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

Good morning everybody and welcome to day 2 40th annual JPMorgan Healthcare Conference. My name is Cory Kasimov. I'm the senior large-cap biotech analyst, and it's my pleasure to introduce Sage Therapeutics and CEO, Barry Greene. Please note that following this presentation, we will move right into a Q&A session. We you can send in questions via the little blue ask a question button in your conference portal. And I'll do my best to work them into the conversation. So with that, Barry, thanks for joining us today, and let me turn things over to you for an update.

Yes. Thanks, Corey, and I want to thank the organizers for JPMorgan for having us here today. It's incredible that we're in another year of virtual, but I'm glad we're doing it. And we'll be making forward-looking statements. And as Corey said, I'm Barry Greene, CEO of Sage Therapeutics. And it's really my pleasure to provide an update on the extraordinary progress that Sage is making on our journey to become the leader in brain health and a top-tier biopharmaceutical company driven by our vision to fearlessly lead the way to create a world with better brain health. Now I joined Sage, as you know, in 2020, because I saw the CNS or brain health as the next frontier of innovation. Today's understanding of the brain feels to me to be in a place where oncology was 15 to 20 years ago. And I was excited by the work that Sage had completed to date. Today, I actually think we're in a more compelling place with the brand and the overall story. It's exciting that Brain Health has seen a renewed wave of attention and innovation in the past years by us and others. Now starting with Slide 3. At Sage, we have a deep expertise in brain circuitry with demonstrated leadership in GABA A and NMDA receptor pathways and a focus on applying unique chemical innovation to develop drugs targeting these pathways in very specific ways. Now our methodology and product engine have resulted in a rich pipeline, including the first and only product approved specifically for postpartum depression. We have 7 new chemical entity development candidates across 12 or more possible indications. And we believe that this was a novel pipeline with the potential to help millions of people suffering from brain health disorders. We do have very robust goals for ongoing growth. And with our product platform approach, we aim to deliver 2 or more INDs per year and to launch a new drug or a new indication every 12 to 24 months starting in 2023. As you know, that's a profile rarely achieved in the biopharmaceutical industry. Now these goals are supported by our strong balance sheet and strategic partnerships that provide flexibility to continue to invest in our robust pipeline. Let me turn to Slide 4. As we're all aware, we are in a brain health pandemic. These graphics show that over the last 20 years, the devastating impact of brain health disorders has increased nearly 100%, incurring high economic and social cost to individuals, families and communities. That clearly has been exacerbated by the COVID pandemic, and the lack of innovation in brain health, where new treatments are needed and the misconception that nothing more can be done and what we have is good enough. At Sage, we believe that patients suffering from these diseases deserve novel treatment approaches designed to address the outcomes that are most important to them. Our focus is driven by a sense of urgency on areas of unmet need that lack adequate effective treatment options. As reflected on Slide 5, our pipeline includes advances in our core therapeutic areas and remains flexible to evolve to new areas where there's an opportunity to make meaningful difference and impact the well-being of millions. I'm excited to take you through our plans for 2022. In today's presentation, I will outline our thoughts on the planned commercialization strategy for zuranolone and review progress on SAGE-718 and SAGE-324. I'm especially pleased to share our plans to initiate 2 Phase II trials with SAGE-718 today, 1 in Parkinson's disease, which we announced at FutureCast and another we're announcing today in Alzheimer's disease and that's in addition to the ongoing Huntington's disease study that we initiated last year. Now beyond the late-stage programs I'll share today, Sage has a robust pipeline designed to improve the lives of people with brain health disorders. With that goal in mind, on Slide 6, I'm excited to share an updated mission for organization that we believe represents our work in brain health disorders. We aim to pioneer solutions to deliver life-changing brand health medicines so every person can thrive. Slide 7 provides an overview of the burden created by the paucity of innovation in depression and mood disorders as well as the stigma around the mental illness that represents a major barrier that stalls action. Mental health is perhaps the most neglected of all health concerns. Many patients affected do not receive the treatment and care they deserve or the outcomes they seek. A survey of MDD patients that we conducted, 68% reported that they were not satisfied with the time they spend on medication, and 75% of patients reported being frustrated with the need to switch and try multiple options to treat their depression. Further research we published in MDD patients are that their initial antidepressant only is on for 7 weeks on average, 7 weeks on average. That's incredible. And they switch their initial antidepression on an average of 2 or more switches in under a year. This results in a significant burden. The time to symptom resolution is delayed for patients, and each line of therapy is associated with poor near and long-term outcomes. And of course, more switches drive rising costs. It's also important to consider the different experiences of many types of patients with MDD. For example, the Fava et al publication data show from STAR*D show that people with MDD who have elevated anxiety as one of the symptoms of their depression have worse near and long-term outcomes. That's with available current treatments. So it's clear that there's a significant need for new approaches and treatment of MDD and what we have now is not enough. Based on the data we've generated to date in clinical trials, as shown on Slide 8, we believe zuranolone has the potential to address the substantial unmet needs and be differentiated from current treatments. The profile we've seen in clinical trials have been very consistent. We see a rapid and sustained reduction in depressive symptoms, a well-tolerated safety profile without destigmatizing adverse events that are often associated with discontinuations of current antidepressions, improvements in quality of life and overall health across domains of feeling, functioning and well-being, the patients report continue after completion of treatment. And as you know, a short course of treatment that can be taken as needed with a novel mechanism of action that may help rebalance neuronal networks. And of course, our approach is very flexible. Ask anybody living with depression. They don't want their lives to be defined by the fact that they have depression. They don't want to be defined as patients, but rather people with important lives, things to do, people to love and goals to accomplish. The data on Slide 9 shows the rapid reduction in depressive symptoms we've seen with zuranolone in clinical trials in MDD and PPD to date. As you can see from the slide, zuranolone shows significant reductions in depressive symptoms at the first time point measured in each study. Now keep in mind, that's only after 1 or 2 evening oral doses, and of course, robust reductions at day 15. What this means for patients is that they can have the potential to get better quickly, enjoy a sense of well-being, have improvements in functioning and return to life they've dreamed of. Now let me turn to the SHORELINE data on Slide 10 to discuss duration of effect. We announced data from the 50-milligram cohort of the SHORELINE study last month, where we saw the majority of patients who responded to the initial zuranolone treatment course received only 1 treatment and 80% received only 1 or 2 treatment courses during their time on this year-long study. For patients, this means the potential of only 2 or 4 weeks of treatment each year. So in other words, the possibility of feeling good and having 48 weeks a year while having to take a pill for my depression. Let me turn to Slide 11. Importantly, the potential of zuranolone is also supported by a benefit observed from patient-reported outcomes in our clinical trials. The SF-36 is a patient-reported quality of life measure that's used to evaluate how person perceives the impact of the disease on their well-being and functioning and how that evolves with treatment. Now this is critical because it accesses what patients are feeling and how they're functioning, not how their medical assessor thinks they're doing, but rather how they're feeling. And this integrated analysis from our completed pivotal placebo-controlled study in MDD and PPD, patients who received zuranolone demonstrated statistically significant improvements from baseline across assessments of well-being and functioning at both day 15, so that's a day off drug, and day 42, 4 weeks off drug, and that's compared to patients who received placebo. Improvements reported by patients treated with zuranolone range from 40% to 60% on the mental health domains and 8% to 12% on the physical and general health domains. These data reinforce the difference experienced by patients treated with zuranolone in these studies. So for example, for those patients with improvements at these levels, mental health status did not cause restrictions in their ability to work. Patients reported improvements in energy levels and reductions in fatigue that enable them to be more engaged in their lives. Patients' improved emotional status allow them to engage with their social activities like visiting with friends and family. have been critically important this time of year. Altogether, the improvements seen across domain describe a patient population that's approaching normal activity and productivity levels. This allows individuals to be more fully engaged in society. Now let me turn to Slide 12. As I mentioned earlier, we know from literature, including Star D, that current antidepressants don't work well in certain subpopulations for people with MDD as they do in others. One such phenotype is MDD with elevated anxiety as a symptom of depression, which is associated with 3 key challenges. First, these individuals have more severe disease. Secondly, they have more difficult to tolerating antidepressants. And, third, we have higher rates of nonresponse to treatment, which, of course, leads to poor longer-term outcomes. Based on its mechanism of action, we believe zuranolone alone may be well suited to help these patients. As you can see on the right side of the slide, in the WATERFALL study, while we see benefits across all patient types, those with MDD with elevated anxiety experienced more robust results. Now we'll certainly share more about MDD with elevated anxiety in the future, but this will be a key to zuranolone. On Slide 13, you can see that zuranolone has been well tolerated across the development program to date, with consistent safety profile and low discontinuation rates. Importantly, as Dr. Clayton points out, the adverse events frequently associated with current antidepressant therapies that leads to discontinuations, such as weight gain, sexual dysfunction, euphoria and sleep disruption, have not been seen to date in our zuranolone studies. Slide 14 demonstrates how the potential benefit risk profile of zuranolone may be distinct from current antidepressants. And let me set this up. This plot -- this graph plots side-by-side data on discontinuation response rates from clinical trials of zuranolone and current antidepressants using metrics with implications for real-world clinical practice. Response rates are plotted on the X axis and discontinue due to adverse events on the Y axis. The similar levels of efficacy and high rates of discontinuation due to adverse events for current antidepressants at 8 weeks are captured in the Green star and the purple dots. The green star represents data from Star D ,while the purple dots are representative basket of current treatments. Now in contrast, shown in dark blue and orange. The integrated response and discontinuation data generated with zuranolone studies to date shows higher response rates and much lower discontinuation rates. Now when we look at the SHORELINE study versus the STAR*D, we can imagine how zuranolone may work in the real world. On Slide 15, we've outlined our planned commercialization approach. This approach is designed of zuranolone is approved to raise the treatment expectations for MDD and PPD and establish zuranolone as a therapy that has the potential to fulfill the high unmet need that continues to persist. We expect that successful commercialization will require multi-stakeholder engagement and that data dissemination with a goal of enabling appropriate patients with MDD and PPD to have access to zuranolone prescribed. know that each of these stakeholder groups influence 1 another. So our planned approach is integrated and comprehensive in nature. Our goal will be to provide education on the compelling benefit risk profile that will inspire appropriate patients with MDD and PPD to ask their health care providers about zuranolone. This needs to be a drug that patients ask for. Mobilize health care providers to proactively identify patient use scenarios in these indications where zuranolone could be especially impactful. Of course, we need to educate and proactively partner with payers, with a goal of enabling at-launch access to MDD and PPD through innovative methods such as value-based agreements. And we'll collaborate with patient advocacy groups and policymakers to raise treatment expectations for MDD and PPD because what we have now is not enough. Slide 16 shows the significant opportunity for new treatment like zuranolone to help patients at various points in their treatment journey. You can see the numbers, and they're very significant. Those adults with MDD who are treated with medication and estimated 6.8 million are initiating new antidepression therapy. These patients can be classified into 4 clusters that represent the patient treatment journey, add-on, switch, restart and treatment naive. This suggests ample opportunity for new treatment therapy that has the potential for flexibility of mono or adjunctive therapy like zuranolone. Also notable, literature suggests that 54% to 66% of people with MDD experience elevated anxiety symptoms as part of their depression, and most believe those numbers are actually underrepresented through burden. This MDD patient population presents a significant challenge for treating physicians and payers because MDD, with elevated anxiety, is associated with poor outcomes, as I've mentioned. Now we've been talking to patients and physicians, and we believe that there are several types of patients with MDD, where the greatest treatment impact, it has to be observed with zuranolone. These 5 use scenarios are detailed on Slide 17. They include treatment-naive young adults, such as college students, of an acute stressor that triggers symptoms and could potentially derail their lives at school or earlier in their careers. People are suffering in antidepressant treatment and still suffering. Those with breakthrough symptoms were in acute triggers such as the death in the family amplifies MDD symptoms despite the treatment they're on. Adherence challenge individuals and older adults where chronic polypharmacy is a challenge. The next steps with zuranolone and development are shown on Slide 18. We expect to start the rolling submission for NED -- for an NDA in MDD early this year and plan to complete our NDA in the second half of 2022 with the clinical module. We look forward to sharing more on our planned approach to commercialization, and we're excited by the potential opportunity to help millions of patients living with MDD. Now let me move on from depression and mood disorders and turn to our neuropsych disorders on Slide 19. Globally, disorders involving cognitive impairment continue to increase. These disorders represent 1 of the greatest areas of unmet need as these diseases result in a significant impact on patients' ability to work, live independently, adhere to medical care and interact with family. I think many of us have had these experiences. The goal of Sage's neuropsych franchise is to preserve independence by providing rapid noticeable and sustained symptomatic involvement improvement in cognitive function early in the disease when patients are still able to function independently. This goal requires forging new pathways for treatment by employing novel endpoints that capture what's most meaningful for patients prior to the onset of their severe dementia and loss of independence. SAGE-718, our lead NDA, NMDA PAM, is being studied for its potential to be distinct from traditional therapies that have, thus far, attempted to slow decline over a long period of time rather than improve function rapidly and durably. That's a big difference. As you can see from the forest part on Slide 20, SAGE-718 has demonstrated improvement on important test of executive function across multiple studies. In the patient groups, impaired NMDA receptor function is thought to be contributing to cognitive impairment either as a consequence of pharmacological challenge or due to disease pathophysiology. I'd also like to call out that in the ketamine exposure study, shown in the forest plot, subjects treated with SAGE-718 demonstrated improvement on the 2 back tests compared to those treated with placebo on multiple time points over the course of the study. Now while this isn't a disease per se, these data are important as SAGE-718 arm showed statistically significant separation from the placebo arm and the improvement seen with SAGE-718 are consistent with those seen in our open-label studies in Huntington's, Parkinson's and Alzheimer's. So all the data kind of do line up. Given our novel approach, it's critical to use endpoints that evaluate the full potential benefit of SAGE-718, especially with respect to areas of higher cognitive function, such as executive function and learning and memory, which allow multitasking and decision-making, critical for maintaining independence. Our strategy for this program, shown on Slide 21, is to lead with a scientifically informed genetically defined more homogeneous orphan indication Huntington's disease, with known deficits in executive function that manifest during prime working years. There's a clear demonstrable impact of cognitive deficits on aspects of independence, such as employment and driving in these patients. And these can occur in patients 30s and 40s, really in the prime of their lives. Now using the regulatory avenues afforded to us with fast track designation and orphan indication, we're engaging with regulatory agencies to define an efficient pathway forward to initial registration in Huntington's. By leveraging the insights gained from these interactions, we believe we'll be better positioned to develop SAGE-718 in broader indications such as Parkinson's and Alzheimer's diseases where there's currently no approved symptomatic treatment targeting the earliest phase of collative decline in these disorders and focused on improvement rather than slowing design. We've learned a great deal about SAGE-718 in studies to date and are excited by the potential of this program. In fact, we believe our confidence is demonstrated by the parallel studies we plan to run with SAGE-718, shown on Slide 22. We're currently enrolling the Phase II DIMENSION study in Huntington's disease and are on track to initiate the Phase II Parkinson's study mid-2022 as we committed in 2021. We're also announcing our plan, as I mentioned, to initiate a randomized Phase II study in Alzheimer's disease in late 2022. We believe the data seen to date support a parallel path starting with Hunting's disease. Now let me turn to movement disorders, where major gaps remain in bringing effective treatment to market as shown on Slide 23. Standards of care are inadequate for many patients suffering from debilitating movement disorders, which can make the simplest activities of daily living difficult or even impossible. For example, in patients with more severe essential tremor, as measured by activities of daily living impairment, more than 90% of these patients have trouble writing, eating, drinking and performing self tasks such as brushing their teeth or getting dressed. 79% have reduced their working hours or have had to change jobs and 56% require caregiver. Slide 24 shows the promising early data with SAGE-324 from Kinetic study. We saw statistically significant reductions in tremor as measured by TETRAS upper limb tremor score where they're maintained through day 29. Importantly, we also saw statistically significant improvements in activities of daily living as measured by the TETRAS-ADL scale. Now I want to take a moment to highlight what improvements like these seen in the study could mean for patients. Individuals with essential tremor experiencing this magnitude of improvement can accomplish activities they've not been previously able to do without significant modifications rates. For example, they can eat and drink independently and dress themselves without assistance, really being able to maintain independence. Slide 25 shows our next step for SAGE-324 program, a Phase IIb study currently enrolling called Kinetic 2. The purpose of this study is to define the dose and frequency for SAGE-324 as a chronic treatment. In addition to the multiple doses, other adjustments to the study have been made. SAGE-324 will be administered at night and participants who are randomized to the 60-milligram dose group will be up-titrated from 50 milligrams to 60 over a designed 6-week period. We believe that these adjustments in this trial design will provide clear data on the potential benefit risk profile with SAGE-324 in ET and define a regimen that if successful, will enable us to prepare confidently for pivotal trials and future commercialization. The programs are viewed today, along with our entire robust portfolio, a result of our proactive predictive productive and patient-focused approach to drug development, as shown on Slide 26. Our deep domain expertise and leadership in neuroactive steroids, including Oxysterol chemistries, enable us to rapidly turn early ideas into clinical proof-of-concept data. With this product platform approach, we believe we can reduce risk in clinical development programs more quickly, and allow us to educate or allocate resources to pursue programs aim to resolve the biggest unmet need for patients across all the brain health disorders that we're working on. We're currently advancing brain health programs that have the potential to help patients at all stages of their life span as shown on Slide 27. Importantly, every product candidate shown here is a Sage-invented new chemical entity, with differentiated target profile designed with pharmacologic characteristics that we believe are well suited to target specific indications the program is pursuing. And as a result, shown on Slide 28, we have an exciting year ahead of us, including our plans to submit the zuranolone NDA, enroll 4 Phase II studies, present additional robust data in scientific forums throughout the year and progress our early-stage pipeline. Now closing on Slide 29, we believe we have a clear path for Sage to become a leader in brain health and a top-tier biopharmaceutical company. We had an incredibly data-rich year in 2021, and we'll further explore those data in 2022 with the potential for greater value creation throughout this year and beyond. Our Deep domain expertise in brain circuitry and leadership in neuroactive steroids have generated a leading brain health pipeline. We have a milestone rich year ahead progressing several late-stage programs across our brain health franchises. We continue to strengthen our team and believe we have the expertise and partnerships in place to focus on commercialization for our later-stage programs. And lastly, the financial flexibility provided by our strong balance sheet and partnerships enable us to continue to invest innovation. And finally, on Slide 30, by seeing the brain differently, we hope to have a positive impact for people suffering from brain health disorders. So Cory, let's move to Q&A. We can bring in Jim, our Chief Development Officer; Kimi, our CFO; and Chris, our Chief Commercialization Officer.

Perfect. Welcome, guys. Thank you all for being here. So as we move into Q&A, I'll just give my typical reminder that you can contribute questions here via the portal, and I'll work them in. But maybe to start, Barry, I found it interesting, the talk that you were giving with regard to MDD with elevated anxiety, can you kind of just go into that a little bit more how you came across this how you found this within your trials and speak a little bit -- I know you had some statistics in there, but speak a little bit more to how well understood this is in the community. It seems like a lot of people who suffer from the comorbidities here.

Yes. Cory, thanks for that question. I'm glad you picked up on that because that's an important part of the story. So throughout the course of last year, the longitudinal study called STAR*D had many publications, some of which talked about where today's antidepressants work well and where they don't work well. One of the papers that was published by Maurizio Fava really spoke to the fact that today's antidepressants, while they work well for a number of phenotypes, actually don't work well for patients with MDD with elevated anxiety. And these patients often require polypharmacy to get their depression, their anxiety, their sleep disorder under control. And I'll ask Jim to talk about why this makes sense for zuranolone as a mechanism of action. So what we did in looking at that paper and understanding the zuranolone mechanism of action, is took a look at those patients in our studies that had MDD with elevated anxiety. And not surprisingly, not only does the zuranolone worked across all of MDD, but it works particularly well on MDD patients with elevated anxiety where today's antidepressants don't. Jim, do you want to comment further?

Yes, absolutely, Barry. Cory, as Barry was saying, there are a substantial proportion of major depression patients who are also suffering from comorbid anxiety. So the numbers vary a little bit in our understanding how big that population is. But I think a reasonable range is somewhere between 45% and 70% of patients are suffering with both MDD and comorbid anxiety. And in our own studies, we see the proportion on the higher end of that range. As far as why this becomes a population of patients who may respond very well to zuranolone, of course, with zuranolone's novel mechanism of action, it is modulating the GABA system. And modulating the GABA system, there's plenty of clinical evidence that has a beneficial effect on anxiety symptoms. And so what we're seeing with zuranolone is the primary effect on depressive symptoms. In addition to that, you're seeing beneficial effects on anxiety symptoms. And that's why you see the graph that you saw, where you have patients who suffer from both symptoms having a really robust response to zuranolone in our clinical trials.

How much can you -- I guess, just thinking through like is this something you're able to educate the marketplace on? Like how much market education would be necessary to -- if this is where -- the data seem pretty compelling what you have so far. To make sure that this is really well understood, like how do you go about doing that with psychiatric disease?

Yes, Cory, so those that treat a significant number of patients know that the burden they have with patients with elevating anxiety and depression patients below anxiety, is significant. They also know that they're prescribing polypharmacy payers know this as well because these patients have poor near- and long-term outcomes and costs a lot more to health care system. So it's really a matter of reminding people where the antidepressants work and where they don't work. And the STAR*D is a very, very robust database where many publications come out. We're certainly going to in scientific exchanges educate there and highlight the various patient types, and maybe Chris can talk about those. We think that, if you've got these patient types in your practice, MDD, with or without elevated anxiety, zuranolone could be particularly useful. Chris, do you want to talk about some of those?

Yes. Sure, Barry. And let me say, Cory, that first and foremost, the patient with MDD with elevated anxiety, it's not just in the engagements that we've had with KOLs that we've heard that recognized as a profound unmet need and opportunity for zuranolone. Anecdotally in the market research, we've heard that as well with practicing clinicians, whether they are psychiatrists or general practice physicians that are seeing large numbers of patients with MDD in this case. So in part, it comes from both of those groups. I think with respect to the patient types that we're looking at, Barry, you covered 5 of them in particular, in the presentation. There's 2 that I'd probably focus on where you think about the intersection of MDD with MDD with elevated anxiety. The first 1 that I'd call out is the patient that is currently on an ADT, but is still suffering from uncontrolled depression. In many cases, that patient is looking for the rapid onset of action associated with their therapy that delivers them the kind of symptom relief that they're looking for, that allows them to maintain that symptom control over a course of time with the short course therapy without the general side effects associated with other antidepressants that are stigmatizing like sexual dysfunction and weight gain, which [indiscernible] of themselves can produce anxiety in some senses. The other 1 that I would call out is, as Barry mentioned, the college student. It's that patient that's been historically, perhaps, naive, but due to a profound trigger that they may be experiencing in their college life, that suddenly, there's an opportunity or there is a need for them to engage with clinicians because of perhaps not just the MDD, but also elevated anxiety associated with that episode. So it's going to be really important for us as an organization as we engage with clinicians to paint the picture of who the patient is for zuranolone, both with MDD and MDD with elevated anxiety as we move forward.

Okay. And I know I've discussed this point with you guys many times by now. I wanted to -- with regard to CORAL, because I keep getting the question, can you talk about the rationale of moving the primary endpoint from day 15 to day 3? And then the ongoing importance, though, of those later time points, day 15 as well as day 42, both to physicians and to regulators when it comes to assessing the profile of zuranolone?

Yes. Absolutely, Cory. So let me take a step back and remind everybody, and it was sort of in this platform virtually last year that we helped everyone understand that we had a good meeting with the FDA about the totality of zuranolone data. And in conjunction with the agency, designed 3 Phase IIIs, 2 an MDD called LANDSCAPE, 1 in PPD called NEST, that the agency guide us if any 1 of which of these Phase IIIs was positive, we had a fileable package. So fortunately, WATERFALL, the first Phase III that read out, was positive and clinically meaningful. We had a meeting with the FDA early September -- or late September, early October, where we confirmed that a positive WATERFALL presented a fileable package. We also confirmed that the agency would like us to start the rolling submission. That's good for them. That's good for us. So we're going to start that early this year and complete kind of the clinical modules second half. So with that in hand, we were able to reconstruct, in conjunction with Biogen and the agency, CORAL for as it was originally intended, which is when you co-administer zuranolone with an antidepressant, you want to see a quick start. Because as we know, antidepressants take 4 to 8 weeks to work if ever. And while the side effects kick in early, the efficacy kicks in late. So Coral, at day 3, should it be statistically significant represents our ability to talk about that quick start. And Chris mentioned, whether you're elderly, whether you're young adult, whether -- like someone would breakthrough symptoms, you want to get better faster, and that's what CORAL will allow us to demonstrate. Now in terms of the later time points, we know this from the ZULRESSO experience we had, where what regulators are looking for is consistency or durability of effect irrespective of what placebo does. And what they don't want to see, what you see with things like benzodiazepines and others is a rebound. So what we're looking for is patients to get better at day 3, better at day 15, stay better out to day 42. What we're not looking for is a rebound of effect. And that's specifically what they don't want to see. So if we can see a knockdown in consistency of effect, we believe that CORAL study will be positively help us on that front. The other important part of CORAL is the safety database. I'll remind you that we have a rich database already of 3,500 patients, about 30% to 40% of which are on a stable antidepressant and the rest are zuranolone as monotherapy. So this provides yet additional data for the co-administration and understanding the zuranolone side effects versus the potential of co-administration of current antidepressant side effects.

Okay. And in your presentation, in terms of the time lines, you mentioned a potential FDA advisory committee. Is this just your expectation or something the FDA suggested? And typically, a potentially treatment changing or a very novel product would go in front of an AdCom. But curious kind of what the level of communication is there at this stage? And what more -- maybe more importantly, what you think regulators will be focusing in on when they're making a decision of whether or not to approve a product like zuranolone?

Yes. Let me talk about the regulatory interface, and then I'll ask Jim to talk about our experience with the brexanolone AdCom, which we think will be similar if we have one. So we don't know specifically that the agency wants an AdCom. What we've talked about is preparing for one. So we and Biogen will be very well prepared for an AdCom should it happen. It may make sense for the agency an AdCom. We're talking about a novel mechanism of action, an oral treatment taking every night for 2 weeks and with a short course treatment. And there aren't things like this, so it represents a new paradigm shifting approach to treating depression. So I think the agency will want to get support moving forward with something like zuranolone. But we don't know yet. We won't know till after we file NDA whether we'll for sure have an AdCom. Jim, do you want to reflect on our ZULRESSO experience and what kind of questions the agency might ask?

Of course. And Corey, you mentioned it in your question, oftentimes with a novel mechanism of action, a novel approach to the FDA wants to have that opportunity to ask questions. And certainly, as I think about the experience we had with the ZULRESSO AdCom, questions were really around understanding certainly this novel approach. The rapidity of onset that we see with this mechanism of action, the durability of response. So Barry mentioned it earlier when he was talking about CORAL. There's certainly interest to understand that the response to zuranolone is durable and that we saw that maintained response over time. We certainly saw that with ZULRESSO. And then the tolerability profile. So understanding what that will look like for patients and understanding how that will fit into current clinical practice.

Okay. And then just with regards to DEA scheduling for zuranolone, would you expect this to be similar to the experience with ZULRESSO?

We do. We expect that after approval, if we're fortunate enough to get that, there's about a 3-month DEA review. So we expect that to occur. Now what's helpful, frankly, in that time frame, as we mentioned, is we're going to file a separate NDA for PPD. So it's possible, Cory, that the timing continues to work out that will have approval for MDD and in the DEA review get an approval for PPD, so we can commercialize both simultaneously.

Okay. All right. I could ask a ton more questions on zuranolone, but in the interest of time, I definitely want to work in a couple on 718 program, you guys certainly seem very excited about. So you're going to have 3 large randomized Phase II studies ongoing, 3 different indications over the course of 2022. Can you kind of just go into a little bit more like what you're hoping to see? What would be meaningful results? And what does this do in terms of triggering development beyond these current studies? Or what would next steps look like?

Right. Let me -- I'll take some of it and then ask Jim to comment on maybe the Huntington's study that we've kicked off and how we're looking at that. So Cory, as I highlighted in the talk, and I won't get into it deeply here because of time, but there's a deep biologic rationale for our SAGE-718 was designed and how the molecule was designed based upon certain deficits on NMDA. So it was a biologic -- specific biologic rationale of design 718. And every step of the way, preclinically, early clinical studies, I mentioned the placebo-controlled ketamine studies, we've seen consistent effects of the drug to improve higher-order cognition, not slow decline, but improve higher-order cognition in as little as a week to 2 weeks. So that's a profound and fundamentally different than anything being done today. So we believe that the data warrant, not only the initiation of Huntington's, Parkinson's, but also Alzheimer's given the consistency of those data that we've seen. And our strategy, and we didn't design this specifically because Huntington's is an orphan disease. It turns out that the biology followed. But because Huntington's is an orphan disease, and we have fast track, that affords us the opportunity to work with the agencies to forge new pathways to get a drug approved that improves cognition, which is not something that's ever been done before. So that's strategically how we're thinking about it. Jim, do you want to talk about the trial designs that we're hoping to see?

Yes, absolutely. So very briefly, in the Huntington's disease study that Barry was talking about, which we're calling dimension, we're looking at building off of what we learned from the earlier studies that we conducted in the Cognex program. So the design for Dimension is a 3-month duration, once daily dosing, double-blind, placebo-controlled study with 2 arms, trying to understand the efficacy of SAGE-718, to improve cognitive performance in HD patients over a 3-month time period.

And this is -- Cory, this is just a great example of us continuing on our expanding and accelerate strategy. And this is really how we're thinking about how best to deploy our capital in a way that creates a lot of value. So these are the kinds of things that we're looking at, say, SAGE-718, 904, 689 all those other components of our pipeline.

Okay. And would the 718 results presumably would that be a 2023 event. Is that what the expectation would be?

Yes. We -- as Jim mentioned, we started to mention last year, we believe that we'll accrue throughout the course of this year and present data next year.

Okay. All right. Listen, guys, I wish we had more time. But unfortunately, that's it for now. But best of luck with all the news you have coming up in 2022 because there is a lot of it. So I appreciate the time that you spend with us as always.

Thanks, Cory. I appreciate the time.

Thanks, Cory.