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

Good morning everyone and thanks for joining the third annual Sage FutureCast and R&D portfolio review event. I'm Helen Rubinstein, Investor Relations at Sage. 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 we will discuss. I'd like to point out that we will be making forward-looking statements on today's call, 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. I'll now turn the call over to Barry Greene, our Chief Executive Officer for opening remarks.

Hi, everyone. Thanks for joining us today and welcome to our third annual FutureCast and R&D and portfolio review. 2021 has been a remarkable year for Sage and I'm pleased to be with you today to review the progress we've made on our strategy to expand and accelerate our pipeline as well as share more on our vision for the future. Our goal is to be the leader in brain health and a top-tier biopharmaceutical company. We believe we have the team, deep science, pipeline, partnerships and balance sheet to do so. Now for those of you joining us for the first time, Sage is a biopharmaceutical company committed to developing novel therapies with the potential to transform the lives of people with debilitating disorders of the brain. Sage has made deep scientific progress in understanding brain circuitry by focusing on GABA-A and NMDA receptor pathways and applying unique chemical innovation in the area of neuroactive steroids including [indiscernible] chemistries. It is this approach that has worked resulting in a rich pipeline of potential treatments focused on brain health that if successfully developed may give patients the opportunity to get their lives back. As you listen to the update shared today, I'm hopeful you'll [indiscernible] development is advancing our journey to become a leader in brain health. We'll begin today's FutureCast with our depression franchise. Dr. Rob Lasser, Vice President of Late-Stage Development, will provide an overview of our productive zuranolone program. Together with our collaboration partner, Biogen, this year we announced positive and clinically meaningful data from 2 trials within the landscape clinical program evaluating the zuranolone for the treatment of major depressive disorder, MDD. This includes the waterfall study, and most recently the SHORELINE study, 50-milligram cohort data. We also confirmed, what we believe is a clear path for the submission of an NDA for zuranolone and [ MDD ], which we expect to start in early 2022 with the first part of our rolling submission. We anticipate the final modules being submitted in the second half of 2022 with an additional associated submission in post partum depression or PPD planned in the first half of 2023. Rob will review the program, our vision for potential clinical uses in MDD and share some compelling perspectives from patients. Then Dr. Helen Colquhoun, Vice President, Early Development will review our neurology franchise and share an update on SAGE-324. This program also partnered with Biogen is emblematic of our predictive approach to drug development. The GABAergic deficits associated with essential tremor ET led Sage to explore GABA PAMs and ET. We have generated data using a predictive analytic approach and believe that the properties of SAGE-324, if confirmed in further development, could be well suited to address the needs of people who are experiencing essential tremor. This group is an underserved patient population that has witnessed limited pharmacologic innovation for more than 50 years. Helen will also walk through the results seen in the KINETIC study, which we believe to be very positive in terms of tremor reductions and activities of daily living, data beneficial to our planned path forward. We know from listening to patients like Lynn, who you'll hear from today that it's critical for people living with essential tremor to be able to improve their ability to perform activities of daily living. We're also joined by Dr. Aaron Koenig, Vice President, Early Development, who will take you through our neuropsychiatry franchise in SAGE-718 program including results we're announcing today from the luminary study of patients with Alzheimer's disease, cognitive dysfunction. I'm absolutely thrilled to highlight that we saw positive signals in the LUMINARY study that further support the findings from earlier studies with SAGE-718. Aaron will walk you through these results in greater detail. We've made progress -- significant progress across our wholly owned program this year. We recently shared that the [ DIMENSION ] study in patients with Huntington's disease is now open to enrollment. And as a reminder, SAGE-718 was granted Fast Track designation for development in Huntington's disease in September. This program is an example of our proactive approach to drug development. Since Sage's founding, we've been driven by the vision that the best approach to modulating NMDA receptors is to leverage knowledge of the brain's endogenous modulatory machinery. Emerging research, including contributions from Sage's scientists and collaborators has shown that a specific brain metabolite 24S-hydroxycholesterol can both modulate NMDA receptors and serve as a potential biomarker to identify patient populations of interest. Our vision for SAGE-718, a novel NDA PAM is to provide a potential oral therapy for disorders where impairment of cognition is one of the main drivers of disability. Although the terminology is mild cognitive impairment, what you'll hear from Aaron and from Dan, who's living with Parkinson's disease is that there's nothing mild about mild cognitive impairment. A key takeaway throughout the presentations that you're hearing today is the patient perspective. The patient voice is critical to help us understand how to meaningfully conduct patient-focused drug development. By remaining steadfast in our commitment to put patients first, we believe we could address the unmet needs for patients, who need new therapies. To conclude, we have a rich pipeline of Sage created innovative programs in development with multiple opportunities to deliver life-changing brain health medicines, so every person can thrive. I'm excited about the future development opportunities for early-stage program candidates and the advancement of our later-stage product candidates with the ultimate goal of regulatory approval and successful commercialization. As we look to 2022 and beyond, we plan to continue to expand and accelerate potential indications for our wholly owned programs and I believe with the potential to make a difference for people living with brain health disorders as well as their families, caregivers, communities and society at large. On a personal note it was over a year ago I joined Sage. I remain highly impressed by the groundbreaking science at Sage and relentless pursuit of new options for patients. The brain as we're all aware is a complex organ. It's been decades since true breakthroughs in brain health disorders have been achieved. Sage is taking on this challenge. We recognize the urgent and escalating need for more treatment for MDD, Alzheimer's, Parkinson's, Huntington's, essential tremor and many other brain health disorders. I'm hopeful that you'll come away from our session today with a deeper understanding of our productive, predictive, proactive and patient-focused approach to drug development. We're well positioned to execute in 2022 working towards our planned second NDA filing as well as advancing our science with a goal to develop ground breaking medicines that meaningfully impact the lives of patients and those who love and care for them. Thank you for your attention. I'll turn it over to Rob. Rob?

Good morning and thanks, Barry. Today, I will review our plans for our U.S. NDA filing in collaboration with our partner Biogen and comment on how zuranolone may be used and who it may benefit, if we're successful in our efforts to obtain approval here in the United States. Let's start with a high-level view of the next 24 months for the zuranolone program. We're focused on completing the outstanding Zuranolone trials in the field as well as forging ahead with the next milestones of NDA development with a planned submission in the second half of 2022. We also expect to share the results of the Coral MDD and SKYLARK PPD studies next year, which will then become part of our MDD and PPD filings accordingly. As with ZULRESSO, we anticipate an FDA advisory committee meeting as an important showcase for zuranolone, which if we're approved, would then be followed by the standard DEA scheduling. We plan to continue enrolling in the long-term SHORELINE study, but an early access program is also in development. We're very excited in anticipation of initiating our pediatric development programs in MDD next year as well. Our experts know that if our pediatric development efforts are successful providing kids rapid relief from depression with zuranolone may enable them to return to the task of childhood more quickly without the side effects commonly associated with treatment. Now let's turn to the profile of zuranolone and how it might be used if approved. On the left panel is the target profile for zuranolone with core antidepressant features based on the data we've generated in the clinical development to date, including speed of onset and a sustained effect beyond the period of dosing. Across our landscape program in MDD, we've seen reductions in core depressive symptoms by day 3. After only 2 weeks of treatment with Zuranolone we saw improvements in depressive symptoms [Audio Gap] rapidly and it's dosed for only 2 weeks. Zuranolone is intended to be used as needed, treating only when symptoms indicate a new depressive episode has arisen. Data from the 50-milligram cohort of our SHORELINE study in MDD showed us that those patients who responded to the initial course of zuranolone and continued in the trial about 55% of them only received the initial treatment during their total experience in the trial. We believe many people suffering with MDD would welcome the potential to trade 52 weeks of daily medication for 2 weeks of Zuranolone treatment if it is approved, while still maintaining benefit over the long term. As to how health care professionals might use zuranolone, if we're successful. We envision after initiating zuranolone in MDD, response to treatment would be assessed as usual, just shifted to day 15 when the treatment course is complete. Those who respond, would then be assessed for stability and durability over the next several weeks. If the response is not durable an alternative intervention can be initiated promptly as indicated. If durable, people would monitor their symptoms with their health professional to determine when an additional 14-day course of zuranolone might be needed. And recall the majority of responders in our Shoreline study did not receive an additional course during their time in the trial. With Zuranolone, an oral capsule taken each evening for 14 days, the treatment course and the response assessment are all complete within a month, the time when standard therapies are just beginning to provide benefit. Finally I'd like to leave you with a challenge. The next time you hear about the brain health crisis made worse by the pandemic, think of how Zuranolone if approved might provide a uniquely different option in treating major depression. Think of treatment-naive young adults including college students, who can have an episode of depression derail their transition into adulthood. Not only could a faster recovery potentially occur, but one without stigma and side effects of taking chronic medication. This may make them more likely to engage with treatment over a potential lifetime of experience with depression. On the other end of the spectrum, think of folks, who I would often see in my geriatric psychiatry practice with a mix of cognitive, anxious and depressive symptoms, which can be very difficult to disentangle. Not only could a faster recovery from their MDD symptoms potentially occur, but clinicians might also be more able to quickly identify depression in the setting of dementia for the right individuals. Moving down the left panel, think of the large number of people with MDD who have consistent tolerability or stigma issues with current treatment making them adherence challenged. Zuranolone has the potential to reduce the number of days on therapy to maintain wellness, which in turn would be expected to mean fewer side effects associated with chronic therapy. Together, these groups alone represent estimated millions of Americans with MDD, who we believe would prefer to spend fewer days on therapy and streamline their MDD care without the need for concern about antidepressant discontinuation syndrome or even needing to agree to months of therapy in order to feel improvement. As we examine the zuranolone data, signs are emerging that people with MDD, who have elevated levels of anxiety as a key symptom of their depression may show particular benefit with zuranolone. For these individuals, the STAR D study tells us that SSRIs are not as effective or as tolerated compared to people who have MDD with lower levels of anxiety. Since we've seen examples of neurosteroids that are effective in postpartum depression and postpartum depression is simply MDD with elevated anxiety in the context of pregnancy and childbirth. It makes sense that individuals with elevated anxiety as part of their depression may see benefit with a GABAergic antidepressant medication. Finally, even for people with MDD and good outcomes on standard therapy, think of the fact that residual symptoms exist and breakthrough episodes occur. As needed zuranolone if approved may be an additional option when there is a need to add on to existing antidepressants. This was indeed the experience of about 1/3 of the people, who enrolled in our zuranolone clinical trials. We thank both those patients as well as depression experts, who have left us with comments such as this. It's feedback like this that makes us so eager to take on the task of bringing zuranolone into the battle against brain health illnesses like MDD and PPD. I'd like to thank you for your attention and turn the platform over to Dr. Helen Colquhoun for insights in our developing neurology franchise and SAGE-324.

Thank you, Rob. Good morning, everyone. My name is Helen Colquhoun and I'm Vice President of Early Development at Sage Therapeutics. I am also the program lead for SAGE-324. Today, we're going to talk about essential tremor, the commonest movement disorder for which there remains a significant unmet need. As the commonest movement disorder, essential tremor is estimated to affect more than 6 million adults in the U.S. There has been a lack of pharmacological innovation over many years for people living with essential tremor. Off-label use of drugs to treat ET is common with only one drug approved for essential tremor, which was approved more than 50 years ago. Health care providers report that around 50% of patients with essential tremor have an inadequate response to the drug treatments currently being used and prescribed. Unfortunately, finding a sustained effective treatment can be a long and difficult journey. ET can have a devastating effect on people's lives in terms of activities of daily living as well as a longer-term loss of independence. Let's hear from someone, who has lived for years with essential tremor to put this into the context of their everyday life. This is Lynn. [Presentation]

Thank you, Lynn, for sharing those insights with us. We have previously published data from early probe studies that suggested that the GABA mechanism might be effective at reducing upper limb tremor amplitude in patients with essential tremor. The probe studies conducted with brexanolone and zuranolone led us to initiate development of SAGE-324 in essential tremor. In our initial clinical study of SAGE-324 in ET, we demonstrated significant tremor amplitude reduction after single doses of 45 and 60 milligrams of 324, which gave us confidence to study SAGE-324 over a 28-day dosing period in the KINETIC trial, which we completed earlier this year. Using our translational methodology, we believe that 60 milligrams daily for a month would result in plasma concentrations at the top end of the therapeutic range for SAGE-324 in essential tremor. Dosing at the top end of the range was important to allow us to assess the full extent of effect of SAGE-324 on tremor as well as its tolerability in patients with ET. In the KINETIC trial we studied where the SAGE-324 will provide sustained tremor reduction for the dose period without rebound or tachyphylaxis. We also wanted to assess whether there were any unexpected safety signals. Let's recap the data from the KINETIC trial and share some new data about activities of daily living that speak to what we have just heard is so important to people like Lynn, who are living with essential tremor. In the KINETIC trial, patients receiving SAGE-324 experienced a greater reduction in upper limb tremor score from baseline to day 29 compared to placebo. As you can see from the figure this reduction was sustained over the entire 28-day duration of dosing and was statistically significant at day 29. There was no evidence of tachyphylaxis. The corresponding percentage reduction from baseline in tremor amplitude was 21% for placebo, and 36% for SAGE-324. In patients with more severe tremor at baseline, SAGE-324 demonstrated a 44% reduction in tremor amplitude compared to 18% on placebo. We have previously presented that the upper limb tremor score was correlated at every time point to the ADL data and now I would like to share with you the results of the TETRAS-ADL subscale scores from the KINETIC trial. The figure shows that SAGE-324 was associated with an improvement in the TETRAS Activities of Daily Living total score over 28 days. compared to placebo. As we heard from Lynn, what is important to patients is being able to improve their ability to perform activities of daily living. Importantly these data from the KINETIC trial indicate that the observed improvement in upper limb tremor was associated with an improved ability to perform ADLs. This association is encouraging and we plan to build on this in our next study by utilizing tools designed to assess the impact SAGE-324 may have on the participants' everyday life. Now let me remind you of the safety and tolerability data we observed in the KINETIC trial. 97% of participants on SAGE-324 reported adverse events compared to [ 57% ] on placebo. Approximately 1/3 of the adverse events reported while on SAGE-324 were severe in nature. No deaths were reported in the study. Two participants reported serious adverse events of mental status changes that were considered to be related to SAGE-324. We anticipated that a high degree of somnolence might occur and that some participants in the study may not tolerate the 60-milligram dose. The protocol therefore allowed dose reduction preceded by a short drug holiday, if intolerable adverse events occurred. In the KINETIC trial, we observed clear evidence of reduction in tremor amplitude and improvement in ADL scores over a month's dosing with SAGE-324. The next important question is whether these positive changes will be sustained over a longer period with a more favorable benefit risk profile, which would support chronic dosing in patients with essential tremor. This is the design of our Phase IIb dose-ranging study, the KINETIC 2 trial. It is a [indiscernible] blinded randomized placebo-controlled study, employing daily oral doses of 15, 30 and 60 milligrams of SAGE-324. The 60-milligram dose will anchor the results to the KINETIC trial and give us data at the top end of the dose range. We anticipate that both the 15 and 30-milligram doses will provide data suggesting a differentiated benefit risk profile from the 60-milligram dose. Dose response will be assessed using the primary endpoint of TETRAS performance subscale upper limb tremor score assessed at day 91 after 3 months dosing. Several other endpoints will be included that will assess activities of daily living and other aspects of daily life that are important to patients. In addition to collecting safety and efficacy data in the KINETIC trial, we interviewed a sample of participants to obtain their perspective on any beneficial or adverse effects that they experienced during the trial. Based on these insights and other learnings from the KINETIC trial, we have made several adjustments to the trial design and drug administration for KINETIC 2. We demonstrated a PK/PD relationship in KINETIC. So we can and will now administer the study drug at night. Dosing at night has been successful in reducing reported somnolence associated with many drugs. In addition, participants randomized to the 60-milligram dose group will be up-titrated from 15 milligrams to 60 milligrams over a 6-week period. Dose titration is commonly used to improve tolerability of drugs in a variety of therapeutic areas including essential tremor. We believe that this trial design will provide clear data on the potential benefit risk profile for SAGE-324 in essential tremor at a dose that if this trial is successful will enable us to prepare confidently for pivotal trials. Finally, we are very excited to report that the KINETIC 2 trial is now open for enrollment. I will now hand over to Aaron Koenig to talk about SAGE-718.

Thanks, Helen. My name is Aaron Koenig and I'm a Vice President in Early Development at Sage. Today, I will be talking about SAGE-718, which is our lead NMDA program as well as the most advanced program in our neuropsychiatry franchise. SAGE-718 is a first-in-class positive allosteric modulator of the NMDA receptor. NMDA receptors play a critical role in neuroplasticity, which is important to the development and maintenance of cognitive abilities. While this receptor has been a target of interest for many years, positive allosteric modulation has only recently been considered as a way to potentially balance the benefits of receptor modulation with a risk for excessive engagement. To date, this approach continues to be validated by our experience with SAGE-718, which in addition to being well tolerated, has been associated with beneficial effects on cognition in early-stage clinical studies. As you heard from Barry, we are very gratified to see positive signals from SAGE-718 and in the recently completed LUMINARY study, particularly given the clinical heterogeneity of Alzheimer's disease and I'm excited to present those data for the first time today. Before I do, however, let me orient you to the overall program in totality of data collected to date. Studies completed to date include a placebo-controlled trial of SAGE-718 in healthy volunteers, who underwent a pharmacologic challenge with the NMDA receptor antagonist ketamine as well as open-label trials in patients with Huntington's disease and Parkinson's disease. To quickly orient you this [ four spot ] provides a standardized view of cognitive test performance in these studies with no change represented by the vertical line at 0, an improvement represented by positive scores to the right. In our double-blind placebo-controlled experimental medicine study using a ketamine challenge, we saw improvement in executive performance on the two back test in individuals treated with SAGE-718, but not placebo over the course of 10 days. In the open-label HD study, notable improvement in executive performance was also observed. The two back findings were further replicated in patients with Parkinson's disease and we saw improvement in other executive tasks as well including the digit symbol substitution and spatial working memory tests. Notably, these changes were not seen in individuals with normal NMDA receptor function and were not associated with changes in simple cognitive processes such as attention or psychomotor speed. Here's what I'll cover for the rest of the presentation. I'll define the term cognition, describe how we measure it and share how cognitive decline can significantly impact patients and their families. Then I'll introduce you to CogNEXT, an innovative trial platform that Sage developed to accelerate the path towards new therapies for neuropsychiatric disorders. Finally, I'll share encouraging data from our first CogNEXT trials. The PARADIGM study in patients with Parkinson's mild cognitive impairment or MCI in the LUMINARY study of patients with MCI and mild dementia due to Alzheimer's. Broadly speaking, cognition is the sum of our mental abilities. As shown here it can be broken down into different parts or domains including executive functioning, learning and memory and others. While you need all of these elements working together to function normally, there are certain domains where even small changes can result in significant impacts to patients. One of these domain's executive functioning can be thought of as the conductor of the cognitive orchestra allowing us to do such things as plan, prioritize, organize and multitask. Another domain learning and memory allows us to acquire, store and retrieve information, both of these domains represent higher-order cognitive processes that underpin our ability to respond to and interact with an ever-changing environment. There are also different ways to describe the magnitude of cognitive change. On the most severe end, the term dementia is used to describe a state of impairment accompanied by loss of functional independence. Historically, this has been where most studies of cognitive treatments are focused, but it's not the whole picture. Upstream of dementia is an area of functioning termed mild cognitive impairment or MCI, a state in which cognitive changes are noticeable, but functioning is reportedly less affected. In reality, however, there is nothing mild about mild cognitive impairment. Changes in cognition can have cascading effects on patients and their ability to maintain functional independence. Cognitive impairment can cause people to lose the ability to perform everyday tasks that you and I might take for granted, like making a shopping list, driving to the store, buying items on that list and driving home and putting them away. These changes may also cause people to give up their livelihood earlier than they had expected. To further highlight this point, you'll now hear from Dan, a patient living with MCI due to Parkinson's disease. [Presentation]

Thanks, Dan. Now let's focus on how Sage is working to innovate in this historically challenging space. Over the last decade, Sage has learned how to effectively leverage quick and efficient open-label trials to probe for promising clinical signals that may eventually translate into new and effective treatments. With our CogNEXT trial platform, we've expanded this concept to apply to studies of cognition. We will share some, but not all the details of this platform since we continue to consider it proprietary to Sage. Assessing cognition can be challenging as cognitive changes can be variable and at times elusive. To address this CogNEXT is built around the concept of high-frequency sampling that generates multiple snapshots of a patient's cognitive performance. True cognitive performance isn't simply measured by how well you do in your first day of a study or how well you do in your last. It's also critical to understand day-to-day variability in the overall shape of the treatment response. A second critical element is comprehensive measurement, covering all of those cognitive domains that I introduced earlier. In CogNEXT, we built a high-precision cognitive battery that allows for measurement of deficits across a range of domains. This is important for a program with SAGE-718 in which we are exploring treatments for a range of disorders that are each characterized by unique cognitive profiles. Using a standardized battery is efficient, but also allows us to compare results across studies, helping us understand the relevant benefits of SAGE-718 in each population. Now let's review results from our first 2 CogNEXT trials, the PARADIGM study in patients with MCI, Parkinson's and the LUMINARY study in patients with MCI and mild dementia due to Alzheimer's. And while we've shared some of the PARADIGM data before this is the first time that we are sharing results from LUMINARY, which to remind you is an open-label study with SAGE-718 in patients with MCI or mild dementia due to Alzheimer's. Globally, PARADIGM and LUMINARY accomplished their stated goals. In addition to demonstrating that SAGE-718 was generally well tolerated in these studies. We gained data that helps us further our understanding of response to treatment across 2 common neurodegenerative disorders. At baseline, the comparison of PARADIGM and LUMINARY shows that Parkinson's patients demonstrated greater impairment in executive performance as expected, while Alzheimer's patients demonstrated greater impairment in learning and memory, also as expected. Similar to our previous placebo-controlled healthy volunteer target engagement study and our open-label Huntington study, Parkinson's patients in PARADIGM demonstrated improved performance on multiple tests of executive functioning over 14 days of treatment. An emerging signal also suggested improved performance on tests of learning and memory over a similar time frame. In LUMINARY treatment effects in Alzheimer's were consistent with those seen in Parkinson's, despite Alzheimer's being a clinically heterogeneous disease that includes a consistent beneficial response on multiple tests of executive functioning as well as improvement on important tests of learning and memory. Now let's dig a bit deeper into these findings. On the right-hand panel, you'll see the tests included in our CogNEXT battery. Let's focus on one of the tasks, the Digit Symbol Substitution task, which is perhaps the most commonly used test in all of neuropsychology. In its original form the test is presented on a sheet of paper and requires a subject to match symbols to numbers according to a key. In CogNEXT, we use a mobile version of the DSST that can be completed on the patient's own iPhone. As a test of executive functioning, this task requires the integration of planning, rule following and organizational abilities. Here is the DSST from both PARADIGM on the left and LUMINARY on the right. The area in white represents the pretreatment baseline period and the area in light orange represents the open-label on-drug treatment area. The first thing to note is that performance during the baseline period is variable, just like we'd expect. Over 7 pretreatment administrations patients do well on certain days and less well in others. Once SAGE-718 is introduced, we noticed improvement on the task, which is accompanied by more consistent day-to-day performance. This is true in both Parkinson's on the left and Alzheimer's on the right and despite differences in baseline performance across the groups, the overall shape of the response looks quite similar with rapid and sustained improvement by the end of treatment. Here's one of the tests of learning and memory, the Pattern Recognition Memory Test, or PRM. In contrast to the DSST, which is performed daily, the PRM is completed on an iPad and administered in the clinic. The subject is presented with a series of visual patterns that are difficult to verbally encode and in the recognition phase of the test, subject is asked to choose between a pattern, they've already seen and a novel pattern. Again, PARADIGM on the left and LUMINARY on the right. Here, you'll see we have fewer time points than the DSST, because this test was performed weekly in the clinic, but we still get a repeated baseline as well as multiple assessments during the on-drug treatment period in light orange. An added feature of this test was a final time point measured 2 weeks after study drug had been completed. Like the DSST we see variable performance during the baseline period, which begins to improve once SAGE-718 is introduced. We also see that day 14 performance levels are more or less preserved at day 28, a full 14 days after study drug has been discontinued. This result is not unexpected both due to the relatively long half-life of SAGE-718 as well as the mechanisms by which it may be working to improve cognitive performance in these patients. And for the last of our deep dives, we have the reaction time test. In this weekly clinic-based test the subject is asked to select and hold a button at the bottom of the iPad. Yellow dots are then presented and a subject must quickly react to select circle in which the dot appears. When we compare PARADIGM and LUMINARY we again see consistency, but that consistency is characterized as we would expect by no change. On this simple test of attention one that requires very limited higher-order cognitive abilities, performance is basically flat during the baseline period, the treatment period and the follow-up period. This suggests that the changes seen on the other tests, higher order assessments of executive functioning as well as learning and memory are not driven by improvement in simple attention or motor speed. These findings are both critical and expected. As we said before, this is a very different profile from stimulants and other known cognitively enhancing agents. In terms of the overall LUMINARY findings, some of which I just highlighted. We see consistent improvement across multiple tests of executive performance as well as improvement on key tests of learning and memory. These improvements occur in the setting of no change in simple attention. We also saw improvement on the MoCA, a global measure of cognition that reached statistical significance at day 28 when compared to baseline. When we compare LUMINARY with PARADIGM, we see a consistent picture emerge, across the board improvement on tests of executive performance as well as improvement on tests of learning and memory. We've also included at the bottom some baseline demographics that give a sense of the characteristics of these two populations. Without going into the details, we feel confident that we are capturing the appropriate patients in these studies, all of whom are suffering cognitive impairment. These are exciting results that we plan to investigate in additional well-controlled clinical studies. Now to leave you with 2 final points. First, SAGE-718 continues to be well tolerated in clinical trials with no serious adverse events and no adverse events leading to treatment discontinuation. This is also true for other safety parameters including laboratory assessments, vital signs, EKGs. Second what we've shared today is only a small piece of the overall development program for SAGE-718 and should be interpreted in the context of the already completed experimental medicine studies in orange, where we saw target engagement of SAGE-718 at the level of the NMDA receptor. Additionally, the studies in pink represent our past, current and planned work in Huntington's, which remains an area of high unmet need that we continue to pursue. Now I will turn it back over to Jim for the conclusion.

Thanks, Aaron, and thanks to all the folks at Sage for the hard work, scientific rigor and the resulting achievements that have brought us to today. I also want to especially thank the patients and advocates, who courageously shared their stories and perspectives, highlighting the urgent need for innovation in brain health. Over the last decade the devastating impact of brain health diseases and the absence of innovation have resulted in significant costs to individuals, families, communities, society and governments. Our entire organization recognizes the need for innovation and we have been incredibly productive this year with the achievement of multiple programs moving forward into later-stage clinical trials based on solid and anticipated data. In fact, we have [ 3 Phase II ] studies we expect to progress in 2022, including [ DIMENSION ], our SAGE 718 study in Huntington's disease that is now open to enrollment and new studies in Parkinson's disease also for SAGE-718 and for SAGE-324 in [indiscernible] program as described by Rob and we believe we have a confirmed path with the FDA to submit an NDA with a plan to file for MDD next year. As you heard from Helen in our neurology franchise, we used our predictive approach to advance our SAGE-324 program to a Phase IIb study in essential tremor. Everything we learned from our programs across the GABA and NMDA platforms supports our predictive approach as we apply this knowledge to our earlier programs defining our path forward. For our neuropsychiatry franchise, Aaron shared our proactive approach to address cognitive impairment in Huntington's disease, Parkinson's disease and Alzheimer's disease with promising readouts in each of these disease areas. It's important to note how much need still exists for patients suffering with these particular diseases. At Sage, we are taking this challenge head on. And based on our experience to date, we are leveraging results from the PARADIGM study to expand into a planned Phase II study in Parkinson's disease. We are also assessing our next steps for Alzheimer's disease based on the LUMINARY study data you heard about for the first time today. In addition to the late-stage development candidates you heard about today, Sage continues to foster our rich pipeline of earlier-stage programs. In our neurology franchise we're excited about the future prospects of SAGE-689. This is an intramuscular delivered GABA PAM that has demonstrated rapid absorption and flexible formulation, which we believe has the potential to treat therapeutic areas that suffer from unmet need including acute agitation, mania or even migraine. Additionally, I'm also pleased to share that IND-enabling preclinical work is continuing for SAGE-319, an oral extra-synaptic GABAA receptor preferring PAM. In our neuropsychiatric franchise, we are making progress with SAGE-904. SAGE-904 is an NMDA PAM product candidate being developed as a potential oral therapy for disorders associated with NMDA hypofunction. We remain on track to complete the SAD study for 904 in 2021 and that study is ongoing. These data will inform the future development path for SAGE-904. In other earlier-stage neuropsychiatric programs, SAGE-421 is an oral NMDA PAM being evaluated for potential use in neurodevelopment disorders and cognitive recovery and rehabilitation and that program is making good progress in preclinical development. In closing our R&D strategy is both proactive and predictive and we will continue to follow the science. Everything we learned from a program can be applied to other programs, leveraging learnings to define the path forward while driving for seamless execution. We also lead with human data to predictively approach drug development with the goal of addressing unmet needs for patients, who need new approaches. We believe this approach may lead to improved chances of success in a number of programs and areas across our depression, neurology and neuropsychiatry franchises. Reviewing our achievements for the year, I'm convinced it's working. The totality of zuranolone data from a landscape clinical development program will inform our planned submission to the FDA next year for MDD. The positive results shared today from the LUMINARY study in patients with Alzheimer's disease are consistent with the signals demonstrating improvements in cognitive performance seen across the SAGE-718 program including in people with Parkinson's and Huntington's disease and as we initiated the Phase II [ DIMENSION ] study in Huntington's disease and received fast track designation from the FDA for our Huntington's program. With this progress, we believe we're on track for our first potential indication for SAGE-718. For SAGE-324, the positive results from the KINETIC study including the ADL data shared today reinforce the potential positive impact this program could have on the lives of people living with essential tremor. These results also inform the design of the KINETIC 2 Phase IIb study, which is now open to enrollment. We look forward to working with Biogen to continue to advance this program for patients with essential tremor. All of this progress sets us up for what we believe will be a strong 2022, positioning us to advance our efforts across our franchises and work towards our goal of delivering 2 or more IND-enabling programs per year by 2023. With that, I'll turn it over to the operator and I will facilitate the Q&A.

[Operator Instructions] And our first question comes from Ami Fadia with Needham.

I had a question on the study for SAGE-324. Can you give us some color on the different doses that the patients ended up with and how that might have correlated with the efficacy seen in the trial and how that has informed the next study that you're going to be conducting?

Of course, I mean, thank you for the question, and good morning, everyone. Thank you for joining us for Sage's third Annual FutureCast. I mean to your question around SAGE-324 and results from the KINETIC TRIAL. As you heard from Helen, we absolutely used a lot of the learnings we took from the KINETIC study and thinking about moving forward into the KINETIC 2 study. So as the initial KINETIC study dosing was done at 60 milligrams, the down titration was a log during the study, and that did occur due to somnolence in a number of cases. So we also -- we looked very much in detail at the results from patients as they all did down titrate. And what you can see, despite SAGE-324's long half-life is activity at multiple levels of exposure. And that really did directly contribute to our design for the KINETIC 2 study, where you see 4 arms in the study, placebo group, and also individual groups at 60 milligrams because we still believe that's an important dose to test. But additional groups at 30 milligrams and 15 milligrams. Those ranges were associated with our learnings from the KINETIC study.

Got it. I have another question on SAGE-217. You mentioned that you're expecting the FDA to host an AdCom. Can you give us some more color around what specifically may be obviously a discussion at the AdCom? And I'm sure the FDA doesn't share those questions right now, but what do you anticipate to be the focus point of discussion?

Sure. Yes. And I think it's a little difficult to say at this point. As you pointed out, AdComs are driven from the agency side of things. And so we'll just have to see as time goes forward what questions are going to be on the agency's mind for the AdCom. It certainly is a fairly common thing for novel mechanisms of action to have an advisory committee meeting. So not all unexpected, and we will prepare ourselves in detail for whatever questions might come up.

And we have a question from Paul Matteis with Stifel.

This is Alex on for Paul. I was wondering if you could talk a little bit about what we know about the relationship between some of these executive function and memory tests that you've been doing with 718? And how they relate to some of the sort of functional cognitive endpoints that you might be using in larger studies in PD, Huntington's and Alzheimer's?

Sure, Alex, and thanks for the question. The question is really around how the different tests align with cognitive domains across the programs. And just to start off by saying we're really excited to be sharing the results from the LUMINARY Study, which you've seen for the first time today. And what's really compelling and exciting to us is the consistency that we're seeing across different patient populations. But maybe I'll ask Aaron to talk about the question in a bit more detail, both in the context of the LUMINARY study, but then what that means across all of the Cognex platform. Aaron?

Thanks, Jim, and thanks so much for the question. Executive functioning is really critical to everyday functioning and this is true across different diseases. Ultimately, what we're focused on here is getting patients better, getting patients feeling better and functioning better and ultimately, hopefully, maintaining their independence. What's notable, I think about what we've shown today and how it also differs from what may be out there in the literature, we're talking about improvement. We're talking about improvement that comes on after less than 2 weeks of treatment, which is really not how other cognitive drugs have been oriented over the years. And so what we really have to do looking forward is rethinking how we measure some of these endpoints and trials. It may be the case that some of the legacy measures included in Alzheimer's trials are less applicable than newer measures. Ultimately, we want to know what's happening at the level of the patient, but something that will affect how their life is functioning, how they're feeling and the overall trajectory of their illness.

And we have a question from Yasmeen Rahimi with Piper Sandler.

Thank you so much for a thoughtful R&D presentation. I have 2 quick questions for you. One is I appreciated breaking down sort of LUMINARY and PARADIGM next to 1 another, and showing the data across 2 test executives at the DSST and PRN. I think it would be helpful to just put it into context of if you had run a placebo arm, what would that response have been? If you just give us an idea of how powerful the efficacy is. And then the second question is on the KINETIC 2 study. How do we know that you're not really leaving efficacy on the table by dose titrating down at 15- and 30-milligram dose group to minimize somnolence? A great job on R&D Day.

Thanks, Yasmeen, and happy to take questions. So to your first question around placebo responding in LUMINARY in the Cognex platform. Of course, as you know, we have taken an intentional strategy of being able to sort of scan rapidly through multiple patient populations with what is a very novel mechanism of action and a very novel compound. And so in order to do that, we have chosen to take an open-label format with those studies. And of course, then that does leave a question of what is placebo response likely to be. And so I think in a couple of minutes, I'll give Aaron a chance to talk about historically how placebo responds in tests and what that might mean. But I think probably what is most compelling for us because I think the -- ultimately, the placebo question is yet to be directly answered, so that would be part of the next ongoing series of studies. But certainly, what's compelling to us as you saw in Aaron's presentation, is that we are seeing a consistency of responding in multiple patient populations in similar tasks. So we're not seeing a random assortment of positives in different tasks. What we're seeing in separate studies across different patient populations are responses in the same time domain and roughly the same magnitude in multiple patient populations. So although that's not a substitute certainly for placebo-controlled data, it is very compelling to us as some evidence of the consistency of signaling that we're seeing across the Cognex platform. Aaron, can you give a little color on how historically placebo responded in some of these tests?

Yes. For sure. I think -- and there's probably 2 points to make. First, if you have a chance later to look back at the second slide, we pointed out all of the performance across all the studies we've done to date. And including in that is a placebo-controlled study in healthy volunteers, who are exposed to ketamine. And we see a pretty marked deficit on functioning in that study, and you can sort of see where improvement lines up relative to some of the other populations. But to answer specifically the question around placebo response, these are patients who have a neurodegenerative illness. They are deficient in the ability to learn and the ability to problem solve. And so their underlying pathology is what's getting in the way. And so it may be the case that the expectation -- the placebo expectations are being on treatment get somewhat to concentrate a little bit better. It doesn't really help you get to solve problems better. And the overall profile that we're seeing here is that subtle intentional changes are not what's driving the change. People are responding as quickly as they did from the first day to the last day of the study. What they seem to be able to do is solve problems better and that's really not something that I would attribute to placebo. But as Jim said, this is the first stage in understanding this novel class of compounds. We have more work to do, but it's very exciting. And I think particularly in an area where there's been high unmet need and a dearth of innovation, I think we have something hopefully to be looking forward to over the next phase of development.

Thanks, Aaron. And Yasmeen, to your question around KINETIC 2. Really, I think the way I would put it is that the full intent of KINETIC 2 is to give us a full understanding of the sort of dose and frequency that is going to be optimal for patients. So recall, we are considering all the data we have on the program, certainly, the KINETIC data from the first KINETIC trial. But we also have open-label data from Phase I work, looking at response to TETRAS with 324 as well as our earlier studies with both ZULRESSO and then separately around zuranolone. So that really gives us a database of information to think about for dosing and to really hit the optimal balance between efficacy and tolerability. And so that's really what KINETIC 2 is designed to do, is not just to demonstrate efficacy over time. This will be a dosing period of 3 months, but really to give us that balance point between what's the best combination of efficacy and tolerability.

Our next question comes from Cory Kasimov with JPMorgan.

Two for me as well. First 1 is something of a follow-up to the last question on placebo response. And I'm just -- I'm curious if you can talk a little bit more on how you carry out the Cognex high-frequency testing. It sounds like a cool concept. Is this validated. And do you have a sense or an expectation that this may actually help to tease out placebo responses instead of measuring just on specific days? And then second question is recognizing you're just getting started with KINETIC 2, can you speak to the level of investigator enthusiasm for the study and how fast you might expect accrual to go here?

Yes. Absolutely, Cory. Thanks for the questions. Yes, and really, the first question around Cognex. As Aaron said in his presentation, we've spent a fair amount of time and energy in optimizing the Cognex platform. And we do believe that there is some proprietary stuff to Sage that it really does optimize responding [Audio Gap]

[Audio Gap] answer the question we have at this stage is seems to be doing something for Cognex and these patients who really had no effective treatments to date.

Mike, anything you'd like to add to that?

Yes. Thanks, Jim. And I think the 1 thing I would add is it's also how we're sequencing the indications as well, too. Starting with Huntington's as our lead indication, is really important for the overall trajectory of the program because it allows us to take a very targeted hypothesis-driven approach that allows us to continue to look at these executive functioning. But again, being excited by the PARADIGM and LUMINARY data, this reinforces that overall trajectory, but it speaks to the overall plan of having a very hypothesis-driven population in Huntington's, but then also continue to explore the breadth of opportunity with 718 as well as other compounds in the NMDA portfolio.

Thanks, Mike. And Cory, to your other question around KINETIC 2, I think the short answer is yes, we're seeing enthusiasm from KOLs around the KINETIC data. And I think as you saw from Helen today, we're seeing robust effects on the performance scale of the TETRAS. That's certainly very important, but equally important we're seeing benefit on activities of daily living. And so I think that has certainly generated a fair amount of enthusiasm. And so we very much look forward to the KINETIC 2 trial, which as the name implies, is directly building off what we've learned from the first KINETIC study.

Our next question comes from Laura Chico with Wedbush Securities.

I guess I wanted to focus on 718 a little bit more. And just to kind of follow up or perhaps ask it differently. I guess what I'm trying to understand better is kind of what is the ultimate registrational path for 718? And I think you recently released details on the [ DIMENSION ] study design. And apologies if I missed this, but there is a little bit more nuanced in the dosing in Huntington's versus Alzheimer's. It appears like a different dose selection strategy being used there. So I guess, a, is Huntington's, the initial indication that we should consider here for 718? And then b, now with the LUMINARY data, I guess I'm just a little confused on how that fits into the scheme here in terms of advancement? And hopefully, that's clear.

Yes. Absolutely, Laura. I mean you really -- it's about what is the development path for the 718 program. And let me answer your questions and then Mike is on the call, who is the program lead for 718, I'll let him give a little bit more color. But I think the short answer to your question is, yes, Huntington's disease remains the lead indication for the 718 program. But let me step back and remember, as we've been talking about with this novel mechanism of action with SAGE-718, we feel that we've got a real opportunity here to improve cognitive health for lots of different patients. And rather than take a focused approach on just 1 indication, that's where the Cognex platform was born to really take this novel approach and understand there are multiple patient populations to benefit. Now that doesn't mean that we aren't very much still focused on the Huntington's patient population. It's a small working size indication, and it really allows us to move forward with understanding in more detail of the profile of SAGE-718. And so the [ DIMENSION ] study, which you referenced, is that placebo-controlled Phase II study that will do just that and give us much more detail about responding in Huntington's patients, certainly in cognitive performance, but also maybe what are some of the consequences of that improved cognivitve performance in their lives. We are also very much excited by the results that we're seeing across the Cognex platform. So certainly, the PARADIGM study, which we had talked about over the summer, but perhaps even more so with the LUMINARY results that we're seeing today. And what we think it means overall is that this is an approach that could be beneficial for a large number of patients. And again, modulation of NMDA receptor function, one of the sort of tenets of neuroscience is that NMDA receptor function is involved in plasticity learning and memory. So it's not surprising, but it is compelling to see evidence of that across multiple clinical populations. So in addition to the [ DIMENSION ] study that's moving forward for 718 in Huntington's disease, we do also plan to initiate in 2022, a placebo-controlled study in Parkinson's disease based on the results that we had seen from PARADIGM over the summer. And then, of course, we need to take into account the results that we're talking about today in Alzheimer's patients with MCI. So there is a another very large patient population, and we would -- we're exploring how we're going to move forward with a study in Alzheimer's disease. So really, we're moving forward in multiple patient populations, and we think that's both an opportunity, but also what the data are telling us and who's responding to this drug. So Mike, any further details to add around the HD pathway?

Yes. Thanks, Jim. And just to reiterate, we believe that 718 has the potential to impact the lives of millions of patients and their families, and we're going to look at multiple options there, yes. But I think the way to think about the 718 program is very similar to what we've done with the GABA where we started with PPD and then moved into depression. And the same thing, we see as Huntington's disease as the focused lead indication, because there is a robust scientific clear rationale that Sage has invested quite a bit in understanding over the last 8 to 10 years. And this is why we're leading with HD because of this focused scientific rationale. But as Jim indicated, as we continue to learn more about 718 using the innovative Cognex platform and seeing such strong consistency of effects across multiple indications, we will continue to evaluate how to approach those, whether it's Parkinson's, whether it's Alzheimer's disease, with rigorous placebo-controlled trials. But Huntington really is the lead indication for a number of reasons as a homogenous patient population where there clearly are these executive functions and a strong mechanistic rationale. The [ DIMENSION ] study has initiated, is enrolling, and we plan to provide more details about the ultimate development pathway for Huntington's as we progress into 2022 as well.

That's very helpful, guys. If I could just sneak in 1 additional question then, actually, maybe 2 little ones. But how should we think about the potential for [ DIMENSION ] to serve as a registrational study? And then could you just remind me what is the longest duration of dosing we've had 718 in patients?

Mike, do you want to take those?

Yes. The [ DIMENSION ] study is intended to be a well-powered, placebo-controlled study at multiple sites, both in the U.S. and ex U.S. potentially as well. We believe that it has all the properties of a well powered placebo-controlled study. As you understand, in a orphan disease, we will continue to engage with the FDA about what the ultimate path to developing 718 in a novel indication space, where there's a clear unmet medical need moving forward as well. And then the second part of the question was around -- sorry, I missed that.

Duration of dosing.

Duration of dosing. Yes, we are -- in our PARADIGM Part B, we are up to 28 days of dosing as well as you remember.

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

This is Andrea on for Salveen. Aaron, 1 question for you. When you look at the various tests measuring, learning and memory, for the PARADIGM and LUMINARY study, just curious what you think might lead some test to detect improvement versus other tests that are not seeing that? And do you believe that's a function of the sensitivity of the individual test? Or does it in any way reflect 718 activity in the various indications?

Yes. It's a really great question. Yes. Thank you. It's a really great question. I think that to take a step back, I think the first thing to realize is this is a new mechanism of action. And when we're talking about drugs for Alzheimer's, Parkinson's, Huntington's, we're not usually talking about improvement, right? So what we are doing now is really for the first time understanding what a profile may look like in terms of response to a potential drug like 718. So I think that's the big picture. And the fact that we've seen a lot of consistency across different platforms, across different drugs. I think we have more work to do in understanding why some tests move and other tests don't. But what I get focused on as a clinician is the overall [ stall ], the overall picture, are we seeing improvement? And are we seeing improvement in areas that matter to patients? Changes in executive functioning, changes in learning and memory, those are the things that cause people to lose their independence, that lose their ability to drive to go to the store, all these types of things. And so we are hitting on those areas that really potentially can drive some change in patients' lives. So I think we have more work to do to understand why some patients respond to 1 test and not the other, but the overall picture to me looks quite positive. And I can speak from having treated these patients that this is moving stuff that we really have never been able to before. Jim, I don't know if you want anything to add in terms of the overall plan moving forward?

No, I think that was a great summary.

Our next question comes from Sumant Kulkarni with Canaccord.

On zuranolone, in the real world, after the initial 2-week course of treatment and first follow-up, can you give us any quantitative metrics on how often a patient may need to see a psychiatrist per year versus a typical patient on traditional SSRI? And on 718, from a clinical trial logistics perspective, how reliable can the digit symbol substitution test for executive functioning be for patients with Parkinson's, for example, given the underlying impaired motor control in that condition?

Yes. Thanks, Sumant. So I think your question around 217 is really around how it's used in the real world and how that will occur as patients come back to their doctors. And I'm going to turn to Rob to talk about that question and how we believe that 217 will be used in the real-world setting.

Thanks, Jim. When we think about the SHORELINE Study and looking at data over the course of that year, you can imagine with 80% of patients only meeting either the initial treatment or 1 additional treatment, the notion of really limiting the number of follow-up visits the patients have can be quite clearly done. But generally, there would be no major difference in the way that clinicians handle zuranolone patients versus others, they would assess the response. And then through whatever mechanism the patients work with the clinicians, whether that's digital tracking, whether that's simply following their mood state and so on, they simply contact their clinician again when they feel a new course may be needed. So really no major changes, if anything, potentially fewer visits.

Thanks, Rob. Yes. Sumant, you had a question around SAGE-718?

Right. Yes. Just how reliable can DSST be for executive functioning given -- especially in Parkinson's given there's an underlying impairment of motor control there?

Yes. So we're looking at DSST as 1 of many metrics of cognitive performance. And one of the things that we value about DSST as you heard from Aaron is that we can -- that can be performed on an iPhone on a daily basis. So it really gives us some complementary data to what we're seeing across the rest of the Cognex platform. So I don't see that test in isolation, but I do see it as very consistent with the findings that we're seeing across the rest of the Cognex platform.

And Jim, let me just dive in a little bit because I know there's been a number of questions on 718 regulatory path. So if we take a step back, we are developing 718 to improve executive function, learning and memory, higher order functions as you heard from Mike and Aaron in general. This has never been done before. We do not believe that kind of the standard measures classically used to study Alzheimer's, if you will, are the right totality of measures to develop a drug like this. So we're actually forging a new pathway with Cognex. And we think that the best place to start because as Mike said, the biologic hypothesis performed this way is in Huntington's disease. As many of you are aware, in orphan diseases, many companies have forged new pathways. So we believe that based on biologic hypothesis and the fact that it's an orphan disease that we can work with agencies to forge us a new pathway with Cognex. We're going to start with Huntington's disease. We believe the current Phase II design is robust. Obviously, this will depend on the data. But if the data are supportive of a path forward, we bet we'll work with the agencies for this study to be an approval study. And then we'll follow with Parkinson's and then we're evaluating Alzheimer's. The last thing I'd add is we are fortunate in our expand and accelerate type of balance sheet should we move forward with both the Huntington's, Parkinson's and Alzheimer's to move forward with all 3 in parallel. So 718, incredibly exciting, starting with Huntington's. We've committed to Parkinson's. We're evaluating Alzheimer's a little more for you on that later. So I hope that's really clear in terms of the path forward.

Our next question comes from Jay Olson with Oppenheimer.

Can you talk about what is considered the greatest unmet need in the treatment of depression? And any feedback you may have gotten from KOLs on the SHORELINE and WATERFALL results to help us understand how zuranolone compares to the standard of care with regards to addressing unmet needs in MDD? And then I had a follow-up on 324, if I could.

Jay, yes, great question. Happy to answer the questions around KOL feedback. And in a moment, I'll let Rob talk in a bit more detail of what kind of feedback we're hearing from KOLs. But I think in general, we're really encouraged by the feedback we're getting. You heard some quotes today from Anita Clayton. And what we're seeing is that as KOLs begin to see the full story of zuranolone and understand the totality of the data, that a lot of them are really excited about the potential for zuranolone. Rob, would you like to give us some specific color about some of the feedback we're hearing from KOLs?

Sure. And I'll remind folks, there's actually a robust literature that also supports this around what both patients and doctors in depression think are the most unmet medical needs. The top 2 consistently are getting better faster and not having to take medication over the long term, whether that's months, or years, right? And so certainly, the data for SHORELINE, which we think is incredibly robust, given that we have over 1,000 patients now, who've entered the trial. That data is just very clear in that open label very real-world trial where patients came in, got treated. And those who responded needed very little in the way of continued treatment over the course of the year. So we think that zuranolone is well aligned with what clinicians and patients think are the current unmet needs, which is I want to get better, faster to get back to my life. And I don't want to have to commit to months or even years of medication, which then mean potentially chronic side effects just to keep my depression at bay. So we think we have an important solution to both of those unmet medical needs.

And then maybe just on 324. You had a significant improvement in upper limb tremor score at day 29 in the KINETIC trial. And I was wondering if there's a correlation between upper limb tremor and ADL scores? And then anything you could do in Phase II to minimize the placebo effect on those scores?

Yes. Absolutely, Jay. And the short answer is yes, there's a pretty robust correlation between the performance scales and the ADLs. And it's not surprising many of the ADL tasks are very much dependent on upper limb. So things like drinking from a glass or eating with the spoon. So not surprising that there is a pretty strong correlation between those scales. And that's something that we saw in KINETIC, and we certainly expect to see in KINETIC 2. I think as far as minimizing placebo refining, we can talk for a long time about placebo responding across all clinical trials. It's certainly something that we're thinking about with the KINETIC 2 study. I think 1 of the things that will be interesting to see and 1 of the differences between KINETIC and KINETIC 2 is we're dosing patients for a longer period of time in KINETIC 2. So whereas it was 28 days in KINETIC, it's a 3-month study for KINETIC 2, and we think that would be something that could contribute to at least controlling any placebo effect that you might see.

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

Two quick ones for me, if I could. For 718, you're showing consistent effects across different domains, but there's may be some subtle differences between Parkinson's and Alzheimer's such as impaired learning memory and MoCA. I'm curious if you believe this mechanism is maybe working differently across the 2 diseases? Or this is just a product of different baseline manifestations of the diseases like lower starting MoCA in the Alzheimer's patients? And then on zuranolone, I'm curious your latest thoughts on dose level with the updated SHORELINE data in hand. It seems that 50 milligrams is giving you similar response rates to 30 milligrams in that study. The Shionogi study showed good efficacy at 30 mgs. 50 milligrams looks like maybe confers greater durability, but that's cost of greater AEs. So I'm just wondering how this shapes your overall filing strategy? What you might expect from regulators on physicians and how the 2 different doses may be approved and used here? Do you envision certain patients starting with 1 dose versus the other?

Sure. Thanks, Brian. To your question around different types of response patterns for Parkinson's versus Alzheimer's disease in the Cognex battery. No, I think it's a good question. These are some of the questions we'll be asking ourselves as you heard from Aaron earlier, we still have plenty to learn about the different response across patient populations. If you go all the way back to the biology and following the science, there's good reason to believe that there's a fair amount of commonality here in the types of effects that modulating the NMDA system might have. But that's part of the reason why it's interesting to be working in a novel clinical space is we have to understand whether some of the differences we see are true differences or whether they're just sort of some of the variability that can happen across individual tests and clinical trials. I think as it's been said a couple of times, what's really compelling is the commonality of pattern of responding across patient populations and across the battery. But I think time will tell or whether there are more subtle differences between patient populations and their response to SAGE-718. And to your other question around dose range for zuranolone. Of course, we -- as you said, we have a number of trials completed at multiple dose ranges. We are -- we believe that 50 milligrams is probably the appropriate dose to start. But I think 1 of the valuable things that we have in the LANDSCAPE and NEST programs overall is that in the totality of the data, we have responses from multiple trials at different doses. And so when we file our NDA, of course, we will be filing all of the data. And it's too early to talk about things like labeling, but we think it's a strength of the program to have the data at multiple levels of dosing. As I said, we think 50 is probably the place to start, but there's a lot of flexibility offered with our understanding at lower doses. Rob, anything you want to add?

Yes. No, I'll just pick up on what you mentioned about really the heterogeneity, right, of the MDD population. So we think that there are going to be patients who benefit from different doses. So I mean -- and remember, that population is also made up of different types of depression. For example, we're seeing folks who have MDD with elevated anxiety, for example, do quite well, which we know in prior treatments, they've not done as well. So it's that heterogeneity of applying it to the dose, which will be our job going into the NDA in discussions with the FDA.

And our next question comes from Gary Nachman with BMO Capital Markets.

First, another 1 on 718. How early in disease were patients in the PARADIGM and LUMINARY studies? I know LUMINARY was in MCI. But how important is it to get these patients earlier in disease to get maximal effect? Or should that not theoretically matter as much? And then just a quick second one on KINETIC 2 and 324. Why are you not using a 45-milligram dose in the Phase IIb? I think it's just the 15, 30 and 60. If patients were titrated down in the Phase II, I think it was the 45 milligram. So just review the down titration that you guys saw a bit more in the KINETIC study?

Sure. Gary, thanks for the question. So the first question around SAGE-718 and when in the time course of disease that to intervene. This is a much broader question. Both of the disorders we're talking about here -- actually, all of the disorders we're talking about Huntington's, Parkinson's and Alzheimer's are progressive diseases as we all know. And patients decline in their performance over time associated with disease. Within individual diseases, that time course can vary quite a bit and certainly across diseases that time course can vary quite a bit. And I think 1 of the questions that we'll be addressing over time is how wide of a window can this mechanism help benefit patients. You could -- certainly, from sort of first principles consider that it's very late in disease where you're starting to have structural problems and neuron loss and things like that, perhaps you wouldn't see as much of a benefit. We have certainly focused intentionally on earlier phases because this is where, as Aaron said, you're starting to see patients' lives being affected. You heard that from Dan earlier today as he talked about his journey in Parkinson's disease. So intervening early and sort of improving cognitive performance is going to be beneficial across all of these patient populations. I think we'll see over time as we do more studies, whether that benefit persists for longer into the progressive phase of diseases. But I think that's going to be a disorder by disorder question to address. And then I think your question around SAGE-324 and the KINETIC 2 trial. I think really, to me, the take-home message is that we're taking the learnings from KINETIC as well as the learnings that we have from our earlier open-label work, which has allowed us to think a lot about PK and PD. And we think that we've got the most efficient design for the KINETIC 2 trial with the doses that we've chosen, 15, 30 and 60, really allow us to sort of best optimize the relationship between dose and efficacy. And that's really what KINETIC 2 is all about is to really maximize the balance between efficacy and tolerability. And that -- so that's the focus of the study and the design is really intended to maximize the chances of demonstrating that.

Our next question comes from Vamil Divan with Mizuho Securities.

So I've been juggling up through things, so I apologize if I missed anything on these 2 questions that I have. But 1, just around 324, I heard the comments you've made around dosing and what you're looking at here going forward. Can you maybe talk about just sort of what level of sedation, somnolence and sort of side effects would be okay in this particular indication? And I guess as you talk about sort of more evening dosing, so if you can give some sense of what your efficacy bars would be as you think about the efficacy need during the day with the adjustments in the dosing? And then the second one, I know this is an R&D-focused event, but we do get a lot of questions on zuranolone just related to sort of pricing dynamics, especially as a shorter duration of treatment, and given the presence of other generic alternatives out there that people will take every day. I don't know now that you've moved a little further along in the process with zuranolone, if you would be willing to share anything more on how you're thinking about pricing the product, that would be very helpful.

Right. So taking your questions, thank you. The question around level of somnolence in essential tremor. I don't think that I would characterize it as a particular level of somnolence that is -- it would be an acceptable versus one that would not. And there's a certain amount of individual variability that's going to be involved in this. As we heard earlier from Lynn, lot of these folks are dealing with life-changing effects of essential tremor. And that is -- I wouldn't minimize how impactful that can be just in being able to sort of put your own clothes on or things like that. And so that does translate to tolerability questions, and we saw that in the KINETIC study. So there are plenty of people, who are willing to tolerate some somnolence in order to experience the benefit that they're seeing. Having said that, we do think that part of the design of the KINETIC 2 study is really to allow us to identify doses where we're seeing clear efficacy or where we can minimize that at somnolence. And so I think that's -- you heard from Helen earlier that things like nighttime dosing, titrating up to the highest dose level. These are things that we believe will positively benefit things like somnolence and tolerability profile overall. And that's really what this is all about is to get to at a level of symptom relief for patients, but allowing them to tolerate things like somnolence. I think that's certainly achievable. And that's really what KINETIC 2 is all about is to find that correct balance between the 2, but there probably isn't a single level of somnolence that will be the target for every patient. And I think around zuranolone, it's pretty early to be talking about pricing for zuranolone. I will say we do feel that the proactive value-based agreement approach is going to be a key driver for the way we think about pricing of zuranolone. But I think to go into the detail beyond that is probably beyond the scope of today's discussion.

And we have a question from Danielle Brill with Raymond James.

This is Alex on for Danielle. I'm going to rewind the SHORELINE for a second. So 50 milligrams of zuranolone had an emergent tremor signal show up as an adverse event. In SHORELINE, considering 324 is being tested for the treatment of essential tremor, I was wondering if you can expand on how you're internally thinking about that finding of zuranolone producing a tremor signal? Do you think it's due to the pharmacological differences between zuranolone and 324? Or alternatively is there something biologically different about essential tremor that makes these patients respond differently to GABA PAM?

Right. Sure. Thanks, Alex. Thanks for the question. And I think, yes, you are right, we have seen a low incident signal of some tremoring in the SHORELINE study with SAGE-217. That's a signal that we're obviously watching. I wouldn't sort of directly equate that to the disorder of essential tremor. So what we're seeing in the zuranolone studies is pharmacologically associated so -- during the dosing phase of 217. Not a completely unexpected adverse event and something that is seen across a number of antidepressant programs at a lower frequency. In the case of essential tremor, you're talking about a disorder where there are structural changes that happen in the brain that are associated with thalamic and cerebellar loops. And it's the ability of GABA modulators to modulate that ongoing alternate signal in those brain circuits that gives you the efficacy for 324 in essential tremor. So there really are 2 different things. But that certainly -- having said that, we follow all the signals we see for adverse events in the zuranolone program very carefully.

Our next question comes from Yatin Suneja with Guggenheim Securities.

This is Eddie on for Yatin. So 1 on zuranolone. I understand most patients will only need 1 or 2 treatments per year. But for a more severe patient with a higher treatment burden, do you expect there to be a label restriction on the max number of courses per year or will that be driven more by payors? And then on 324, for the ADL, it looks like you're seeing a slight diminishing of response even with dosing up to day 29. So are you confident that with longer term that you can reverse that trend even with those lower dose levels?

And yes. And to your question around zuranolone dosing and as you said, what we saw from the SHORELINE study is that the majority of patients really only need 1 course of treatment for the year. And when you look at either 1 or 2 courses for the calendar year, you're talking about a large proportion of the total overall patients. Doesn't mean that some patients may not require additional treatment. And that is something -- it's a little early to talk about labeling specifically, but that's certainly something that we see in the data and that we'll be talking about with the agency. Rob, would you want to add any more specifics to the question?

No. I think that is part of our discussion, moving into NDA with the FDA. So we certainly don't expect much, but we'll interact with respect to the numbers of treatments that we've seen used in the trial and just remind folks that with additional uses we haven't seen any change either in response or side effect profile. So again, the evidence very much supports the well-tolerated nature of zuranolone.

Thanks, Rob. Yes, to your question around 324 and ADLs, I think important to remember in the KINETIC study, a relatively small study, the ADLs were an important secondary endpoint, but the study wasn't necessarily powered to detect changes in ADLs. And so in fact, despite that, we see a robust effect on ADLs that mirrors the response that we see with the performance scale, the upper limb tremor score. Now I'll remind you that in the upper limb tremor score, which is the primary endpoint, the study was powered to detect, we saw a nice robust and sustained response out through the end of the treatment period. So not concerned by that apparent drop off in ADLs. I think probably has more to do with trial size and recall that we did have some dropouts in the study due to somnolence. So much more likely to be power and related, but of course, that will be a question that will be addressed in the KINETIC 2 study.

Our last question comes from Neena Bitritto-Garg with Citi.

So I just want to go back to SHORELINE for a minute. I'm just curious what kind of feedback you've gotten from investigators in the study and then maybe from patients in terms of the actual retreatment criteria that were used in the study? I believe patients have to have their MD scores return to 20 or higher. So I'm just kind of curious if there were any investigators who were interested in redosing patients earlier than that?

Sure. Thank you for the question. And it really is around what are the retreatment rules, if you will, in the Shoreline study. And as you said, the patients are followed on a regular basis every 2 weeks with depression scale until when their symptoms recurring is the trigger for in consultation with their provider to treat again. But that's -- I think that's the broader answer for your question around how different KOLs we're anticipating in the short line study and the questions around additional retreatment, I'm going to turn to Rob to sort of talk about that in a bit more detail.

Thanks. I'll remind everyone that over the full study, we had patients do self reports with the PHQ-9 every 2 weeks and come into the study if they found that those scores were high for assessment formally with HAM-D. I'll remind folks in looking at the data, however, patients continue on with respect to the potential emergence of symptoms, meaning if someone may have a HAM-D score of 15, they typically don't sit there for very long. Meaning as patients progress with worsening of symptoms, we see that progression occur such that it would only be probably a week or 2 earlier if we were to treat at a slightly lower level. So we still feel that we're capturing everyone certainly in time to provide them a rapid relief and excited because our data also indicates that some of the digital tools that we're using could anticipate and identify folks, who need a treatment several weeks even before they may be able to contact their clinicians. So a lot of interesting data on tracking people over time, but it would simply from our data suggest that patients would just get treated a week or 2 earlier with respect to folks who may have lower than a 20 at HAM-D when they're assessed.

Thank you, and that's all the questions we have in the queue. I'd like to turn the call back to Barry Greene, CEO, for the closing remarks.

Thank you, and thanks, everybody, for being with us this morning. It's an exciting time at Sage. Hopefully, what you've heard from us is excitement around the new LUMINARY Alzheimer's data and SAGE-718. We are, in fact, forging a new pathway here, and it's a very exciting place to be developing a new medicine that improves cognition. That's very different than studies have been done to date, which are trying to measure progression and slowing progression rather than improvement. So we're really excited about the path forward for SAGE-718 starting in Huntington's disease, we've committed to Parkinson's disease, and we're actively evaluating Alzheimer's as well. You've heard from SAGE-324 that KINETIC 2 is open and enrolling. So we're excited for that path forward. We think we have the right Phase II design so that we develop SAGE-324 as a chronic treatment. And as you heard from Jim, the key is to develop a profile here for patients to stay on the drug chronically to improve their essential tremor. And we heard from Lynn just how devastating that is in her activities of daily living. And finally, we are very excited with the path forward for zuranolone. You've heard from Rob some use cases. You've heard that people are looking for a fast acting [Audio Gap].

This concludes today's conference call. Thank you for participating. You may now disconnect.