This conference call transcript was computer generated and almost certianly contains errors. This transcript is provided for information purposes only.EarningsCall, LLC makes no representation about the accuracy of the aforementioned transcript, and you are cautioned not to place undue reliance on the information provided by the transcript.
spk03: Good morning. Welcome to Sage Therapeutics' fourth quarter and fourth year 2020 financial results conference call. Currently, all participants are in a listen-only mode. This call is being webcast live on the investor and media section of Sage's website at sagerx.com. This call is the property of Sage Therapeutics, and recordings, reproduction, or transmission of this call without the express written consent of Sage Therapeutics is strictly prohibited. Please note that this call is being recorded. I would now like to introduce Jeff Boyle, Vice President, Investor Relations at Sage.
spk15: Good morning, and thank you for joining Sage Therapeutics' fourth quarter and full year 2020 financial results conference call. Before I begin, I encourage everyone to go to the investor and media section of our website at sagerx.com where you can find the press release related to today's call, as well as the slides that contain supplemental details. I'd like to point out that we'll be making forward-looking statements which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. Please consult the risk factors discussed in today's press release and in our SEC filings for additional details. With me on the call today are Barry Green, our Chief Executive Officer, who will set some context and provide some opening remarks. Steve Canes, our Chief Medical Officer, who will review our clinical progress to date. And Kim Iagucci, our Chief Financial Officer, who will provide a financial overview. We will then be joined in the Q&A by Mike Clunan, our Chief Operating Officer. And with that, I'll turn the call over to Barry. Thanks, Jeff. And thank you, everyone, for joining us this morning. The end of 2020 and the beginning of 2021 have been terrific for Sage, and we're pleased to update you on the progress we're making in our efforts to build the leading brain health company, positioning Sage to become a top-tier biopharmaceutical company. With the pandemic raging, the U.S. engaged in destructive political discourse and events highlighting once again the work to be done to eliminate racism and racial injustice. 2020 was a particularly challenging year for all of us. And on top of that, SAGE had additional significant challenges to work through. I'm proud to see, however, that the SAGE team demonstrated grit and determination with a commitment to science, innovation, and execution throughout 2020 and into 2021. And despite these headwinds, 2020 was a year marked by progress across our entire pipeline. Today, we have three programs in late-stage development with five ongoing Phase III trials due to readout this year. Additionally, we have five mid- and early-stage programs in clinical development, and we're committed to a goal of developing two or more high-quality IND-enabling investigational products per year by 2023. SAGE is tackling big problems of global health in areas where there has been little innovation over the past few decades. In just under a decade since the company was founded, we've made deep scientific progress in understanding brain circuitry by focusing on the GABA-A and NMDA pathways, and applying unique chemical innovation in the areas of neuroactive steroids, including oxysterol chemistries. The team has created innovative potential therapeutics focused on allosteric modulation, building from knowledge of endogenous starting points to target receptors that dial in specific properties to engage these pathways with highly tailored approaches. As you all know, I joined SAGE's CO in December. I believe Sage's mission, making medicines that matter so people can get better and stay better, is achievable through the innovative ways Sage discovers and develops medicines. Importantly, our approach to date has worked. Sage developed the first-ever treatment specifically approved for women with postpartum depression and has a rich pipeline of potential treatments focused on brain health that, if successfully developed, will give patients the opportunity to get their lives back. We have an extraordinary opportunity to transform the lives of millions of people with brain health disorders. SAGE is at the forefront of developing therapeutics targeting brain health disorders. I believe this is the next frontier of innovation. What I saw and continue to see in SAGE is scientific rigor with a proven track record of successfully converting robust chemical capability into a rich pipeline of novel clinical programs. a deep pipeline with multiple franchises, strong collaboration partners, the resources needed to become the leader in brain health, and mission-driven employees who are determined to make a difference in the lives of patients. And that cannot be underestimated. But what I was particularly struck by, and what I consider to be one of our core strengths, is that we are one of the few brain health companies that drives drug development every step of the way. from SAGE-created development programs through research into clinical development and approval. I'd like to walk through some of the highlights of 2020. In November, we announced a transformational global collaboration with Biogen for Xeranilone and SAGE-324. We believe Biogen is the right partner, and this collaboration gives us the opportunity to reimagine depression and essential tremor while also potentially expanding and accelerating development of innovative brain health treatments on a global scale. we now have the potential to reach over 450 million people around the world with our innovative product candidates if we're successful. And with an experienced partner for Zaranolone and Sage 324 and more than $2 billion of capital, we're in a stronger position than ever to accelerate not only the development of our late-stage GABA programs, but also our promising NMDA platform and the development of our novel discovery programs, advancing our mission of making medicines that matter. In October 2020, we announced positive interim data from the open-label Phase III Shoreline Study 30-milligram dose. This first-of-a-kind, naturalistic, longitudinal clinical development trial conducted as part of our program in major depressive disorder is designed to naturalistically follow patients with MDD and evaluate the safety and tolerability of both the 30- and 50-milligram doses of ziranolone in adults for up to one year. Importantly, The interim data showed that more than 70% of patients who responded to an initial course of treatment with 30 milligrams of ziranolone needed just two or fewer two-week treatments in a one-year follow-up period. That's a total of two to four weeks of treatment, or better yet, 48 weeks without ziranolone treatment. For patients, this alternative approach to treatment could mean they are no longer defined every day by their depression. Additionally, Zoranilone was well-polarized in the study with a safety profile consistent with results to date. We believe these data reinforce the potential of Zoranilone to become an as-needed treatment option for patients with MDD. Steve will provide additional learnings from Shoreline later in the call. I will say these data are very consistent with what we've seen with Zoranilone in clinical trials to date with more than 3,000 subjects or patients' dose. We've seen a rapid onset of activity durable effect over the study period, clinically meaningful improvements in depressive symptoms, and Zoranolin has been generally well-tolerated. If Zoranolin continues to perform as well as these data demonstrate, and we succeed in obtaining the necessary regulatory approvals, it will be a significant advance in how depression is treated. And SAGE, along with our collaboration partners, will be well-positioned to help patients across the globe deal with the brain health pandemic that hundreds of millions of people are today facing. I'm incredibly impressed by the SAGE team and what they've accomplished over the last year. We initiated six new clinical trials across our portfolio in 2020 and demonstrated our ability to adapt and work flexibly across our organization. 2021 promises to be a catalyst-rich year with 10 readouts expected across our multi-franchise brain health portfolio. If successful, we believe we have ability to pursue treatments for diseases that affect hundreds of millions of people worldwide. With that, I will turn the call over to Steve to discuss the progress in our clinical development programs.
spk02: Steve?
spk14: Thanks, Barry, and good morning, everyone. I'll begin with an overview of our lead clinical program, Zoranilone, currently being studied for the treatment of major depressive disorder, or MDD, and postpartum depression, or PPD, in collaboration with Biogen. In 2020, we initiated six clinical trials across our portfolio, three of which were phase three pivotal studies with Zoranilone. We believe these, if successful, will be supportive of an innovative approach to treating MDD and PPD. In designing these studies, we've diligently leveraged the learnings from our prior studies with Zoranilone, including the mountain study. Our development program is designed to achieve an NDA as efficiently as possible and the ongoing studies may support paths to approval with three distinct opportunities to address patient needs. I'll begin with MDD. Last year, we initiated the pivotal phase three waterfall study investigating a two-week course of Zoranilone 50 milligrams for treatment of MDD episodes. Today, we announced that this study is now closed to enrollment with more than 525 patients expected to be randomized, and we're on track to report data in the first half of this year. These data, if positive, will further support our belief that depressive episodes can be treated as needed, a paradigm-shifting approach. We are also evaluating Zoranilone in the Phase III Open Label Shoreline Study, designed to naturalistically follow patients with MDD and evaluate the safety and tolerability of Zoranilone with a two-week course of treatment as administered as needed in adults for up to a year. In May 2020, The study was amended to include a 50 milligram dose of Zoranilone. And in October of 2020, we reported positive interim top line data from patients who received the 30 milligram dose and the initial patients in the 50 milligram cohort. Findings from the interim data announced in October showed that nearly half of trial participants with a positive response to the first 14-day course of Zoranilone 30 milligrams did not need an additional Zoranilone treatment course throughout the year. and more than 70% required two courses of treatment or less. In the 30-milligram cohort, the most common adverse events were somnolence, headache, and dizziness, and most adverse events were mild or moderate. For those who needed re-treatment with the 30-milligram dose, safety, tolerability, and efficacy results were similar to those seen with the initial treatment course and were similar in nature and frequency to those previously reported for completed xeraniline studies. In the initial patients treated with two weeks of Zoranilone 50 milligrams, 75% of patients achieved response and 48% achieved remission. In this analysis, response was defined as a decrease in HAMD 17 score of at least 50%, and remission was defined as HAMD at or below 7. The adverse event profile in this interim look at 50 milligrams was similar to that seen in patients who received 30 milligrams of Zoranilone. And while the most common adverse events were observed to be somewhat more frequent in the 50 milligram cohort, they were similar in severity to the events seen with 30 milligrams. Most adverse events were mild or moderate. And in patients who received 0 and 50 milligrams, after having received 30 milligrams previously, higher rates and levels of intensity with AEs were also noted. We believe these interim data are supportive of an as-needed approach to treatment and look forward to the additional readouts from the shoreline study expected this year. Our Phase III CORAL study evaluating Zoranilone as an acute rapid response therapy in patients with MDD when co-initiated with a newly administered standard antidepressant therapy is progressing as planned. This placebo-controlled trial is investigating a two-week course of Zoranilone 50 milligrams when co-initiated with an open-label antidepressant in patients with MDD. We anticipate reporting top-line data later this year. Turning to PPD. Recall, we have a positive pivotal trial with Zoranilone 30 milligrams in PPD, the Robin study, and we continue to dose patients in our second pivotal trial, the Phase 3 Skylark study, investigating Zoranilone as an oral therapy in women with PPD. This placebo-controlled trial is evaluating a two-week course of Zoranilone 50 milligrams in women with PPD. Top-line data from the Skylark study are anticipated later this year. If successful in these trials, and in our efforts to obtain regulatory approval, we believe Zoranilone may offer not only a clinically differentiated treatment option, but also a commercially differentiated approach. A treat as needed, rapid acting therapy, which has been consistently positioned by physicians, patients, and payers as a positive target profile. This approach is reflective of our overall strategy, leveraging learnings to quickly adapt all with the mission of bringing medicines that matter to people with brain health disorders. Turning now to our neurology franchise, we remain on track in our Phase II double-blind kinetic study of SAGE324, 60 milligrams, and essential tremor, and plan to report data early this year. We're encouraged by the potential of SAGE324, as earlier open-label data demonstrated pharmacologic characteristics we believe are well-suited for development opportunities in essential tremor and beyond. To put the kinetic study in context, we're looking for a 30% to 50% sustained reduction in tremor from baseline. Because for this initial Phase II trial, we're dosing near the top of the expected effective range, we expect to see an AE profile consistent with GABA PAMs, including somnolence or sleepiness. If we see sustained efficacy and there are no surprising AEs, the next step would be to continue development with a Phase IIb trial to optimize dose, administration, and including a potential to explore additional formulations if needed. And we anticipate expanding the indications we're pursuing for both Zoranilone and SAGE-324 as part of our collaboration with Biogen. Beyond SAGE-324, we continue to build out our GABA-A pipeline with the progression of SAGE-689, an investigational product with rapid absorption, low PK variability, and solid formulation flexibility, which we expect to advance in a Phase I SAD earlier this year. Sage 69 provides multiple potential pathways for us to explore CNS disorders with unmet need, including acute agitation, mania, or even migraine. Additionally, we plan to advance Sage 319, an oral extrasynaptic GABA-A receptor-preferring PAM for preclinical studies for potential use in disorders of social interaction. Lastly, moving to the portfolio of investigational products in our neuropsychiatry franchise, We were evaluating SAGE718, our first-in-class NMDA receptor PAM, in development as a potential oral therapy for cognitive disorders associated with NMDA receptor dysfunction. In earlier studies, including a Phase I study in patients with early Huntington's disease, SAGE718 was well-tolerated. In addition, patients demonstrated improved performance in assessments of executive functioning compared to baseline. We believe the data we generated in our Phase I program support our hypothesis that SAGE 718 may be relevant to multiple disorders with impaired cognitive dysfunction, including Huntington's, Alzheimer's, and Parkinson's disease. Early this year, we expect to report top-line data from the ongoing Phase IIa paradigm study, an open-label trial of SAGE 718 in patients with Parkinson's disease cognitive dysfunction. In addition, we have initiated dosing in the luminary Phase IIa open-label trial in patients with Alzheimer's disease with mild cognitive impairment and mild dementia, and expect to report top-line data from that study later this year. Phase 904 is our next NMDA receptor PAM product candidate, a potential oral therapy for disorders associated with NMDA hypofunction, currently in Phase I testing. We expect to complete Phase I SAD and MAD studies this year and determine the path forward for this wholly-owned product candidate. Additionally, we recently introduced SAGE421, an oral NMDA receptor PAM that we plan to study for potential use in neurodevelopmental disorders and cognitive recovery and rehabilitation. We plan to advance SAGE421 to preclinical studies later this year. So as you can see, we have a milestone-rich year in front of us with 10 data readouts and other key milestones expected this year. Before I turn the call over to Kimi, I'd like to thank the entire SAGE team for their continued dedication throughout these challenging and unprecedented times. Now more than ever, patients suffering with mental health issues need better, more effective treatments, and we're working tirelessly to deliver on our promise of bringing such treatments to patients so they can get better sooner. I'd also like to thank the patients, their families and caregivers, and investigators who participate in our studies. Their contribution in the face of a global pandemic is invaluable. With that, I'll turn the call over to Kimi.
spk02: Thanks, Steve. 2020 was an important year for Sage, setting the stage for a catalyst-rich 2021. During the year, we made great progress advancing across all of our franchises, including multiple new clinical trials and progressing the pipeline, all in the context of a global COVID pandemic. From a financial standpoint, We ended the year with a strong balance sheet with more than $2.1 billion in cash. We entered 2021 with a strategic collaboration partner in Biogen and the financial and operational flexibility to continue to build the company. We have the opportunity to maximize the investment in Xeranalone and Stage 324 together with Biogen. Additionally, our balance sheet gives us the ability to invest more aggressively in our wholly owned pipeline. including our novel NMDA modulators and other programs. Let me now turn to highlights from our fourth quarter and end of year 2020 financial results. As a result of our collaboration with Biogen, we recorded $1.1 billion in net revenue in the fourth quarter. This included $1.7 million from Villarresto sales and $1.1 billion of collaboration revenue recognized in the fourth quarter. That was compared to $2 million in revenue from Xereso sales for the same period of 2019. Selling, general, and administrative expenses were $53.5 million in the fourth quarter compared to $85.1 million in the fourth quarter of 2019. We ended the year with $197 million in SG&A expenses compared to $345.8 million for the same period of 2019. The decrease in SG&A expenses was primarily due to the restructuring that the company announced during the second quarter of 2020. Research and development expenses were $81.7 million in the fourth quarter compared to $91.3 million for the same period in 2019. We ended the year with $292.7 million in R&D expenses compared to $368.8 million for the same period of 2019. The decrease was primarily a result of the completion of the mountain study and decreased spending for clinical pharmacology studies that was partially offset by an increase in spending for the waterfall and skylark study. We reported a net income of $974.9 million for the fourth quarter of 2020 and $606.1 million for the full year of 2020. That was compared to a net loss of $168.7 million and $680.2 million, respectively, for the comparable periods of 2019. In both periods, the difference was due to the collaboration revenue from Biogen. Finally, we continue to maintain a solid financial foundation, ending the year with $2.1 billion in cash, cash equivalents, restricted cash, and marketable securities. And we anticipate a cash balance of more than $1.7 billion at the end of 2021. We're not anticipating any milestone payments from our collaborations in 2021. As you've heard me say before, we take a deliberate and portfolio approach to our investments. Looking at the year ahead, we plan to continue to invest thoughtfully to sequence programs we believe have a potential to create year, mid, and long-term value. I believe our strong balance sheet will enable us to continue to advance meaningful pipelines and support many near-term opportunities this year with 10 clinical data readouts expected throughout 2021. Before I turn it over to Barry, I want to reflect on the nine and a half years since our founding and think about the value we've created and the progress we've made. I believe we're not only well positioned to deliver on our mission of making medicines that matter, but also well-positioned in our efforts to build a top-tier biopharmaceutical company capable of providing significant value to patients and their families, HCPs, and shareholders. We look forward to multiple milestone events over the coming year. I'll now turn it back to Barry for his closing comments.
spk15: Thanks, Kimmy, and thanks, everyone, for joining us this morning. I'm very pleased with the significant progress made throughout 2020 as a result of our disciplined execution and strategic planning, positioning us for a catalyst-rich 2021 with 10 data readouts expected across our clinical programs. The team has built a strong foundation for near, mid, and long-term value creation opportunities for patients and shareholders. Our leading brain health pipeline includes differentiated, innovative programs across three core franchises, and exclusively feature SAGE-created innovation. And our collaboration with Biogen will enable our plans to expand and accelerate our pipeline. We're very excited about the potential for significant milestones throughout this year as we build on the current pipeline, including our goal of delivering two or more I&D-enabling programs per year by 2023. And we've already begun to realize this expansion and acceleration with the progression of four early-stage programs announced earlier this year. I'd like to conclude with two thoughts. First, we remain thankful for the continued dedication of our employees and patient advocates, patients and their families, caregivers, and investigators who participate in our studies. Their continued contributions in the face of significant challenges throughout the year are invaluable. And second, I believe stage-created innovation has the potential to redefine what's possible and build the future care for brain health disorders. We're well positioned to continue advancing our multi-franchise strategy and to further our mission of making medicines that matter so people with brain health disorders can get better sooner. At this point, I'll turn it over to Jeff to handle the Q&A with the operator. Jeff? Thanks, Barry. Before I turn it over to the operator, I'll ask that you limit yourself to one question. If you have an additional question, feel free to return to the queue. And now I'll turn it over to the operator. Operator?
spk03: Thank you. To ask a question, you will need to press star then 1 on your telephone. To withdraw your question, please press the pound key. Our first question comes from the line of Laura Chico with WebBus Securities.
spk01: Your line is now open. Good morning. Thanks for the update, and thanks for taking the question. On landscape, I'm wondering if we could revisit the regulatory strategy here. So a number of readouts coming up, starting with waterfall in the coming months, but many of the other readouts like shoreline, skylark, coral, those aren't arriving until later this year. So I guess I'm trying to understand what would you actually need to see in waterfall to advance towards a filing independent of those other readouts? Thanks.
spk15: Yeah, Laura, let me make some opening comments, and then I'll turn it over to Steve. So what we said historically was we have three distinct paths and three distinct opportunities with the landscape study. Obviously, we're all looking forward to waterfall. And, you know, in these studies, the data will matter. It's not entirely clear other than sort of a positive study in waterfall, the totality of data, but we're working closely with the agency in understanding waterfall to achieve that. Now, I'll also say that we've said historically that the Redwood study, which was designed to answer questions at a time where data didn't exist, and that's dosing throughout the course of the year, is a study that we believe at SAGE no longer needs to be run because those questions, given the shoreline data that Steve articulated on the call, 70% of patients only needed one or two doses in the course of the year, really provide data that answers that question. So it's our belief, Seth, that You know, waterfall will be very helpful, but that the Redwood study is something that we likely would not like to run. Obviously, if the agency exists upon it, that's a study we're capable of running, potentially as a post-marketing approval study. So that's what I can say at this point. Steve, more to add?
spk14: Sure. You know, I think you recognize this, Laura. We have multiple data readouts, and you said it. The way to think about the program is there are multiple independent approaches to filing and ultimately approval, and we're committed to finding the most efficient way possible to file for patients. And, you know, obviously one of them is MDD, which is the waterfall study, and all the rest of the program, I mean, there's a lot of other information besides simply the FXT trials. Second is CORAL, which is the rapid response therapy when administered with an antidepressant. Third is PPD. So, you know, as Barry said, the filing strategy will really be led by the data. The way that we'll do this is we will put all of the materials that we have together, you know, after our next additional readout. We do this each time, have discussions with the agency under a breakthrough to propose a path forward. And the way I think about it is there are lots of potential ways forward, but the data is very much going to lead the way.
spk01: Thank you.
spk03: Thank you. Our next question comes from the line of Andrew Desai with Jefferies. Your line is now open.
spk17: Thanks, and good morning, everyone. It's great to see that you've completed enrollment in waterfalls. And so my question is, how should we be thinking about the overall effect of the 50-meg dose in the waterfall study? Obviously, there's a primary endpoint on HAMD at day 15, but maybe talk about what kind of response and remission rates even out to day 42, would be very compelling to you. Thanks.
spk15: Thanks, Andrew. And I'll make some opening comments and ask for Steve to provide more color. Yes, we're incredibly excited that we were able to upsize the study to provide a more robust study and complete enrollment on time so that we have a first half data readout as we committed. So that's very exciting. You know, the upsizing of the study obviously allows more powering on all the endpoints, and also allows us to look at some subset analysis as well. And Steve can go into that a little bit more. You know, because of the unique nature of ziranolone, and that is a benefit-risk, as we've articulated, different than the 30-plus antidepressants approved over the last 30 years, we believe that, to put it simply, a positive study provides meaningful benefit for patients. and is the kind of data we're looking for, you know, irrespective of the point change. So we're looking for a positive study and looking at primary, secondary endpoints and some of the subset analysis. Steve, do you want to provide more color?
spk14: Sure. You know, the landscape program is, you know, obviously it's our top priority. We continue to invest in it. And, you know, we took the opportunity to increase the size of the trial, and, yeah, now we've announced that we've completed enrollment. The goal, of course, is always to hit the primary endpoint. This is an acute efficacy study. It's a study that we need in order to move forward in MDB. It's an essential study for us. What we were able to do by increasing the trial size is be able to start looking at some of the secondary endpoints. And you mentioned time points. That's one piece of it. The other pieces have to do with You know, are there subgroups of patients? What does it look like in men? What does it look like in women? A lot of the kinds of things that we've talked about before with our trials. You know, the things that I can say is, you know, every bit of data that we have is pointing to a very consistent profile. We've seen, you know, rapid response. We've seen good tolerability. We've seen long, durable effects where patients that have gotten better remain better. Those are the things that we're looking for in the trial. To some extent, it's less about statistical significance than any of those time points. It's more about extracting as much clear data from the trial as we can, which allows us in a really efficient way to make the most use of the study in the event that it's positive. So that's the way we think about it. You know, everything is designed for the primary endpoint. The rest of it is really to provide additional detail.
spk17: Very good. Thank you, guys.
spk14: Thanks, Andrew.
spk03: Thank you. Our next question comes from the line of Paul Matisse with Stifel. Your line is now open.
spk11: Hey, great. Thanks so much for taking the question. If you don't mind, I really wanted to hone in on the upsizing of the waterfall study a little bit more. I guess I know that there's a rationale for powering for secondary endpoints, but it's not like the presence of important secondaries in this trial are new. That was always known all along. So is there anything else or anything else behind the upsizing? And I guess the reason why I'm asking is I do remember Mountain being upsized due to kind of a blinded overview of the patient mix not being ideal. And I guess I just kind of wanted to make sure there isn't anything else besides just this being upsized in a way that's opportunistic. Thanks a lot.
spk15: Yeah, Paul, thanks for asking the question. I'll provide some context and then ask Steve to comment further. So the first thing I'll say is there was no data review that led to a decision to upsize. So unlike a previous study, that wasn't what drove it. The real ability to upsize was driven, unfortunately, by the unbelievable increase we're seeing in depressive episodes, largely due to the raging pandemic. So there was an opportunity. If I step back, Paul, you know, at Sage, and this is true for companies across the industry. When companies design their Phase 3s, we estimate effect size and variability and then try to design the most efficient trial necessary to hit the right p-value because we all want to use capital appropriately and obviously we want to subject as few patients to a Phase 3 trial. Because of the increase in depression across the United States and the world, And without increasing our use of balance sheet or timeframe, we were really able to upsize just because there were so many more events. And as Steve commented earlier, it provides us to do subset analysis and understand the impact of Zoranilin across these patient groups more effectively. So really happy we've done it, and I'm happy that we've closed enrollment and continue to point to a first-half readout. Steve, you want to add to that?
spk14: That pretty much summarizes it. You know, if you recall, we originally provided guidance that the study would be completed in 2021. And when it was clear that we would be able to fully enroll and potentially even enroll further, we tightened up that guidance to where we are now. And that's pretty much it. If there were other things, of course, we'd be talking about them as we did with Mountain. But, yeah, no, it's a great opportunity to extract information in a really efficient way. The machinery is all there. There's enormous interest in the study among the investigators as well as patients, likely, as Barry said, due to the fact that, you know, there are increasing rates of depression, unfortunately. And, you know, if we have the opportunity to get even more information from the studies, we'll take that opportunity every time.
spk11: Excellent. Thanks a lot for clarifying that.
spk14: Thanks, Paul.
spk03: Thank you. Our next question comes from the line of Akash Tewari with Wolf Research. Your line is now open.
spk16: Hi, this is Leo for Akash. Thank you for taking the question. We know from the PK of the multi-dose H324, we saw a significant accumulation of the drug in the body over time. So I wonder, how do you plan to further optimize the formulation to prevent the exposure to getting too high? And the other question I have is about waterfall enrollment. Do you verify the enrolled patients needed to have prior confirmed MDD episode so they are not just have one situational MDD episode due to the COVID pandemic? Thank you.
spk15: Yeah. Thanks, Niu. Let's take, Steve, do you want to take the waterfall first and then we can loop back on three, two, four?
spk14: Sure. The patients in waterfall are the same patients that we've used across all of our studies. The only requirement that we have is that the person has an MDD episode at the time of enrollment, whether it was their first or second episode in their lifetime. We don't anticipate, you know, perhaps you're curious about whether or not we think that major depressive episodes in the context of the COVID pandemic are somehow different. We view that as simply the kind of stressor that can cause increased rates of major depression, but all patients need to meet normal criteria for a major depressive episode depressed mood for several weeks with overall neurovegetative signs and symptoms, concentration, weight loss, sleep disruption, and so forth. So all of the patients that are enrolled need a formal diagnosis of MDD, and that's the patient population that's been under study. Barry, you want to go back to before?
spk15: Yeah, let me move. Just a comment on that's great, Steve, for Waterfall. And just to put a finer point on it, As you've known, we've demonstrated with Shoreline, we believe that while patients with depression is a chronic symptom, it's driven by depressive episodes. And whether those episodes are driven by the pandemic, genetics, or having a baby, we're demonstrating that with the two-week course of Zorano and thus far with the data, we're helping patients get better faster. So what Steve just said is consistent with what we've been saying all along. In terms of 324, let me... let me just take a step back and remind you what we're trying to answer. And we're trying to answer in this Phase 2 study, can we see the overall benefit to patients in sustained improvement? So what I'm looking for is 30% to 50% improvement in essential tremor over the dosing period, which is 30 days, and making sure those effects are sustainable. Secondly, I'm looking for an adverse event profile that's consistent with data we've seen so far. So we expect... Given the dose we're giving here, we expect adverse events. And then, as Steve articulated, we plan on doing a Phase IIb after this study, given the data to where some dose frequency and potential formulations. And just recall, there's never been a trial like this before. It's a first Phase II where we're assessing this dose so that we see an effect size and understand the adverse event protocol being consistent without any kind of new adverse events. Steve, you want to add more?
spk14: Sure. The kinds of things that we look for, and I know we sometimes talk about pharmacokinetics, there are a lot of ways to overall identify steady state, but it really comes down to dose exploration, you know, and various potentially formulations. Those might not be necessary. What we do is look at the data from the trial, understand with much more granularity what a month of dosing does in terms of our overall exposures, and go from there. And that's exactly what the team is going to do. So this is what phase two is about. It's optimizing the dosing scheme, the time of day where we dose, the frequency of dosing, potentially formulations, all based on optimizing the profile for the drug once you know that it's showing the benefits that we're expecting. So that's exactly how we'll go and we'll be able to articulate a plan when we have the data and be able to speak to it with more detail.
spk16: Thank you. That's very helpful. Thanks, Neal.
spk03: Thank you. As a reminder, we ask that you please limit yourself to one question. Our next question comes from the line of with Guggenheim Partners.
spk00: Your line is now open. Hey, guys. Good morning, everyone. Thank you for taking my question. Just clarification questions for me. For the essential tremor study, so the primary endpoint is Tetris performance subscale. When you say 30% to 50% reduction in tremor, are you referring to reduction in this particular scale? Can you help us clarify, and what do you see with standard of care in that particular scale? subscale. And then the other clarification question is on the waterfall study. It seems like there have been multiple changes in the, or multiple sample size adjustment. I think initially it was 240, moved to 370 in October, then 575 in January, and now you're saying it's 525. So can you help us sort through those changes? Thanks.
spk15: Yeah, let me quickly do waterfall, and then we can turn the essential tremor question over to Steve to answer. So, you know, as we've said, Several different times. We had an opportunity to increase the size, so we did. We did that without much additional capital and without changing timelines because of how much depression we're seeing out in the world. And we've answered sort of the subset analysis and others. The other number you see out there from clintrials.gov, I will just say that please allow us to provide guidance rather than trying to get guidance from clintrials.gov. It's there for a different purpose, not to provide guidance to analysts. Steve, you want to take the central tremor question?
spk14: Sure. You know, just to remind everyone, we've been prototyping work in the central tremor, understanding which measurements to use, emphasizing those subscales and other scales that demonstrate and track most closely with disability. And that leads to the performance scales, and particularly ones that track to upper limb tremor scores. So in the phase two, we're using that as a way of detecting the signal. What we've seen so far across all of our compounds, and this goes way back to Brixanilone, is, as Barry said, a 30% to 50% reduction. And it's not just the level of reduction. It's also in the percent of patients that show that response. So we're seeing some really impressive, robust effects with this mechanism that we're looking at. It's one of the reasons why we're so excited and our partners at Biogen are so excited about moving forward with the program. What we'll do is look at those results, of course, and then understand with our team, with patient advocacy groups, as well as with the FDA, what will ultimately be a registration endpoint. So, you know, for now, yes, we're focusing on upper limb trauma. We think that's a really important one. And, you know, what we're looking to see, and Barry mentioned this, we're looking to see both the improvement as well as the sustained improvement over the course of the full dosing period.
spk00: Thank you so much. Thanks, Justin.
spk03: Thank you. Our next question comes from the line of Jay Olson with Oppenheimer. Your line is now open.
spk13: Oh, hi. Congrats on all the progress, and thank you for taking our questions. For the paradigm study of stage 718 in Parkinson's mild cognitive impairment, recognizing that primary endpoint is safety-related, could you maybe talk about what sort of efficacy signals you'll be looking for in the top-line results and also comment on the rationale behind studying suicidality in this patient's population? And then maybe if you could address similar questions for the luminary study. Thank you.
spk15: Absolutely.
spk14: Steve, you want to take that? Sure. You can get a good sense of the kind of things that we're looking at for what we've reported previously for Huntington's. So we do a standard assessment of cognition. It's a battery of tests that look across all of cognition. What we've seen so far and what we'll be interested to see in Parkinson's is improvements in executive function and overall sort of high-level cognitive ability. And there are a lot of ways to look at that. It's everything from complex working memory tasks to the ability to solve abstract, um, uh, abstract, essentially puzzles. So those are the kinds of things that we look at for initial signals. Um, and, and, and they've shown some pretty impressive results so far, both in experimental models and healthy volunteers, as well as in, um, in patients with Huntington's. We started with Huntington's because the mechanism itself is related closely to some deficits that we've seen in the biochemistry and biomarkers. of patients with Huntington's, but we think the mechanism may extend well past simply that patient population. That's exactly what we're studying now. So more to come there, but the kinds of things that we've looked at, neurocognitive measures broadly, are the ones that we're looking for. With regard to suicidality, that's something that we include in all our trials. It's actually an FDA requirement. It's really a safety measure. This is the Columbia Suicidality Rating Scale. All drugs that get into the CNS need to be assessed to make sure that we're not causing any undue complications, but it's not around any specific concern there or concern about potential benefit for suicidality. So thanks for asking that question. That's one that's always included in all of our trials, and you'll see it in almost all, it should be in all, CNS trials as well.
spk15: Yeah, and, Jay, thanks for the question. I guess I would just remind you that this is our first-in-class NMDA receptor PAMP, And we're excited to see these data because it really sets up not just 718, but the rest of the whole NMDA platform. Great.
spk13: Thanks for taking the questions.
spk03: Thank you. Our next question comes from the line of Salveen Richter with Goldman Sachs. Your line is now open.
spk10: Good morning. Thanks for taking my question. Could you just provide some insight into what other formulations you could look to explore for SAGE 324 and before it?
spk15: Yeah, let me provide some overall thoughts, and thanks for the question, Sylvain. So, you know, as we've been saying, what we're trying to see in this Phase IIa is the efficacy 30%, 50% that's sustained in an adverse event profile that's not surprising. We are giving a very big dose, so we expect to see the adverse events we've seen with these kind of molecules. As Steve said, it depends on the data. We may not have to change formulations. We may be able to use dose and frequency in the Phase IIb. Or we may look at formulations that provide less of a peak to trough and more of a sustained area under the curve versus having a large CMAG. So there's a number of different ways we can go. Steve, you want to maybe provide some additional color?
spk14: No, I think that pretty much covers it. I think what we're just simply talking about is the process of Phase II and optimizing medication. You know, recall there hasn't been a medicine for patients with essential tremor in the last half a century. We're really working closely with physicians and patient advocacy groups to identify what profile would be ideal for those patients, and we want to make sure that we get that right. So as Mary said, the data will very much lead the way. You know, we'll understand much more about the parameters of the drug after a month of dosing, which will be well into steady state, so we'll understand a lot more about it. And if there's things that we need, I think what we're saying is if there's things that we need to do, we'll do those things. But that's not necessarily the case. We just need to see what the data are and then take it from there.
spk10: Thank you.
spk15: Thanks, Sylvain.
spk03: Thank you. Our next question comes from the line of Tazine Ahmad with Bank of America. Your line is now open.
spk04: Hi. I wanted to get further clarification on essential tremors. understanding you're looking at it for 30 days and understanding some of the clarification you just provided, but what level of confidence does that give you about longer-term durability when you're looking at it over that period of time? I think the reason why I'm asking is there are multiple companies that are trying to pursue ET in some fashion, and we're just trying to get a sense, albeit early, of where we think your program could be distinguished from others. Thanks.
spk15: Yeah, thanks, Dazine. Steve, you want to take that?
spk14: Yeah. So, Tazin, it's a great question. You know, I think I mentioned this before. We've been doing prototype work with this mechanism in particular, which is unique in the field, for essential tremor for quite some time. And we started years ago where we explored the role of GABA-positive modulators with Sage 547, which is now Xelresso. And, you know, we've been using primarily relatively short periods of dosing. One of the key questions that we'll be looking to answer is, you know, with prolonged dosing, do we see any changes in overall response rate? If those responses get improved over time, which is what we saw with stage 2 and 7 in a trial several years ago, and those are maintained, we know that we're on the right track. You know, with a month of dosing, you know, one of the things you might be concerned about is tachyphylaxis. we're working with these with drugs that are hitting the extra synaptic receptors and none of the models we've been using to see tachypallaxis. So that's something that we want to demonstrate for essential tremor in patients with a month of dosing. Uh, we believe that gives us great confidence to move forward with chronic dosing for conditions where, um, where obviously the need for ongoing treatment is necessary. So first study with a new mechanism in a patient population about 50 years, And we'll learn a lot from this trial. That's something that we've been really looking forward to getting to for quite some time. And the data that we've had to date has been really encouraging.
spk03: Thank you. Our next question comes from the line of Shuman Kulkarni with Canaccord. Your line is now open.
spk08: Good morning. Thanks for taking my question. If we go back to Mountain, one of the reasons why that trial may not have worked as well was that some patients simply may not have taken the treatment. So what specifically is being done in the logistics of the waterfall study to ensure patient compliance, especially given the environment today where the pandemic is quite different versus when Mountain was run?
spk15: Yeah, great. Steve, you want to take that?
spk14: Sure. You know, we talked about this a little over a year ago about Mountain, and, you know, One of the things we noticed in the trial is there were some patients who didn't have medication, didn't take medication, and when removed from the analysis, the study itself was positive. We shared that not because the rates of noncompliance were particularly high. We do use a number of methods to ensure compliance and ones that can be followed remotely. It was more to give a color on what we're seeing in terms of the consistent profile of the drug, meaning that when people take the drug, it works. The other thing we learned from Mountain is that for patients, there's a threshold above which exposure increases the overall rate of response. So while we know that there'll always be some patients that don't take medication, we do all of our diligence and additional measures have been in place to assure to the degree that we can. patients are participating, but the rates that we had seen previously were not particularly high for trials. What we did do, and what's going to be really important, is we've increased the dose to ensure that a higher percentage of patients that are in the trial are above that threshold. We've also increased the handy cutoff score for enrollment of the studies based on the ability to see higher signal-to-noise. So what we did is we took the learnings from Mountain and looked at it from the scientific perspective, from a safety perspective, from a drug development perspective, and applied those learnings to Waterfall.
spk08: Got it. Thanks.
spk14: Thank you.
spk03: Thank you. Our next question comes from the line of Corey Casimo with J.P. Morgan. Your line is now open.
spk12: Hey, good morning, guys. I think I know the answer to this question. We've had a couple people ask me this morning, so I'll ask you. With patient accrual and the waterfall now complete, can you just remind us of how much follow-up you'll wait for before starting your data analysis process? Is it the 15-day primary, or are you going to wait for all patients to get through the full 42-day follow-up period that will capture the secondary endpoints, as well as, I think that's the approach you took with Mountain. Thank you.
spk15: Yeah, thanks, Corey. And, Steve, do you want to talk about, at a high level, the process for database lock and how we go forward? Sure.
spk14: Sure. I'll just remind everybody this is a Phase III trial of a breakthrough program. That's a regulatory study that's done with all of the diligence quality that that entails. So what we will do is we'll continue enrolling up through the last patient, their last visit. We'll continue to do the appropriate level of source verification, which includes the understanding every data point that's been entered by investigators and ensure that those are appropriately entered and of high quality, and then we begin the analysis process. So it's a very detailed process that anyone would go through after the completion of a trial. We've been planning for this since the initiation of this study. Recall, this is in all of our Phase III programs, Phase II programs, all of the ones that we're working on now, we're all initiated during the pandemic, so we have processes and procedures that ensure that quality. And when all of that is completed, then we run the analysis. So, yeah, the last patient enrolled has to be back through the entire trial. We'll lock the database and then begin the analysis.
spk12: Great. Thank you. Thanks, Corey.
spk03: Thank you. Our next question comes from the line of Ritu Baral with Cowan. Your line is now open.
spk05: Hey, guys. Thanks for taking the question. I just wanted to check in on what high-level safety we're seeing across the landscape study, not just waterfall, but also coral and any sort of loss of consciousness that that population is susceptible to. I'm sorry, Skylark. and whether you're concerned about overlapping sedation in coral with new onset SSRIs on top of ziranolone.
spk15: Let me provide a high level, then maybe Steve can provide more color. And Riku, thanks for the question. As we've talked about, we've dosed over 3,000 subjects slash patients with ziranolone. And what we've seen consistently across that 3,000 number is a rapid onset of activity, efficacy in two to three days, durability, and a very, very consistent adverse event profile. So we're not seeing anything new or different across the ongoing trials. But Steve, do you want anything more to add?
spk14: Yeah. What I can speak to, read to, since the trials that you're referring to are ongoing, I can speak to the places that we look to understand those safety questions. And with regard to the 50 milligrams, With or without antidepressants, you can look to the initial data cuts that we put out for the Shoreline study, for example, where about a third of the patients are on underlying antidepressants. And across all of our studies, somewhere between a quarter and all patients have been on underlying SSRIs or other antidepressants. And so we really are able to understand that profile, and it really doesn't have a The reports, I would say, reflect that overall patient population. And what we've been seeing so far is a very consistent profile. It's a large database of subjects. We'll obviously have more information as the waterfall, coral, and Skylark studies readout. We'll be able to speak to those trials with more specificity.
spk15: The other thing I'd add, just for a point of clarity, Ritu, is that The sleepiness that we're seeing in the evening is actually very helpful in the context of depression because it potentially helps rewire a patient's sleep architecture. Many of these patients are on sleep aids because one of the challenges they have is they can't sleep. You know, what you worry about is sleepiness far into the next day, and that we're just not seeing much of.
spk05: Great. Thanks for taking the question.
spk03: Thank you. Our next question comes from the line of Nina Betrido-Gorg with Citi. Your line is now open.
spk06: Hey, guys. Thanks for taking my question. So I just want to go back to a central tremor for a minute. So I think in the Phase Ib study for stage 3 to 4, the lower 45-Mig dose that was tested there had a reduction of about 25% on the Tetris upper limb score, and I think the 60-Mig dose had somewhere around like 40%, So I guess, can you just talk a little bit about kind of the therapeutic window? I mean, it sounds like, you know, altering the formulation is one of the options, but, you know, given your commentary around kind of safety and, you know, kind of the efficacy data from the phase on B, can you just talk a little bit about the therapeutic window and thoughts on that and the ability to kind of use a lower dose and see similar efficacy?
spk15: Sure, Nina. Steve, you want to take that?
spk14: Yeah. These are sort of standard questions for a Phase II study. So recall the results that you're referring to have to do with single doses. It is a long half-life drug. So what we'll need to understand is what are the effects that we see with repeated dosing, and we know that we'll be approaching steady state. It will be about a week in at this dose, and that will allow us to dial in what exposures are really necessary in order to see benefits. So these are all pieces of a puzzle to understand what the profile is of the drug. There are a few bits of data that I can point out that kind of have you understand what the data, what we're looking to see. So with Sage 217, for example, which is similarly a long half-life, we did 14 days of dosing. And there, with each individual day, we saw continued improvement over time. Obviously, that's related to continued exposure and response. So what we'll do and what we did in this trial is dose, as Barry said, at the top of the range. That allows us to ensure that we're seeing the kinds of signals that we're looking for, and then we'll use that to model how and which doses to test in subsequent trials. So, again, we've answered a few questions about formulation. I wouldn't necessarily think that's the solution. There are a lot of ways to address the ideal profile, whether that be dosing scheme, time of day, frequency of dosing. All of those are tools at our disposal to optimize the profile of the drug. So remember, it's the active pharmaceutical ingredient, the drug inside of the drug. It's how it's administered. It's when and in what frequency that really determines what its overall profile is. The other thing I would say is that 324 in animal models had a wider therapeutic window against somnolence, versus efficacy in our animal models of tremor and so forth. So we do think that this was ideally selected for this patient population. The job of the Phase II program is to really optimize that profile before we make the final plans for subsequent development into the later phase.
spk04: Great. Thank you.
spk14: Thank you.
spk03: Thank you. Our last question comes from the line of Gary Notchman with BMO Capital Markets. Your line is now open.
spk07: Good morning. It's Rafael Sardar on for Gary. With Sage 718, if data from Paradigm show a strong signal of efficacy, would you plan on potentially moving forward with a larger study pretty quickly in Parkinson's or Huntington's, or would you first want to see data from Luminary? Thanks.
spk15: Yeah, Rafi, at this point, it's too early to provide specific path on the clinical development plan. Obviously, we want to see the Parkinson's data. We have the Huntington's data. And just kind of to bookend it, you know, one end of the bookend could be with Huntington's data or Parkinson's data, we move independently in those paths. The other end of the bookend is we see improvement in cognition executive function across all three neurodegenerative diseases. We kind of do a basket study. So we're working through that right now. We're talking to the agency about the best path forward, and we'll share more when we have a clearer path. Thanks. Thanks, Robbie.
spk03: Thank you. This concludes today's question and answer session. I will now turn the call back to Barry Green for closing remarks.
spk15: Well, thanks, everyone. We appreciate you being with us this morning and for all those great questions. Obviously, 2021 is setting up to be a very exciting year for Sage, a year of transformational that I believe will allow us to start to continue on our path to being a leading brain health company and continue on our path to build a top tier biopharmaceutical company. So thanks for your time. Take care. Be safe.
spk03: Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.
Disclaimer