day 3. The potential to treat as needed as we released the data we saw from SHORELINE demonstrated that 70% of subjects require 2 or fewer treatments in the 1-year follow-up period, and hopefully, that continues further. And these important features have come with a generally well-tolerated safety profile to date. I believe that these data demonstrate and what our ongoing Phase-III studies continue to evaluate is the potential for patients to get better faster, stay better and get their lives back. Now let's turn to Slide 14. You can see how the landscape clinical development program for zuranolone is designed to support a regulatory filing as efficiently as possible. With 3 ongoing studies where each, if positive, potentially supports a unique filing pathway, one in PPD and 2 in MDD. We'll work closely with regulators here. But as you can see, our goal is to create optionality for patients and for their physicians. Now beyond MDD and PPD, as shown on Slide 15, we expect to expand development into other depressive and mood disorders. Importantly, we expect to have data readouts in 2021 that have positive support parallel development. Let me now turn to Slide 16. Beyond depression and mood disorders, we're applying our understanding of how modifying key brain receptors like GABAA impacts brain function at the network level, with our other novel GABA modulators, which are differentiated and could be well suited for a variety of conditions, things like essential tremor, epilepsy and Parkinson's disease. Now in this context, one of our key focus areas is movement disorder. Beyond the quantitative patient numbers and economic burden demonstrated by the graph on Slide 17, which are certainly significant, movement disorders can lead patients to feel frustrated and embarrassed while others are left significantly disabled and unable to fully care for themselves. Let's turn to Slide 18. Essential tremor is a neurodegenerative condition and the most common movement disorder. It's estimated to affect more than 6 million people, and that's in the U.S. alone. It can impact young people, too, even in their teenage years. Imagine your teenage daughter unable to communicate with her friends, including the inability to text because of her tremors. Essential tremor can make the simplest activities of daily life difficult, if not impossible, and a substantial mental health impact on the caregivers as well. Incredibly, the last pharmacological treatment was approved in 1967, folks, that's more than 50 years ago. The GABAergic effects associated with ET led Sage to consider whether GABA PAMs could be effective for essential tremor. Now following the translational approach that Sage has used, we started by investigating brexanolone and zuranolone and the data generated gave us confidence to progress SAGE-324, which is the lead compound in our neurology franchise. We believe it's well suited for development in essential tremor. Now to support that point, let's look at the graph on the right from a Phase I open-label study using a single dose of SAGE-324. Let me set this up. The blue line in this figure shows the reduction over time and combined upper limb tremor amplitude. The red line shows the plasma concentrations of SAGE-324 over the time -- the same time scale. I think these data show a striking PK/PD relationship as the plasma concentrations of SAGE-324 increase after a single dose and the tremor amplitude decreases. You can also see that as plasma concentrations diminish, the tremor amplitude increases. Importantly, and we hope promising, not back to baseline. With repeat dosing and an optimized PK profile, our goal would be to maintain plasma concentrations above an effective threshold for the entire dose interval and translate that profile into sustained tremor symptom control. This thinking is a key of our ongoing development work. Sustained tremor control could give patients their lives back. For example, we heard from a man in the September FutureCast that he would simply love to be able to feed himself soup. Now let's go to Slide 19. You'll see that our collaboration with Biogen will potentially allow us to accelerate clinical development of SAGE-324. And importantly, we expect to report data from the Phase II KINETIC study early this year. Now let's turn to our neuropsychiatric franchise. As we've seen with both mood and movement disorders, there's a drastic need for innovative treatments for disorders of cognition. The graph on Slide 20 is only part of the story. We're talking about disorders that have major health and economic impact on not only the patients who suffer, but also their caregivers, families and society broadly. And the prevalence of these disorders, as you're well aware, continues to increase without any meaningful advances in treatment. Sage has created a portfolio of investigational products targeting NMDA receptors. As noted on Slide 21, NMDA receptors constitute a major class of excitatory receptors in the brain, and play a fundamental role in regulating brain function. As with our GABA platform, we're driven by the vision that the best approach to modulating NMDA receptors is to leverage the brain's endogenous modulatory machinery. Now we've been able to dial in the degree of modulation with novel Sage inventive compounds, ranging from strong positive modulators to full negative modulators. And importantly, we've seen several proprietary biomarkers that Sage has founded that will guide our path. Among this portfolio, 2 programs, 718 and 904, have entered clinical testing. I'll talk about 904 in a moment, but let me walk you through why we're so excited about exploring the potential of our wholly-owned SAGE-718, being developed to benefit patients with disorders like Huntington's, Alzheimer's and Parkinson's disease. Let me turn to Slide 22. The importance of NMDA receptors in learning, memory and complex cognition, including executive function, is actually very well understood. It's important to remember that executive function can be thought of as the conductor of the brain orchestra, required for the skills needed to plan and carry out complex tasks. Now for most of us, these are frankly, things we do every day. It's our ability to organize, we problem solve, we multitask. Without these skills, independent living becomes increasingly difficult and unfortunately for many, impossible. SAGE-718 is a first-in-class developmental program that may offer an ability to augment the key cognitive domain of executive functioning. And the signals we've seen thus far with SAGE-718, including data measuring cognitive performance, while early, are very encouraging. The graph on the right demonstrates improvements in work memory using a two-back test. These data were observed in a Phase I trial in patients with Huntington's disease. We believe that these findings are really unique and unlike the profile of anything we've seen. Now if these data play out in our planned development efforts, they could be potentially transformative for patients. As an example, a patient suffering might be able to one day make a shopping list, drive to the grocery store, buy all the items on her list, put them away and remember where she stored them. For many, that would give them their lives back. Now in addition to our early trial in Huntington's, and as you can see on Slide 23, we're anticipating data from trials with SAGE-718 in Parkinson's dysfunction early this year. We also plan to initiate a trial in Alzheimer's cognitive dysfunction early this year as well, and we believe we'll be able to report those data later this year. Now let me move on to our early-stage pipeline and proprietary product engine. The Sage team has created a portfolio of proprietary wholly-owned programs targeting NMDA receptors. On Slide 26 is SAGE-904, the next NMDA receptor. We designed 904 specifically to investigate neurodevelopmental disorders. We'll provide additional information at an upcoming FutureCast later this year. But I can tell you we're planning to accelerate development of this program with anticipated Phase I data later in 2021. These data will inform our further development path for SAGE-904. On Slide 26 is SAGE-689. We believe there's multiple development opportunities for an IM delivery in areas where acute use with fast onset is of value. SAGE-689 is a potent investigational product with rapid absorption, good viability, and we have solid formulation flexibility here as well. The characteristic of SAGE-689 provide multiple pathways for us to explore unmet needs of patients with such diverse conditions as acute agitation, mania or even migraine. Let's turn to Slide 27, where we see SAGE-319 and SAGE-421, both with differentiated characteristics informed by our iterative R&D process. We focus on understanding how modifying key brain receptors like GABAA and NMDA impact brain function at the network level. We recently announced plans to progress both SAGE-319 and SAGE-421 into preclinical studies. And with these 2 programs, we've done what we've always done: follow the science, generate important data, match those data with development opportunities to address particular unmet needs. Now Slide 28 reinforces our methodology for applying scientific knowledge from program to program, leveraging learnings to define the path forward and doing so with seamless execution. In the September 2020 FutureCast, we reviewed our proactive and predictive approach that led to our current pipeline, one we believe is a leading pipeline in brain health. We'll continue to demonstrate a productive drug development approach going forward. On FutureCast, you heard that we start with preclinical models to look at potential impact of our molecules on the network function in various experimental systems. We then look for translatable endpoints in clinical development that could be used to understand how our candidate drugs may influence the human brain. In addition to quantitative endpoints, we work closely with investigators and patients to look for big effects on things that matter most to patients. And as a result, as shown on Slide 29, we have a milestone-rich year in front of us with 10 data readouts and other key milestones expected this year. 2021 is certainly going to be a very exciting year for Sage. And finally, Slide 30. I hope my update provides a clear plan for Sage's mission to become a top-tier biopharmaceutical company to make medicines that matter in brain health for patients worldwide. Our disciplined execution in 2020 create a strong foundation for near, mid and long-term value creation opportunities for patients and shareholders. Our leading brain health pipeline spans 3 core franchises each with differentiated innovation programs, featuring Sage-created NCEs, and we're building on the current pipeline towards our goal of delivering 2 or more high-quality IND-enabling programs by 2023. As I mentioned, this year, 2021 will be a catalyst-rich year with meaningful data expected to flow across all franchise. If our development efforts are successful, we've got the expertise in place to drive for effective patient access and global commercial execution. And certainly, our financial flexibility enables continued investment in innovation. On our final slide, 31, because seeing the brain differently, we hope to have a positive impact for people suffering from brain health disorders. Thank you for your attention. Cory, I think we can move to Q&A. I'd like to bring in Steve, Sage's Chief Medical Officer; and Kimi, Sage's Chief Financial Officer.

Perfect. Thank you, Barry, and hi, Steve and Kimi. All right. So we'll start the Q&A. We have about 20 minutes for it. I'll remind everybody who's watching this session that you can ask a question via the portal, and we'll get to as many of those as we can over this time. But maybe just to start, and I know, Barry, you mentioned it briefly upfront in your presentation. Can you just kind of go a little bit more into the drivers behind the recent CEO change, and why you picked this role kind of at this time? Why was this the right fit for you right now?

Yes. And Cory, thanks for asking. So look, as I was exiting Alnylam and appreciating the work that Alnylam was actually doing with Regeneron, I saw a great promise in CNS. And frankly, that's where I wanted to focus. And I made the comment in my prepared remarks, I think CNS today is sort of where oncology was 15 or 20 years ago. So CNS is where I wanted to focus. Now in parallel to that, and unbeknown to me, Jeff, who's a phenomenal translational scientist is having conversations with the Board about a potential new role. So timing is really right to strengthen the leadership team and continue the mission that Sage started out, to make medicines that matter. I'm thrilled to be here, and I'm really happy with the progress that we're making.

Okay. Great. So the other obvious big strategic move that recently took place is the deal with Biogen. Interested in kind of the rationale and the thinking behind that and what this means, not only in terms of the obvious economics surrounding zuranolone and SAGE-324. But more broadly, for those assets in the remaining pipeline, what this enables Sage to do?

Yes. And Cory, I think that's the point. Great deals like this happen at moments in time. Biogen clearly was impressed with what Sage was doing, our leading programs. And for Sage, the -- this is about company building with a partner that we'll work with to understand the paradigm shift first needed for depression. And then as you mentioned, we have a full pipeline behind 217 and 324. Now on 217 and 324, the Biogen partnerships allows us to continue to move with MDD and PPD for 217, essential tremor for 324. But importantly, we can also explore additional indications in parallel. If it was just us alone, we would have had to do it in a very serial way. And as you mentioned, importantly, we plan on accelerating SAGE-718, SAGE-904, SAGE-689 and then bring SAGE-421 and SAGE-319 into preclinical studies. Again, as a stand-alone basis, these things would be sitting on the shelf being ready to move forward. So we -- you ask why now, if you look at kind of the NPV of accelerating 6, 9, 12 months ahead of time, it creates exceptional value rather than waiting to progress these programs.

All right. And I mean this is kind of a follow-on to that, but it's one of the more popular questions or common questions we've gotten since you reached this, is like kind of why agree to this ahead of a major binary, at least that's how investors perceive it with WATERFALL, instead of waiting until you had all of your cards in hand?

Well, I mean we're certainly excited by WATERFALL and all the lessons we've learned from previous studies that have gone into WATERFALL. But as I mentioned, this was a good moment in time. Biogen was very interested. And I guess, just to summarize it, the ability to accelerate the entirety of our pipeline, as we've articulated now, 6, 9, 12 months ahead of time, really made doing the deal now worth it. We're looking forward to a bunch of data readouts this year, and that will provide data to guide our paths forward for a number of programs.

Okay. And then last question I'm seeing on this front, Kimi, I'm sure you get this one quite a bit. It's just the price that Biogen paid, what does this suggest about the assumed valuation for zuranolone?

Yes. Kimi, why don't you take that one?

Okay. Great. So I think really, how do we think about the value of the deal is what you're getting at Cory. And there's 3 key elements that we think about. It was really the overall economics, it was the ability to enhance the value of the deal and make it bigger than what it is, what it would have been alone and certainly about accelerating the other parts of our pipeline. So if you just go through the pieces, the economics, one of the largest brain health deals that's happened, potentially $3.1 billion of cash and I'm happy to say that we received $1.5 billion of that on New Year's Eve. So we go into the new year with $2.1 billion of cash in the balance sheet. So great terms. And with regards to that, we also have profit sharing and cost sharing immediately, we have milestones and we have royalties on ex use components. So there's the economics that we thought were really compelling. And then there were certainly the point of expanding the pie. Barry alluded to, we have the opportunity now to do things more quickly, right? So we can do GAD or bipolar sooner than we probably would have on our own. We also have the opportunity now to be global with the -- with what Biogen has to offer. And certainly, from a launch perspective, when you think about the trajectory and the ability for us to work with Biogen, a company that's launched many drugs, we have that infrastructure that we can rely upon immediately. And then lastly, there's the acceleration of our internal pipeline, as Barry pointed out, 718, 689, 904. These are all opportunities as well as our discovery assets that we're able to now aggressively invest in. So the collaboration really provides a lot of strategic, financial and operational flexibility for the company.

Just to round that out, and I should have mentioned this earlier, but Kimi appropriately said it, using -- even in development now for zuranolone and 324, we can leverage the Biogen global capability and to conduct studies now around the world, increasing speed with a bigger end. And that's of tremendous value.

Okay. Makes sense. Must have been nice to have that amount of money hit the bank account before the end of the year, too. So as we think ahead to all the data you have, and Barry you highlighted in your presentation, there's going to be a lot of it this year. Obviously, a lot of focus on zuranolone. So maybe if we take a step back first and think what we learned in 2020 and the takeaways from your SHORELINE data as well as the 6-month look at MOUNTAIN, can you talk about how that informs your outlook for zuranolone?

Yes. I'll let Steve walk you through the data, but let me just say this to start. And I mentioned this in the presentation. I think the data support the hypothesis that depressive episodes can be treated as needed, which is remarkable innovation. I showed the graph where zuranolone seems to be the first drug in 35 years that really differentiates an efficacy and safety profile, providing benefit to patients. But let me get Steve to walk you through the data.

Sure. For SHORELINE and MOUNTAIN, the keys of those studies -- first of all, for SHORELINE, this is the largest naturalistic study ever conducted in development program for major depression. And it's designed to demonstrate a few things. First and foremost, we want to see safety in terms of retreatment and tolerability and retreatment. We also want to understand the patterns of need for patients to be retreated. Recall, we're talking about treating patients for 2 weeks at a time, treating them for depressive episodes. And we want to know the fundamental question, how many times might a person need to be retreated. And how well does our medication perform at each of those potential recurrences. So what do we see? So first of all, both in 2 doses, 30 milligrams as well as 50 milligrams, zuranolone was well tolerated. It was very consistent across all of our studies now. And that was very comforting, particularly as we saw the initial data with the 50-milligram dose. Moreover, 70% of subjects in the 30-milligram group required no more than 2 treatments over the course of the year, half of them only recorded -- only required one treatment in the year. So very supportive, as Barry said, of this treat-as-needed approach. Patients don't have rapid rebound to their prior therapies, really important fundamental data. And then lastly, in SHORELINE, what we were looking to see is our patient's response is consistent. In the 30-milligram treatment group, we saw about a 70%, almost 72% response rate as well as about a 40% remission rate. And when we go to 50 milligrams, we saw incrementally increased response rate at 75% with a remission rate of 48%, close to 50%. So we're really seeing both overall increases in response or remission, the same time course, changes from baseline very rapidly demonstrated, as well as a very long-term benefit in many patients. So something we demonstrated from SHORELINE. SHORELINE is still ongoing, so we're collecting more data in the 30- and 50-milligram groups, but very supportive of where we need to be for long-term therapy. Moving right to MOUNTAIN. Well, what we did in MOUNTAIN is follow the patients that have been treated in the trial out through 6 months. This is our first look at long-term therapy. This is not powered for -- to detect statistical significant differences or anything like that from placebo. But we really wanted to understand what happens over the long haul. First and foremost, we did not see any signals of withdrawal or rebound after the drug was stopped, very similar to what we've seen in SHORELINE. We didn't see any additional drug-related adverse events or changes in labs or ECG measures, anything like that. And perhaps most importantly, we didn't see changes in suicidality ratings either. So we really are able to follow patients in these trials quite appropriately. Perhaps the most striking, patients who got better stay better. 75% of the patients who responded at day 15 maintained their response out through 6 months, very consistent with what we saw in SHORELINE. And this is regardless of whether or not they were put on an antidepressant subsequently. This is true for the overall population, regardless of the treatment arm. So we're really seeing that patients who get better stay well over the long haul. And lastly, for patients with HAM-D scores of greater than 24 -- HAM-D scores of 24 baseline, we had seen improvements over placebo that was sustained. And even that difference from placebo was sustained out through 6 months. And so we are seeing incremental improvements with 30. The drug itself continues to show a very consistent response and now long-term response as well.

Okay. So how do you think all this then feeds into the pending WATERFALL study? Obviously, the longer-term data doesn't do much for the more acute nature of this. But the lessons that you learned from the initial MOUNTAIN study and how that informed the design of WATERFALL gives you confidence that this is poised for success.

Well, we look at the entire landscape program as a whole, and every time a study is completed, we leverage those learnings. We really do a deep dive into what we've understood from the trials. And there's lots of technical pieces that we can get into in the studies. But we've incorporated all of those learnings from MOUNTAIN directly into the WATERFALL study as well as into CORAL and SKYLARK studies as well. The new studies are testing the 50-milligram dose. I mentioned briefly that we're now seeing our tolerability data with 50-milligram dose. And we've also increased the inclusion criteria to HAM-D scores of greater than 24. We know that when patients are at the higher end of that moderate to severe spectrum, we see much stronger signals easier to demonstrate a change from baseline. And beyond that, we've tightened up some of the administration directions to the physicians as well as to the patients; take during dinner instead of with some amount of food, we continue to remind the investigators to really keep patients on a very regular schedule for administration. And lastly, and this is sort of generally true. We always look at the performance of the sites and all of our investigators and continue to work with the ones that are giving us the highest quality data.

And Steve, you might want to just comment on how the bigger end also helps.

Yes. So we get a lot of questions about this things, Barry. We have increased the size of the trial as we -- as the year was ending, we've announced that. One of the things we can do, when the study is enrolling as well as it is in MOUNTAIN -- in WATERFALL, we expect data in the first half of the year, it allows us to increase the sample size to more fully interrogate secondary endpoints, whether that's subgroups of patients that were included, people with a prior history of depression or underlying antidepressants or even look at the potential statistically significant differences at different time points and secondary end points. We just able to really extract as much value as possible from the investments that we made in getting the studies underway. So things continue, knock wood, to -- the study continues to enroll well, and we're looking forward to having those data this year.

Okay. So then one of the newer potential indications here, rapid response therapy. When you think about this opportunity and the type of market education that would be needed, relative to your initial approach with zuranolone, in many ways it seems like it would be materially easier because you're not asking for a sort of a sea change in how physicians approach treating their patients. Can you talk about the potential differential here? And how this might help kind of more quickly broaden the overall market for the product?

Yes. I'll let Steve comment in a moment, but I will say, Cory, maybe for RRT, but generally across depressive disorders, we're going to have our work to do with Biogen. This is an area where we have to educate the health care providing community that treating depression by itself with an SSRI or other antidepressants or with a product like zuranolone, can be used and be treated as near episodically. So as we talked about, the Phase III program provide regulatory options and optionality for physicians and patients. I think it's going to take data, drug in physicians' hands and many physicians seeing with their own eyes the beneficial impact that zuranolone does have. But in 30 years of doing this, when you're working on a paradigm shift, having a great drug with a broad therapeutic index, a good benefit risk profile, in physicians' hands to see the difference, that's what's going to start moving people's thought process that maybe depression can be treated as needed episodically. Steve, do you want to comment?

Sure. So I'll say, speaking as a psychiatrist, I mean, I know what the expectations are around what people think when they think of treatment for depression and it is typically chronic treatment, keep the patients on their medications. And that's led to all sorts of challenges in the field, people who have difficulties coming off of their antidepressants and so forth. So to change the hearts and minds of physicians as well as patients, we need to generate the data. We know that there are physicians who initially may want to use zuranolone in combination with antidepressants, at least until they are comfortable with zuranolone and as we build our set of data that really underlies the entire approach that we're taking. So the way that we're doing that, and one of the ways that we're doing that is by generating data with our RRT study or the CORAL study. So if -- as we receive approval on the indication, it will give us an opportunity to leverage the profile for physicians, get it in their hands, let patients and payers understand what a rapidly acting antidepressant is and how best to use it for their patients. We can take a phased approach to changing the physician's treatment and help them build on their own experiences. And if we're successful, WATERFALL is successful, in particular, we'll be able to help physicians understand how to move away from the sort of the prior approach of only treating patients chronically and to treat appropriate patients for subsequent episodes.

Okay. For SAGE-718, can you help us understand what's -- I guess, with the Parkinson's program first, understand what positive data would look like here. And if those are indeed encouraging, what potential next steps might be.

Yes. Steve, do you want to take that?

Sure. So with 718, we've been looking at a very unique mechanism. So this is an NMDA positive modulator. It's a first-in-class mechanism. And what we've seen so far is a very compelling data improvement of executive function, and Barry touched on that during the presentation. What we're doing right now is initiating a series of exploratory studies in a variety of indications where cognition and particularly executive function and working memory are impaired. So we've seen it, very compelling and stable in Huntington's disease. Now we're looking in Parkinson's as well as in Alzheimer's. First and foremost, we're looking for a signal. We want to see whether or not that effect replicates or if not, if there are other activities in cognition that are improved by this mechanism. We'll use that for deciding which indication or indications we take over into subsequent development.

Okay. And I have a question from the audience here, probably on the heels of this Biogen deal for SAGE-718, plans to keep yourself for the U.S. in the future versus potentially seeking a partner for something like this, too?

Yes. I mentioned that in the presentation. But what's very exciting about the Biogen deal is assuming zuranolone, 324 are positive to move forward, it gives us lots of experience in the commercial realm, frankly, before we have to decide what we do with 718. I'd like to keep 718 and commercialize it on our own, as many geographies as possible. And Biogen gives us the optionality to make that decision.

Okay. Well, we're just about out of time here. So I think we got to end it there. Thank you guys very much. Appreciate it. Great talking to you as always.

Thanks, Cory.

Appreciate it. Thanks, everyone.

All right. Thanks a lot.