SAGE (2021 - Q4)

Good morning. Welcome to SAGE Therapeutics Fourth Quarter and Full Year 2021 Financial Results Conference Call. Currently, all participants are in listen-only mode. This call is being webcast live on the Investors & Media section of SAGE's website at sagerx.com. This call is the property of SAGE Therapeutics and recordings, reproduction, or transmissions of this call without the written consent of SAGE Therapeutics is strictly prohibited. Please note that this call is being recorded. I would now like to introduce Helen Rubinstein, Director of Investor Relations at SAGE. Helen Ru

Good morning and thank you for joining SAGE Therapeutics fourth quarter and full-year 2021 financial results conference call. Before we begin, I encourage everyone to go to the Investors & Media section of our website at sagerx.com, where you can find a press release related to today's call, as well as the slides that contain supplemental details. I'd like to point out that we will be making forward-looking statements, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. Please consult the Risk Factors discussed in today's press release and in our SEC filings for additional detail. We will begin the call with prepared remarks by Barry Greene, our Chief Executive Officer, who will provide an overview of the progress from the previous quarter and full-year 2021. We will also be joined by Jim Doherty, our Chief Development Officer, who will review recent development progress across our programs, and Kimi Iguchi, our Chief Financial Officer, who will review the financials results from the quarter. Chris Benecchi, our Chief Commercial Officer, will join for Q&A. With that, I'll now turn the call over to Barry.

Thanks, Helen, and thank you everyone for joining us this morning. Before I begin, I want to take a moment to acknowledge the major events happening in the world stage this morning. We're watching along with the rest of the world and our thoughts and prayers are with all those affected. Rest assured we'll be focused in doing what we can, developing innovative medicines for brain health. And now let me turn back to our quarterly call. 2021 was an important year for SAGE and going into 2022; we're well-positioned to advance our mission to pioneer solutions to deliver life-changing brain health medicines, so every person can thrive. By leveraging our significant expertise in brain circuitry with demonstrated leadership in GABAA and NMDA receptor pathways, we've developed a robust pipeline of programs, including six new chemical entity development candidates across 11 or more possible indications. We believe that with this novel pipeline, we have the potential to help the millions of people suffering from the unmet need in brain health disorders. And we look forward to helping as many as we can in the years to come. I'd like to begin by providing some context on MDD and PPD. Families living with depression have not been well served. Largely stigmatized, depression is the dark shadow of human illness. Current treatments are just not working well enough with little innovation in the last 60 years, the profile of treatments remain unchanged despite 35 approved treatments in the last 30 years. Prevalence and impact continue to worsen with a three to fourfold increase in people experience symptoms of depression since the start of the COVID-19 pandemic and an estimated one in eight women with a recent live birth experiencing postpartum depression. The economic implications are as dire as the health implications. In 2020, economists estimated that depression and mood disorders cost the U.S. alone over $784 billion. Change is needed. We need medicines that work faster, last longer or well tolerated and look beyond depression as a lifelong chronic illness. The current treatment approach results in a try and error pattern. Delays in resolving MDD symptoms as seen with current antidepressants are often associated with more severe depression, increased relapse rates, and worse long-term clinical outcomes. We believe patients deserve better. As a society, we can do better. Innovative thinking leads to valuable advancements that benefit society. The riskiest thing we can do for people is to maintain the status quo and believe that what we have is good enough. The data are clear for the nearly 7 million people diagnosed with MDD and prescribed antidepressant each year, the average course of therapy is only seven weeks and 80% of patients change treatments once or twice within the first year. And among those that have changed treatments, 50% change within the first month, patients clearly need more from their therapy. That's why we believe there's a significant opportunity for new therapy in the treatment of MDD like zuranolone, if approved. One MDD population subset that stands apart and its need for new treatment options are those with MDD with elevated anxiety, as a symptom of their depression. According to literature, which often refers to this population as anxious depression, up to two-thirds of people with MDD experience elevated anxiety symptoms as part of their depression. Based on its mechanism of action and data seen in studies to-date, we believe zuranolone maybe well suited to help these people. We look forward to sharing more about MDD with elevated anxiety in the future but be sure this is going to be a key focus going forward. If we're successful in our efforts we've commercialized a partnership engagement with all stakeholders, patients, healthcare professionals, payers, patient advocacy groups, and policymakers. These engagements are needed to enact the change necessary for MDD and PPD patients to get the care they deserve and for appropriate patients with MDD and PPD to receive zuranolone if approved. We remain on track to start the rolling NDA submission in MDD early this year, and plan to complete the submission in the second half of 2022. As we shared previously, the planned NDA will include efficacy data from five studies. MDD-201B, WATERFALL, ROBIN and CORAL, and the Japanese study. In addition to data from the SHORELINE study on repeat treatment efficacy sustained beyond the treatment period, and lastly, safety data from the entirety of the program. We also plan to submit an associated NDA with zuranolone in PPD in the first half of 2023, pending completion and results from the SKYLARK study. We announced this morning that the FDA granted fast-track designation for zuranolone in PPD. Fast-track designation is granted to drug candidates that treat serious or life-threatening conditions and demonstrate the potential to address unmet medical needs. Now turning to the recent advances in our neuropsych franchise led by SAGE-718, a wholly-owned first-in-class an NMDA receptor PAM being developed as the potential oral therapy for cognitive disorders associated with NMDA receptor dysfunction. In our last quarterly call, we announced that SAGE-718 was awarded fast-track designation by the FDA for development as a potential treatment for Huntington's disease, specifically Huntington's cognitive impairment. This designation was partially attributed to the promising early data we generated on our Phase 1 study of SAGE-718, which demonstrated improvements in cognitive performance in patients with Huntington's cognitive impairment. Patients are now enrolling in our Phase 2 placebo-controlled DIMENSION study, evaluating SAGE-718 in HD cognitive impairment. And we plan to expand our work in this indication by initiating the Phase 2 placebo-controlled SURVEYOR study in mid-2022 and begin an open label extensive study in HD cognition in late 2022. We're also advancing SAGE-718 in patients with mild cognitive impairment due to Parkinson's disease. A placebo-controlled Phase 2 study evaluating SAGE-718 in patients with mild cognitive impairment or MCI due to Parkinson's in mid-2022. Finally, SAGE-718 is also being evaluated as a potential treatment for patient [Technical Difficulty]. We recently announced that SAGE-718 demonstrated improved performance from baseline on multiple cognitive function tests in patients with mild cognitive impairment and mild dementia due to Alzheimer's. These singles observed in the open label LUMINARY study, were consistent with those seen in Parkinson's and Huntington's trials. We plan to initiate a placebo-controlled Phase 2 study in SAGE-718 in patients with MCI and mild dementia due to Alzheimer's, which is expected to begin enrolling later this year. We've also made great progress on our neurology franchise, which features SAGE-324, another internally developed compound that is part of our collaboration with Biogen. Currently, SAGE-324 is being evaluated as a potential treatment for patients suffering from essential tremor, ET, and other neurological disorders. Jim will provide more insight in this program and updates for the year. I'd like to take a moment to thank the SAGE team for their hard work commitment and dedication on behalf of patients. 2021 was a data rich year, and we realized important program advancements in multiple disease areas across all three of our brain health franchises. This work last year built a solid foundation for continued progress in 2022. And I'm excited by what the future holds for SAGE. Additionally, I believe our balance sheet provides us the strategic and operational flexibility to continue to grow our pipeline, as we continue to evaluate each investment diligently, to ensure our decision-making positions us well and our efforts to create long-term value. In closing, I'm confident we have the opportunity to build on the momentum from the fourth quarter and throughout 2021 to generate continued success in 2022, as we advanced our journey to become the leader in brain health and a top tier biopharmaceutical company. Now I'd like to turn the call over to Jim for more detailed discussion of our recent call data and a preview of our expectations for 2022. Jim?

Thanks Barry and good morning everyone. Throughout 2021 and in recent weeks, we've made important progress across our three brain health franchises, and I'm pleased to highlight our next steps for each program. Starting with our depression franchise, we recently announced top-line results from our CORAL study evaluating the efficacy and safety of zuranolone when co-initiated with standard antidepressant treatment or ADT, compared to standard of care ADT co-initiated with placebo in patients with major depressive disorder or MDD. The CORAL study was designed to address whether the rapid onset of efficacy seen with zuranolone in our clinical trials would benefit people with MDD when co-initiated with an ADT. Zuranolone co-initiated with an ADT met the primary endpoint in CORAL demonstrating a statistically significant reduction in HAMD-17 scores at day three, the first measured time point compared to standard of care ADT co-initiated with placebo. Zuranolone, co-initiated with an ADT also met the key secondary endpoint of statistically significant improvement in depressive symptoms over the full two week treatment period at all scheduled visits. Taken together, these endpoints demonstrated a significant benefit of zuranolone in the rapid reduction of depressive symptoms in the CORAL study. Additionally, zuranolone co-initiated with in ADT was well tolerated with no new safety signals attributable to zuranolone identified. Importantly, analysis of results from the WATERFALL and SHORELINE studies identified MDD with elevated anxiety at baseline as a subgroup that is particularly responsive to zuranolone. When treated with standard of care ADTs, this subgroup of patients which represents up to 66% of all MDD patients is less responsive to treatment. In the CORAL study, this pre-specified MDD subgroup was more responsive when co-initiated with a standard of care ADT, than standard of care ADT co-initiated with placebo, as measured by the primary and key secondary endpoints. This finding is important. It's always important in drug development to know where your drug works best, and of course, critical in guiding potential commercial use. Finally, a few thoughts regarding zuranolone's mechanism of action. At the start of the LANDSCAPE and NEST programs, we hypothesize that zuranolone could lead to rapid and sustained improvement of depressive symptoms through restoration of key neuronal networks dysregulated by depression. Clinical trials with zuranolone to-date have generated efficacy and safety data supporting this hypothesis with zuranolone demonstrating the ability to address depressive episodes in a broad spectrum of patients with MDD with a varying profile of depressive symptoms. Zuranolone enhances the function of GABAA receptors, key elements in the brain's primary inhibitory system. GABAergic neurotransmission is vital for normal brain function and significant evidence shows that GABAergic function may be disrupted in depression. Importantly, zuranolone has three major effects on the GABAergic system, enhancing synaptic GABAA receptor function, enhancing extrasynaptic GABAA receptor function and enhancing GABAA receptor expression. These effects of zuranolone we believe all contributes to its clinical profile in treating depression. We're often asked whether members of another class of GABAA receptor enhancers the benzodiazepines have the same effects as zuranolone. The short answer is they don't. Although benzodiazepines share one of the effects with zuranolone, namely enhancement of synaptic GABAA receptors, they cannot match the full profile of zuranolone as they neither enhance extrasynaptic GABAA receptors nor enhance GABAA receptor expression. Benzodiazepines are non-antidepressant drugs, while they are useful medicines that treat a variety of conditions including anxiety and insomnia; they are not approved to treat depressive disorders either alone or in combination with antidepressants. They reported to have minimal effects on depressive symptoms as monotherapy and in some cases have been reported to worsen depressive symptoms. Anxiety and depressive symptoms can also return after cessation of treatment with benzodiazepines. Finally, benzodiazepines carry significant safety considerations both alone and in combination with ADT, including the risk of dependence and withdrawal symptoms, cognitive impacts and drug likeability. With zuranolone, we've seen improvement of both core depression symptoms as well as anxiety symptoms in patients with MDD and PPD in the LANDSCAPE and NEST programs with a differentiated tolerability profile. In the CORAL settings, zuranolone was co-initiated with one of five major antidepressant drugs in current use, including both SSRIs and SNRIs. The demonstration in the CORAL study of significant benefit for zuranolone co-administration with the standard of care ADTs over treatment with standard of care ADTs alone at day three, and over the treatment period was not a small feet. We also looked forward to results from those four subjects who have enrolled in the SHORELINE retreatment study. These data will contribute significantly to a full understanding of the durability of responses to zuranolone in treating MDD. Additionally, in the fourth quarter of 2021 we reported positive data from the zuranolone 50 milligram cohort in the ongoing SHORELINE study in patients with MDD. The SHORELINE study is a naturalistic safety and tolerability study to investigate as needed repeat treatment with zuranolone over a one-year period in patients with MDD. In the zuranolone 50 milligram cohort, the majority of patients who responded to an initial zuranolone treatment course received only one treatment in total, and 80% received only one or two treatment courses during their time in this yearlong study. This means the potential for only two or four weeks of treatment each year. Safety profile on this cohort was consistent with other studies. There was also no dependence, drug likeability or additional side effects. These data will be very useful in our NDA filing. As you may be aware of the FDA has communicated that real world evidence increasingly plays a role as a component in regulatory decision making. We are confident that the SHORELINE study the largest prospective naturalistic study done in MDD aligns with the FDA's efforts to emphasize real world evidence that will transform patient healthcare and drug development. Enrollment in the SHORELINE study is ongoing and has surpassed 1,000 patients. We now have six positive trials with zuranolone in MDD and PPD in the LANDSCAPE and NEST programs. And the profile we have seen in clinical trials to-date includes rapid and sustained reductions in depressive symptoms, a well-tolerated safety profile, improvements in quality of life and overall health across domains of feelings, functioning and well-being that were reported by patients and continued after completion of treatment. A short course of treatment that can be taken as needed with a novel mechanism of action, and a flexible treatment approach that may provide optionality to HCPs and patients. To reiterate our filing strategy, we plan to begin the rolling submission for MDD in early 2022, with the non-clinical modules submitted first. The clinical module will likely be the last module submitted for this filing expected to occur in the second half of 2022. Additionally, the ongoing Phase 3 SKYLARK study of zuranolone in PPD is on track to read-out in mid-2022. We're looking forward to sharing more through several upcoming presentations at scientific forums this year, as outlined on Slide 29 of our corporate presentation. Turning to our neuropsychiatry franchise, we continue to advance the development of SAGE-718 our lead NMDA receptor positive allosteric modulator that is a potential oral therapy for disorders where impairment of cognition is one of the main drivers of disability. SAGE-718 was recently granted Fast Track Designation as a potential treatment for cognitive impairment in Huntington's disease or HD, which is an important benefit in our development efforts to bring this therapy to patients. With the data from the SAGE-718 in HD patients in Phase 1 in hand, we have now begun dosing patients in the dimension study a placebo-controlled Phase 2 study of SAGE-718 in HD cognitive impairment. Additionally, we look forward to initiating enrollment in the SURVEYOR study. Our second Phase 2 study in HD cognitive impairment, expected to commence in mid-2022 with an open label extension study planned to initiate in late 2022. We're also advancing SAGE-718 in patients with mild cognitive impairment due to Parkinson's disease or PD. The paradigm study evaluated patients with mild cognitive impairment due to PD. Based on the positive impact that SAGE-718 had on multiple domains of cognition in that study, we plan to initiate a Phase 2 placebo-controlled study of SAGE-718 in patients with mild cognitive impairment due to PD in mid-2022. Finally, we are advancing SAGE-718 in patients with mild cognitive impairment and mild dementias due to Alzheimer's disease or AD. In the fourth quarter of 2021, we announced positive results from the LUMINARY study demonstrating the patients with mild cognitive impairment and mild dementias due to AD who were on SAGE-718 experienced improved performance from baseline on multiple tests of cognitive function. We expect to initiate a placebo-controlled Phase 2 study with SAGE-718 in patients with mild cognitive impairment and mild dementia due to AD in late 2022. Our confidence in the data seems to-date with SAGE-718 has led us to develop a very robust program across diseases of unmet need. Now I'd like to highlight the advancements made in our neurology franchise led by SAGE-324, a next-generation positive allosteric modulator of GABAA receptors, which we believe hold significant potential in the treatment of neurological conditions like Essential Tremor or ET. Based in part on the positive data from the KINETIC study reported earlier in 2021, we recently initiated a Phase 2b KINETIC 2 dose ranging study evaluating SAGE-324 in ET in late 2021. KINETIC 2 is designed to optimize the dose and frequency of SAGE-324 in ET. I'm pleased to share that the first patient has been dosed in the KINETIC 2 study. In closing, our R&D strategy is both proactive and predictive. Everything we learned from a program can be applied to other programs, leveraging knowledge to define the path forward, while driving for seamless execution, with the goal of addressing unmet needs for patients who need new approaches. We believe our strategy may lead to improve chances of success across depression, neurology, and neuropsychiatric franchises. I'm convinced; our strategy is working, and look forward to providing updates across our three franchises this year. Now I'll turn the call over to Kimi for a review of our financials. Kimi?

Thanks, Jim. 2021 was a pivotal year for Sage. We made important progress across all three of our brain health franchises and achieved key milestones towards our long-term corporate goals. I'm proud of the work we've achieved at SAGE illustrated by the numerous data readout, presentations at medical conferences, and scientific forums and the presentation and the preparation is well underway for the planned filing of our NDA for zuranolone. I'd like to reiterate what Barry noted in his opening remarks. We're well-positioned to advance our mission to pioneer solutions to deliver life changing brain health medicine so every person can thrive. We're poised to achieve what we believe will be a significant progress in 2022, based on tremendous opportunity we have to invest in our robust portfolio. We have a unique opportunity to accelerate our clinical and corporate progress supported by a strong balance sheet. 2022 will be a year of focused execution the year where, if successful, we aspire to create significant value for our society, especially patients, healthcare providers and our shareholders. I'd like to start by highlighting our fourth quarter and end of the year 2021 financial and then provide some remarks on our financial guidance. We recorded $1.6 million in net revenue in the fourth quarter from the sales of ZULRESSO. That compares to $1.7 million of net revenue from the sales of ZULRESSO for the same period in 2020. For the full-year, net revenues for the sale of ZULRESSO in 2021 were $6.3 million compared to $6.7 million in 2020. We remain committed to moms, their families, and all those in impacted by PPD. Research and development expenses were $75.4 million in the fourth quarter, including $9.1 million of non-cash stock-based compensation expense. That was compared to $81.7 million, including $10.1 million of non-cash stock-based compensation expense for same period of 2020. R&D expenses for the full-year were $283.2 million, including $49.7 million of non-cash stock-based compensation expense in 2021, compared to $292 million, excuse me, $292.7 million, including $42.4 million of non-cash stock-based compensation expense in 2020. This reflects the impact of our collaboration with Biogen, as we recognized a reduction in expenses of $79.8 million due to reimbursement under the collaboration. However, this reduction in R&D expenses was partially offset by an increase in spending on our wholly-owned pipeline. We expect to continue to invest in advancing our wholly-owned pipeline in 2022 in a smart and disciplined way. Selling, general and administrative expenses were $51.6 million, including $11.5 million of non-cash stock-based compensation expense in the fourth quarter. That's compared to $53.5 million, including $10.6 million of non-cash stock-based compensation expense for the same period of 2020. SG&A expenses for the full-year were $183.5 million, including $54.9 million of non-cash stock-based compensation expense in 2021 compared to $197 million, including $51.8 million of non-cash stock-based compensation expense in 2020. The decrease in SG&A were primarily driven by the reimbursement from our collaboration with Biogen. As we prepare for the potential launch of zuranolone we expect SG&A expense will increase in 2022. Recall the collaboration includes 50:50 cost sharing in the United States for zuranolone and SAGE-324. We reported a net loss of $124.7 million for the fourth quarter compared to net income of $974.9 million for the comparable period of 2020. For the year-end December 31, 2021, net loss was $457.9 million compared to net income of $606.1 million for the same period in 2020. In both periods, the decrease was due to the collaboration revenue from Biogen in the fourth quarter of 2020. As a reminder in the fourth quarter of 2020, SAGE recorded a $1.1 billion of collaboration revenue from Biogen that consisted of an upfront payment of $875 million plus $232.5 million in excess proceeds from the equity investment under the stock purchase agreement. Finally, we continue to maintain a solid financial foundation ending the year with $1.7 billion in cash, cash equivalent and marketable securities. Turning to financial guidance for 2022, we expect to end the year with approximately $1.3 billion of cash and cash equivalents. We do not anticipate any milestones from collaborations in 2022. Finally, we believe our cash and cash equivalents, ongoing collaboration funding, and potential revenue will support our operations into 2025. At SAGE, we pride ourselves in being courageous, innovative, and efficient across everything we do, always with the line sight on how this work can benefit patient. I look forward to providing updates on our progress. I'll now turn it over to Helen to handle Q&A with the operator. Helen?

Thanks, Kimi. Before I turn it over to the operator, I'll ask that you limit yourself to one question. If you have an additional question, please feel free to return to the queue. Now I'll turn it over to the operator to handle Q&A. Operator?

Thank you. [Operator Instructions]. Our first question comes from Salveen Richter with Goldman Sachs. Your line is open.

Thanks for taking the question. This is Andrea on for Salveen. I'm just curious on the feedback you've received from physicians post the CORAL results, has their view on how they would use the drug or maybe even who they would treat changed in any way. Thanks so much.

Yes, Andrea, thanks for the question. I'll start and I'll ask Jim to comment because we have received quite amount of feedback. I can tell you that the feedback we've seen from potential prescribers post CORAL is quite encouraging, the rapidity of effect and the well-tolerated profile in fact, some -- in some instances in the GI effect improved profile when zuranolone is combined with an antidepressant really opened eyes and was very encouraging in the minds of KOL. I will also tell you that the prospective analysis that we did with MDD with elevated anxiety was particularly interesting. As we talked on the call, MDD with elevated anxiety are also called anxious depression, are patients that are not well served by current standard of care. That's well documented, literature including STAR*D. So they we're very interested in having a new drug to treat a patient population that they have said historically is very, very hard to treat. Let me ask Jim to talk about additional feedback, and then maybe Chris can talk about some of the patient types that we're hearing from potential prescribers. Jim?

Sure, Barry. And as Barry mentioned a lot of encouraging feedback really across a couple of different domains, certainly, when you think about the CORAL study, we're talking about co-initiation with a standard of care antidepressant. And we had chosen in our design to include sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine. So really a broad sampling of the standard of care antidepressants in an open label format and physicians were impressed both with the ability of zuranolone to demonstrate in improved performance over that broad range of antidepressants, also quite a bit of interest in the tolerability profile of zuranolone relative to other standard of care antidepressants. And finally, just to reiterate to Barry's point, we're very, very encouraged by the results that we've seen in the cohort of subjects who show elevated anxiety at baseline, who seem to be very sensitive to treatment with zuranolone which is in contrast to as we keep hearing from KOLs. There the challenge in treating those patients with standard of care antidepressants. So overall, we've been very pleased with the feedback we've been hearing so far from KOLs. Chris, do you want to talk a little bit about patient types?

Yes, I think with respect to patient types, first, let me take a step back, when you consider what's happening in this marketplace, 70% of patients are either initiating or switching therapies over the course of a year. And as Barry pointed out, many of those patients are switching multiple times in a given year. So what clinicians are really looking for is a therapy that works rapidly, that sustains effect over time doesn't carry the stigmatizing side effects of some of the other therapies like sexual dysfunction and weight gain. And quite frankly, can be taken in a short course over a shortened time period that allows them to sustained effect over as we know from our studies up to a year. So with that said, when you have conversations with clinicians, whether the KOLs or those that are out in practice every day treating patients that are suffering with MDD and PPD, they're looking for those attributes of a therapy, a therapy that works rapidly and sustained effect. And with CORAL, what we've effectively done is we've said, with this therapy, there's an opportunity to demonstrate rapid efficacy as early as day three and with studies like SHORELINE did to pair that up that there's the sustained effect over time. So when you think about the practical patients that these physicians may see it may be a young adult, like a college student, or someone starting their first job who really needs that rapid and lasting effective therapy without those stigmatizing side effects. And quite frankly, that patient may also present with elevated anxiety as a feature of their MDD that they're telling us that patient's like that young adult or an older adult that can't really stand to be on chronic therapy for the rest of their life and is really looking for therapy that works rapidly and lasts. That may be another particularly good place to go. So there's a number of patient types that we've heard. But again, it's pairing CORAL with the other work that we have, and really reinforcing the opportunity to make a difference in the lives of patients who need a therapy like zuranolone.

Thank you. Our next question comes from Cory Kasimov with JPMorgan. Your line is open.

Hi, good morning. Thanks for the question. This is Tiffany on for Cory. Just one on 718, so with multiple large randomized Phase 2 trials and these different indications out for the year and at SAGE in Huntington, can you characterize what you would consider meaningful results in each of these three populations? And we're also just interested in how long these trials will take. Is it fair to expect data in 2023? Thanks.

Yes, Tiffany, I'll start and I'll ask Jim to comment further. So, yes, 2023 is certainly possible, although when as we start trials is really important to get sites up and running and understand what accrual rates look like before we can provide proper guidance. And we'll do that as soon as we can. But let me take a step back. So SAGE-718, as we highlighted, is a first-in-class positive also modulator targeting NMDA. We are studying SAGE-718 to demonstrate the improvement in cognitive impairment across a variety of neurological diseases. And as we highlighted in the call, and in past calls, we have seen data in Huntington's, Parkinson's and Alzheimer's, consistent with the ketamine placebo-controlled study, where we saw significant -- significant, significant impact between placebo and drug. And the data that we're seeing across all three neurodegenerative diseases is consistent with that. You mentioned the word large trial. So unlike drugs that are trying to demonstrate changes to disease progression, and in fact are studying the slow decline of cognition over a long period of time, recreate requiring long timeframes and big ends, we believe that the features of SAGE-718 will allow us to conduct shorter-term trials with a smaller end because we're actually measuring, sustained or even improvement in cognition. So we're really excited across all three of these neurodegenerative diseases. Jim, you want to provide some more?

Yes, Barry. Just a little bit of detail around the DIMENSION study for SAGE-718. I think the key of course is to replicate the findings that we've seen from our earlier studies that Barry is referring to; we're actually seeing improvements in cognitive performance over a two week or so period of time. So the DIMENSION study, as will be the case for the PD and AD studies as well is intended -- is a three months study, placebo-controlled really looking to replicate that benefit that we've seen with SAGE-718 improving cognitive performance in both executive function and working memory domains.

Our next question comes from Yasmeen Rahimi with Piper Sandler. Your line is open.

Good morning team. Thank you for taking my questions. I would love to hear your thoughts as we head into the SKYLARK data, just to level set obviously, the ROBIN data in about 150 patients showed a four point difference in HAMD-17. The effects were continued throughout day 42. So remind us as we head into SKYLARK like what are changes that were introduced into the study compared to ROBIN, which should be our expectation given that this is a 50 milligram dose group and ROBIN ran 30 meg, so I think I would love to hear your thoughts as we head into the data, whether we should be expecting equally as good ROBIN data better than ROBIN data and maybe some rationale around it could be helpful. Thank you for the longwinded question.

Thanks, Yas. I'll provide some context. And then I'll ask Jim, to really get into the details of SKYLARK and the changes. You've highlighted reading the 50 milligram dose in the SKYLARK. So it's a bigger, it's a bigger study of higher dose more centers. And I'll also highlight that PPD often presents as depression with elevated anxiety. So we're really enthusiastic about helping moms in SKYLARK trial. Jim, you want to talk about some of the other specific differences and what we expect?

Sure, Barry. I think, of course Yas, the key point is the design of SKYLARK is intended to be similar to the design to ROBIN. So we haven't made that many changes in the overall set of design. I think you've already highlighted the major one I would point out, which is the dose is 50 milligrams, where the dose in ROBIN was 30 milligrams. And what we've seen from other studies in the program, and notably in the SHORELINE and WATERFALL studies, 50 milligram dose, as predicted seems to have an impact in overall response in the positive direction where in the WATERFALL study, we saw significant certainly higher numbers of patients showing the beneficial effect of the 50 milligram dose. I think the other major element that's different in the SKYLARK study is the overall size of the study. So it is a larger study than the ROBIN study. So with those differences in mind, we're really expecting to see a similar kind of response in the SKYLARK study that we've seen in the ROBIN study and I would also note the profile similar to what we've seen in PPD studies with zuranolone.

Yes, we're really excited by helping the envelope for SKYLARK and moving forward PPD as well.

Thank you. Our next question comes from Laura Chico with Wedbush Securities. Your line is open.

Hey, good morning, guys. Thanks for taking the question. Just a follow-up on SKYLARK, I apologize if I've missed this, but I guess my question would be, can you just remind us around the powering assumptions for SKYLARK at both the 15 day and 42 day endpoint. I guess what I'm trying to understand is how we should be thinking about the magnitude of effect at both of those time points? Thank you very much.

Yes, Laura, thanks. Jim, you want to take that?

Sure, Laura, as you know, we don't get into the specifics of powering assumptions for ongoing studies. But I think similar to the question we were just talking about, we really have been guided by results from earlier studies, most notably the ROBIN study and are thinking for the design of the SKYLARK study. So we're confident that we've got the study size appropriately to demonstrate a significant difference for zuranolone at the key time points, of course the primary endpoint being at day 15.

Right. And let me just, thanks Jim. And let me just emphasize that we expect to see a statistically significant difference at 15, we don't necessarily expect to see that at day 42. The key here is that these moms get better fast and stay better. It's quite possible and it can be expected that at day 42 the placebo arm catches up. Thanks, Laura.

Thank you. Our next question comes from Ami Fadia with Needham & Company. Your line is open.

Hi, good morning. Thanks for taking my questions. Just with regards to SAGE-718, could you layout for us the clinical development strategy beyond the Phase 2 trials that you are planning to initiate this year what would be the next step? And how do we think about kind of the timeline? And what would be the endpoints that the FDA would need for an indication in NCI across Huntington's, Parkinson's and AD? Thanks.

Yes, Ami, thank you. And thanks for your note this morning. So I'll start and I'll ask Jim to elaborate further. So as you've highlighted, I mean, we've started the Phase 2 studies with Huntington's disease, and it's a program rather than just a single study. And as we articulated, we plan on starting the Phase 2 Parkinson's study midyear and the Alzheimer's study towards -- more towards the end of the year. We are starting with Huntington's because the biologic hypothesis of SAGE-718 started with Huntington, but it also is advantageous for us to start in a disease where we have fast track. But that's also an orphan disease because we can work with the agencies to make sure that we have the endpoints that that matter. And to be frank, if the Phase 2 studies are wildly positive, we will certainly work with the agencies to understand next steps, including potential registration on top of those Phase 2. It's likely that with Parkinson's and Alzheimer's will require bigger or Phase 3 studies. Jim, do you want to talk about endpoints and how we're thinking about CogNEXT and specific disease endpoints?

Absolutely. Yes. And I mean, as we think about the development program for SAGE-718, we talk a lot about following the science. As Barry mentioned, in each of the different indications, we do have good evidence for both NMDA receptor involvement in those patients. But through our earlier work, also showing some reasons to believe that SAGE-718 is improving cognitive performance for all these patients. And then it really is also about efficient design. So Barry mentioned in the case for Huntington's disease, this is -- it makes sense from the science point of view but also offers a different pathway forward with an orphan population. I think we'll have to see in the PD and AD patient populations, what the path beyond the next set of studies looks like. But we tend to think in terms of what we would call serially de-risking. So we're adding to the evidence that we have with this very novel mechanism of action. To that point, as we think about endpoint, the primary endpoints in this set of studies are designed to directly follow-up on the work that we've done in our CogNEXT program. But we're also very well aware that the FDA and other regulatory agencies are interested in understanding the real world benefits of improving cognitive performance. So in our studies, we're also looking at ways of bridging to measures of function that would be meaningful for patients with these various disorders. So It's -- there are several things going on as you enter this phase, really were -- the main effort is to show a significant benefit in cognitive performance relative to placebo, but we also will be looking at understanding how that translates into benefits that are meaningful to patients. And we think that will be an important part of the program moving forward.

Got it. And then just a quick follow-up so in Huntington, would a three-month endpoint to be adequate for approval? Do you have visibility at this stage about that?

Yes. Ami, not -- not quite yet. I mean we are engaged with the agency to talk about durability. Again, we're doing something that's never been done before demonstrating the potential improvement in cognition, which we think we can demonstrate over a short period of time. We've seen it in a couple of weeks. We now want to demonstrate it across three months. And as I mentioned, if the studies are very positive, we'll be aggressive in working with the agencies to figure out how we can get this drug to more Huntington patients to start.

Thank you. Our next question comes from Paul Matteis with Stifel. Your line is open.

Hey, thanks so much for taking my question. I wanted to use this opportunity to maybe ask about sort of the two bear cases that are floating around on SAGE with the stock where it is and maybe one on the regulatory side and one on the commercial side. On the regulatory side, I think the question I get a lot, I'm sure other analysts do too, centers around the as-needed dosing approach, SHORELINE and whether or not with the totality of the data, physicians and regulators are going to have enough information on how to dose the drug? And how to kind of think about in SHORELINE, there was the six-week interval between doses and how will that all sort of play out in real world in depression practices? And then on the commercial side, I think the other area of skepticism, right, is an overarching view that changing the treatment paradigm is hard generating use for a new branded drug that's more expensive than primary care practices is hard and that maybe the lower-hanging fruit, you could argue would be in treatment refractory patients or pricing higher and really prioritizing PPD and MDD subpopulations. And so I'm sure you guys have heard this a lot. I certainly hear it a lot. And I would love your perspective on both of those issues? Thanks so much.

Yes, Paul, thanks for the question. So let me start with both regulatory and commercial. And then I'll ask Jim to comment further on regulatory and Chris to comment further on commercial. So I'll remind you that at the beginning of last year, we articulated that we designed a LANDSCAPE and NEST programs in conjunction with the FDA, two studies in MDD, one in PPD, any one of which is positive, constituted a fileable package. In the fall of last year, following positive WATERFALL we reiterated the consistency of discussions we've had with the agency that WATERFALL constitute a filing package. However, there were two outstanding studies, one in MDD CORAL and one in PPD SKYLARK and they suggested and we agreed that we first filed an MDD, including the CORAL study and then with PPD, including the SKYLARK study. So we're thrilled, and we've discussed it, the CORAL was positive. Now the other theme running through the year is that we observed in the literature that patients with MDD with elevating anxiety or anxious depression, as well documented literature were not well served with current antidepressant. We did a retrospective analysis across our data and discovered that zuranolone was particularly useful in MDD, but particularly with MDD with elevated anxiety. And then we prospectively designed that that population, that subpopulation into the CORAL study. And that's about two-thirds of those annually diagnosed with MDD not well served with antidepressant. So you can see that we have a very rich package for MDD with a pre-declined subpopulation, MDD with anxious -- with elevated anxiety that current standard of care doesn't work well. So we're quite enthusiastic about the regulatory path forward. Obviously, following SKYLARK will file an NDA for PPD. So we're really excited about both MDD and PPD and have a subpopulation in particular, to guide potential treating physicians where the drugs just don't work well today. So it's not like I've got a whole bunch of opportunities in my arsenal to help these cases with MDD with elevated anxiety. And now turning to commercial, and Chris can highlight it, there's five particular patient types that are not well served with current antidepressants where zuranolone, particularly those with MDD with elevated anxiety can work particularly well. And also, we're leaning in with proactive value-based agreements. So what we're trying to do is work with payers to share risks, so they have budget certainty and understand the right patients to treat with zuranolone so that we don't get staffed. We don't get blocked. There isn't a whole lot of paperwork to make sure that a patient in need of zuranolone gets it. So again, we've got work to do on the commercial side, but we particularly have ways that we're guiding potential prescribers on very specific patient types. So all in there, Jim, you want to talk more about regulatory and then Chris maybe pickup on the commercial piece?

Yes. And Paul, I think what I would want to emphasize is when you step back and look at the program, we're talking about, yes, six positive trials at this point and eight trials overall looking at patients with depression, so 3,500 patients. And again, as you think about assembling the whole package of zuranolone, we have data both as monotherapy as add-on with co-initiation with or without antidepressants, standard of care antidepressants, multiple antidepressants, multiple patient populations, as Barry was saying, demographics across a very wide range and truly a differentiated tolerability profile. As you think about all of those elements, of course, that was the original intent in the broad LANDSCAPE and NEST program is to provide a series of data points to help both providers, patients, payers an understanding of this differentiated novel approach with zuranolone. So we're very excited and we're very comfortable moving forward as we assemble this package that we have the right information to help people understand how to best use zuranolone moving forward. Chris?

Yes, thanks, Jim. And to add context Paul, to what Barry already said, given around the commercialization thinking that we're currently employing. We're out speaking to practicing clinicians every day. We're talking to payers, whether they're national payers, regional payers, PBMs, or IDNs. And certainly, we're engaging with patients and patient advocacy groups to really understand what it is that they're looking for in new therapy. And I think in Barry's remarks, he hit it really well. This is not a well satisfied market. And as I mentioned earlier, there's a substantial amount of switching going on because patients are looking for better options, clinicians are looking for better options for their patients. And payers certainly recognize that with respect to what they see at a planned level, that there is not a satisfied patient population there with respect to either the efficacy or the safety with the access that they have to currently available ADTs. And it's an even more dire situation in the PPD world where there are even fewer treatment options for those moms that are really looking for care. So with that being said, we recognize and as I mentioned earlier, in the conversation that there are five patient types, I've spoken about the treatment age in young adult and the older adult. There -- there are many patients that are on ADTs that are still suffering. There are patients that are experiencing breakthrough symptoms associated with their depression because there's a death of a loved one or perhaps a job change or their adherence challenge patients who quite frankly, never get to really experience the benefit of their ADT, because they don't have the time to wait six or seven weeks in order to see that benefit or the side effects to through them from ultimately reaching the efficacy that they so desperately want and deserve. So with that being said, as you think about it, MDD with elevated anxiety is a thread that connects many of those patient types, whether they're MDD patients or PPD patients. And we have an opportunity to do better with zuranolone for all these patients and provide them with a rapid and lasting therapy that they deserve.

Thanks. Can I ask one quick follow-up? Just this is all really helpful. On SHORELINE specifically, this is I think, where Jim, I just wanted to get your feedback on regulatory. Historically antidepressants, right have been approved with acute evidence of efficacy, as you've alluded to, and then open label extension data. And this whole idea of maintenance of benefit is usually a post-marketing issue. But given away this drug is dosed, right, I think the maintenance question comes into play probably earlier. Do you agree with that? And I guess, if you're talking to a doctor, and they say, hey, if I give this drug for a few weeks, and the patient does better, and then they feel worse three weeks later? How does kind of re-dosing work? Because I think in the SHORELINE study, you're restricted to not re-dose for at least six weeks. And I'm just wondering if this is a regulatory question or not? Or if you think I'm harping on something that's ultimately irrelevant. Thanks?

Jim, you want to start and I can round it out. And thanks, Paul, for the question.

Absolutely. Yes, Paul so I would distinguish, of course, in a clinical trial, we have very specific parameters in the protocol. But really, this study was designed to address exactly the question that you're asking, which is, what are the conditions on which subjects would need retreatment? And so we do have some very specific metrics in there that can be used. But I think really, the important point is that what you're seeing in the study is that the -- for the vast majority of patients that actually is a relatively long interval, right? So you've got a 50 milligrams, the majority of patients over 50%. It's that one, two week course for a year, and you're up to about 80%, when you look at one or two courses. So I think, yes, this is something that will need to be addressed in practice. But I don't think that it's going to be that complex, a process for physicians to move to. And the study in SHORELINE is designed to provide that real world evidence of exactly how to do that.

Yes. And just to just to round it out, and thanks, Jim, you just round it out. From a commercial perspective, Paul, we imagine that that most of the patient population will be that two to four weeks of drug. There'll be very few that need the third, fourth or fifth dose. And if someone takes two weeks and rebounds immediately, that's not how zuranolone was designed. For the 75% of patients that respond in SHORELINE. It's for that group, there will be some were a different chronic medication may be more appropriate and zuranolone is not the right answer. But, for those patients, particularly MDD with elevated anxiety zuranolone is the right drug to reach for.

Thank you. [Operator Instructions]. Our next question comes from Tazeen Ahmad with Bank of America. Your line is open.

Hi, guys, good morning. Here is my one question. So if you do -- if you do end up in a discussion with the agency and the agency feels like maybe at least initially, this drug might be best served for induction therapy, and maybe you need to submit additional data over time. Is that a scenario that you've planned for? And how should we think about what the initial commercial opportunity would be if that's the case? Thanks.

Thanks, Tazeen. Thanks for your one question. So we -- and Jim's highlighted this. With now CORAL, we have data in over 3,500 patients. We have data with zuranolone monotherapy, about two-thirds of the patients before CORAL were monotherapy, but a third, were on top of a stable antidepressant. And then CORAL, as we've highlighted was the first time we have data was around when we co-initiated with the five different standard of care antidepressants that Jim's highlighted. So we think we have a very rich package. The new induction or not, so zuranolone is meant to treat for two weeks, get someone better fast as measured at day three and keep them better. As we've already highlighted, SHORELINE indicates the majority of patients in the SHORELINE, which is more a real world situation, only required two week treatment. So induction or not, I think the majority of patients out in the commercial world will try it -- will require two weeks in the course of year and maybe even longer. I mean, the SHORELINE study, follow them for a year. I'll also remind you that we're rolling patients from CORAL onto SHORELINE. So it'd be quite interesting as those data rollout to understand what happens with zuranolone CORAL issue with antidepressant versus antidepressant alone, and how many retreatments that that group needs. Chris anything to add?

Yes, there's something that I would add. And I think Barry, you covered this really thoroughly. But taking a step back, clinicians want to send patients home with a solution when they prescribe a product. And they want that solution to work rapidly and to last over time. And quite frankly, with respect to the data that we've already demonstrated, we've seen that this therapy works rapidly as early as day three, it sustains effect out to a year, and it has the safety profile that is unmatched with respect to some of the other therapies that are out there with respect to sexual dysfunction or weight gain or the fact that we haven't seen it with zuranolone. And the ability to take this over the short course is incredibly desirable for patients who don't want to be on chronic therapy in perpetuity for the rest of their lives. So we believe that with what we're delivering, we are delivering a therapy, putting it in the hands of clinicians to ultimately enable patients to go home with solution that as early day 3, they'll know that it works.

Thank you. Our next question comes from Yatin Suneja with Guggenheim. Your line is open.

Hey guys, thank you for taking my question. So question is on the future application or additional application of zuranolone? So specifically in anxiety, I think across the landscape studies, you have seen benefit in patients that have elevated anxiety. What is your view on evaluating; maybe think studying zuranolone in acute anxiety? And can you also talk about like other indication I understand MDD, PPD are very big opportunities, but like other indication other applications of this pathway? Thank you.

Yes, thanks for the question. I'll start, and I'll ask Jim to kind of round it out. So as we've talked about before, and you just said, we've got almost 7 million people per year in the United States alone that are diagnosed with MDD and prescribed an antidepressant and one in eight women experiencing live birth experience PPD so that those opportunities are very large. Our strategy along with our collaborators is really to do what we need to do to win in MDD and PPD, including a robust Phase 3, Phase 4 program following hope to see an approval of zuranolone. So that's the strategy. Now there are other areas that we've talked about developing general anxiety disorder, seasonal anxiety disorder, which will be things we'll be talking about in the future. But the real focus is to make sure that we have all the data we need to continue to provide the marketplace for appreciation of how to best use zuranolone in MDD and PPD. Jim, do you want to add?

I would only add that we are certainly we have additional endpoints on our studies that we use to sort of fully understand the overall profiles of zuranolone. But to Barry's point, there's a significant focus on the indications that we're currently talking about. We are continuing to collect data on anxiety benefits. We've talked earlier about the benefits of zuranolone on sleep. So of course, there are additional effects to zuranolone that we think could be of benefit, but those are for later evaluation.

Got it. Could I squeeze one more, it's on the P&L for Kimi. So with most of the studies or Phase 3 studies now behind us, can you just help us model R&D going forward, should we expect it to go down? I understand you gave the cash guidance and also about G&A or SG&A, as you start thinking about commercialization? Is it like a second half ramp up? Just help there? Thank you.

Yes. Let me start. So as you very well know, we're partnered on zuranolone and SAGE-324 with Biogen and get significant reimbursement for our efforts. And of course, Biogen is doing the heavy lift ex-U.S. for both programs in which we get royalty. So we're very enthusiastic about the partnership. As we've highlighted, SAGE-718, particularly starting with an orphan disease like Huntington's is a product that we can globalize on, and that's our strategy. We will -- assuming positive data, strong data approval package. We intend on bringing SAGE-718 to as many countries as it makes sense for us to do given the success of zuranolone, 324 in our balance sheet. So we do plan on recognizing revenues from multiple countries around the world in the future for SAGE-718. Kimi, do you want to take the rest?

Sure. So the question on expenses and want to think about there. During the year, we did talk about the fact that we believe that our operating expenses were going to increase, and that really related to the execution of our expand and accelerate strategy some of which Barry just highlighted with SAGE-718, when you look into 2022, we're going to have three clinical trials across three indications in SAGE-718. So that will be a big program. We're also and we committed to making a digital investments in our early clinical and research engine. Again, there is where we want to really leverage what we have our expertise in brain circuitry and making sure that we have our next clinical candidates. So those -- the expand and accelerate strategy will continue to execute on 2022. So that again will lead to increases in R&D expenses over the year. On the SG&A front, we will see additional increases in SG&A, again, as we continue to ramp the prelaunch activities together with Biogen.

Thank you. Our next question comes from Douglas Tsao with H.C. Wainright. Your line is open.

Thanks. Good morning and thanks for taking the questions. I was just curious in terms of the CORAL data in terms of the day 3 benefit that we saw, was there sort of a disproportionate benefit in any of the domains of MDD. And I'm just curious how big a contributor to the improvement were some of the sleep components? And also, I guess, perhaps, CORAL to the areas sort of where you really see improvement change from day 3 to day 15? Thank you.

Yes. Thanks for the question. So I'll start, and then Jim, maybe you can carry it down. We presented top-line data. We'll certainly present breakdowns of components of HAMD-17 in future congresses. But as we've seen in -- saw improvement across most of the domains in HAMD-17. It wasn't just one particular feature or not. But Jim, do you want to talk about your thoughts there?

I think that's the key point, Barry. What we have seen consistently is improvements across all of the domains of the HAMD-17 with zuranolone and that will be the same thing for CORAL. We will, of course, be digging in more detail into individual pieces of data and communicating that as we go-forward. So we will be looking at the distribution of HAMD scores over time. But I think the key point is that we see as a pretty consistent picture of effects of zuranolone across the domains of the HAMD.

Our next question comes from Jay Olson with Oppenheimer. Your line is open.

Hey, guys. This is Matt on for Jay. Thank you for taking our questions. Barry, I was going to ask you specifically a question. Just curious since you joined as CEO I believe, since December 2020 already just curious how you viewed the evolution of SAGE since you took over and also if your vision for the company has changed at all since that time? And also just how you view personally the next 3 to 5 years. I really appreciate it.

Hey, Matt, thanks. Look, it's been phenomenal in terms of what everyone at SAGE has accomplished and how we work with our collaborators, both in Japan and at Biogen and the progress. When I started, as you mentioned, in 2020, we had three late-stage programs ran on SAGE-324 and SAGE-718 and a number of studies in front of us. We stand here today with a robust pipeline. Those three late-stage programs are continuing to move forward. In fact, we're preparing to file the NDA for zuranolone earlier this year. So everything we planned on doing is actually being certainly being executed. Obviously, the weakness of Biotech across the board starting in February last year certainly isn't helpful for any of us. But as you heard from me and from Kimi, we have a very strong balance sheet to execute on or expand and accelerate. So the view that I had coming in that we could be the leaders in brain health and a top-tier biopharmaceutical company remain we're on track to make that happen.

Our next question comes from Akash Tewari with Jefferies. Your line is open.

Hi, thank you taking our questions. This is Leo [ph] for Akash. Could you help us understand the real commercial opportunity in PPD? And obviously, ZULRESSO launch has been just quite disappointing, but what have you learned from engaging that market? How many patients can you identify as a low-hanging fruit? And how many of those issues had diagnosing of this patient type being? What specifically about zuranolone would allow you to expand this market beyond the success ZULRESSO have? Thank you.

Yes, thanks for the question. Chris, do you want to start and then I can round it out.

Yes. Thanks, Barry. So as you may be aware, there are one in eight women who with a recent live birth experience have experienced postpartum depression, and that's not acceptable with respect to really those moms having to suffer through the symptoms of depression. And as we've noted earlier, the anxiety that's often associated with that. So respect to the postpartum community, we know that there's an opportunity for us to do better with respect to our ability to provide them with a solution like ZULRESSO or subsequently zuranolone, if approved. So with that being said, we've learned a tremendous amount from our experience with ZULRESSO around how to engage with clinicians how to engage with patients and patient advocacy organizations and also how to engage with payers to assure the availability and the access to medications like ZULRESSO so that as we move forward, that we have a really strong knowledge base to build on that we can introduce zuranolone into that market and into that community. Now one of the questions you asked is the points of differentiation and how that may impact commercialization. Certainly, ZULRESSO with respect to how it's administered in office is very different from zuranolone as an oral formulation that enables moms to take the therapy in the comfort of their own home over a two-week short course of therapy in order to see the benefits that we've seen in our clinical studies to-date. So with respect to how we see this evolving, it's going to profoundly change the way postpartum depression is treated. Now that moms will have the opportunity to take something that has the safety and the efficacy profile of zuranolone. And as I said there's a substantial number of these women who really need a therapy because right now in the marketplace, there is not something other than ZULRESSO that's meeting their needs. Barry?

Yes, Chris, thank you. And let me just round that out. So because we're in the market right now we are understanding really important pieces of how to treat the people, it's very important. Moms are taken care of by OBGs until the baby is born, and all focus turns to the baby and off the mom. So understanding prescreening questionnaires that need to be put in place, they're available our check on mom's program, making sure that every mom has a plan for the fourth trimester, a number of capability of putting in place now will help. And really, many of the KOLs vision is to understand moms at risk and send them home with a prescription, for zuranolone should they need it. So they aren't in danger or endangering the babies or family. So we're certainly learning a lot and we'll be well prepared to help, as Chris said, the one in eight live births that have potential to suffer from PPD.

Thank you. Our next question comes from Sumant Kulkarni with Canaccord. Your line is open.

Good morning. Thanks for taking my question. So what are some of the specific factors that might prevent immediate zuranolone retreatment? Is it patient response characteristics such as the average duration of maybe an MDD episode or more related to the pharmacology of the drug itself? I guess this goes back to what were the main variables that made you focus on 14 days of therapy versus, say, a more acute 3 days or 28 days to potentially ensure more durability?

Yes, Sumant, thanks for the question. And Jim, do you want to start and then I'll again provide some color at the end.

Yes, of course, Barry. And Sumant really, I don't -- I wouldn't say that there are pharmacological aspects. I mean what we're seeing is a rapid response to zuranolone. And what you see by the end of that two-week course is a pretty robust response and a response that has achieved it's close to a maximum response. So it is much more about benefit being seen with the two-week course of treatment than anything to do with the pharmacology.

Yes, thanks, Jim. And Sumant, again, I remind you that the observation that's been made by SAGE and collaborators is that neuro networks are dysfunctional in very specific ways when people are living with depression, and zuranolone is designed to reregulate those neuro network spectrum normative state. And the two-week course of treatment was, of course, hypothesized to make that happen. As Jim said, we're seeing that happen very well in the majority of patients as evidenced by SHORELINE. Now in terms of specific retreatment, keep in mind that a patient will come in with a dark and mood, often elevated anxiety inability to sleep. They'll know in two, three days that if zuranolone is working for them or not. And again, the majority of patients, it does and the instructions that the office will give is it should work in a couple of days. We'll check in with you in two or three days. And after you're done your therapy in the weeks following, if your mood darkens, your anxiety increases, your sleep is further disrupted, let's either refill or call the office for a retreatment. It really will be pretty straightforward in the real world.

Our last question comes from Vikram Purohit with Morgan Stanley. Your line is open.

Great. Good morning. Thanks for taking my question. So I had two on SAGE-324. So for the Phase 2 study expected to begin in mid-2022, what can you say at this point about study design, particularly about which additional parameters beyond safety that you might anticipate evaluating here? And secondly, what level of regulatory interaction have you had on 324 and what do you think the path is to a pivotal program here?

Yes. So let me start and then I'll ask Jim. So we -- the design for the KINETIC 2 study is in our materials on our slides. But quickly, it's a multimode study with the objective of having a dose in frequency to move SAGE-324 into a Phase 3 study. We're studying tremor amplification or reduction in tremor amplification as well as activity as daily living at 15, 30 and then 60-milligram dose. And for those that are on the 60-milligram dose, we're titrating over a very specific six-week period to do that. And we're looking at the kind of parameters we looked at for the KINETIC study. I'll remind you that in the KINETIC study, we saw a statistically significant reduction in tremor amplitude. We also saw a correlation between activities of daily living and reduction in tremor amplitude, which is very helpful for path forward because it's likely that the Phase 3 study will be that feel function well-being activity of daily living type study. So that's how we think the path -- the path forward will look. Jim anything to add?

I think what I would add, Barry, is conceptually -- and Barry said it, the endpoint in the study is similar to the endpoint from the KINETIC study and that's important for continuity but it's also important that we -- as we think the pivotal studies, we also build that bridge to endpoints that are consistent with the benefit the patients are going to receive. So activities of daily living will be an element of the study. So we have both the bridge to the primary endpoint that compares to back of the KINETIC, but also looking forward, we'll be looking at showing what are the benefits to patients in their daily lives that this reduction in tremor is providing.

Thank you. And that's all the time we have for questions. I'd like to turn the call back to Barry Greene for closing remarks.

Thanks, everyone. Thank you, Operator. We really appreciate everyone joining us today for the progress we made for all of 2021, specifically our fourth quarter. I'm grateful for the entire Sage team, our patients, caregivers, clinical investigators and all dedicated so much to advance our mission to become a leader in brain health. I think the progress we made last year really sets us up for a strong 2022 and beyond. As I said in the call, I'm very confident that we are emerging as a leader in brain health. And over the next couple of years, we'll be a top-tier biopharmaceutical company. Thank you.

Goodbye.

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