Q2 2020 SAGE Therapeutics Inc Earnings Call

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I want to the Sage Therapeutics second quarter 2020 financial results conference call at this time optimize ARNA listen only mode. That's just because presentation. There will be a question answer session.

Operator: You are joining the SAGE Therapeutics Second Quarter 2020 Financial Results Conference Call. At this time, all participant lines are in a listening mode. After the speaker's presentation, there will be a question and answer session. If you would like to ask a question during the session, you will need to press * 1 on your telephone.

That's a question during the session the need to press star one of your telephone.

Operator: Please be advised that today's conference is being recorded. If you require any further assistance, please press star 0. I would now like to hand the conference over to your speaker today, Jeff Boyle, Senior Director, Investor Relations. Thank you.

Please be advised to today's conference is being recorded.

Ocwen further system Star zero.

I would now like to kinda comping over to speak today, Jeff well Senior director Investor Relations. Thank you. Please go ahead Sir.

Good morning, Thank you for joining Sage Therapeutics second quarter 2020 financial results Conference call.

Jeff Boyle: Good morning, and thank you for joining SAGE Therapeutics' second quarter 2020 financial results conference call. Before we begin, I encourage everyone to go to the Investor and Media section of our website at sagerx.com, where you can find the press release related to today's call, as well as the slides that contain supplemental details. I would like to point out that we will be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially.

Before we begin I encourage everyone to go to the Investor and media section of our website at <unk> Dot Com, we can find the press release related to today's call as well as it applies the containing supplemental details.

I would like to point out that we'll be making forward looking statements, which are based on our current expectations and beliefs.

Statements are subject to certain risks and uncertainty and our actual results may differ materially. Please consult the risk factors discussed in todays press release and interestingly filings for additional details.

Jeff Boyle: Please consult the risk factors discussed in today's press release and in our SEC filings for additional details. We will begin the call with prepared remarks by Dr. Jeff Jonas, our Chief Executive Officer; Mike Clunan, our Chief Business Officer; and Kimi Iguchi, our Chief Financial Officer. We will then be joined for the Q&A session of the call by Dr. Steve Kames, our Chief Medical Officer, and Jim Doherty, our Chief Research Officer. I will now turn the call over to... Thanks, Jeff.

We will begin the call with prepared remarks by Dr., Jeff Jonas Our Chief Executive Officer, Mike Cronin, Our Chief business Officer, and can you go to our Chief Financial Officer. We will then be joined for the Q and especially on the call by Dr., Steve came to our Chief Medical Officer, and Jim Doherty, Our Chief Research Officer.

Well now turn the call over to John.

Thanks, Jeff.

Jeff Jonas: And thanks, everyone, for joining us this morning. We're pleased to update you today on our second quarter and progress across our development programs. Today, I'll provide an overview of our second quarter activity and discuss our depression, neuropsych, and neurology franchises. Then Mike will provide a more detailed business update, and lastly, Kimi will provide an update on financials.

And thanks, everyone for joining us this morning.

We're pleased to update you today, and our second quarter with progress across our development programs today I'll provide an overview of our second quarter activity and discuss our depression narrow psych and neurology franchises, then Mike will provide a more detailed business update and lastly can be will provide an update on financials.

As all of you are aware, we're operating in a new environment with the challenges at the global covert 19 pandemic. However, even in the face of these challenges I'm pleased to report that execution of our clinical programs remains on track.

Jeff Jonas: As all of you are aware, we're operating in a new environment with the challenges of the global COVID-19 pandemic. However, even in the face of these challenges, I'm pleased to report that the execution of our clinical programs remains on track. We're aware that some companies have made the decision to stop or pause recruiting or enrollment in clinical trials, but I'm pleased that the teams at SAGE were proactive in their planning and management of our trials. As you know, our lead clinical asset is ziranylone in studies for major depressive disorder and postpartum depression. Additionally, we have SAGE 324 in development for essential tremor, and SAGE 718, which we are exploring based on early study findings we believe are compelling for its potential in areas where executive function is impaired. Based on our progress in the last six months, we expect to have numerous catalysts coming over the next 18 months. We've been able to advance several programs and have had strong enrollment to date, and those are antelope and waterfall studies.

Well aware that some companies made the decision to stop a pause recruiting or enrollment in clinical trials, but I'm pleased that the teams that phage were proactive in their planning and management of our trials.

As you know our lead clinical asset is around alone and studies from major depressive disorder and postpartum depression.

Additionally, we have phase three to four in development for a central tremor, and Sage 708, which we're exploring based on early study findings, we believe our compelling for its potential in areas, where he executive function is impaired.

Based on our progress in the last six months, we expect to have numerous catalysts coming over the next 18 months.

We've been able to advance several programs and it had strong enrollment to date and I was around alone waterfall study.

Jeff Jonas: We have been dosing subjects with 50 mg in our SHERLINE study as well and have advanced the anticipated top-line readout for our SAGE 324 Tremor Study to the latter part of 2020 or the first quarter of 2021. Thus, we are running on or ahead of schedule across our development programs. In sum, during the second quarter, we initiated four new clinical trials across two franchises. I'd like to comment further on our depression franchise.

We haven't dosing subjects with 50 milligrams and North Carolina study as well and advance the anticipated topline readout for our stage three to four tremor study to the latter part of 2020 or the first quarter of 2021. So we are running on or ahead of schedule across our development programs.

In sum during the second quarter, we initiated for new clinical trials across two franchises.

I'd like to comment further on a depression franchise.

Jeff Jonas: We set out to develop a therapy that we believe, if successfully developed and approved, will be an important and unique option for people with major depressive disorder (MDD). Our clinical programs are designed to answer very specific questions to achieve this goal, and we are implementing in a stepwise progression. We believe that patients want to get well quickly and stay well, and many would prefer not to undergo chronic pharmacotherapy. In this light, we believe both Zolreso in postpartum depression and zaranolone in MDD and PPD have pharmacological characteristics consistent with this type of approach.

We set out to develop a therapy that we believe if successfully developed and approved will be an important and unique option for people with major depressive disorder or N D. R.

Our clinical programs are designed to answer very specific questions to achieve this goal.

And we are executing in a stepwise progression.

We believe that patients want to get well quickly and stay well and many would prefer not to undergo chronic pharmacotherapy.

In this flight we believe both so rest so in postpartum depression, and Saran alone and MDD M. P. D have pharmacological characteristics consistent with this type of approach.

Jeff Jonas: As a reminder, our Zoranolone program has been designed to achieve a first NDA as efficiently as possible, with three ongoing studies where each, with a positive outcome, supports a unique potential filing pathway. For each pathway, we believe just one additional positive acute study is needed to show efficacy. As noted earlier, we made significant progress toward this goal by initiating dosing with 50 mg in our Phase III Waterfall Study in patients with MDD. Based on our enrollment, which has now surpassed 50%, we have updated our anticipated completion date for the Waterfall Study to the first half of 2021.

As a reminder, I was around alone program has been designed to achieve a first and D.A. as efficiently as possible with three ongoing studies were each with a positive outcome supports the unique potential filing pathway for each pathway. We believe just one additional positive acute study is needed to show efficacy.

As noted earlier, we made significant progress towards this goal by initiating dosing with 50 milligram in our phase three waterfall study in patients with MDD.

Based on our enrollment which has now surpassed 50%.

We've updated our anticipated completion date for the waterfall study to the first half of 2021.

Jeff Jonas: We've also initiated dosing in a postpartum study, our Phase 3 Skylark program. Top-line data from the Skylark study is anticipated in 2021. And finally, as noted earlier, we initiated dosing in the 50 milligram cohort of our Phase 3 open-label Shoreline study. Top-line data from the SHERLINE study, 30 mg, is expected by the end of this year, and it is also possible we will have preliminary data from patients who received 50 mg in the study by year-end as well. We're also on track to commence dosing in the Phase 3 choral study later this year. Recall, the choral study is looking at seranilone 50 mg as an acute rapid response therapy in MDD when co-initiated with a newly administered standard antidepressant.

We've also initiated dosing in a post bottom study that fit our phase three Skylark program topline data from the Skylark study as anticipated and 2021.

And finally as noted earlier, we initiated dosing in the 50 milligram cohort of our phase three open label shoreline study.

Topline data from the sure line study 30 milligrams is expected by the end of this year and it is also possible. We will have preliminary data from patients who received 50 milligrams him to study by year end as well.

We're also on track to commenced dosing in the phase three coral study later this year recall the call study is looking at around 50 milligrams as an acute rapid response therapy and MDD when co initiated with a newly administered standard antidepressant.

Jeff Jonas: Michael will talk about the utility of this potential indication later in the call, but what I can say is that we now have three shots on goal to bring Zaranolone to market. Today, we're also reporting results from the six-month follow-up arm of the Mountain Study. As we set out to understand more about the durability of xeranolone, we asked what happens to treatment responders at six months? This has been an important question in an area of speculation, as clinicians need to understand the treatment path for patients who respond to xeronala.

Mike will talk about the utility of this potential indication later in the call, but what I can say is that we now have three shots on goal to brings around alone to market.

Today, we're also reporting results from the six month follow up are from the mountain study.

As we set out to understand more about the durability of Saran alone, we asked what happens to treating the responders or six months.

This has been an important question in an area of speculation as coalitions need to understand the treatment path for patients who respond is around alone.

As part of the Mountain study subjects will offer the opportunity to participate in a six month blinded follow up to assess durability of response in those patients who responded after 14 days or treatment. As a reminder, the study was not powered to detect statistical significance from placebo beyond day 15.

Jeff Jonas: As part of the Mountain Study, subjects were offered the opportunity to participate in a six-month blinded follow-up to assess durability of response in those patients who responded after 14 days of treatment. As a reminder, the study was not powered to detect statistical significance from placebo beyond day 15. About half of the study participants elected to participate in the follow-up, and we were pleased to see that more than 80% of those completed the six-month follow-up period. There were no drug-related adverse events, changes in labs, EKG measures, vital signs, or suicidality ratings seen following exposure to xeranilone, and there were no signals of withdrawal or rebound after treatment with xeranilone was completed at day 14.

About half the study participants elected to participate in the follow up and we were pleased to see that more than 80% of those completed the six my follow up period.

There were no drug related adverse events changes in labs, you kg measures vital signs or suicidality ratings seen following exposure to is around alone and there were no signals of withdrawal a rebound after treatment with is around alone was completed at day 14.

We were also pleased to see that approximately 75% of the patients who responded is around 30 milligrams. A day 15 maintain their response rate at the last follow up on day 180 to.

This was true of the overall population regardless of treatment arm, but more importantly for those who showed significant benefit from is around 11 30 milligrams that is the population with a happy greater than or equal to 24, a baseline the improvement over placebo seen a day 15 was sustained over the full six month period and at no time.

Jeff Jonas: We were also pleased to see that approximately 75% of the patients who responded to Zaranulone 30 mg at day 15 maintained their response rate at the last follow-up on day 182. This was true of the overall population, regardless of treatment arm. But more importantly, for those who showed significant benefit from Zoranolone 30 milligrams, that is, the population with a HAMD greater than or equal to 24 at baseline, the improvement over placebo seen at day 15 was sustained over the full six-month period, and at no time during the follow-up period did the change from baseline and HAMD in the placebo arm surpass that in the Zoranolone 30 milligram arm. This suggests This benefit was seen regardless of whether or not the patient was being treated with an SSRI.

During the follow up period due to change from baseline and Hamdi input into placebo arm surpass that ends around along 30 milligram arm. This suggests the persistence of benefit following the initial two weeks around alone course.

This benefit was seen regardless of whether or not the track patient was treated with SSR rise.

We believe these data support our vision for unique treatment profile for is around alone for people with MDD.

We understand development of an as needed therapy in MDD runs entirely counter to the status quo of assuming all patients require chronic drug treatment and we understand two decades of one approach will require data to effect change.

We believe these data are another step along that path.

We're looking forward to the topline data read out for this Iran alone 30 milligram cohort in the sure line study, which we expect will be reported by the ended the year.

Jeff Jonas: We believe these data support our vision for a unique treatment profile for seranolone for people with MDD. However, developing an as-needed therapy, an MDD, runs entirely counter to the status quo of assuming all patients require chronic drug treatment, and we understand two decades of one approach will require data to affect change. We believe these data are another step along that path. We're looking forward to the top-line data readout for the Zoranolone 30 mg cohort in the Shoreline study, which we expect will be reported by the end of the year.

Before I move on I want to reemphasize that our goal of MDD is nothing less than to offer a disruptive distinct and novel treatment approach for patients.

There are already several things we've observed in clinical trials with rental on to date, which we believe along with a six month data suggest the potential for is around alone to be uniquely situated for this approach.

First we've observed rapidity of response within days that has been consistently observed across our studies.

Second the drug has been well tolerated in these studies with more than 2500 subjects.

There's been no adverse event of loss of cautiousness, including up to doses of 90 milligrams evaluated in our clinical pharmacology studies and third there'd been no signals, a rebound or withdrawal after the drug as stocked.

I'm, sometimes asked why we're looking to treat depression like a medical condition, rather than a chronic disease that labels a person as a mental health patient.

Jeff Jonas: Before I move on, I want to reemphasize that our goal of MDD is nothing less than to offer a disruptive, distinct, and novel treatment approach for patients. There are already several things we've observed in clinical trials with Zoranolone to date that we believe, along with our six-month data, suggest the potential for Zoranolone to be uniquely situated for this approach. First, we've observed rapidity of response within days that has been consistently observed across our studies. Second, the drug has been well tolerated in these studies with more than 2,500 subjects. There have been no adverse events of loss of consciousness, including up to doses of 90 mg evaluated in our clinical pharmacology studies.

It's long been recognized that the preference or reliance on chronic pharmacotherapy is a problem in psychiatry.

And the numbers bear this out.

17 million, new diagnosed as a year for major depression, but nearly twice that many people remain on treatment for two years or more.

We see this is an area of substantial unmet medical as a side on the heat.

If we're successful Saran alone has the potential to allow patients to get treated get better quickly and not require another treatment until when or if he or she has another depressive episode.

As you might expect when treating any other medical condition.

Now turning to a new development with Brexit alone, we're pleased to announce it under the FDA Corona virus treatment acceleration program or see tap brick standalone has been cleared for a phase three study in people with advanced Cove at 19 related acute respiratory distress syndrome or a rds.

Jeff Jonas: And third, there have been no signals of rebound or withdrawal after the drug has stopped. I'm sometimes asked why we are looking to treat depression like a medical condition rather than a chronic disease that labels a person as a mental health patient. It's long been recognized that the preference or reliance on chronic pharmacotherapy is a problem in psychiatry, and the numbers bear this out. Seventeen million new diagnoses a year for major depression, but nearly twice that many people remain on treatment for two years or more. We see this as an area of substantial unmet medical and societal need. If we are successful, seranolone has the potential to allow patients to get treated, get better quickly, and not require another treatment until when or if he or she has another depressive episode, as you might expect when treating any other medical condition.

This announcement comes after several months of analysis of Brexit alone clinical and preclinical data.

As many of you know we already had extensive ice you experience and generated significant critical care data with Brexit alone in our Srs Sea trials.

Sage also has extensive chemical equity and medical chemistry experience and we've been looking at other ways, our compounds may impact peripheral receptor systems.

The brick sat on trial and covert 19 related a rds will evolve several leading academic centers.

Sage has undertaken this initiative, believing there is a sound rationale to test whether brick standalone may be able to mitigate the morbidity and mortality associated with cobot related a rds. It's also we believe the right thing to do.

We look forward to answering further questions about this trial during our upcoming Investor Day plan for September.

Turning now to our neurology franchise, we have begun dosing in our phase two double blind study.

Which we're calling kinetic with phase 324 at 60 milligrams and essential tremor as a reminder, essential tremor is the most common movement disorder in the U.S. affecting an estimated 6 million people in our country.

Jeff Jonas: Now, turning to a new development with Brexanilone, we are pleased to announce that, under the FDA's Coronavirus Treatment Acceleration Program, or CTAP, Brexanilone has been cleared for a Phase III study in people with advanced COVID-19-related acute respiratory distress syndrome, or ARDS. This announcement comes after several months of analysis of Brexanilone clinical and preclinical data. As many of you know, we already have extensive ICU experience and generated significant critical care data with Brexanilone in our SRSC trials. SAGE also has extensive chemical equity and medical chemistry experience, and we've been looking at other ways our compounds may impact peripheral receptor systems. The BRICS Aniline Trial and COVID-19 related ARDS will involve several leading academic centers. SAGE has undertaken this initiative believing there is a sound rationale to test whether Brexanolone may be able to mitigate the morbidity and mortality associated with COVID-19-related ARDS. It's also, we believe, the right thing to do.

Earlier open label data with Phase 324 demonstrated the compound with a pharmacologic characteristics. We believe are well suited for development opportunities not only in essential tremor, but also in epilepsy in Parkinson's disease.

We anticipate reporting topline data from the essential tremor trial in the fourth quarter this year or the first quarter of 2021.

We're also on track to initiate our phase two way open label study with Sage seven when eight in the second half of 2020, the lead asset in our neuro Psych franchise, and our most advanced and M.D.A. Pam in patients with Parkinson's disease cognitive dysfunction.

Results from this study, which we're calling the paradigm study well informed the potential advancement of say seven when a in various disorders as cognitive dysfunction.

As a reminder, in early studies say ceremony was well tolerated and patients as well as healthy volunteers demonstrated improved performance compared to baseline on assessments of executive functioning.

We believe the data we generated in our phase one program support our apoptosis. The Sage 7.8 may be relevant to multiple disorders with impaired cognitive dysfunction, including Huntingtons, Alzheimer's and Parkinson's disease.

Before I turn it over to Mike I want to share my appreciation for the team its age.

The team is executing well across all franchises to advance our therapies as quickly as possible for the benefit of patients and families.

We believe we've created a novel drug company successfully able to convert our chemical equity library into a rich pipeline of clinical assets that a new chemical entities and not just re purpose molecules. So under with that I'll turn the call over to Mike.

Thanks, Jeff and good morning, everyone as Jeff mentioned, we made significant progress over the last quarter with the initiation of four new clinical trials, we built upon the rigorous participation and resource allocation. We began the first quarter as we continue advancing programs across our depression, neurology and neural side franchise.

Jeff Jonas: We look forward to answering further questions about this trial during our upcoming Investor Day plan for September. Turning now to our neurology franchise, we have begun dosing in our Phase 2 double-blind study, which we are calling Kinetic with SAGE 324 at 60 mg in a central tremor. As a reminder, essential tremor is the most common movement disorder in the U.S., affecting an estimated 6 million people in our country.

Me out a bit of perspective, how we're thinking about positioning the differentiated profiles around alone in our depression franchise.

Successfully developed in approved we have consistently observed rapid response within days and good Tolerability and Saran alone in our Winski clinical program to date.

Jeff Jonas: Earlier open-label data with SAGE 324 demonstrated that it is a compound with the pharmacologic characteristics we believe are well-suited for development opportunities, not only in essential tremor but also in epilepsy and Parkinson's disease. We anticipate reporting top-line data from the essential tremor trial in the fourth quarter of this year or the first quarter of 2021. We're also on track to initiate our Phase IIa Open Label Study with SAGE 718 in the second half of 2020, the lead asset in our neuropsych franchise and our most advanced NMDA PAM in patients with Parkinson's Disease Cognitive Dysfunction. Results from this study, which we are calling the Paradigm Study, will inform the potential advancement of SAGE 718 in various disorders of cognitive dysfunction.

Rapid action in depression, you've also seen in our ongoing and planned trials will be an important profile fours around alone whether you'd have to sonically or treat as needed or at the rapid response for our t. therapy wouldn't hold initiated with a new antidepressants.

Physicians patients and payers have consistently viewed the many unique characteristics of this target profile positively.

As you know we initiated dosing in the waterfall study and updated our guidance on anticipated data read out to the first half of 2021.

We also initiated dosing in our PD study skylark as well as the 50 milligram cohort in the ongoing strolling stuff.

We are on track to begin dosing in the cool study the acute rapid response with a newly administered antidepressants stuff.

During the second half of the year.

As we think about the ending for serene alone. If we're successful changing the paradigm by moving towards a treatment as needed.

SATA option.

Going to be physicians, who wants to use around alone at least initially in combination with traditional antidepressants until they get comfortable with Orient alone as a standalone agent.

Jeff Jonas: As a reminder, in early studies, SAGE 708 was well-tolerated, and patients as well as healthy volunteers demonstrated improved performance compared to baseline on assessments of executive functioning. We believe the data we generated in our Phase 1 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. Before I turn it over to Mike, I want to share my appreciation for the team at SAGE. The team is executing well across all franchises to advance our therapies as quickly as possible for the benefit of patients and families. We believe we've created a novel drug company successfully able to convert our chemical equity library into a rich pipeline of clinical assets that are new chemical entities and not just repurposed molecules. So with that, I'll turn the call over to Mike.

This is consistent with the Coral study design, which we are on track to initiate this year.

If the call study is positive.

That's the first seek regulatory approval for uses around alone when co initiated with a new antidepressants in the treatment of MDD.

If we receive approval in this indication would give us an opportunity to leverage the profile for physicians patients and payers picking real world experience was around alone and better understand the rapid acting profile.

And if waterfall and the longer term safety data are positive we think the combination of the our t. experience and the Retreatment data from shoreline and Redwood will expand the labeling and use making the transition to episodic suite as needed much more efficient.

The physicians will be able to take a phased approach and changing the treatment paradigm building on their own experiences along the way from using is around alone in conjunction with a newly administered antidepressants to prevent relapse to the use of Iran loan as needed or episodic lead to treat subsequent episodes.

The receptivity to a unique target profile here and there we have heard the questions on durability, including what happens after de 15 and de 42 with the six month Mountain data, we just announced and with the shoreline data anticipated by the ended the year, we continue to build our datasets to help answer some of the questions we into.

Mike Clunan: Thanks, Jeff, and good morning, everyone. As Jeff mentioned, we've made significant progress over the last quarter with the initiation of four new clinical trials. We've built upon the rigorous prioritization and resource allocation we began in the first quarter as we continue advancing programs across our depression, neurology, and neuropsych franchise. Let me add a bit of perspective on how we're thinking about positioning the differentiated profile of Zoranolone in our depression franchise if it is successfully developed and approved. We have consistently observed rapid response within days and good tolerability of zaranolone in our landscape clinical program to date. Rapid action in depression, if also seen in our ongoing and planned trials, would be an important profile for xeranilone, whether used episodically or treated as needed, or as a rapid response or RRT therapy when co-initiated with a new antidepressant.

I mean, receiving from key stakeholders.

We want to get patients and physicians another option in the treatment of MTD and if we're successful we believe the ran alone can offer not only a clinically differentiated treatment option, but also it commercially differentiated approach. This is another example of our overall strategy, we leveraged learnings and quickly adapt or.

All the mission and bringing medicines that matter for people with brain health disorders.

With still left so we are executing as expected.

Revenue during the quarter was 1.1 million and as anticipated was impacted by cobot 19, as multiple hospitals continue to prioritize their bed capacity, reducing elected admissions like the rest so.

Crusade Central we remain close to all the free inside the tier to understand their ability to treat TV patients and any shifts and their approach.

We will continue to support geographies with active existing treating sites and support PPD patients through the process.

Mike Clunan: Physicians, patients, and payers have consistently viewed the many unique characteristics of this target profile positively. As you know, we initiated dosing in the Waterfall Study and updated our guidance on an anticipated data readout in the first half of 2021. We also initiated dosing in our PPD study, Skylark, as well as the 50 milligram cohort in the ongoing Shoreline Study. We are on track to begin dosing in the coral study, the acute rapid response to a newly administered antidepressant study during the second half of the year. As we think about the end game for xeranilone, if we're successful changing the paradigm by moving towards a treatment as needed or episodic option, there are going to be physicians who will want to use xeranilone, at least initially, in combination with traditional antidepressants until they get comfortable with norenalone as a standalone agent.

Given the ongoing surge in a number of cases of totaling 19 in the U.S. and continuing concerns about the pandemic across the country.

Company expects the significant adverse impact of the pandemic onto a rough iressa revenues to continue.

Jeff provided a thorough update on the clinical progress we've made with stage three to four and essential tremor and our plans to say seven one any indications involving cognitive dysfunction.

Ill spend just a few minutes discussing the tremendous on that need for patients suffering from these disorders.

With 80, you're talking about the most common movement disorder.

[noise] estimated 6 million plus people in the U.S.

Right, it's high prevalence only about 20% of people with 80 seek treatment.

And for cognitive dysfunction associated with diseases like Huntingtons, well, we've already seen in urban signal pointing toward the potential for improvement and executive function and other neurodegenerative conditions that manifest with executive function deficits like Alzheimer's and Parkinson's, we're talking about the potential to improve cognitive dysfunction symptoms.

That track closely with functioning in the real world.

Mike Clunan: This is consistent with the coral study design, which we are on track to initiate this year. If the CORAL study is positive, we expect to first seek regulatory approval for the use of zaranolone when co-initiated with a new antidepressant in the treatment of MDD. If we receive approval in this syndication, it will give us an opportunity to leverage the profile for physicians, patients, and payers to gain real-world experience with seranolone and better understand the rapid-acting profile. And if Waterfall and the longer-term safety data are positive, we think the combination of the RRT experience and the retreatment data from Shoreline and Redwood will expand the labeling and use, making the transition to episodic, This means that physicians would be able to take a phased approach to changing the treatment paradigm, building on their own experiences along the way, from using xaranlone in conjunction with a newly administered antidepressant to prevent relapse, to the use of xaranlone as needed or episodically to treat subsequent episodes.

By improving these symptoms our goal is to provide patients with the opportunity to remain more cotton valley intact, and potentially routinely ability to live and thrive independently.

And so we believe say three to four and Sage seven money if successfully developed in food have the potential become truly innovative treatment options with the potential to help millions of people and their families.

Before I turn it over to me I also want to take a minute to express my appreciation for the team at stage. They have worked tirelessly and executing with precision during these challenging times and supporting our mission to bring medicines that matter to people with brain health disorders, I feel as confident as ever better execution against a well thought out strategies.

I will enable us to get medicines that matter to patients as quickly as possible and now I'll turn the call over the coming to review our financials.

Thanks, Mike.

This is the your execution for stage with cash on hand anticipated to support operations into choice.

You have clearly defined passport designs advanced programs across three greenhouse franchise.

I experienced team is working to create value by converting our extensive chemical and equity into a rich pipeline clinical assets in areas of unmet medical need.

Mike Clunan: The receptivity to a unique target profile is there. We have heard questions on durability, including what happens after day 15 and day 42. With the six-month mountain data we just announced and with the shoreline data anticipated by the end of the year, we continue to build our data sets to help answer some of the questions we anticipate receiving from Key Stakeholders.

We remain true to our mission.

As a reminder, we started the quarter with a difficult, but prudent decision to restructure the organization.

Well, we ended the quarter with extensive list of accomplishments and progress and you heard from Jeff and life.

As we move into the second half of the year, we do that with a solid financial position to continue to build on those achievement.

Mike Clunan: We want to give patients and physicians another option in the treatment of MDD. And if we are successful, we believe that Ranalone can offer not only a clinically differentiated treatment option but also a commercially differentiated approach. This is another example of our overall strategy. We leverage learnings and quickly adapt, all with the mission of bringing medicines that matter to people with brain health disorders. With Soreso, we are executing as expected. Revenue during the quarter was $1.1 million, and, as anticipated, was impacted by COVID-19, as multiple hospitals continue to prioritize their bed capacity, reducing elective admissions like Zola Resta.

As you've heard me say many times before assays, we take a portfolio approach, how we think about resource allocation with the goal to maximize the value of out.

Hi, Reprioritizing kidding, rethinking how to deploy resources.

We anticipate annualized cost savings as a result of their structuring of approximately 170 million.

These savings are intended to help stage advance our mission to deliver medicines that matter because people were hearing is Brent Saunders.

I'll now walk you through the highlights of our second quarter 2020 financial results.

Revenues were 1.1 million in the second quarter from sales of the last out compared to 8.5 million a collaboration revenue from the shionogi collaboration for the same period in 2016.

As Mike noted earlier, so vessel revenues have been significantly affected by Colin nights in anyway.

Mike Clunan: Through SAGE Central, we can remain close to all the treating sites of care to understand their ability to treat PPE patients and any shifts in their approach. We will continue to support geographies with active existing treating sites and support PPD patients through the process. Given the ongoing surge in the number of cases of COVID-19 in the U.S. and continuing concerns about the pandemic across the country, the company expects the significant adverse impact of the pandemic on Zoretta revenues to continue.

And we expect this significant adverse impact of the pandemic on vessel revenue to continue.

Selling general and administrative expenses with 38.2 million in the second quarter compared to 18.2 million in the first quarter 2020.

Our reduction in commercial support for the rest, though was the primary driver a decrease in yesterday in the second quarter.

And as part of the restructuring we recorded a charge of 20 million in the second quarter.

Research and development expenses were 73.3 million in the second quarter compared to 89.1 million the second quarter 2019.

Mike Clunan: Jeff provided a thorough update on the clinical progress we've made with SAGE 324, an essential tremor, and our plans with SAGE 718 and indications involving cognitive dysfunction. I'll spend just a few minutes discussing the tremendous unmet need for patients suffering from youth disorder. With ET, we are talking about the most common movement disorder affecting an estimated 6 million people in the U.S. However, despite its high prevalence, only about 20% of people with E.T. Seek treatment.

The decrease was primarily primarily related to the completion of the mouse study and a decrease in the noncash stock compensation expense.

Finally, we reported a net loss of 136.3 million for the second quarter, a 2020 compared to 100.

<unk> point 2 million for the first quarter of this year.

We ended the quarter with 757 million cash cash equivalents restricted cash and marketable security.

Mike Clunan: And for cognitive dysfunction associated with diseases like Huntington's, where we've already seen an early signal pointing toward the potential for improvement in executive function, and other neurodegenerative conditions that manifest with executive functioning deficits like Alzheimer's and Parkinson's. We're talking about the potential to improve cognitive dysfunction symptoms that track closely with functioning in the real world. By improving these symptoms, our goal is to provide patients with the opportunity to remain more cognitively intact and potentially retain the ability to live and thrive independently. And so, we believe SAGE 324 and SAGE 718, if successfully developed and approved, have the potential to become truly innovative treatment options with the potential to help millions of people and their families. Before I turn it over to Kimi, I also want to take a minute to express my appreciation for the team at SAGE.

As previously stated we anticipate ending year with approximately 550 million in cash, which we expect will provide runway slot into 2022.

We're looking forward to the second half the year, we anticipate continued savings for restructuring and resource reallocation.

In closing, we expect the second half its 2020 would be highlighted the proof point to illustrate our ability to execute.

Okay, the progression of the pipeline.

The value of our chemical equity.

This will be accomplished impart by the strength of our balance sheet and I'm confident that we had bitumen place it seems to execute on all the opportunity.

We look forward to sharing ongoing update.

I'll now turn it over to Jeff for closing comments.

Thanks, Jeremy and thanks to everybody and good morning, everyone.

I just want to make a few more comments prior to you are going to question and answer I think as you've heard today that the execution of our clinical programs remains either on track or ahead of schedule a match no small part to the efforts of the folks at stage working through these programs our goal remains constant with respectively.

Mike Clunan: They have worked tirelessly to execute with precision during these challenging times and supported our mission to bring medicines that matter to people with brain health disorders. I feel as confident as ever that our execution against well-thought-out strategies will enable us to get medicines that matter to patients as quickly as possible. And now, I'll turn the call over to Kimi to review our financial plan.

Around alone we are looking to disrupt the treatment Marlin depression, we understand that is something that may be hard to do but it's something that we think meets an important unmet medical need in the treatment of psychiatric disorders.

Kimi E. Iguchi: Thanks, Mike. This is the year of execution for SAGE, with cash on hand anticipated to support operations into 2022. We have a clearly defined path forward designed to advance programs across three brain health franchises. Our experienced team is working to create value by converting our extensive chemical equity into a rich pipeline of clinical assets in areas of unmet medical need. We remain true to our mission. As a reminder, we started the quarter with a difficult but prudent decision to restructure the organization.

As you heard today with our with our phase three initiation.

For brick standalone into Kobin related and already yes.

We have an a distinct and active discovery group of medicinal chemistry group and we're looking to leverage at expertise as we move forward.

We have clearly defined pathways to advance all of our programs across all of our franchises and as you can hear today, we have a catalyst rich.

Year, and a half upcoming where we hope to report on this progress over time.

So with that let me open the call two questions.

As a reminder to ask a question you need to press star one of your telephone.

Withdraw your question press the pound key please standby we've compiled acuity roster.

Our first question comes from a cost worry Wolfe research your line is okay.

Kimi E. Iguchi: But we ended the quarter with the extensive list of accomplishments and progress that you heard from Jeff and Mike. As we move into the second half of the year, we do so with a solid financial position to continue to build on those achievements. As you've heard me say many times before, at SAGE, we take a portfolio approach to how we think about resource allocation with the goal of maximizing the value of our offer. By reprioritizing our activities and rethinking how to deploy our resources, we anticipate annualized cost savings as a result of the restructuring of approximately $170 million.

Hey, guys. Thanks, so much of the question I have you if I may.

Dig into what did you make those can and cannot help with so number one will the 50 make sure that patients who take two on Devon without a proper meal with the old Navy get into a therapeutic drug concentration or would that just not be possible. If you don't take it with food.

Similar to what the patients in the mountains study generally heavier than the Robin study and what the 50 make those allow for a greater percentage of the patient they hit at therapeutic threshold and then lastly can you give some color on how your PK curve evolve overtime as you go permit single ascending dose the mall store ascending dose for Q1 seven.

Kimi E. Iguchi: These savings are intended to help SAGE advance our mission to deliver medicines that matter to people with serious brain health disorders. I'll now walk you through the highlights of our second quarter 2020 financial results. Revenues were $1.1 million in the second quarter from sales of Xerresso, compared to $0.5 million of collaboration revenues from the Chianogi collaboration for the same period in 2019. As Mike noted earlier, Soreto revenues have been significantly affected by COVID-19 in the U.S., and we expect the significant adverse impact of the pandemic on Zillow Reservoir revenues to continue. Selling general and administrative expenses were $38.2 million A reduction in commercial support for Zoresto was the primary driver of the decrease in SG&A in the second quarter.

Like visually how does that PK look like and how would you define someone who would be low exposure versus high exposure. Thank you.

Hey, it's Jeff I'm going to start and I'm going to turn this over to Jim.

Just a broad commentary one of the.

Goals of any drug development program as a fixing the proper ghost and.

The.

The metrics and the Biomarkers and the analyses required are not necessarily straightforward I know people like to look at it that way, but they're not and as a company. We I just have to say that as I think you're alluding to picking the right dose can be challenging and in fact, we think that the 50 is a good dose as we've mentioned earlier, we've now so stopped and.

Hi, Andy it's very well tolerated and so we're comfortable about the 50 milligram dose and but that that analysis that has led us to the 50 in some spark remains proprietary we realize that this could be a competitive advantage for the company. We know we have a lot of fast followers looking at these mechanisms. So a lot of this we just haven't.

Kimi E. Iguchi: And as part of the restructuring, we recorded a charge of $28 million in the second quarter. Research and development expenses were $73.3 million in the second quarter, compared to $89.1 million in the second quarter of 2019. The decrease was primarily related to the completion of the Mountain Study and a decrease in non-cash stock-based compensation. Finally, we reported a net loss of $136.3 million for the second quarter of 2020 compared to $168.2 million for the first quarter of this year. We ended the quarter with $757 million in cash, cash equivalents, restricted cash, and marketable securities.

Not disclose and will not to schools.

With that said, though the performance of the 50 to date I think as we've mentioned Dot earlier has been has been quite satisfactory, we've not going up to 90 milligrams and and so we're very pleased with that I'm going to turn the rest of this over to Jim Dirty.

[noise] access.

Yes, the answer a couple of your questions in a little bit more detail so first around.

The 60 milligram and Teekay is as Jeff said, we are quite confident in the performance of the 50 milligram dose from the data that we've seen so far and so yes, we are confident that but dosing is 50 milligrams. We are moving the population.

To a range of exposures that we can just be consistent with efficacy I think obviously each individual person responsible differently, but we do think that this does gives us the race balance the spokes into an efficacious range you answer your question around body mass I would say that are all of our trials, we see a pretty.

Kimi E. Iguchi: As previously stated, we anticipate ending the year with approximately $550 million in cash, which we expect will provide runway for us into 2022. We're looking forward to the second half of the year. We anticipate continued savings for our structuring and resource reality. In closing, we expect the second half of 2020 will be highlighted with proof points to illustrate our ability to execute, showcase the progression of the pipeline, and show the value of our chemicals. This will be accomplished in part by the strength of our balance sheet, and I'm confident that we have the right team in place at SAGE to execute on all the opportunities. We look forward to sharing our ongoing updates. I'll now turn it over to Jeff for closing comments. Thanks, Kimi, and thanks, everybody, and good morning, everyone.

Consistent picture of body mass for individuals.

Pretty consistent with the with the most the U.S. population.

And then to your point around PK profiles, yes, we think that the the PK profile. We're is around loan, which we call was designed to have a once a day genetics in human.

Gives us really a very good opportunity to sort of keep the exposure levels, where we think they need to be as yet you see in our studies.

Across a population.

Thanks, a lot.

Thank you as a reminder, ladies and gentlemen, we have could you. Please limit yourself to one question. Our next question comes from properties with Stifel. Your line is open.

Kimi E. Iguchi: I just want to make a few more comments prior to going to question and answer. I think, as you've heard today, that the execution of our clinical programs remains either on track or ahead of schedule, and that's no small part of the efforts of the folks at SAGE working through these programs. Our goal remains constant with respect to Zoran alone.

Hey, Great Bank. So much I just have a a quick follow up on this mountain six month data can you just quantitatively speak to how you declines responder maintenance of response at six months you know I guess in the phase two MDD study, we saw a couple points up creep in Ham D.

Jeff Jonas: We are looking to disrupt the treatment model for depression. We understand that that may be hard to do, but it's something that we think meets an important unmet medical need in the treatment of psychiatric disorders. As you've heard today with our Phase III initiation for a BRIC standalone for COVID-related ARDS. We have a distinct and active discovery group and medicinal chemistry group, and we're looking to leverage that expertise as we move forward. We have clearly defined pathways to advance all of our programs across all of our franchises, and as you can hear today, we have a catalyst-rich, year and a half ahead where we hope to report on this progress over time. So with that, let me open the call to questions. As a reminder, to ask a question, you will need to press star 1 on your telephone. To withdraw your question, press the pound key.

Good day 15 to 42, it would would kind of something in that margin of error constitute maintain response and then I was wondering if you could just comment on the proportion of patients that initiated in assets arise during follow up and how this kind of all informs your expectations for shoreline. Thank you.

I'll take this I think then I'll turn it over to Jim couple of point I'd want to make up first is one of the interesting findings that all the six month data has shown runs counter to the current mythology around depression that you have to stay on a drug and that's the that's the sort of most striking binding to me and I think to us.

As we move forward to this notion that if you have to pressure you don't have to be on an antidepressant for the rest of your life and so that so that's number one I think what really came home and it. If you look at the population that had a response and I think thats. The you know the 24 and above what do you see there is it actually have a constant very constant separate.

Operator: Please stand by while we compile the Q&A roster. Our first question comes from Akash Tewari with Wolf Research. Your line is open. Hey guys, thanks so much for the questions. I have a few, if I may.

Question pretty steady between drug and placebo and what that indicated initially and then what suggests is that you respond to the drug you continue to respond to the drug even after the drug stop and we think that it is unique finding with respect to anti depressants. This will also what made us that what encourages us about these data and if we also.

Akash Tewari: So I wanted to dig into what the 50 mg dose can and cannot help with. So number one, will the 50 mg dose ensure that patients who take 217 without a proper meal would still maybe get into a therapeutic drug concentration, or would that just not be possible if you don't take it with food? Number two, were the patients in the Mountain Study generally heavier than in the Robin Study, and will the 50 mg dose allow for a greater percentage of those patients to hit a therapeutic threshold? And then lastly, can you give some color on how your PK curve evolves over time as you go from a single ascending dose to multiple ascending doses for 217? Like visually, what does that PK look like, and how would you define someone who is low exposure versus high exposure?

It gives us a lot of optimism about shoreline and that is only a very small number of patients actually started new anti depressants and overall I'd say it was only a handful and overall, it's only about 30% of the patients.

We're on SS arise during the study. So this really does run counter to the dogma.

The dogma about depression that you have to be on a drug into your you must be chronically treated and for US. It's very its has been very encouraging when you see that almost 75% of the patients maintain their response and the end with the 24 and above which of course is the relevant population, where we had a positive endpoint that responses maintained out to Uh huh.

Jeff Jonas: Hey, it's Jeff. I'm going to start and then I'm going to turn this over to Jim. This is just some broad commentary. One of the goals of any drug development program is to fix the proper dose. The metrics and the biomarkers and the analyses required are not necessarily straightforward. I know people like to look at it that way, but they're not.

Good and 82 days.

The study was not powered for significant but even then the P value. There was 0.06. So this was a very strong finding and when I think that I can say exceeded our expectations I'm, Jim you want to add anything else to that.

I think I, just would reiterate Jeff that.

Jeff Jonas: And as a company, I just have to say that, as I think you're alluding to, picking the right dose can be challenging. And in fact, we think that 50 is a good dose, as we've mentioned earlier. We've now dosed up to 90. It's very well tolerated. And so we're comfortable about the 50 milligram dose. But that analysis that has led us to the 50, in some part, remains proprietary. We realize that this could be a competitive advantage for the company, and we know we have a lot of fast followers looking at these mechanisms. So a lot of this we just have not disclosed and will not.

When you look at the data I think the key messages that patients who are seeing a benefit. This is we're getting better at the day 50 ton point are staying better so bode well put the detailed data together from the mouse study for presentation later, but the answer to your question is the scores are pretty similar.

Or to what they were in those early days up as well.

Great. Thank you very much.

Thank you. Our next question comes from Zeena much with Bank of America. Your line is open.

Hi, guys. Good morning, Thanks for taking my question I wanted to focus on essential tremor, if I could can you give up a little bit of color on why you think it'll be important to look at the primary endpoint at day 29.

Jeff Jonas: With that said, though, the performance of the 50 to date, I think, as we've mentioned earlier, has been quite satisfactory. We've now gone up to 90 milligrams, and so we're very pleased with that. I'm going to turn the rest of this over to Jim Doherty. Hi Chef.

And then as it relates to upper limb tremor score can you walk us through the importance of that and how position in that particular score in general as it relate TP. Thanks.

Jim Doherty: Hi Akash, to answer a couple of your questions in a little bit more detail, so first, around the 50 milligram and PK, as Jeff said, we are quite confident in the performance of the 50 milligram dose from the data that we've seen so far. And so, yes, we are confident that by dosing at 50 milligrams, we are moving the population into a range of exposures that we think is going to be consistent with efficacy. Obviously, each individual person responds a little bit differently, but we do think that this dose gives us the right balance that puts folks into an effective range. Yes, to your question around body mass, I would say that in all of our trials, we see a pretty consistent picture of body mass for individuals and, you know, pretty consistent with most of the U.S. population. And then, to your point about PK profiles, yes, we think that the PK profile for Zaranulone, which we recall was designed to have once-a-day kinetics in humans, gives us really a very good opportunity Thanks a lot.

Yes, the Mr., Jim I'll take that one and then I'll I'll, let Steve delaying and elements around your question around how positions to see upper limb square.

Of course, the study that we're talking about the was initiated for stage three two or the kinetic study is building on what we've already learned both from our earlier programs, but importantly from the work we did last year in the three to four program, where we confirmed that.

In order to share like three to four has a significant ability to reduce system tremor and essential tremor patients, whose those were done with acute dosing and so we are an important stage of progression for the program since with farmers a chronic disorders. So that's one of the time point is our next step in showing a sustainable.

So the of the response to through Q4 that we've seen earlier.

And I'll mention around upper limb scores.

That is one of the most sensitive measures were essential tremor visions and also one of the most troubling when you think about.

Daily lives than what people are trying to do but Steve Let me, let me have you jump in a disciplined.

Sure we've been looking at this quite a bit dizziness, you know we've been working in essential tremor since early days with initially with so rather than to Oneseven as Jim said, we've seen very consistent results across the board, we consult with experts in the field and they have told US we the upper limb tremor is the most ability.

Jim Doherty: Thank you. As a reminder, ladies and gentlemen, we ask that you please limit yourself to one question. Our next question comes from Paul Matteis with Spiegel. Your line is open. Hey, great. Thanks so much.

Being a part of the said the complex league tremor anywhere the inability to do things like right or shrink or or in its intention to ever. So the more you try to do something the where's the the tremor guess those are the things that really getting patients way other day to day basis. So there's a few things that we really been focusing on one the upper limb score we have to make sure that.

Paul Andrew Matteis: I just have a quick follow-up on this six-month data. Can you just quantitatively speak to how you defined responder or maintenance of response at six months? You know, in the Phase 2 MDD study, we saw a couple-point increase in HAMD from day 15 to 42. Would something in that margin of error constitute maintained response?

Improved across the board and that's something that we've seen consistently the other is given the level of use of accelerometers and other wearables. If somebody were of the track throughout the day. So there are real advantages in understanding the signal our understanding the effects on patients as well as the ability to understand what impact our dollar program.

Jeff Jonas: And then I was wondering if you could just comment on the proportion of patients that initiated an SSRI during follow-up and how this kind of all informs your expectations for Shoreline. Thanks. I'll take this, I think, and then I'll turn it over to Jim. There are a couple of points I'd want to make. First, you know, one of the interesting findings that all the six-month data shows runs counter to the current mythology around depression, that you have to stay on a drug. And that's the sort of most striking finding to me, and I think to us, as we move forward with this notion that if you have depression, you don't have to be on an antidepressant for the rest of your life. And so that's number one.

You have on this patient throughout the day.

Okay. Thank you.

Thank you. Our next question comes from Brian Abrahams with RBC capital markets. Your line is open.

Hi, This is David you on for Brian.

Awesome first looking ahead, how how are you thinking about the around different the process and evolving ahead of any potential long launch and maybe that through his thoughts on how the pandemic might have affected double haul.

Telemedicine and how you see that we're evolving ahead of the next couple of years and then the second question.

Just going back a waterfall trial enrollment that is being I know that there is definitely synergies from the mountain trial.

Jeff Jonas: And I think what really came home, and if you look at the population that had a response, and I think that's, you know, the 24 and above, what you see there is actually a constant, a very constant separation, pretty steady, between drug and placebo. And what that indicated initially, and what it suggests, is that if you respond to the drug, you continue to respond to the drug, even after the drug has stopped. And we think that is a unique finding. With respect to antidepressants, and this is also what made us, that which encourages us about these data, and which also gives us a lot of optimism about Shoreline, and that is, only a very small number of patients actually started new antidepressants. And overall, I'd say it was only a handful.

Just wondering if any economic reason for why enrollment might be better.

Two of them BB trials, including oral and R&D.

Okay. This is Jeff that Joe Thanks for the question.

In General I think we're seeing an increased incidence of reporting of people would mood disorders, but.

Psychiatry and depression has always been a major area of unmet medical need and so I think what we're seeing in the mountains study there a couple of things that we're seeing them out.

And other your second question first one is there is increasing interest among people who were doing depression study looking at novel therapies, and if you think about all the therapies that are currently in development. They all have they all really are of a kind except for is around a lot. They are six two to six to eight weeks and then chronic pharmacotherapy for as long as.

The physician is requires that we just think that patients deserved another option and we're seeing tremendous interest in our studies because the.

Jeff Jonas: And overall, only about 30% of the patients were on SSRIs during the study. So this really does run counter to the dog. The dogma about depression, that you have to be on a drug and that you must be chronically treated. And for us, it has been very encouraging when you see that almost 75% of the patients maintain their response. And with the 24 and above, which of course is the relevant population where we had a positive endpoint, that response was maintained out to 182 days. The study was not powered for significance, but even then, the p-value there was 0.06. So this was a very strong finding and one, I think, that I have to say exceeded our expectations. Jim, do you want to add anything else to that?

Right I'm going to data really so far enough with the six month data I think it's even more so.

That there maybe a different and unique way to treat depression. So we view that as an area of interest in an area of uptake that has really spurred interest in our trials also the team has done a great job I mean, I think they I think as I said at the start a lot of people.

Have.

Stopped their studies I thought they couldn't do studies and our teams really have done a nice job proactively preparing for the <unk> for this environment and up and the reality is there a lot of people who are depressed now the second point is that.

Jim Doherty: I think I just would reiterate, Jeff, that when you look at the data, I think that the key message is that patients who are seeing a benefit, patients who are getting better at that day 15 time point, are staying better. So, Paul, you know, we'll put the detailed data together from the Mound Study for a presentation later. But, you know, the answer to your question is, you know, the scores are pretty similar to what they were in those early days of the 1960s.

As you as you if you think about the face of depression I think that's really something that we are really interested in changing and with covert I think what you're seeing is a greater recognition of the importance of mental health the importance of any of morbidity associated with depression.

As of lack of function and lack of opportunity lack of engagement and it's brought home as people are not distracted by work and have more time with their families where people can be where depressing it'd be diagnosed we don't think the diagnosis is changed obviously, we think it using rigorous criteria. We can find people who have made real depression versus reactive to.

Jim Doherty: Great. Thank you very much. Thank you. Our next question comes from Tazeen Ahmad with Bank of America. Your line is open.

Tazeen Ahmad: Hi guys, good morning. Thanks for taking my question. I wanted to focus on essential tremor, if I could. Can you give us a little bit of color on why you think it'll be important to look at the primary endpoint at day 29? And then, as it relates to the upper limb tremor score, can you walk us through the importance of that and how physicians view that particular score in general as it relates to ET? Thanks. Yes, Tazeen, this is Jim.

Question, which is what we're distinctly not treating but we do think that base. It depression is treating and I and we believe very firmly in fact, probably more now than we have into past that there is a real need for not putting everyone who gets depressed on a drug therapy for years and years and years, we think that is around along with its profile with its ability to show.

Rapid response with its tolerability profile really can offer a disruptive and unique approach to treating depression, especially as the treatment of depression becomes ever more recognize its something thats an area of unmet medical need.

Jim Doherty: I'll take that one, and then I'll ask Steve DeWayne in a couple minutes to run your question around how physicians perceive the upper limb score. So, of course, the study that we're talking about that was initiated for SAGE 324, the kinetic study, is building on what we've already learned, both from our earlier programs, but importantly from the work we did last year in the 324 program, where we confirmed that neuroactive scare like 324 has a significant ability to reduce tremor in essential tremor patients. Those studies were done with acute dosing, and so we are at an important stage of progression for the program. Essential tremor is a chronic disorder, and so that 28-day time point is our next step in showing the sustainability of the response to 324 that we've seen. And I'll mention upper limb scores, that is one of the most sensitive measures for essential tremor patients and also one of the most troubling when you think about daily life and what people are trying to do. But, Steve, let me have you... Sure.

Yeah, maybe just let me this is Mike let me just add onto that Jeff I think you said it well and I also think just thinking about our t. shots on goal that Jeff alluded to before right. We have the arty option for patients and we also have the end game for us getting its product or treat as needed and as Jeff said like there has not been a molecule like saran loan that is given that will give the physicians.

And patients this opportunity to treat has rapidly within days and see that effectively successfully get either archie or the episodic treatments over the line and the way we see this playing out is we'll be able to move this paradigm in time right. So we will evolve the paradigm, but we can start with the R.R.T. indication allow patients and physicians to get comfortable with the rapid acting nature others around low.

And while they are using an in combination with the antidepressants standard antidepressants as they get that real world experience and we can publish redwood data in the shoreline date, and they get more comfortable with or treatment data that will give us the opportunity expanded label and to evolve that paired onto that treatment as needed approach that we think is really important for patients and that's what we hear back from patients.

This is this is what's important to them and it's a given its giving them multiple approaches as to how to treat MDD and I don't allow us a chance to evolve that paradigm overtime.

Thank you.

Steve Kames: We've been looking at this quite a bit, Tazeen, as you know. We've been working on essential tremor since the early days, initially with Soreso, then 217, and as Jim said, we've seen very consistent results across the board. We consult with experts in the field, and they tell us that upper limb tremor is the most debilitating part of the symptom complex.

As a reminder, we ask that you. Please limit yourself to one question you May press star one to re queue for any additional questions.

Next question comes from Ritu Baral with Cowen Your line is open.

Hi. This is my line for me Ken. Thank you for taking the claims and congrats on the progress.

I was wondering if you could maybe.

Steve Kames: The other advantage is that, given the level of use of accelerometers and other wearables, it's something that we're able to track throughout the day. So there are real advantages in understanding the signal, understanding the effects on patients, as well as the ability to understand what impact our development program may have on those patients throughout the day. Okay, thank you.

The dropout rates or maybe patient follow up that you've seen a short line maybe coding had any impact on your ability to follow up a patient can you remind us if patients need to come in for the treatment I think management telematics.

Thank you.

This is Jeff.

We've not seen much of an issue with that and I think we we've always use various maneuvers to ensure.

Brian Corey Abrahams: Thank you. Our next question comes from Brian Abrahams with RBC Capital Markets. Your line is open.

Compliance in terms of a follow up and if you take a look at our six month data compared to most psychiatric trials. We have an astonishing amount of follow up I think was almost 80% that's really I mean, I I done there's a long time and that's a very good follow up number and it's part of this is due to the diligence of the teams and the nature of the trial designs that we.

David Cici: Hi, this is David Cici on behalf of Zion. Just two quick questions. First, looking ahead, how are you thinking about the landscape of depression evolving ahead of any potential launch? Maybe just your latest thoughts on how the pandemic might have affected mental health and telemedicine and how you see that potentially evolving in the next couple of years. And then the second question, just going back to the Waterfall trial and the enrollment that you're seeing, I know that there are definitely synergies from the Mountain trial, but I'm just wondering if you see any extrinsic reasons for why enrollment might be better as a possible read-through to the other MDT trials, including CORAL in RRT. Okay, this is Jeff.

Weve instituted to encourage patients to maintain the blind and I I you know if you look at what we did with with mountain in particular.

I would argue that yeah I can't I don't think we can just we can find another six month blinded follow up of any drug.

After the drug has been discontinued ingress watch these patients nationalistically. So we havent seen really this much as an issue as I mentioned, we've done a number of internal maneuvers to.

Jeff Jonas: Thanks for the question. You know, in general, I think we're seeing an increased incidence of reporting of people with mood disorders. But, you know, psychiatry and depression have always been a major area of unmet medical need. And so I think what we're seeing in the Mountain Study, there are a couple of things that we're seeing in the Mountain Study. And I'll go to your second question first. One is that there is an increasing interest among people who are doing depression studies looking at novel therapies. And if you think about all the therapies that are currently in development, they are all really of a kind except for Zoranolone. They are, you know, two to six to eight weeks and then chronic pharmacotherapy, you know, for as long as the physician requires it.

Sure compliance and the team has done a great job at that but.

In one of the things about cobot is it that I think people are depressed they do need treatment and depression serious medical this disorder and it has not discouraged patients from either participating in trials or in their follow up.

Great. Thank you.

Thank you. Our next question comes from Salveen Richter with Goldman Sachs. Your line is open.

Good morning, Thanks for taking my question.

Hi, Kcl six month follow up cohort in coal Mountain study could you just help us understand how to placebo and 20 milligram arms compared to the 30 milligram.

Jeff Jonas: We just think that patients deserve another option, and we're seeing tremendous interest in our studies because the Zoranolone data really, so far, and with the six-month data, I think it's even more so, suggests that there may be a different and unique way to treat depression. So we view that as an area of interest and an area of uptake that has really spurred interest in our trials. Also, the team has done a great job. I mean, I think they, you know, I think, as I said at the start, a lot of people have and Dr. David Hicks.

Uh huh.

Actually I will start I'm going to turn it over to Jim. So remember in the overall trial, we did not achieve significance and so as but the interesting findings in the overall population as regardless of treatment.

In the overall population that that the patients who got better tended to stay better. So the so we were interested and again that runs counter to the current dogma about depression, which was we were fascinated by because it's not like you would expect what people have been taught but but we've seen this in most of our studies and at six months, we've seen the same theme regardless of treat.

Jeff Jonas: I want to thank all of you for coming today. I want to thank you all for coming today. I want to thank you all for coming today. I want to thank you all for coming today. I want to thank you all for coming today. I want to thank you all for coming today. I want to thank you all for coming today.

The problem with of course in the overall population is that what do you see is like with any medical disorder. When people whoever people are when they get better they get better that would be two of our community acquired pneumonia study where people get better.

Versus penicillin, but if you think finding in the mountains study was in the relevant population, where we saw a treatment effect 24 and above and that's why we look at it there. We saw continued separation from placebo and that that persisted.

Mike Clunan: I want to thank you all, Yeah, maybe just let me, this is Mike, add on to that, Jeff. I think you said it well, and I also think, if you think about our two shots on goal that Jeff alluded to before, right, we have the RRT option for patients, and then we also have the end game for us, which is getting it episodic or treating as needed. And as Jeff said, there has not been a molecule like Zoranilone that has been given that will give physicians and patients this opportunity to treat as rapidly within days and see that effect if we successfully get either RRT or the episodic treatments over the line. And the way we see this playing out is we'll be able to move this paradigm in time, right, so we will evolve the paradigm, but we can start with the RRT indication, allow patients and physicians to get comfortable with the rapid-acting nature of Zoranilone while they're using it in combination with antidepressants, standard antidepressants.

Whether or not the patient was on NSS arrive and I and as and.

It is important to note that minority of the pays only 30% were on accessorized. So this is a really unique finding for us and one that we think continues to its in a stepwise fashion de risks our thesis that there is a way to treat patients with depression with a drug that acts rapidly.

And can get people better without the necessity for maintenance therapy I'm just thinking of the we think is it a pretty unique finding we are going to publish this and prepare for presentation. Because we think some of the science is important and it's likely we'll wait for the shoreline data because we think that there's a lot we've learned now about the.

The natural history of depression in the modern World that is really runs counter to all the dogma that I think people except that if you are depressed you are a chronic mental patient and we've been very encouraged by the six month data and we think its unique and we're looking forward at we will be publishing it and presenting it.

Mike Clunan: As they get that real-world experience, and we can publish Redwood data and Shoreline data, and they get more comfortable with their treatment data, that'll give us the opportunity to expand the label and to evolve that paradigm to that treatment as needed approach that we think is really important for patients. And that's what we hear back from patients and physicians. This is what's important to them.

Okay. Thank you.

Thank you. Our next question comes from Andrew side with Jefferies. Your line is open.

Thanks, Good morning, maybe just a follow up on sardines question of course and press release.

Customer Lisa noted a large majority.

Patients maintain response I regard regardless of arm. So I'm just wondering for the placebo arm conceptually I could have durable response.

That you saw.

Mike Clunan: And it's giving them multiple approaches as to how to treat MDD and giving us a chance to evolve that paradigm over time. Thank you. As a reminder, we ask that you please limit yourself to one question. You may press star 1 to requeue for any additional questions. Our next question comes from Ritu Baral with Kellen. Your line is open.

To be attributed to background SSR ice kicking in after six to eight weeks or what could be the explanation on that thanks.

Well. This is Jeff I mean, you have to pretend that if you look of the looked at this like a regular disease. So in the original study obviously you didnt have significant separation. So it's hard to interpret those data.

What you're seeing in the in the large in the 20, so and again just imagine if you have anyone spontaneously remitting from any disease.

Ritu Subhalaksmi Baral: Hi, this is Marla from RIT too. I'm wondering if you could maybe speak to the dropout rate or maybe the follow-up that you're seeing was shoreline. Did COVID have any This is Jeff. You know, we've not seen much of an issue with that, and I think we've always used various maneuvers to assure compliance in terms of follow-up. And if you take a look at our six-month data, compared to most psychiatric trials, we have an astonishing amount of follow-up. I think it was almost 80%. That's really, I mean, I've done this a long time, and that's a very good follow-up number. And part of this is due to the diligence of the teams and the nature of the trial designs that we've instituted to encourage patients to maintain the blind. And I, you know, if you look at what we did with Mountain in particular, I'd argue that I don't think we can find another six-month blinded follow-up of any drug after the drug has been discontinued and let's watch these patients naturally. So we haven't really seen this much as an issue.

They spontaneously remit. So if you have one patient that remission curve will look the same as 100 patients. So it's hard to make much of the overall population except to say, yes, you're right. They everyone was a lot an antidepressant they could have rescue therapy. So that's why wouldn't the study we turn to the 24 and above where the study show difference.

And that's why the which of course, the relevant population and that's a majority of the patients in the study in there you don't see any drifted off.

You just simply see the patients 75% of agents maintain their response outfit six months. The other point to make and remember is that the relevant question and we're not really dealing with it today because I don't want it we don't want to be we don't want to sort of cherry pick the data if you look at responders.

The majority almost the large majority maintained their response and.

Even without intervention.

When when you go back to the early days and I think someone mentioned this earlier when you look at curves in the original study you sort of see those curves creep up sometimes accrued down you know you Gotta remember those curves represent combinations of non responders and responder. So here, we did a blinded study after six months and we just we just observe stuff.

Really I understand for everyone. Its counter intuitive, but it looks as though the natural history of depression remembering two thirds of these patients were in essence arise it actually looks like a medical disorder.

Jeff Jonas: As I mentioned, we've done a number of internal maneuvers to ensure compliance, and the team has done a great job at that. But one of the things about COVID is that I think people are depressed. They do need treatment, and depression is a serious medical disorder, and it has not discouraged patients from either participating in trials or in their follow-up. Thank you. Our next question comes from Salveen Richter with Goldman Sachs. Your line is open.

We know depression, waxes, and wanes and it looks as though that it looks just like any other medical disorder. If you get better and you have an assessment treating you stay better it differences in all of these approaches even in the mountain. The original study the patients on drug get show separation from placebo much more very rapidly within days. So you do see.

Salveen Jaswal Richter: Good morning. Thanks for taking my question. With regard to the six-month follow-up cohort in the Mountain Study, could you just help us understand how the placebo in the 20-milligram arms compared to the 30-milligram arm at six months? I'll start, and I'm going to turn it over to Jim.

Benefit within the first two weeks, even though in the in mountain you didn't see.

Didnt quite achieving significant and for us plus the six month data that really supports the utility and the rapid rate. Our t. approach, we do see early separation as well as our overall thesis that one can treat depression very differently.

Jeff Jonas: So, you know, remember in the overall trial we did not achieve significance, but the interesting finding in the overall population is regardless of, in the overall pocket, that the patients who got better tended to stay better. So we were interested, and again, that runs counter to the current dogma about depression, which we were fascinated by because it's not what people have been taught. But we've seen this in most of our studies, and at six months, we've seen the same thing, regardless of treatment. The problem with this, of course, in the overall population is that, like with any medical disorder, whoever people are, when they get better, they get better. That would be true of a community-acquired pneumonia study where people get better versus penicillin.

Great that makes sense. Thanks for the added color.

You bet.

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

Hey, guys. Thank you for taking my question on congrats on the faster than expected enrollment it's all the trials.

Just a question quick one on on mountain have you looked at the date down in terms of its consistency between men and women you know given that this news steroid is more implicated in.

Did in them and any differences you saw.

In sort of the response and then the second part of the question that I think Jeff you didn't mention a p. bagby over to the point shakes I missed it could you just tell me or just come from what you were that's been true in the mountain funnel. Thank you.

Jeff Jonas: But the interesting finding in the Mountain study was in the relevant population, where we saw a treatment effect, 24 and above, and that's why we looked at it. There, we saw a continued separation from placebo, and that persisted whether or not the patient was on an SSRI.

I'll answer the quickly then I'll turn it over to Jim.

We had we wasn't we looked at the difference that whether it was maintained on the 24 and above right. So if you're looking to see if there's a difference you got to start with the population where there was a difference and that was not the majority of the population was 24 and above and even though wasn't power for significant after six months on the blinded analysis.

Jeff Jonas: It is important to note that only a minority of the patients, only 30%, were on SSRIs. So this is a really unique finding for us, and one that we think continues to, in a stepwise fashion, de-risks our thesis that there is a way to treat patients with depression with a drug that acts rapidly and can get people better without the necessity for maintenance therapy. Just so you know, we think this is a pretty unique finding, and we are going to publish this and prepare for presentation because we think some of the science is important, and it's likely we'll wait for the shoreline data because we think that there's a lot we've learned now about the natural history of depression in the modern world that really runs counter to all the dogma that I think people accept that if you're depressed, you Okay, thank you.

The P value between placebo and drug was about 0.06, so it almost enormous maintained its significance. After six months, which was we thought a very remarkable finding considering that you know that this was a long term study it wasn't car for that.

Ill turn the rest over to Jim.

Yeah and to your other question. We yes of course, we have looked for whether or not there are differences between men and women as well as the number of other demographic factors in the study in the short answer is we don't see any difference between genders and study.

Thank you. Our next question comes from Thomas leveraged with <unk> Morgan Stanley. Your line is open.

Good morning, Thanks for taking my question My other question about Sage seven when a the topline data in Parkinson's disease. This expected later this year, what kind of data do you need to see to move. This program ahead next year. Thank you.

[noise], yes. So this is this agenda I'll take that one so the study that we're talking about is looking at the effects of see some one a relatively short term dosing in parkinsons patients with cognitive impairment and what we're doing is building off the results that we had talked to you all that.

Andrew Tsai: Thank you. Our next question comes from Andrew Tsai with Jefferies. Your line is open.

Jeff Jonas: Thanks. Good morning. Maybe just to follow up on Salveen's question, of course, and the press release noted a large majority of patients maintained response regardless of arm. So I'm just wondering, for the placebo arm, conceptually, could a durable response that you saw be attributed to background SSRIs kicking in after six to eight weeks? Or what could be the explanation of that?

To the end of last year, showing that in Huntingtons patients were able to see acutely an improvement in executive function and other aspects of cognitive function and so because this is such a novel space and because it's such a novel approach.

Jeff Jonas: Well, this is Jeff. I mean, you have to pretend that if you look at this, you look at this like a regular disease. So in the original study, obviously, we didn't have any significant separation, so it's hard to interpret those data. What you're seeing in the large, and again, just imagine if you had anyone spontaneously remitting from any disease. And that's why, which is, of course, the relevant population. And that's the majority of the patients in the study. And there you don't see any drift at all.

And because we were so happy to see the results would be saw from the huntingtons patients rather than move forward with the very first patient population that we saw into.

More detailed placebo controlled study you decided to pause and go through the activity of looking at various patient population. So that's what this study is now we're going to essentially run a similar short duration study in open label format in tons in Parkinsons patients similar to what we did in Huntington stations to.

Jeff Jonas: You just simply see the patients; 75% of the patients maintain their response out to six months. The other point to make and remember is that the relevant question, and we're not really dealing with it today because we don't wanna sort of cherry pick the data. If you look at responders, the majority, almost a large majority, maintained their response even without intervention.

If that's another patient population that's a benefit we'll also look in other words generate disorders and really this is all built on the role of the in India receptor in cognitive function. There's reason to believe that you can see abroad improvements in cognitive function across more than one patient population and so that's what we'll do with the.

Jeff Jonas: And when you go back to the early days, and I think someone mentioned this earlier, where you look at curves in the original study, you sort of see those curves creep up and sometimes they'll creep down. You know, you gotta remember, those curves represent combinations of non-responders and responders. So here, we did a blinded study out to six months, and we just observed stability. I understand that for everyone it's counterintuitive, but it looks as though the natural history of depression, remembering that two-thirds of these patients weren't unnecessarily treated, actually looks like a medical disorder.

The next study in PD patients is really looked to see if we can expand the results that we've seen to date in HCV patients.

Great. Thank you.

Thank you. Our next question comes from Neenah, but can you tell with Citi. Your line is open.

Hi, Thanks for taking my question. So just wanted to ask a quick one on the regulatory strategy I know you talked a little bit about you know kind of next steps. Once you have some initial data in MDT into these upcoming studies, but.

Once you get data from waterfall I guess, what's kind of that the plan for Redwood are are you going to wait until you have data from waterfall or do you and Pete maybe reinstating that study a little bit earlier. Thanks.

Jeff Jonas: You know, we know depression waxes and wanes, and it looks as though it looks just like any other medical disorder. If you get better, and you have a successful treatment, you stay better. The difference is, in all of these approaches, even in Mountain, the original study, the patients on drugs show separation from placebo much more, very rapidly within days. So you do see benefit within the first two weeks, even though in Mountain you didn't see, didn't quite achieve its significance. And for us, plus the six-month data, that really supports the utility and the rapid RRT approach, where you do see early separation, as well as our overall thesis that one can treat depression very directly. Great, that makes sense. Thanks for the added color.

Thanks for the question right I think obviously it will depend on the data from waterfall than the data from sure line right now we still have to have some larger study or some study like like the longer term analysis, but when we see waterfall one of the things.

We were going to have to take a hard look at is.

Based on the six month data, we're not seeing a lot of relapses. If you think about patients getting this drug treatment and youre thinking about 75% of patients maintaining their effect, regardless of background therapy or no background therapy, yes, that's something we'll have we'll need to take up of the agency. Because initially we had looked at we'd only I follow up data out.

Yatin Suneja: You bet. Our next question comes from Yatin Suneja with Guggenheim Partners. Your line is open. Hey guys, thank you for taking my question and congratulations on the faster than expected enrollment in some of the trials. Just a quick one on Mountaine.

Good day, 42, and we had assumed that people would need sort of.

Recurrent treatment I think that assumption, so far as being challenged by the six month data.

And we'll have to take a look hard hard look at shoreline and shoreline, which we're optimistic about now based on the six month data gives us something like that will weaken well, we'll revisit what what the what long term data we might need.

Jeff Jonas: Have you looked at the data in terms of its consistency between men and women? You know, given that this neurosteroid is more implicated in women, any differences you saw in sort of the responses? And the second part of the question is, I think Jeff, you did mention a p-value of 0.6. I missed it.

If if we're if port at waterfall reports out positively on Steve or Jim you want to anything to that.

Yeah, I'll, just say a few things I mean first of all just to remind everyone. This is a program that's proceeding under breakthrough therapy designation, which gives us an opportunity to how interactions across the board.

Jeff Jonas: Could you just tell me or just confirm what you were referring to in the Mountaine follow-up? I'll answer the quick one, then I'll turn it over to Jim. We looked at the difference, whether it was maintained on the 24 and above, right? So if you're looking to see if there's a difference, you've got to start with the population where there was a difference. And that was because the majority of the population was 24 and above.

And so as we as a data unfold, we're able to interact with with the FDA and talk about what the potential pathways forward. Our has breakthrough because we share our understanding of the urgency for developing an entirely new therapy and that's what this whole program is been designed to do so yeah. When we have data will do we always it was just go.

Jeff Jonas: And even though it wasn't powered for significance, after six months, on the blinded analysis, the p-value between placebo and drug was about.06, so it almost maintained its significance after six months, which was, we thought, a very remarkable finding considering that this was a long-term study and it wasn't powered for that. I'll turn the rest over to Jim. And to your other question, yes, of course, we have looked for whether or not there are differences between men and women, as well as a number of other demographic factors in the study. And the short answer is we don't see any difference between genders in the study.

Back to the agency remember, it's not just the clinical efficacy data. It's also clear farm data and everything else that we've been consistently showing across the board now with more than 2500 patients that have been exposed the drug we have a very clear idea on the with the overall adverse event profile safety profile is so a lot of information.

Comes through all of which will lead to.

The most efficient regulatory strategy forward so.

That's a lot of words to say as the data unfolds, we'll have those discussions and identify the most efficient path forward for patients.

Jim Doherty: Thank you. Our next question comes from Thomas Lavery with Morgan Stanley. Your line is open.

Thank you. Our next question comes from Cory Kasimov from Jpmorgan. Your line is okay.

Thomas Lavery: Good morning, and thanks for taking my question. I have a question about SAGE 718. The top-line data for Parkinson's disease is expected later this year. What kind of data do you need to move this program ahead next year? Thank you. Yeah, so this is Jim Doherty. I'll take that one.

Hey, good morning, guys. Thanks for sit in the end so for the Archie study that's on top to begin in the second half do you plan to piggyback on top of your existing MDD sites will they be separate I guess Im just curious how fast. This can go since it sounds like this would represent the initial MDD filing. Thank you.

Jim Doherty: So the study that we're talking about is looking at the effects of SAGE Skeptimum 1.8 with relatively short-term dosing in Parkinson's patients with cognitive impairment. And what we're doing is building off the results that we talked to you all about at the end of last year, showing that in Parkinson's patients, we're able to see an improvement in executive function and other aspects of cognitive function. And so because this is such a novel space and because this is such a novel approach, and because we were so happy to see the results that we saw in the Huntington's patients, rather than move forward with the very first patient population that we saw into a more detailed placebo-controlled study, we decided to pause and go through the activity of looking at various patient populations.

Yes, so there'll be a combination of site that may have waterfalls, moving quit we have a lot of really well but.

Well performing sites I think for water.

So I think that we'll we'll continue to try to actually go quickly I think that one of the lessons of waterfall in the lessons of this whole of this year has been that our ability to leverage.

Our infrastructure that we've developed over time and the team's ability to move quickly from protocol to protocol, so well be doing that as well. We do think the design of these studies, we do design to studies to be a night, but one of a better word palatable.

To the investigators insights and one of the advantages of is around alone and general has been that to be course of therapy patient potential patient benefit quickly has been very Acs has been agreed with a lot of enthusiasm.

By treating clinicians so were that's one of the encouraging things that we've seen throughout all of this.

Jim Doherty: So that's what this study is now. We're going to essentially run a similar short-duration study in an open-label format in Parkinson's patients, similar to what we did in Huntington's patients, to see if that's another patient population that can benefit. We'll also look at other neurodegenerative disorders. And really, this is all built on the role of the NMDA receptor in cognitive function.

Jim I don't know if you want to anything to that.

Yes, I was just adds up the we have a pretty large network of sites and so we're confident that we're going to run all the studies.

And keep ourselves on track for all.

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

Hi, This is kind of gone for Laura Thanks for taking the question.

So on Skylark.

For the rest of ourselves, we're clearly impacted by cobot and while the extended disruptions appear to have stabilized.

With data in 2021, how should we be thinking about the number of sites that will be necessary for prevention modus before we outpatient. Thank you.

Jim Doherty: There's reason to believe that you can see a broad improvement in cognitive function across more than one patient population. And so that's what we'll do with the next study in PD patients, really look to see if we can expand the results that we've seen to date in HD patients. Great, thank you.

Sure. Thanks for the questions as Jim Yes, I think the important thing to remember we're skylark is that with surround alone. What we're talking about is an outpatient therapy and so that's just a different.

Neena Marie Bitritto: Thank you. Our next question comes from Neena Bitritto with Citi. Your line is open.

Opportunity than what's with so wrestle, but certainly from a recruiting perspective, we're anticipating that we're going to be able to recruit for the sounded like study.

Jeff Jonas: Hey, thanks for taking the question. So I just wanted to ask a quick one on kind of the regulatory strategy. I know you talked a little bit about, you know, kind of next steps once you have some initial data in MDD and some of these upcoming studies, but once you get data from Waterfall, I guess, you know, what's the plan for Redwood? Are you going to wait until you have data from Waterfall?

Comparable way to what we're seeing on in our other studies was around alone. It's a it's a smaller patient population and so of course, there will be an impact there.

But I think the probably the most important thing is that within oral drug in an outpatient setting is.

Steve as you want to add anything.

Jeff Jonas: Or do you anticipate maybe re-initiating that study a little bit earlier? Thanks for the question. I think, obviously, it will depend on the data from Waterfall and the data from Shoreline.

Yeah, I was just say either with the with Covance my preferred to that is impacting patients I'm sort of being able to be admitted to hospital for treatment.

Jeff Jonas: Right now, we still have to have some larger study or some study like a longer-term analysis. But when we see Waterfall, one of the things we're going to have to take a hard look at is whether, based on the six-month data, we're not seeing a lot of relapses. When you're thinking about patients getting the drug treatment and you're thinking about 75% of patients maintaining their effects, regardless of background therapy or no background therapy, that's something we'll need to take up with the agency. Because initially, we had only had follow-up data out to day 42, and we had assumed that people would need sort of a Recovery Treatment. I think that assumption so far is being challenged by the six, and we'll have to take a hard look at Shoreline. Shoreline, which we're optimistic about now based on the six-month data, gives us something like that. We'll revisit what long-term data we might need if Waterfall reports out positively. Steve or Jim, do you want to add anything to that?

On the other side of that of course is that there's enormous unmet need and that's only growing with increased isolation of women in the in the face of being delivering without significant others living room, and having to go and without the support of of family members and so forth the rates and and potential interest income and postpartum depression is on.

The growing so as as Jim said, you know the the trial itself is now patient trial. It gets around some of those logistical challenges and just based on her experience with execution, we anticipate being able to enroll that oh in in a very similar way as we have with waterfall up to the important issue, it's an important disorder and one that.

We've been committed to for a long time.

Yeah, and I'll just coming this is Mike as well I think just it's important for a couple of points. One is as we said we have those distinct pass now offers around what we have the TV path with Skylark right. One study will be able to seek approval. There we have the two paths with MDD, both the our t. indication and the episodic and the one point I'll also make income in combination with thing.

Very different profiles, writing on the TV decide between zero Russow and ran low right. The rapid acting nature is still there, but an oral therapy that patients are going out to go into hospital to receive the 60 arent fusion. My we're still very excited about the tpd market and what we things around along can do there.

Steve Kames: Yeah, I'll just say a few things. First of all, just to remind everyone, this is a program that's proceeding under breakthrough therapy designation, which gives us an opportunity to have interactions across the board. And so, as the data unfolds, we're able to interact with the FDA and talk about what the potential pathways forward are as breakthroughs because we share our understanding of the urgency of developing an entirely new therapy, and that's what this whole program has been designed to do. Thank you. Our next question comes from Corey Kasimov with J.P. Morgan. Your line is open.

Okay. Thanks, so much.

Okay.

Thank you and I last question from Jay Olson with Oppenheimer. Your line is open.

Oh, hi, thanks for taking the question.

Were you surprised by the durability of their analysts on and the six month mountain follow up and how do you plan to leverage the that finding a with regards to your filing strategy and ultimately your target product profile for is around.

Corey Kasimov: Hey, good morning, guys. Thanks for fitting me in. So for the RRT study that's on tap to begin in the second half, do you plan to piggyback on top of your existing MDD sites, or will they be separate? I guess I'm just curious how fast this can go, since it sounds like this would represent the initial MDD filing. Thank you. There will be a combination of sites. Waterfall is moving quickly.

Hi, This is Jeff thanks for that question.

You know I don't want to use the word surprise I I guess I'd say, we were gratified that the data that we've acquired to date over all of our studies.

Can be now be extended out to six months.

Yes.

We are aware and I said in my opening remarks that this is really counter to the narrative about depression that you and list that patients enlist themselves chronic mental health patients for the rest of their lives that there's still a delicate that they have to stay on on treatment for years and years and and and those of US who are treating these patients we've always want.

Jeff Jonas: We have a lot of really well-performing sites, and I think that we'll continue to try to go quickly. I think that one of the lessons of Waterfall and of this year has been our ability to leverage our infrastructure that we've developed over time and the team's ability to move quickly from protocol to protocol. We'll be doing that as well. We do think the design of these studies, we design the studies to be, for want of a better word, palatable, to the investigators and sites. And one of the advantages of Zoranolone in general has been that, you know, a two-week course of therapy, patient, potential patient benefit quickly, has been very, you know, has been greeted with a lot of enthusiasm by treating clinicians. So we're, that's one of the encouraging things that we've seen throughout all of this. Jim, I don't know if you want to add anything to that.

It's something better.

And we wanted something different and so I I think we've been gratified by it I.

I do think that.

The data really do I wouldn't say surprised with the data really don't when count is like I think Steve and I about Skijus don't run counter to our personal experience isn't how used to treat patients, but it really does it is surprisingly inconsistent with the pharmaco mythology about how to treat depression and so we do think that.

Use data we continue to this is just another step.

And we do think that these data, though do inform what might come from shoreline and if we can sustain this we think the profile the drug will be unique.

Jeff Jonas: Yeah, I would just add, Jeff, that we have a pretty large network of sites, and so we're confident that we're going to be able to run all the studies and keep ourselves on track for all of them. Thank you. Our next question comes from Laura Chico with Gladbush Security. Your line is open.

We think that the ability to get patients better more rapidly.

I have a tolerable side effect profile and to.

Eliminate the necessity for automatic chronic pharmacotherapy will be in a really important treatment option for patients that otherwise are looking at years potentially years of Sri therapy. So we're very encouraged by and we would it we intend to think about how we could disrupt the treat.

Jim Doherty: Hi, this is Kenneth on behalf of Laura. Thanks for taking the question. So on Skylark, the rest of the cells were clearly impacted by COVID, and while the extended disruptions appear to have stabilized. With data in 2021, how should we be thinking about the number of sites that will be necessary for recruitment?

And from a paradigm and that'll be of course mikes job once we have the data.

But we do think these data are an important next step.

Laura Kathryn Chico: And will this be fully outpatient? Sure, thanks for the question. This is Jen.

Where you're not seeing rebound you're not seeing withdraw you seeing very good you're not seeing any sign.

Jim Doherty: Yeah, I think the important thing to remember for Skylark is that with Soranolone, what we're talking about is an outpatient therapy, and so that's just a different opportunity than with Soretso, but certainly from a recruiting perspective, we're anticipating that we're going to be able to recruit for the Skylark study in a comparable way to what we're seeing in our other studies with Soran It's a smaller patient population, and so of course, there'll be an impact there. But I think probably the most important thing is that with an oral drug in an outpatient setting, it's Steve, did you want to add anything? Yeah, I was just saying, you know, with COVID, Mike referred to that as impacting patients, sort of being able to be admitted to the hospital for treatment.

We're seeing really good durability now the other thing I point out, though as we said early on that the thesis behind these drugs in the mechanism behind some of the newest storage is the ability to alter post synaptic receptor trafficking and we've always thought about restoring normal homeostatic mechanisms and the brain and in that respect we've always been.

Lee that's around alone is a distinct.

It's not really what other people call an anti depressant.

It's something different it's something that normalizes mood potentially normalizes neural circuitry and potentially offers a reset of mood function. So we think the six month data really represent this sort of paradigm shift and how one can think about major depressive disorders. So we add so we do think we were that they were on the way to doing it.

Jim Doherty: On the other side of that, of course, is that there's enormous unmet need, and that's only growing. With increased isolation of women in the face of delivering without significant others in the living room and having to go home without the support of family members and so forth, the rates and potential interest in, you know, postpartum depression are only growing.

We think that this will be an important treatment option for patients and it's one we intend to continue to pursue it.

Super helpful. Thanks for taking the questions.

Thank you I'd now like you turn the call back over to Jeff Jones for closing remarks.

Well again, thanks, everyone for joining us this morning, I know, you're all bid and hope everyone is happy healthy and your families are helping to.

To close I, just want to reiterate three important points.

Jim Doherty: So, as Jim said, the trial itself is an outpatient trial. It gets around some of those logistical challenges, and just based on our experience with execution, we anticipate being able to enroll that in a very similar way as we have with waterfall. It's an important issue.

The team at stage has done a great job executing on our clinical programs all of which remain on track or ahead of schedule.

As you've heard today, we have numerous catalyst over the next 18 months and Sage is really proud of our discovery made a dismal chemistry group, they're developing that's really what makes us unique a rich pipeline of novel, an attorney that certainly develop clinical assets with which we believe have the potential to help literally millions of people so with that.

Steve Kames: It's an important disorder and one that we've been committed to for a long time. Yeah, and I'll just come in, this is Mike as well. I think just, it's important for a couple of points. One is, as we've said, we have those distinct paths now for Zoranilone. We have the PPD path with Skylark, right?

Forward to updating all of you in the future with all of our milestones and help all of you stay well and have a great day.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating you may now disconnect.

Mike Clunan: One study, and we'll be able to seek approval there. We have two paths with NDD, both the RRT indication and the episodic. And the one point I'll also make, combined with what's being said, very different profiles, right?

[music].

Mike Clunan: On the PPD side, between Zoreso and Zoranilone, right? The rapid-acting nature is still there, but in oral therapy, patients aren't gonna have to go into a hospital to receive the 60-hour infusion. We're still very excited about the PPD market and what we think Zoranilone can do. Okay, thanks so much.

Jay Olson: Thank you. And our last question is from Jay Olson with Oppenheimer. Your line is open.

Jeff Jonas: Hi, thanks for taking the question. Were you surprised by the durability of xeranilone in the 6-month Mountain follow-up? And how do you plan to leverage that finding with regard to your filing strategy and ultimately your target product profile for xeranilone? This is Jeff. Thanks for that question. You know, I don't want to use the word surprise.

Jeff Jonas: I guess I'd say we were gratified that the data that we've acquired to date over all of our studies can now be extended out to six months. We're aware, and as I said in my opening remarks, that this is really counter to the narrative about depression, that you enlist, that patients enlist themselves as chronic mental health patients for the rest of their lives, that they're so fragile that they have to stay on treatment for years and years. And, and, and those of us who treat these patients, you know, we've always wanted something better. And We wanted something different.

Jeff Jonas: And so I think we've been gratified by it. I do think that The data really do, I wouldn't say surprise, but the data really, you know, don't run counter to, I think Steve and I are both psychiatrists, don't run counter to our personal experiences and how we used to treat patients. But it really does, it is surprisingly inconsistent with the pharmacomythology about how to treat patients. And so we do think that these data, we continue to, this is just another step. And we do think that these data, though, do inform what might come from Shoreline.

Jeff Jonas: And if we can sustain this, you know, we think the profile of the drug will be unique. We think that, you know, the ability to get patients better more rapidly, to have a tolerable side effect profile, and to eliminate the necessity for automatic chronic pharmacotherapy will be a really important treatment option for patients that otherwise are looking at years, potentially years of SSRI therapy. So we're very encouraged by it, and we intend to think about how we could disrupt the treatment paradigm. And that will be, of course, Mike's job once we have the data.

[music].

Jeff Jonas: But we do think these data are an important next step, where, you know, you're not seeing rebound, you're not seeing withdrawal, you're seeing very good, you're not seeing any signs, you know, you're seeing really good durability. Now, the other thing I point out, though, is we said early on that the thesis behind these drugs and the mechanism behind some of the neurosteroids is the ability to alter postsynaptic receptor And we've always thought about restoring normal homeostatic mechanisms in the brain. And in that respect, we've always believed that seranolone is a distinct model. It's not really what other people call an antidepressant. It's something different.

Jeff Jonas: It's something that normalizes mood, potentially normalizes neural circuitry, and potentially offers a reset of mood function. So we think the six-month data really represents this sort of paradigm shift in how one can think about major depressive disorder. We do think that we're on the way to doing it. We think that this will be an important treatment option for patients, and it's one we intend to continue to pursue. That's super helpful.

Jeff Jonas: Thanks for taking the question. Thank you, and now I'd like to turn the call back over to Jeff Jonas for closing remarks. Well, again, thank you everyone for joining us this morning. I know you're all busy, and I hope everyone's healthy and your families are healthy.

Jeff Jonas: To close, I just want to reiterate three important points. The team at SAGE has done a great job executing on our clinical programs, all of which remain on track or ahead. As you've heard today, we have numerous catalysts over the next 18 months, and SAGE is really proud of our Discovery Medicinal Chemistry Group for developing this really, what makes us unique, a rich pipeline of novel and internally developed clinical assets, which we believe have the potential to help literally millions of people. So with that, I'm looking forward to updating all of you in the future with all of our milestones, and I hope all of you stay well. Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect. BF-WATCH TV 2021 BF-WATCH TV 2021, SAGE Therapeutics Inc. All Rights Reserved. I will not be able to do that.

Operator: ....

Operator: Ladies and gentlemen, thank you for standing by, and welcome to the SAGE Therapeutics 2nd Quarter 2020 Financial Results Conference Call. At this time, all participant lines are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 1 on your telephone. Please be advised that today's conference is being recorded. If you require any further assistance, please press star 0. I would now like to hand the conference over to your speaker today, Jeff Boyle, Senior Director, Investor Relations. Thank you. Please go ahead.

Jeff Boyle: Good morning, and thank you for joining SAGE Therapeutics' second quarter 2020 financial results conference call. Before we begin, I encourage everyone to go to the investor and media section of our website at sagerx.com, where you can find the press release related to today's call, as well as the slides that contain supplemental details. I would like to point out that we will be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially.

Jeff Boyle: Please consult the risk factors discussed in today's press release and in our SEC filings for additional details. We will begin the call with prepared remarks by Dr. Jeff Jonas, our Chief Executive Officer; Mike Clunan, our Chief Business Officer; and Kimi Iguchi, our Chief Financial Officer. We will then be joined for the Q&A session of the call by Dr. Steve Kaines, our Chief Medical Officer, and Jim Doherty, our Chief Research Officer. I will now turn the call over to...

Jeff Jonas: Thanks, Jeff. And thanks everyone for joining us this morning. We're pleased to update you today on our second quarter and progress across our development programs. Today, I'll provide an overview of our second quarter activity and discuss our depression, neuropsych, and neurology franchises. Then Mike will provide a more detailed business update, and lastly, Kimi will provide an update on financials.

Jeff Jonas: As all of you are aware, we're operating in a new environment with the challenges of the global COVID-19 pandemic. However, even in the face of these challenges, I'm pleased to report that the execution of our clinical programs remains on track. We're aware that some companies have made the decision to stop or pause recruiting or enrollment in clinical trials, but I'm pleased that the teams at SAGE were proactive in their planning and management of our trials. As you know, our lead clinical asset is Zoranolone, and studies for major depressive disorder and postpartum depression. Additionally, we have SAGE 324 in development for essential tremor, and SAGE 718, which we are exploring based on early study findings we believe are compelling for its potential in areas where executive function is impaired.

[music].

Jeff Jonas: Based on our progress in the last six months, we expect to have numerous catalysts coming over the next 18 months. We've been able to advance several programs and have had strong enrollment to date in our Zoranilone Waterfall Study. We have been dosing subjects with 50mg in our SHERLONG study as well and have advanced the anticipated top-line readout for our SAGE 324 Tremor Study to the latter part of 2020 or the first quarter of 2021. Thus, we are running on or ahead of schedule across our development programs. In sum, during the second quarter, we initiated four new clinical trials across two franchises.

Jeff Jonas: I'd like to comment further on our depression franchise. We set out to develop a therapy that we believe, if successfully developed and approved, will be an important and unique option for people with major depressive disorder, or MDD. Our clinical programs are designed to answer very specific questions to achieve this goal, and we are implementing in a stepwise progression. We believe that patients want to get well quickly and stay well, and many would prefer not to undergo chronic pharmacotherapy. In this light, we believe both Zolreso in postpartum depression and zaranolone in MDD and PPD have pharmacological characteristics consistent with this type of approach.

Jeff Jonas: As a reminder, our Zoranolone program has been designed to achieve a first NDA as efficiently as possible, with three ongoing studies where each, with a positive outcome, supports a unique potential filing pathway. For each pathway, we believe just one additional positive acute study is needed to show efficacy. As noted earlier, we made significant progress towards this goal by initiating dosing with 50 mg in our Phase III Waterfall Study in patients with MDD. Based on our enrollment, which has now surpassed 50%, we have updated our anticipated completion date for the Waterfall Study to the first half of 2021.

Jeff Jonas: We've also initiated dosing in a postpartum study, our Phase III Skylark program. Top-line data from the Skylark study is anticipated in 2021. And finally, as noted earlier, we initiated dosing in the 50 milligram cohort of our Phase III Open Label Shoreline study. Top-line data from the SHERALINE study, 30 mg, is expected by the end of this year, and it is also possible we will have preliminary data from patients who receive 50 mg in the study by year end as well. We're also on track to commence dosing in the Phase III choral study later this year. Recall, the choral study is looking at seranolone 50 mg as an acute rapid response therapy, an MDD, when co-initiated with a newly administered standard antidepressant.

Jeff Jonas: Mike will talk about the utility of this potential indication later in the call, but what I can say is that we now have three shots on goal to bring Zaranolone to market. Today, we're also reporting results from the six-month follow-up arm of the Mountain Study. As we set out to understand more about the durability of Zoranolone, we asked, what happens to treatment responders at six months?

[music].

Jeff Jonas: This has been an important question in an area of speculation, as clinicians need to understand the treatment path for patients who respond to Zoraniline. As part of the Mountain Study, subjects were offered the opportunity to participate in a six-month blinded follow-up to assess durability of response in those patients who responded after 14 days of treatment. As a reminder, the study was not powered to detect statistical significance from placebo beyond date 15. About half of the study participants elected to participate in the follow-up, and we were pleased to see that more than 80% of those completed the six-month follow-up period. There were no drug-related adverse events, changes in labs, EKG measures, vital signs, or suicidality ratings seen following exposure to zaranolone, and there were no signals of withdrawal or rebound after treatment with zaranolone was completed at day 14.

Ladies and gentlemen, thank you for standing by.

I want to the Sage Therapeutics second quarter 2020 financial results conference call at this time optimize Arnaud its mode.

Just because presentation there'll be a question answer session.

You asked the question during the session you want me to press Star one of your telephone.

Please be advised that today's call forget stay recorded.

Acquiring further specifically the stars Arrow.

I would now like to have a copper, though what you speak today, Jeff oil senior director Investor Relations. Thank you. Please go ahead Sir.

Jeff Jonas: We were also pleased to see that approximately 75% of the patients who responded to Zoranil on 30 mg at day 15 maintained their response rate at the last follow-up on day 182. This was true of the overall population, regardless of treatment arm. But more importantly, for those who showed significant benefit from ziranylone at 30 milligrams, that is, the population with a HAMD greater than or equal to 24 at baseline, the improvement over placebo seen at day 15 was sustained over the full six-month period, and at no time during the follow-up period did the change from baseline in HAMD in the placebo arm surpass that in the ziranylone 30 milligram arm. This suggests This benefit was seen regardless of whether or not the patient was being treated with an SSRI.

[music].

Good morning, and thank you for joining Sage Therapeutics second quarter 2020 financial results Conference call.

I would again I encourage everyone to go to the best your immediate section of our website <unk> Dot Com, where you can find the press release related today's call as well as it applies the containing supplemental detail.

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 todays press release, and then resi filings for additional details.

Jeff Jonas: We believe these data support our vision for a unique treatment profile for seranolone for people with MDD. However, developing an as-needed therapy in MDD runs entirely counter to the status quo of assuming all patients require chronic drug treatment, and we understand two decades of one approach will require data to effect change. We believe these data are another step along that path. We're looking forward to the top-line data readout for the Zaranulon 30 mg cohort in the Shoreline study, which we expect will be reported by the end of the year. Before I move on, I want to reemphasize that our goal of MDD is nothing less than to offer a disruptive, distinct, and novel treatment approach for patients. There are already several things we've observed in clinical trials with Zoranolone to date that we believe, along with our six-month data, suggest the potential for Zoranolone to be uniquely situated for this approach. First, we observed rapidity of response within days, and that has been consistently observed across our study. Second, the drug has been well tolerated in these studies with more than 2,500 subjects. There have been no adverse events of loss of consciousness, including up to doses of 90 milligrams evaluated in our clinical pharmacology studies.

We will begin the call prepared remarks by Dr., John That's our Chief Executive Officer, Mike Cronin, Our Chief business Officer, and Kimi Iguchi, our Chief Financial Officer, We will then be join pretty queuing, especially on the call by Dr., Steve Games, Our Chief Medical Officer, and Jim Doherty, Our Chief Research Officer.

I'll now turn the call over to John.

Thanks, Jeff.

Hi, Thanks, everyone for joining us this morning.

We're pleased to update you today on our second quarter with progress across our development programs today I'll provide an overview of our second quarter activity I, just got sucked depression narrow psych and neurology franchise is then Mike will provide a more detailed business update and lastly can be will provide an update on financials.

As all of you are aware, we're operating at a new environment with the challenges at the global Kobe 19 pandemic. However, even in the face of these challenges I'm pleased to report that execution of our clinical programs remains on track.

Jeff Jonas: And third, there have been no signals of rebound or withdrawal after the drug has stopped. I'm sometimes asked why we are looking to treat depression like a medical condition rather than a chronic disease that labels a person as a mental health patient. It's long been recognized that the preference or reliance on chronic pharmacotherapy is a problem in psychiatry, and the numbers bear this out. Seventeen million new diagnoses a year for major depression, but nearly twice that many people remain on treatment for two years or more. We see this as an area of substantial unmet medical and societal need. If we are successful, seraniline has the potential to allow patients to get treated, get better quickly, and not require another treatment until when or if he or she has another depressive episode, as you might expect when treating any other medical condition.

We're aware that some companies made the decision to stop a pause recruiting or enrollment in clinical trials, but I'm pleased that the teams that stage, what proactive in their planning and management of our trials.

As you know our lead clinical asset is around alone in studies from major depressive disorder, and postpartum depression I.

Additionally, we have stage three to four in development for essential tremor, and Sage seven and eight which we are exploring based on early study findings, we believe our compelling for rich potential in areas, where executive function is impaired.

Based on our progress in the last six months, we expect to have numerous catalysts coming over the next 18 months.

We've been able to advance several programs and it had strong enrollment to date now is right alone waterfall study.

We have been dosing subjects with 50 milligrams and North Carolina study as well and advance the anticipated topline read out for our stage three to four tremor study to the latter part of 2020 or the first quarter of 2021. So we are running on or ahead of schedule across our development programs.

Jeff Jonas: Now, turning to a new development with Brexanilone, we are pleased to announce that, under the FDA's Coronavirus Treatment Acceleration Program, or CTAP, Brexanilone has been cleared for a Phase III study in people with advanced COVID-19-related acute respiratory distress syndrome, or ARDS. This announcement comes after several months of analysis of Brexanilone clinical and preclinical data. As many of you know, we already have extensive ICU experience and generated significant critical care data with Brexanilone in our SRSE trials. SAGE also has extensive chemical equity and medical chemistry experience, and we've been looking at other ways our compounds may impact peripheral receptor systems. The BRICS Aniline trial and COVID-19 related ARDS will involve several leading academic centers. SAGE has undertaken this initiative believing there is a sound rationale to test whether Brexanolone may be able to mitigate the morbidity and mortality associated with COVID-19-related ARDS. It's also, we believe, the right thing to do.

In sum during the second quarter, we initiated for new clinical trials across two franchises.

I'd like to comment further on a depression franchise.

We set out to develop a therapy that we believe if successfully developed at approved will be an important and unique option for people with major depressive disorder or N D. R.

Our clinical programs are designed to answer very specific questions to achieve this goal.

And we are executing in a stepwise progression.

We believe that patients want to get well quickly and stay well and many would prefer not to undergo chronic pharmacotherapy.

In this flight we believe boats will rest so in postpartum depression and is around alone in MDD MPPD have pharmacological characteristics consistent with this type of approach.

As a reminder, Iran alone program has been designed to achieve a first and D.A. as efficiently as possible with three ongoing studies, where each with a positive outcome supports the unique potential filing pathway for each pathway. We believe just one additional positive acute study is needed to show efficacy.

As noted earlier, we made significant progress towards this goal by initiating dosing with 50 milligram in our phase the waterfall study in patients with MDD.

Based on our enrollment which has now surpassed 50%.

We have updated our anticipated completion date for the waterfall study to the first half of 2021.

Jeff Jonas: We look forward to answering further questions about this trial during our upcoming Investor Day event in September. Turning now to our neurology franchise, we have begun dosing in our Phase 2 double-blind study, which we are calling Kinetic, with SAGE 324 at 60 mg in a central tremor. As a reminder, essential tremor is the most common movement disorder in the U.S., affecting an estimated 6 million people in our country

We've also initiated dosing in a post bottom study that fit our phase three Skylife program topline data from the Skylark study as anticipated and 2021.

Finally, as noted earlier, we initiated dosing in the 50 milligram cohort of our phase three open label shoreline study.

Topline data from the shoreline study 30 milligrams is expected by the end of this year and it is also possible. We will have preliminary data from patients who received 50 milligrams him to study by year end as well.

We're also on track to commenced dosing in the phase three coral study later this year recall the call studies looking at around 50 milligrams as an acute rapid response to therapy and MDD when co initiated with a newly administered standard answer depressant.

Jeff Jonas: Earlier open-label data with SAGE 324 demonstrated that it is a compound with the pharmacologic characteristics we believe are well-suited for development opportunities, not only in essential tremor but also in epilepsy and Parkinson's disease. We anticipate reporting top-line data from the essential tremor trial in the fourth quarter of this year or the first quarter of 2021. We're also on track to initiate our Phase 2a open-label study with SAGE 718 in the second half of 2020, the lead asset in our neuropsych franchise and our most advanced NMDA PAM in patients with Parkinson's disease cognitive dysfunction. Results from this study, which we are calling the Paradigm Study, will inform the potential advancement of SAGE 718 in various disorders with cognitive dysfunction.

Michael talked about the utility of this potential indication later in the call, but what I can say is that we now have three shots on goal to brings rattle onto market.

Today, we're also reporting results from the six month follow up are from the mountain study.

As we set out to understand more about the durability of Saran alone, we asked what happens to treating the responders or six months.

This has been an important question in an area of speculation as coalitions need to understand the treatment path for patients who respond is around alone.

As part of the Mountain study subjects will offer the opportunity to participate in a six month blinded follow up to assess durability of response and those patients who responded after 14 days or treatment. As a reminder, the study was not powered to detect statistical significance from placebo beyond day 15.

About half the study participants elected to participate in the follow up and we were pleased to see at more than 80% of those are completed the six my follow up period.

Jeff Jonas: As a reminder, in early studies, SAGE 708 was well-tolerated, and patients as well as healthy volunteers demonstrated improved performance compared to baseline on assessments of executive functioning. We believe the data we generated in our Phase 1 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. Before I turn it over to Mike, I want to share my appreciation for the team at SAGE. The team is executing well across all franchises to advance our therapies as quickly as possible for the benefit of patients and families. We believe we've created a novel drug company successfully able to convert our chemical equity library into a rich pipeline of clinical assets that are new chemical entities and not just repurposed molecules. So with that, I'll turn the call over to Mike.

There were no drug related adverse events changes in labs, you kg measures vitals lives or Suicidality ratings seen following exposure does around alone and there were no signals of withdrawal a rebound after treatment with is around alone was completed at day 14.

We were also pleased to see that approximately 75% of the patients who responded is around 30 milligrams. A day 15 maintained their response rate at the last follow up on day 180 to.

This was true of the overall population regardless of treatment arm, but more importantly for those who show significant benefit firms around 11, 30 milligrams that is the population with a heavy greater than or equal to 24 baseline the improvement over placebo seen a day 15 west sustained over the full six month period and at no time.

During the follow up period to the change from baseline in Hamdi input in the placebo arm surpassed that is around 30 milligram arm. This suggests that persistence of benefit following the initial two weeks around a lot of course.

Mike Clunan: Thanks, Jeff, and good morning, everyone. As Jeff mentioned, we've made significant progress over the last quarter with the initiation of four new clinical trials. We've built upon the rigorous prioritization and resource allocation we began in the first quarter as we continue advancing programs across our depression, neurology, and neuropsych franchises. Let me add a bit of perspective on how we're thinking about positioning the differentiated profile of Zoranolone in our depression franchise, if successfully developed and approved. We have consistently observed rapid response within days and good tolerability of zaranolone in our landscape clinical program to date. Rapid action in depression, if also seen in our ongoing and planned trials, would be an important profile for xeranolone, whether used episodically, or treated as needed, or as a rapid response or RRT therapy when co-initiated with a new antidepressant.

This benefit was seen regardless of whether or not the try patient was treated with SSR rise.

We believe these data support our vision for unique treatment profile for is around alone for people with MDD.

We understand development of an as needed therapy in MDD runs entirely counter to the status quo of assuming all patients require chronic drug treatment and we understand two decades of one approach we've acquired data to effect change.

We believe these data are another step along that path.

We're looking forward to the topline data read out, but there is around 30 milligram cohort and the sure lied study, which we expect will be reported by the ended the year.

Before I move on I want to reemphasize that our goal of MDD is nothing less that to offer a disruptive distinct and novel treatment approach for patients.

They are already several things we've observed in clinical trials with rental on to date, which we believe along with our six month data suggest the potential for is around allowed to be uniquely situated for this approach.

First we've observed propensity of response within days that has been consistently observed across our studies.

Mike Clunan: Physicians, patients, and payers have consistently viewed the many unique characteristics of this target profile positively. As you know, we initiated dosing in the Waterfall Study and updated our guidance on an anticipated data readout in the first half of 2021. We also initiated dosing in our PPD study, Skylark, as well as the 50 milligram cohort in the ongoing Shoreline Study. We are on track to begin dosing in the coral study, the acute rapid response to a newly administered antidepressant study during the second half of the year. As we think about the end game for xeranilone, if we're successful in changing the paradigm by moving towards a treatment as needed or episodic option, there are going to be physicians who will want to use xeranilone, at least initially, in combination with traditional antidepressants until they get comfortable with Doranalone as a standalone agent. This is consistent with the Coral Study Design, which we are on track to initiate this If the CORAL study is positive, we expect to first seek regulatory approval for the use of zaranolone when co-initiated with a new antidepressant in the treatment of MDD.

Second the drug has been well tolerated in these studies with more than 2500 subjects.

There'd be no adverse events of loss of cautiousness, including up to doses of 90 milligrams evaluated clinical pharmacology studies and third there'll be no signals a rebound to withdraw after the drugs stocked.

I'm, sometimes asked why we are looking to treat depression like a medical condition, rather than a chronic disease that labels the person as a mental health patient.

It's long been recognized that the preference or reliance on chronic pharmacotherapy is a problem in psychiatry.

And the numbers bear this out.

17 million, new diagnosed as the year for major depression, but nearly twice that many people remain on treatment for two years or more.

We see this is an area of substantial unmet medical as societal need.

If we're successful so right along has the potential to allow patients to get treated get better quickly and not require another treatment until when or if he or she has another depressive episode.

As you might expect when treating any other medical condition.

Now turning to a new development with Brexit alone. We are pleased to announce it under the FDA Corona virus treatment acceleration program or see tap brick sat alone has been cleared for a phase three study in people with advanced Cove at 19 related acute respiratory distress syndrome.

Mike Clunan: If we receive approval for this indication, it will give us an opportunity to leverage the profile for physicians, patients, and payers to gain real-world experience with seranolone and better understand the rapid-acting profile. And if Waterfall and the longer-term safety data are positive, we think the combination of the RRT experience and the retreatment data from Shoreline and Redwood will expand the labeling and use, making the transition to episodic, treat- This means that physicians would be able to take a phased approach to changing the treatment paradigm, building on their own experiences along the way, from using xaranlone in conjunction with a newly administered antidepressant to prevent relapse, to the use of xaranlone as needed or episodically to treat subsequent episodes.

Yes.

This announcement comes after several months of analysis of Brexit alone clinical and preclinical data.

As many of you know we already had extensive ice you experience and generated significant critical care data with Brexit alone in our Srs Sea trials.

Sage also has extensive chemical equity and medical chemistry experience and we even looking at other ways, our compounds may impact peripheral receptor systems.

Direct sat on trial uncovered 19 related a rds will evolve several leading academic centers.

Sage has undertaken this initiative, believing there is a sound rationale the test whether brick standalone may be able to mitigate the morbidity and mortality associated with coded related a rds. It's also we believe the right thing to do.

We look forward to answering further questions about this trial during our upcoming Investor Day plan for September.

Mike Clunan: The receptivity to a unique target profile is there. We have heard the questions on durability, including what happens after day 15 and day 42. With the six-month mountain data we just announced and with the shoreline data anticipated by the end of the year, we continue to build our data sets to help answer some of the questions we anticipate receiving from Keys-Bacle.

Turning now to our neurology franchise, we have begun dosing in our phase two double blind study.

Which we're calling kinetic with phase 324 at 60 milligrams and essential tremor as a reminder, essential tremor is the most common movement disorder in the U.S. affecting an estimated 6 million people in our country.

Earlier open label data with Phase 324 demonstrated the compound with a pharmacologic characteristics. We believe are well suited for development opportunities not only in essential tremor, but also in epilepsy in Parkinson's disease.

Mike Clunan: We want to give patients and physicians another option in the treatment of MDD. And if we are successful, we believe Zaranulone can offer not only a clinically differentiated treatment option but also a commercially differentiated approach. This is another example of our overall strategy. We leverage learnings and quickly adapt, all with the mission of bringing medicines that matter to people with brain health disorders. With Soreso, we are executing as expected. Revenue during the quarter was $1.1 million and, as anticipated, was impacted by COVID-19 as multiple hospitals continued to prioritize their bed capacity, reducing elective admissions like Zola Resta.

We anticipate reporting topline data from the essential tremor trial in the fourth quarter over this year or the first quarter of 2021.

We're also on track to initiate our phase two way open label study with Sage 7.8 in the second half of 2020, the lead asset in our neuro Psych franchise on our most advanced and Mds Pam in patients with Parkinson's disease cognitive dysfunction.

Results from this study, which we're calling the paradigm study well informed the potential advancement of say 7.8 in various disorders as cognitive dysfunction.

As a reminder, and only studies face M&A was well tolerated and patients as well as healthy volunteers demonstrated improved performance compared to baseline on assessments of executive functioning.

We believe the data we generated in our phase one program support ipod assess the stage several in eight may be relevant to multiple disorders with impaired cognitive dysfunction, including Huntingtons, Alzheimer's and Parkinson's disease.

Mike Clunan: Through SAGE Central, we remain close to all the treating sites of care to understand their ability to treat PPD patients and any shifts in their approach. We will continue to support geographies with active, existing treating sites and support PPD patients through the process. Given the ongoing surge in the number of cases of COVID-19 in the U.S. and continuing concerns about the pandemic across the country, the company expects the significant adverse impact of the pandemic on Zorreta revenues to continue.

Before I turn it over to Mike I want to share my appreciation for the team at Sage.

The team is executing well across all franchises to advance our therapies as quickly as possible for the benefit of patients and families.

We believe we've created a novel drug companies successfully able to convert our chemical equity library into a rich pipeline of clinical assets at a new chemical entities and not just re purpose molecules. So under with that I'll turn the call over to Mike.

Thanks, Jeff and good morning, everyone as Jeff mentioned, we made significant progress over the last quarter with the initiation of four new clinical trials. We've built upon the rigorous participation in a resource allocation. We began in the first quarter as we continue advancing programs across our depression, neurology and neuro site franchises.

Mike Clunan: Jeff provided a thorough update on the clinical progress we've made with SAGE 324, an essential tremor, and our plans with SAGE 718 and indications involving cognitive dysfunction. I'll spend just a few minutes discussing the tremendous unmet need for patients suffering from these disorders. With ET, we are talking about the most common movement disorder affecting an estimated 6 million people in the U.S. However, despite its high prevalence, only about 20% of people with E.T. Seek treatment.

At a bit of perspective, how we're thinking about positioning the differentiated profile durrant alone in our depression franchise.

Successfully developed an approved we have consistently observed rapid response within days and good Tolerability of Saran alone in our landscape clinical program to date.

Rapid fashion and depression, you've also seen in our ongoing and planned trials will be an important profile for is around loan whether use episodic or.

Mike Clunan: And for cognitive dysfunction associated with diseases like Huntington's, where we've already seen an early signal pointing toward the potential for improvement in executive function, and other neurodegenerative conditions that manifest with executive functioning deficits like Alzheimer's and Parkinson's. We're talking about the potential to improve cognitive dysfunction symptoms that track closely with functioning in the real world. By improving these symptoms, our goal is to provide patients with the opportunity to remain more cognitively intact and potentially retain the ability to live and thrive independently. And so, we believe SAGE 324 and SAGE 718, if successfully developed and approved, have the potential to become truly innovative treatment options with the potential to help millions of people and their families. Before I turn it over to Kimi, I also want to take a minute to express my appreciation for the team at SAGE.

Or treat as needed or as a rapid response for our T. therapy, when co initiated with a new antidepressants.

Physicians patients and payers have consistently viewed the many unique characteristics of this target profile positively.

As you know we initiated dosing in the waterfall study and updating our guidance on an anticipated data read out to the first half of 2021.

We also initiated dosing in our PPD study skylark as well as the 50 milligram cohort in the ongoing frontline study.

We're on track to begin dosing in the call study the acute rapid response with a newly administered antidepressants steps.

During the second half of the here.

As we think about the endgame furthering alone if we're successful changing the paradigm by moving towards a treatment as needed or episodic option. There are going to be physicians, who will want to use our and loan at least initially in combination with traditional antidepressants until they get comfortable with saran alone as a standalone agent.

This is consistent with the Coral study design, which we are on track to initiate this year.

If the call study is positive we expect to first seek regulatory approval for use as around alone when co initiated with a new antidepressants in the treatment of MDD.

Mike Clunan: They have worked tirelessly to execute with precision during these challenging times and supported our mission to bring medicines that matter to people with brain health disorders. I feel as confident as ever that our execution against well-thought-out strategies will enable us to get medicines that matter to patients as quickly as possible. And now, I'll turn the call over to Kimi to review our financial plan.

If we receive approval in this indication it would give us an opportunity to leverage the profile of physicians patients and payers to gain real world experience with Saran alone and better understand the rapid acting profile.

Kimi E. Iguchi: Thanks, Mike. This is the year of execution for SAGE, with cash on hand anticipated to support operations into 2022. We have a clearly defined path forward designed to advance programs across three brain health franchises. Our experienced team is working to create value by converting our extensive chemical equity into a rich pipeline of clinical assets in areas of unmet medical need. We remain true to our mission. As a reminder, we started the quarter with a difficult but prudent decision to restructure the organization.

And if waterfall and the longer term safety data are positive we think the combination of the Archie experience and the Retreatment data from shoreline and Redwood will expand the labeling and use making the transition to episodic treat as needed much more efficient.

The physicians would be able to take a phased approach in changing the treatment paradigm building on their own experiences along the way from using is around alone in conjunction with a newly administered antidepressants to prevent relapse to the use of saran loan as needed or episodic lead to treat subsequent episodes.

Kimi E. Iguchi: But we ended the quarter with the extensive list of accomplishments and progress that you heard from Jeff and Mike. As we move into the second half of the year, we do so with a solid financial position to continue to build on those achievements. As you've heard me say many times before, at SAGE, we take a portfolio approach to how we think about resource allocation with the goal to maximize the value of our By reprioritizing our activities and rethinking how to deploy our resources, we anticipate annualized cost savings as a result of the restructuring of approximately $170 million.

The receptivity to a unique target profile is there we have heard the questions on durability, including what happens after day 15 empty 42 with the six month Mountain data, we just announced and with the shoreline data anticipated by the ended the year. We continue to build our data sets to help answer some of the qwest.

Eight receiving some key stakeholders.

We want to get patients and physicians another option in the treatment of MDD and if we're successful we believe the rent alone can offer not only a clinically differentiated treatment option, but also commercially differentiated approach. This is another example of our overall strategy, we leveraged learnings and quickly adapt or.

All the mission and bringing medicines that matter for people with brain health disorders.

Kimi E. Iguchi: These savings are intended to help SAGE advance our mission to deliver medicines that matter to people with serious brain health disorders. I'll now walk you through the highlights of our second quarter 2020 financial results. Revenues were $1.1 million in the second quarter from sales of Zorresso, compared to $0.5 million of collaboration revenues from the Chianogi collaboration for the same period in 2019. As Mike noted earlier, Silvestro revenues have been significantly affected by COVID-19 in the U.S., and we expect the significant adverse impact of the pandemic on Zillowrestle revenues to continue. Selling general and administrative expenses were $38.2 million in the Our reduction in commercial support for Zoresto was the primary driver of the decrease in SG&A in the second quarter.

With still left so we are executing as expected.

Revenue during the quarter was 1.1 million and as anticipated was impacted by cobot 19, as multiple hospitals continue to prioritize their bed capacity, reducing elected admissions like the rest so.

Crusade Central we remain close to all between sites of care.

Understand their ability to treat PV patients and any shifts and their approach.

We will continue to support geographies with active existing treating sites and support PPD patients through the process.

Given the ongoing surge in a number of cases of totaled 19 in the U.S.

And continuing concerns about the pandemic across the country.

Company expects the significant adverse impact of the pandemic onto a rough the rest of revenues to continue.

Jeff provided a thorough update on the clinical progress we've made with stage three to four and essential tremor and our plans with say 718 indications involving cognitive dysfunction.

Ill spend just a few minutes discussing the tremendous unmet need for patients suffering from these disorders with 80, we're talking about the most common movement disorder affecting the estimated 6 million plus people in the us.

Kimi E. Iguchi: And as part of the restructuring, we recorded a charge of $28 million in the second quarter. Research and development expenses were $73.3 million in the second quarter compared to $89.1 million in the second quarter of 2019. The decrease was primarily related to the completion of the Mountain Study and a decrease in non-cash stock-based compensation. Finally, we reported a net loss of $136.3 million for the second quarter of 2020 compared to $168.2 million for the first quarter of this year. We ended the quarter with $757 million in cash, cash equivalents, restricted cash, and marketable security.

Right, it's high prevalence only about 20% of people with 80 seek treatment.

And for cognitive dysfunction associated with diseases like Huntingtons, well, we've already seen early signal pointing toward the potential for improvement and executive function and other neurodegenerative conditions that manifest with executive function deficit slight Alzheimer's and Parkinson's, we're talking about the potential to improve cognitive dysfunction symptoms.

That track closely with functioning in the real world by improving the symptoms. Our goal is to buy patients with the opportunity to remain more positively impact and potentially retain ability to live and thrive independently.

And so we believe stage three to four and Sage seven wondering if successfully developed in food have the potential become truly innovative treatment options with the potential to help millions of people and their families.

Kimi E. Iguchi: As previously stated, we anticipate ending the year with approximately $550 million in cash, which we expect will provide runway for us into 2022. We're looking forward to the second half of the year. We anticipate continued savings from our structuring and resource reallocation. In closing, we expect the second half of 2020 will be highlighted with proof points to illustrate our ability to execute, showcase the progression of the pipeline, and show the value of our chemicals. This will be accomplished in part by the strength of our balance sheet, and I'm confident that we have the right team in place at SAGE to execute on all the opportunities. We look forward to sharing our ongoing updates. I'll now turn it over to Jeff for closing comments. Thanks, Kimi, and thanks, everybody, and good morning, everyone.

Before I turn it over Kenny I also want to take a minute express my appreciation for the team at stage. They have worked tirelessly and executing with precision during these challenging times and supporting our mission to bring medicines that matter to people with brain health disorders.

As confident as ever that our execution against a well thought out strategies will enable us to get medicines that matter to patients as quickly as possible and now I'll turn the call over the coming to review our financials.

Thanks, Mike.

This is in your execution for stage with cash on hand anticipated support operations into trains right.

We have clearly defined path forward design to advance programs across the Lee greenhouse franchise.

Jeff Jonas: I just want to make a few more comments prior to our going to question and answer. I think, as you've heard today, that the execution of our clinical programs remains either on track or ahead of schedule, and that's no small part of the efforts of the folks at SAGE working through these programs. Our goal remains constant with respect to Zoranolone.

I experienced team is working to create value by converting our extensive chemical and equity into a rich pipeline of clinical assets in areas of unmet medical need.

We remain true to our Nelson.

As a reminder, we started the quarter with a difficult, but prudent decision to restructure the are going to Wilson.

Well, we ended the quarter with extensive list of accomplishments and progress that you heard from Jeff in line.

Jeff Jonas: We are looking to disrupt the treatment model for depression. We understand that that may be hard to do, but it's something that we think meets an important unmet medical need in the treatment of psychiatric disorders. As you've heard today with our phase three initiation for a BRICSAN loan to COVID-related ARDS, we have a distinct and active discovery group and medicinal chemistry group, and we're looking to leverage that expertise as we move forward. We have clearly defined pathways to advance all of our programs across all of our franchises.

As we move into the second half of the year, we do that was solid financial position to continue to build on those achievement.

As you've heard me say many times before exchange, we take a portfolio approach to how we think about resource allocation with a goal to maximize the value of our assets.

By Reprioritizing kidding, rethinking how to deploy our resources.

We anticipate annualized cost savings as a result of then structuring of approximately 117 million.

We havent I attended the uptake advance our mission to deliver medicines that mattered to people were hearing is Brent Saunders.

Jeff Jonas: And as you can hear today, we have a catalyst-rich..., year-and-a-half upcoming where we hope to report on this progress over time. So with that, let me open the call to questions. As a reminder, to ask a question, you will need to press star 1 on your telephone. To withdraw your question, press the pound key.

I'll now walk you through the highlights of our second quarter 2020, so without.

Revenues were 1.1 million in the second quarter from sales of Alaska.

Parents, a point 5 million of collaboration revenue from the Shionogi collaboration for the same period in 2016.

Operator: Please stand by while we compile the Q&A roster. Our first question comes from Akash Tewari with Wolf Research. Your line is open. Hey guys, thanks so much for the questions. I have a few, if I may.

As Mike noted earlier, so ratable revenue.

Secondly affected by Colin nights in Euro.

And we expect this significant adverse impact of the pandemic on vessel revenue taking four.

Akash Tewari: So I wanted to dig into what the 50 MIG dose can and cannot help with. So, number one, will the 50 MIG dose ensure that patients who take 217 without a proper meal would still maybe get into a therapeutic drug concentration? Or would that just not be possible if you don't take it with food?

Selling general and administrative expenses with 38.2 million in the second quarter compared to 88.2 million in the first quarter 2020.

Our reduction in commercial support from the West So was the primary driver of the decrease in yesterday in the second quarter.

Jeff Jonas: Number two, were the patients in the Mountain Study generally heavier than the Robin Study? And will the 50 MIG dose allow for a greater percentage of those patients to hit a therapeutic threshold? And then lastly, can you give some color on how your PK curves evolve over time as you go from a single ascending dose to multiple ascending doses for 217? Like visually, what does that PK look like?

And as part of the restructuring we recorded a charge of 20 million in second quarter.

Research and development expenses.

73.3 million in the second quarter compared to 89.1 million the second quarter swimming pool.

The decrease was primarily primarily related to the completion of the mountain study and a decrease in the noncash stock based compensation expense.

Jeff Jonas: And how would you define someone who would be low exposure versus high exposure? Thank you. Hey, it's Jeff.

Finally, we reported a net loss of 136.3 million for the second quarter of 2020 compared to a high.

Jeff Jonas: I'm going to start and then I'm going to turn this over to Jim. This is just some broad commentary. One of the problems with any drug development program is fixing the proper dose. The metrics and the biomarkers and the analyses required are not necessarily straightforward. I know people like to look at it that way, but they're not.

2 million for the first quarter of this year.

We ended the quarter with 757 million cash cash equivalents restricted cash and marketable security.

As previously stated we anticipate ending the year with approximately $550 million cash, which we expect will provide runway for us into 2022.

Jeff Jonas: And as a company, I just have to say that, as you're alluding to, picking the right dose can be challenging. And in fact, we think that 50 is a good dose, as we've mentioned earlier. We've now dosed up to 90. It's very well tolerated.

We're looking forward to the second half of the year, we anticipate continued savings from restructuring and resource reallocation.

Jeff Jonas: And so we're comfortable about the 50 milligram dose. But that analysis that has led us to the 50, in some part, remains proprietary. We realize that this could be a competitive advantage for the company, and we know we have a lot of fast followers looking at these mechanisms. So a lot of this we just have not disclosed and will not. With that said, though, the performance of the 50 to date, I think, as we've mentioned earlier, has been quite satisfactory. We've now gone up to 90 milligrams, and so we're very pleased with that. I'm going to turn the rest of this over to Jim Doherty. Thanks, Jeff. Hi Akash.

In closing we expect the second half at 2020 will be highlighted at this point to illustrate our ability to execute.

Showcased the progression of the pipeline.

Until the value of our chemical equity.

Yes, we accomplished impart by the strength of our balance sheet and I'm confident that we have the breakeven place it seems to execute on all the application.

We look forward to sharing ongoing update.

Now I'll turn it over to Jeff for closing comments.

Thanks, Kevin and thanks, everybody.

Good morning, everyone.

I just want to make a few more comments prior to you are going to question and answer I think as you've heard today that the execution of our clinical programs remains either on track or ahead of schedule a match no small parts of the efforts at the folks at stage.

Jim Doherty: Yes, to answer a couple of your questions in a little bit more detail, so first, around the 50 milligram and PK, as Jeff said, we are quite confident in the performance of the 50 milligram dose from the data that we've seen so far. And so, yes, we are confident that by dosing at 50 milligrams, we are moving the population into a range of exposures that we think is going to be consistent with efficacy. I think, obviously, each individual person responds a little bit differently, but we do think that this dose gives us the right balance that puts folks into an effective range. Yes, to your question about body mass, I would say that in all of our trials, we see a pretty consistent picture of body mass for individuals and, you know, pretty consistent with most of the U.S. population. And then, to your point around PK profiles, yes, we think that the PK profile for Zaranulone, which, recall, was designed to have once-a-day kinetics in humans, gives us, really, a very good opportunity to sort of keep the exposure levels where we think they need to be to see efficacy in our studies across a population. Thanks a lot.

Working through these programs our goal remains constant with respect is around alone. We are looking to disrupt the treatment Marlin depression, we understand that is something that may be hard to do but it's something that we think meets an important unmet medical need in the treatment of psychiatric disorders.

As you heard today with our with our phase three initiation.

For brick standalone into Kobin related already asked.

We havent distinct and active discovery group of medicinal chemistry, and we're looking to leverage at expertise as we move forward.

We have clearly defined pathways to advance all of our programming across all of our franchises and as you can hear today, we have a catalyst rich.

Year, and a half upcoming where we hope to report on this progress over time.

So with that let me open the call two questions.

As a reminder to ask a question you will need to press star one of your telephone.

Withdraw your question press the pound key please standby we've compiled acuity roster.

Our first question comes from a cost worry with Wolfe Research. Your line is open.

Jim Doherty: As a reminder, ladies and gentlemen, we ask that you please limit yourself to one question. Our next question comes from Paul Matteis with Steeple. Your line is open. Hey, great. Thanks so much.

Hey, guys. Thanks, so much of the question I have you if I may.

So I wanted to dig into what the 15 make those CAD and cannot help with so number one.

So the 50 make sure that patient to take two on seven without a proper meal with ill maybe get into a therapeutic drug concentration or would that just not be possible. If you don't take it with food.

Paul Andrew Matteis: I just have a quick follow-up on this six-month data. Can you just quantitatively speak to how you defined responder or maintenance of response at six months? You know, in the Phase 2 MDD study, we saw a couple-point increase in HAMD from day 15 to 42. Would something in that margin of error constitute maintained response?

Number two where the patients in the mountains study generally heavier than the Robin study and while the 50 Meg don't allow for a greater percentage of the patient they hit a therapeutic thresholds and then lastly can you give some color on how your T.K. curve evolve overtime as you go permit single ascending dose the multiple ascending dose for Q1 seven.

Jeff Jonas: And then I was wondering if you could just comment on the proportion of patients that initiated an SSRI during follow-up and how this kind of all informs your expectations for Shoreline. Thank you. I'll take this, I think, and then I'll turn it over to Jim.

Like visually how does that PK look like and how would you find someone who would be low exposure versus high exposure. Thank you.

Hey, it's Jeff I'm going to start and I'm going to turn this over to Jim.

Jeff Jonas: A couple of points I want to make. First, one of the interesting findings that all the six-month data has shown runs counter to the current mythology around depression, that you have to stay on a drug. And that's the sort of most striking finding to me, and I think to us, as we move forward with this notion that if you have depression, you don't have to be on an antidepressant for the rest of your life. And so that's number one.

Just some broad commentary one of the.

Goals of any drug development program is a fixing the proper ghosts and.

The.

The metrics and the Biomarkers and the analyses required are not necessarily straightforward I know people like to look at it that way, but they're not and as a company. We I just have to say that.

I think you're alluding to picking the right dose can be challenging and in fact, we think that the 50 is a good dose as we've mentioned earlier, we've now does start to 90.

Very well tolerated.

Jeff Jonas: And I think what really came home, and if you look at the population that had a response, and I think that's the 24 and above, what you see there is actually a constant, a very constant separation, pretty steady, between drug and placebo. And what that indicated initially, and what it suggests, is that if you respond to the drug, you continue to respond to the drug, even after the drug has stopped. And we think that is a unique finding. With respect to antidepressants, and this is also what made us, what encourages us about these data, and which also gives us a lot of optimism about Shoreline, and that is that only a very small number of patients actually started new antidepressants. And overall, I'd say it was only a handful.

And so we're comfortable about the 50 milligram doesn't but that that analysis that has led us to the 50 in some spark remains proprietary.

We realize that this could be a competitive advantage for the company. We know we have a lot of fast followers looking at these mechanisms. So a lot of this we just have not disclose and will not.

With that said, though the performance of the 50 to date I think as we've mentioned dot earlier has been has been quite satisfactory, we've not going up to 90 milligrams and so we're very pleased with that I'm going to turn the rest of this over to Jim Darby.

Thanks, Jeff.

Yes to answer a couple of your questions in a little bit more detail so first around.

The 60 milligram and Teekay is as Jeff said, we are quite confident in the performance of the 50 milligram dose from the data we've seen so far and so yes, we are confident that by dosing at 50 milligrams, we are moving the population.

Jeff Jonas: And overall, only about 30% of the patients were on SSRIs during the study. So this really does run counter to the dogma. The Dogma About Depression, that you have to be on a drug and that you must be chronically treated. And for us, it has been very encouraging when you see that almost 75% of the patients maintain their response. And with the 24 and above, which of course is the relevant population where we had a positive endpoint, that response was maintained out to 182 days. The study was not powered for significance, but even then, the p-value there was 0.06. So this was a very strong finding and one, I think, that I have to say exceeded our expectations. Jim, do you want to add anything else to that?

Q a range of exposures that we think is consistent with efficacy I think obviously each individual person responsible with differently, but we do think that this dose gives us the race balance.

Folks into an efficacious range, yes to your question around body mass I would say that all of our trials, we see a pretty consistent picture of the body mass for individuals.

Pretty consistent with the with the most the U.S. population.

And then to your point around PK profiles, yes, we think that the PK profile or is around loan, which we call is designed to do you have a once a day genetics in human.

Gives us really a very good opportunity to sort of the exposure levels, where we think they need to be.

And our study.

Jim Doherty: I think I just would reiterate, Jeff, that when you look at the data, I think that the key message is that patients who are seeing a benefit, patients who are getting better at that day 15 time point, are staying better. So, Paul, you know, we'll put the detailed data together from the Mound Study for a presentation later. But, you know, the answer to your question is, you know, the scores are pretty similar to what they were in those early days out in the 60s. Great, thank you very much.

Across a population.

Thanks, a lot.

Thank you as a reminder, ladies and gentlemen, we ask that you. Please limit yourself to one question. Our next question comes from Paul Mathias with Stifel. Your line is open.

Hey, great.

Thanks, So much I just have a quick follow up on this mountain six month data can you just quantitatively speak to how you declines responder maintenance of response at six months I guess in the phase two MDD study, we saw a couple points up creep in Ham D from day 15 to 42.

What would kind of something in that margin of error constitute maintain response and then I was wondering if you could just comment on the proportion of patients that initiated in Sri during follow up and how this kind of all informed your expectations for Charlotte. Thank you.

Tazeen Ahmad: Thank you. Our next question comes from Tazeen Ahmad with Bank of America. Your line is open.

Jim Doherty: Hi guys, good morning. Thanks for taking my question. I wanted to focus on essential tremor, if I could. Can you give us a little bit of color on why you think it'll be important to look at the primary endpoint at day 29? And then, as it relates to the upper limb tremor score, can you walk us through the importance of that and how physicians view that particular score in general as it relates to ET? Thanks. Yes, Tazeen, this is Jim.

I'll take this I think you then I'll turn it over to Jim couple of point I'd want to make up first is one of the interesting findings that all the six month data has shown runs counter to the current mythology around depression that you have to stay on a drug and that's the that's the sort of most striking binding to me and I think to us.

Steve Kames: I'll take that one, and then I'll ask Steve DeWayne in a couple minutes about your question about how physicians perceive the upper limb score. So, of course, the study that we're talking about that was initiated for SAGE 324, the kinetic study, is building on what we've already learned, both from our earlier programs but, importantly, from the work we did last year in the 324 program where we confirmed that neuroactive scare like 324 has a significant ability to reduce tremor in essential tremor patients. Those studies were done with acute dosing, and so we are at an important stage of progression for the program. Tremor is a chronic disorder, and so that 28-day time point is our next step in showing the sustainability of the response to 324 that we've seen. And I'll mention upper limb scores, that is one of the most sensitive measures for essential tremor patients and also one of the most troubling when you think about daily life and what people are trying to do. But Steve, let me have you... Sure.

As we move forward to this notion that you have to pressure you don't have to be on and ended at present for the rest of year life and so so that's number one I think what really came home and if you look at the population that had a response I think thats up 24 and above what do you see there is it actually have a constant very constant separate.

Patient pretty steady, which mean drug and placebo and what that indicated initially and at what suggests is that you respond to the drug you continue to respond to the drug even after the drug stopping and we think that it is unique finding with respect to anti depressants. This would also what made us what encourages us about these data that was we also.

It gives us a lot of optimism about shoreline and that is only a very small number of patients actually started new anti depressants and overall I'd say it was only a handful and overall, it's only about 30% of agents.

We're on assets arise during the study. So this really does run counter to the dogma.

The dogma about depression that you have to be on a drug into your you must be chronically treated and for US. It's very its has been very encouraging when you see that almost 75% of the patients maintain their response and the and with the 24 and above which of course is the relevant population, where we had a positive endpoint that response is maintained out too.

Steve Kames: We've been looking at this quite a bit, Tazeen, as you know. We've been working on essential tremor since the early days, initially with Soreso, then 217. And as Jim said, we've seen very consistent results across the board. We consult with experts in the field, and they tell us that upper limb tremor is the most debilitating part of the symptom complex.

Good and 82 days.

Just the study was not powered for significant but even then the P value. There was 0.06. So this was a very strong finding and when I think that I can say exceeded our expectations. Jim you want to add anything else to that.

Brian Corey Abrahams: The other advantage is that, given the level of use of accelerometers and other wearables, it's something that we're able to track throughout the day. So there are real advantages in understanding the signal, understanding the effects on patients, as well as the ability to understand what impact our development program may have on those patients throughout the day. Okay, thank you.

I think I just would reiterate it Jeff that when you look at the data I think the key messages that patients who are seeing a benefit patients who are getting better at that date 15 time point are staying better. So Paul will put the detailed data together from the mouse study for presentation later, but the answer to your.

David Cici: Thank you. Our next question comes from Brian Abrahams with RBC Capital Markets. Your line is open. Hi, this is David Ciccio. I'm on behalf of Brian.

Second is the scores are pretty similar to what they were in those early days up as well.

Great. Thank you very much.

Thank you. Our next question comes from Zeena much with Bank of America. Your line is open.

Jeff Jonas: Just two quick questions. First, looking ahead, how are you thinking about the landscape of depression evolving ahead of any potential launch? Maybe just your latest thoughts on how the pandemic might have affected mental health and telemedicine and how you see that potentially evolving ahead of the next couple of years. And then, the second question, just going back to the Waterfall trial and the enrollment that you're seeing. I know that there are definitely synergies from the Mountain trial, but I'm just wondering if you see any extrinsic reasons for why enrollment might be better as a Okay, this is Jeff.

Hi, guys. Good morning, Thanks for taking my question I wanted to focus on essential tremor, if I could.

Can you give us a little bit of color on why you think it'll be important to look at the primary endpoint at day 29, and then as.

Relates to.

Upper limb tremors score can you walk us through the importance of bad and how position in that particular or in general as it relate pp bank.

Yes, the Mr., Jim I'll take that one and then I'll, let Steve the Wayne and elements are on your question around how positions to see upper limb score.

So of course, the study that we're talking about that was initiated.

Jeff Jonas: Thanks for the question. You know, in general, I think we're seeing an increased incidence of reporting of people with mood disorders. But, you know, psychiatry and depression have always been a major area of unmet medical need. And so, I think what we're seeing in the Mountain Study, there are a couple of things that we're seeing in the Mountain Study. And I'll go to your second question first.

Message through two or the kinetic study is building on what we've already learned both from our earlier programs, but importantly from.

The work we did last year in that three to four program, where we confirmed that.

There are to share like three to four has a significant ability to reduce tremor and essential tremor patients. Those those were done with acute dosing and so we are an important stage of progression for the program since the term or is a chronic disorder and so thats one of the time point is our next step in showing.

Jeff Jonas: One is that there is increasing interest among people who are doing depression studies looking at novel therapies. And if you think about all the therapies that are currently in development, they are all really of a kind except for Zoranolone. They are, you know, two to six to eight weeks, and then chronic pharmacotherapy for as long as the physician requires it. We just think that patients deserve another option. And we're seeing tremendous interest in our studies because the Zoranolone data really, so far, and with the six-month data, I think it's even more so, suggests that there may be a different and unique way to treat depression. So, we view that as an area of interest and an area of uptake that has really spurred interest in our trials. Also, the team has done a great job.

Sustainability of the response to through Q4 that we've seen earlier.

And I'll mention around upper limb scores.

That is one of the most sensitive measures for essential tremor patients and also one of the most troubling when you think about.

Daily life than what people are trying to do.

Steve Let me.

Sure we've been looking at this quite a bit dizziness, you know even working essential tremor since early days with initially with so rather than to one seven as Jim said, we've seen very consistent results across the board.

Consult with experts in the field and they have told us we.

Upper limb tremor is the most debilitating part of this has been complex leg up tremor anywhere the inability to do things like right or shrink or or and its intention tremor. So the more you try to do something the where's the the tremor guess those are the things that really getting patients labor day to day basis. So there's a few things that we've really been focusing.

Jeff Jonas: I mean, I think they, you know, I think, as I said at the start, a lot of people have, And our team has really done a nice job proactively preparing for this environment. But the reality is, there are a lot of people who are depressed. Now, the second point is that, if you think about the face of depression, I think that's really something that we are really interested in changing. And with COVID, I think what you're seeing is a greater recognition of the importance of mental health, the importance of any morbidity associated with depression, you know, in terms of lack of function and lack of opportunity, you know, and lack of engagement. And it's brought home as people are not distracted by work and have more time with their families, where depression can be diagnosed.

On one the upper limb score we have to make sure that's improved across the board and that's something that we've seen consistently the other is given the level of use of accelerometers and other wearables. If somebody were of the track throughout the day. So there are real advantages in understanding the signal our understanding effects on patients as well as the ability to undersea.

And what impact our development program may have on this patient throughout the day.

Okay. Thank you.

Thank you. Our next question comes from Brian Abrahams with RBC capital markets. Your line is open.

Hi, This is David visit on for Brian.

Two quick questions first looking ahead, how are you thinking about the land the prostone evolving ahead of any potential long launch and maybe just do it on how the pandemic might have affected ventral hall.

And telemedicine, how do you see that that's where evolving ahead of the next couple of Euro and then second question.

Jeff Jonas: We don't think the diagnosis has changed, obviously. We think that using rigorous criteria, we can find people who have real depression versus reactive depression, which is what we're distinctly not treating. But we do think the face of depression is treating it. And we believe very firmly, in fact, probably more now than we have in the past, that there is a real need to not put everyone who gets depressed on drug therapy for years and years and years. We think that, you know, Zoranolone, with its profile, its ability to show rapid response, and its tolerability profile, really can offer a disruptive and unique approach to treating depression, especially as the treatment of depression becomes ever more recognized as something that's an area of unmet medical need. Yeah, maybe just let me, this is Mike, just add on to that, Jeff.

Just going back a waterfall trial.

Enrollment that you're seeing.

One other definitely synergies from the mountains trial, but I'm just wondering if yes.

Reason for why enrollment might be better.

Possible grid.

Maybe trials, including oral and are too.

Okay. This is Jeff Thank Joe Thanks for the question.

In General I think we're seeing an increased incidence of reporting of people would mood disorders, but.

Psychiatry and depression has always been a major area of unmet medical need and so I think what we're seeing in the mountains study is there a couple of things that we're seeing them out.

And I've got to your second question first one is there is increasing interest among people who were doing depression study looking at novel therapies, and if you think about all the therapies that are currently in development. They all have they all really our other kind acceptors around a lot. They are 62 to six to eight weeks and then chronic pharmacotherapy.

Jeff Jonas: I think you said it well, and I also think just, if you think about our two shots on goal that Jeff alluded to before, right, we have the RRT option for patients, and then we also have the end game for us is getting it episodic or treat as needed. And as Jeff said, like, there has not been a molecule like xeraniline that is given that will give the physicians and patients this opportunity to treat as rapidly within days and to see that effect if we successfully get either RRT or the episodic treatments over the line. And the way we see this playing out is we'll be able to move this paradigm in time, right, so we will evolve the paradigm, but we can start with the RRT indication, allow patients and physicians to get comfortable with the rapid-acting nature of xeraniline while they're using it in combination with the antidepressants, standard antidepressants, as they get that real-world experience, and we can publish Redwood data and the Shoreline data, and they get more comfortable with their treatment data, that'll give us the opportunity to expand the label and to evolve that paradigm to that treatment as needed approach that we think is really important for patients.

As long as the position is requires that we just think that patients deserve another option and we're seeing tremendous interest in our studies because the.

Right on data really so far enough with the six month data I think it's even more so if that there may be a different and unique way to treat depression. So we view that as an area of interest in an area of uptake that has really spurred interest in our trials also the team has done a great job I mean, I think Dave I.

I think as I said at the start a lot of people.

Path.

Hi stop their studies I thought they couldn't do studies and our teams really have done a nice job the proactively preparing.

For the for this environment and and the reality is there a lot of people who are depressed now the second point is that.

As you as you if you think about the face of depression I think that's really something that we are really interested in change and with co that I think what youre seeing is a greater recognition of the importance of mental health the importance of any of morbidity associated with depression in terms of lack of function and lack of opportunity lack of engagement.

Jeff Jonas: And that's what we hear back from patients and physicians. This is what's important to them, and it's giving them multiple approaches as to how to treat MDD and giving us a chance to evolve that paradigm over time. Thank you. As a reminder, we ask that you please limit yourself to one question. You may press star 1 to requeue for any additional questions. Our next question comes from Ritu Baral with Kellen. Your line is open. Hi, this is Lila Antariku. I'm wondering if you could maybe speak to the dropout rates, or maybe not. This is Jeff.

And it's brought home as people are not distracted by work and have more time with their families where people can be where depressing to be diagnosed we don't think the diagnosis is change obviously, we think it using rigorous criteria, we get by people, who have made real depression versus reactive depression, which is what we're distinctly not treating but we do think that base of depression.

Treating and I and we believe very firmly in fact.

Probably more now than we have in the past that there is a real need but not putting everyone who gets depressed on a drug therapy for years and years and years, we think that right along with its profile with its ability to show rapid response with the Tolerability profile really can offer a disruptive and unique approach to treating depression, especially.

Jeff Jonas: You know, we've not seen much of an issue with that, and I think we've always used various maneuvers to assure compliance in terms of follow-up. And if you take a look at our six-month data, compared to most psychiatric trials, we have an astonishing amount of follow-up. I think it was almost 80%.

Really as the treatment of depression becomes ever more recognize its something thats an area of unmet medical need.

Jeff Jonas: That's really, I mean, I've done this a long time, and that's a very good follow-up number. And part of this is due to the diligence of the teams and the nature of the trial designs that we've instituted to encourage patients to maintain the blind. And I, you know, if you look at what we did with Mountain in particular, I'd argue that I don't think we can find another six-month blinded follow-up of any drug after the drug has been discontinued and let's watch these patients naturally. So we haven't seen this much of an issue.

Yes, maybe just let me this is Mike we just add onto that Jeff I think you said it well and I also think just think about our two shots on goal as Jeff alluded to before we have the arty option for patients and then we also have the end game for us getting its product or treat as needed and as Jeff said like there has not been a molecule like saran alone that is given that will give the physicians and payers.

Patients this opportunity to treat has rapidly within days and see that effect that we successfully get artsy or the episodic treatments over the line and the way we see this playing out as well be able to move this paradigm in time right. So we will evolve the paradigm, but we can start with the RT indication allow patients and physicians to get comfortable with the rapid acting nature, obviously, we're in loan loss.

They are using in combination with the antidepressants standard antidepressants as they get that real world experience and we can publish redwood data and the shoreline data they get more comfortable other treatment data that will give us the opportunity expanded label and to evolve that paired onto that treatment as needed approach that we think is really important for patients and that's what we hear back from patient physician.

Jeff Jonas: As I mentioned, we've done a number of internal maneuvers to ensure compliance, and the team has done a great job at that. But one of the things about COVID is that I think people are depressed. They do need treatment, and depression is a serious medical disorder, and it has not discouraged patients from either participating in trials or in their follow-up. Thank you. Our next question comes from Salveen Richter with Goldman Sachs. Your line is open.

This is what's important to them and it's a given its giving them multiple approaches as to how to treat MDD and allow us a chance to evolve that paradigm overtime.

Thank you as a reminder, we ask that you. Please limit yourself to one question you May press star one to re queue for any additional questions.

Salveen Jaswal Richter: Good morning. Thanks for taking my question. With regard to the six-month follow-up cohort in the Mountain Study, could you just help us understand how the placebo in the 20-milligram arms compared to the 30-milligram arm at six months? I'll start, and I'm going to turn it over to Jim.

Our next question comes from Ritu Baral with Cowen Your line is open.

Hi. This is my line for me Ken. Thank you for taking the question. Congrats on the progress of five I was wondering if you could maybe to the dropout rates or maybe patient follow up that your stainless shoreline, maybe comment have any impact on your ability to follow up of patients can you remind us patients need to come in for the treatment, where they can initiate telematics.

Jeff Jonas: So, you know, remember in the overall trial we did not achieve significance, but the interesting finding in the overall population is regardless of, in the overall pocket, that the patients who got better tended to stay better. So we were interested, and again, that runs counter to the current dogma about depression, which we were fascinated by because it's not what people have been taught. But we've seen this in most of our studies, and at six months, we've seen the same thing, regardless of treatment. The problem with this, of course, in the overall population is that, like with any medical disorder, whoever people are, when they get better, they get better. That would be true of a community-acquired pneumonia study where people get better versus penicillin.

Thank you.

This is Jeff.

We've not seen much of an issue with that and I think we we've always use various maneuvers to assure.

Compliance in terms of follow up and if you take a look at our six month data compared to most psychiatric trial, we have an astonishing amount of follow up I think was almost 80%. That's really I mean I've done there's a long time and Thats a very good follow up number and it's part of this is due to the diligence or the teams and the nature of the trial design that we.

We instituted to encourage patients to maintain the blind and.

Jeff Jonas: But the interesting finding in the Mountain study was in the relevant population, where we saw a treatment effect, 24 and above, and that's why we looked at it. There, we saw a continued separation from placebo. And that persisted whether or not the patient was on an SSRI. It is important to note that a minority of the patients, only 30%, were on SSRIs. So this is a really unique finding for us, and one that we think continues to, in a stepwise fashion, de-risks our thesis, that there is a way to treat patients with depression with a drug that acts rapidly and Can Get People Better Without the Necessity for Maintenance Therapy. Just so you know, we think this is a pretty unique finding, and we are going to publish this and prepare for presentation because we think some of the science is

I you know if you look at what we did with with mountain in particular.

I would argue that I can't I don't think we can spot we can find another six month blinded follow up of any drug.

After the drug has been discontinued ingress watch these patients nationalistically. So we havent seen really this much as an issue.

As I mentioned, we've done a number of internal maneuvers to.

Sure compliance and the team has done a great job at that but.

In one of the things about cobot is it that I think people are depressed they do need treatment and depression serious medical this disorder and it has not discouraged patients might have participating and trials or in their follow up.

Great. Thank you.

Thank you. Our next question comes from Salveen Richter with Goldman Sachs. Your line is open.

Jeff Jonas: And it's likely we'll wait for the shoreline data because we think there's a lot we've learned now about the natural history of depression in the modern world that really runs counter to... I think people accept that if you're depressed, you are a chronic mental patient, and we've been very encouraged by the six-month data, and we think it's unique, and we're looking forward to it. We will be publishing it and presenting it. Great, thank you.

Good morning, Thanks for taking my question quickly Kcl six month follow up cohort in Mountain study could you just help us understand how to placebo in 20 milligram arms compared to the 30 milligram.

Okay.

Actually I will start I'm going to turn it over to Jim. So remember in the overall trial, we did not achieve significant since the last but the interesting finding in the in the overall population as regardless of treatment.

In the overall population that debt the patients you got better tended to stay better. So the so where we were interested and again that runs counter to the current dogma about depression, which was we were fascinated by because it's not what you would it what people have been taught but but we've seen this in most of our studies and at six months, we've seen the same thing regardless of treat.

Andrew Tsai: Thank you. Our next question comes from Andrew Tsai with Jefferies. Your line is open.

Jeff Jonas: Thanks. Good morning. Maybe just to follow up on Salveen's question. Of course, in the press release, it noted a large majority of patients maintained response regardless of arm. So I'm just wondering, for the placebo arm, conceptually, could a durable response that you saw be attributed to background SSRIs kicking in after six to eight weeks? Or what could be the explanation of that? Well, this is Jeff.

The problem with of course in the overall population is that what do you see is like with any medical disorder. When people whoever people are when they get better they get better that would be two of our community acquired pneumonia study where people get better.

Versus penicillin, but you think finding in the mountains study was in the relevant population, but we saw a treatment effect 24 and above and that's why we looked at it there. We saw continued separation from placebo and that that persisted.

Jeff Jonas: I mean, you have to pretend that if you look at this, look at this like a regular disease. So in the original study, obviously, we didn't have any significant separation. So it's hard to interpret those data. What you're seeing in the big picture, and again, just imagine if you had anyone spontaneously remitting from any disease. They spontaneously remit. So if you have one patient, that remission curve will look the same as 100. So it's hard to make much of the overall population except to say, yes, you're right.

Whether or not the patient was on NSS arrive and I and as and.

It is important to note that minority of the page only 30% were on assets arise. So this is a really unique finding for us and one that we think continues to is in a stepwise fashion de risks our thesis that there is a way to treat patients with depression with a drug that acts rapidly.

Jeff Jonas: Everyone was allowed an antidepressant. They could have rescue therapy. So that's why, when the study started, we turned to the 24 and above, where the studies showed that. And that's why, which is, of course, the relevant population. And that's the majority of the patients in the study. And there, you don't see any drift at all.

And can get people better without the necessity for maintenance therapy.

Definitely know that we think is it a pretty unique finding we are going to publish this and prepare for presentation. Because we think some of the size is important and it's likely we'll wait for the shoreline data because we think that there's a lot we've learnt now about the.

The natural history of depression in the modern world that is really runs counter.

Jeff Jonas: You just simply see the patients; 75% of the patients maintain their response out to six months. The other point to make and remember is that the relevant question, and we're not really dealing with it today because we don't wanna be, we don't wanna sort of cherry pick the data. If you look at responders, the majority, almost the large majority, maintained their response even without intervention.

I think people except that if you are depressed you are a chronic mental patient than we've been very encouraged by the six month data and we think its unique and we're looking forward at we will be publishing it and presenting it.

Okay. Thank you.

Thank you. Our next question comes from Andrew side with Jefferies. Your line is open.

Thanks, Good morning, maybe just a follow up on solid gains question of course and press release.

Press release, I noted a large majority.

Patients maintain response.

Regardless of arm. So I'm, just wondering for the placebo arm conceptually.

Jeff Jonas: And when you go back to the early days, and I think someone mentioned this earlier, where you look at curves in the original study, you sort of see those curves creep up and sometimes they'll creep down. You know, you gotta remember, those curves represent combinations of non-responders and responders. So here, we did a blinded study out to six months, and we just observed stability. I understand that for everyone it's counterintuitive, but it looks as though the natural history of depression, remembering that two-thirds of these patients weren't anesthetized, actually looks like a medical disorder.

Durable response.

That you saw.

Be attributed to background SSR ice kicking in after six eight weeks or what could be the explanation on that thanks.

Well. This is Jeff I mean, you have to pretend that if you look of the look at this like a regular disease. So in the original study obviously you didnt have significant separation. So it's hard to interpret those data.

What you're seeing in the in the large in that 20, so and again just imagine if you have anyone spontaneously remitting from any disease.

Dave spontaneous remit. So if you have one patient that remission curve will look the same as 100 patients. So it's hard to make much of the overall population except to say, yes, you're right everyone was a lot an antidepressant they could have rescue therapy. So thats why when the study we turn to the 24 and above where the study showed difference.

Jeff Jonas: You know, we know depression waxes and wanes, and it looks as though it looks just like any other medical disorder. If you get better, and you have a successful treatment, you stay better. The difference is, in all of these approaches, even in Mountain, the original study, the patients on drugs show separation from placebo much more, very rapidly within days. So you do see benefit within the first two weeks, even though in Mountain you didn't see, didn't quite achieve its significance. And for us, plus the six-month data, that really supports the utility and the rapid RRT approach, where you do see early separation, as well as our overall thesis that one can treat depression very differently. Great, that makes sense. Thanks for the added color.

And that's why the which of course, the relevant population and Thats a majority of the patients in the study and there you don't see any direct at all.

You just simply see the patients 75% of agents maintain their response outfit six months.

Other point to make and remember is that the relevant question. Then we're not really dealing with it today because I don't want it we don't want to be we don't want to sort of cherry pick the data if you look at responders.

The majority almost the large majority maintain their response and.

Even without intervention and.

When you go back to the early days and I think someone mentioned this earlier when you look at curves in the original study you sort of see those curves creep up sometimes accrued down.

You got to remember those curves represent combinations of non responders and respond or so here, we need a blinded study out to six months and we just we just observe stability I understand for everyone is counter intuitive, but it looks as though the natural history of depression remembering two thirds of these patients Werner NSS arise it actually.

Jeff Jonas: You bet. Our next question comes from Yatin Suneja with Guggenheim Partners. Your line is open. Hey guys, thank you for taking my question and congratulations on the faster than expected enrollment in some of the trials. Just a quick one on Mountaine.

It looks like a medical disorder.

Yatin Suneja: Have you looked at the data in terms of its consistency between men and women? You know, given that this neurosteroid is more implicated in women, any differences you saw in sort of the responses? And the second part of the question is, I think, Jeff, you did mention a p-value of 0.6. I missed it.

We know depression, waxes, and wanes and it looks as though that it looks just like any other medical disorder. If you get better and you have an exceptional treatment you stay better differences in all of these approaches even in the mountain. The original study the patients on drug get.

Joe separation from placebo much more very rapidly within days. So you do see benefit within the first two weeks, even though and mountain you Didnt see.

Jeff Jonas: Could you just tell me or just confirm what you were referring to in the Mountaine follow-up? I'll answer the quick one, then I'll turn it over to Jim. We looked at the difference, whether it was maintained on the 24 and above, right? So if you're looking to see if there's a difference, you've got to start with the population where there was a difference. And that was because the majority of the population was 24 and above.

I didnt quite achieving significant and for us plus the six month data that really supports the utility and the rapid growth. Our t. approach, we do see early separation as well as our overall thesis that one can treat depression very differently.

Great that makes sense. Thanks for the added color.

You bet.

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

Hey, guys. Thank you for taking my question on congrats on the faster than expected enrollment it's all the trials.

Jeff Jonas: And even though it wasn't powered for significance out to six months, on the blinded analysis, the p-value between placebo and drug was about.06, so it almost maintained its significance out to six months, which was, we thought, a very remarkable finding considering that this was a long-term study and it wasn't powered for that. I'll turn the rest over to Jim. And to your other question, yes, of course, we have looked for whether or not there are differences between men and women, as well as a number of other demographic factors in the study, and the short answer is that we don't see any difference between genders in the study.

Just a question quick one on mountain have you looked at the date.

So thats consistency between men and women.

Given that this neo steroid is more implicated in.

Acted in them and any differences you saw in sort of the responses and then the second part of the question that I think Jeff you Didnt mention a P value of the G. the point shakes.

I missed it could you just tell me I'll just come from what you have that's been true in the mountain follow ups. Thank you.

I'll answer the quick one then I'll turn it over to Jim.

We had it wasn't we looked at the difference that whether it was maintained on the 24 and above right. So if you're looking at sea Theres. A difference you got to start with the population where there was a difference and that was not the majority of the population was 24 and above and even though wasn't power for a significant after six months on the blinded analysis.

Jim Doherty: Thank you. Our next question comes from Thomas Lavery with Morgan Stanley. Your line is open. Good morning, and thanks for taking my question. I have a question about SAGE 718.

Value between placebo and drug was about 0.06, so it almost it almost maintained its significance out six months, which was we thought it very remarkable finding considering that that this was a long term studying it wasn't car for that.

Thomas Lavery: The top-line data in Parkinson's disease is expected later this year. What kind of data do you need to move this program ahead next year? Thank you. Yeah, so this is Jim Doherty. I'll take that one.

I will turn the rest over to Jim.

Yeah and to your other question, we yes of course, we have looked or whether or not there are differences between men and women as well as the number of other demographic factors in the study in the short answer is we don't see any difference between genders and study.

Jim Doherty: So the study that we're talking about is looking at the effects of SAGE 718 with relatively short-term dosing in Parkinson's patients with cognitive impairment. And what we're doing is building off the results that we talked to you all about at the end of last year, showing that in Parkinson's patients, we're able to see an improvement in executive function and other aspects of cognitive function. And so because this is such a novel space and because this is such a novel approach, and because we were so happy to see the results that we saw in the Huntington's patients, rather than move forward with the very first patient population that we saw into a more detailed placebo-controlled study, we decided to pause and go through the activity of looking at various patient populations.

Yes.

Thank you. Our next question comes from Thomas Library with Morgan Stanley. Your line is open.

Good morning, Thanks for taking my question. The other question about Sage seven when a.

The topline data in Parkinson's disease. This expected.

Later this year, what kind of data do you need to see to move. This program ahead next year. Thank you.

Yes. So this is this is Jim Darby.

So this study that we're talking about is looking at the effects of Sage 718, with relatively short term dosing in parkinsons patients with cognitive impairment and what we're doing is building off the results that we had to talk to you all about to the end of last year showing that in.

Jim Doherty: So that's what this study is now. We're going to essentially run a similar short-duration study in an open-label format in Parkinson's patients, similar to what we did in Huntington's patients, to see if that's another patient population that can benefit. We'll also look at other neurodegenerative disorders. And really, this is all built on the role of the NMDA receptor in cognitive function.

His patients were able to see acutely an improvement in executive function and other aspect to cognitive function and so.

Because this is such a novel space and because it's such a novel approach.

And because we were so.

Jim Doherty: There's reason to believe that you can see a broad improvement in cognitive function across more than one patient population. And so that's what we'll do with the next study in PD patients, really look to see if we can expand the results that we've seen to date in HD patients. Great, thank you.

Happy to see the results that we saw from the huntingtons patients rather than move forward with the very first patient population that we saw into.

More detailed placebo controlled study, we decided to pause and go through the activity of looking at various patient population. So that's what this study is now.

Neena Marie Bitritto: Thank you. Our next question comes from Neena Bitritto with Citi. Your line is open.

We're going to essentially run a similar short duration study in open label format in tons in Parkinsons patients similar to what we did in Huntington stations to see if thats. Another patient population benefit. We'll also look in other words generate disorders and really this is all built on the role of the in India.

Jeff Jonas: Hey, thanks for taking the question. So I just wanted to ask a quick one on kind of the regulatory strategy. I know you talked a little bit about, you know, kind of next steps once you have some initial data in MDD and some of these upcoming studies, but once you get data from waterfall, I guess, you know, what's the plan for Redwood? Are you going to wait until you have data from waterfall?

Cognitive functions as reasons to believe that you can see abroad improvements in cognitive function across more than one patient population and so that's what we'll do with the next study in PD patients is really look to see if we can expand the results that we've seen to date initiation.

Great. Thank you.

Jeff Jonas: Or do you anticipate maybe reinitiating that study a little bit earlier? Thanks for the question. I think, obviously, it will depend on the data from Waterfall and the data from Shoreline.

Okay.

Thank you. Our next question comes from Neenah, but can you tell with Citi. Your line is open.

Hi, Thanks for taking my question. So just wanted to ask a quick one on the regulatory strategy I know you talked a little bit about kind of next steps. Once you have some initial data in MDT into these upcoming studies, but.

Jeff Jonas: Right now, we still think we have to have some larger study or some study like the longer-term analysis. But when we see Waterfall, one of the things we're going to have to take a hard look at is that based on the six-month data, we're not seeing a lot of relapses. When you think about patients getting the drug treatment and you think about 75% of patients maintaining their effects, regardless of background therapy or no background therapy, that's something we'll need to take up with the agency. Because initially, we had only had follow-up data out to day 42, and we had assumed that people would need sort of a Recovery Treatment. I think that assumption so far is being challenged by the six, and we'll have to look hard to look at Shoreline, and Shoreline, which we're optimistic about now, based on the six-month data, gives us something like that. We'll revisit what long-term data we might need if Waterfall reports out positively. Steve or Jim, do you want to add anything to that?

Once you get data from waterfall I guess, what's kind of that the plan for Red what are you going to wait until you have data from waterfall or do you and maybe written shading setting a little bit earlier. Thanks.

[music].

Thanks for the question right I think obviously it will depend on the data from waterfall in the data from shoreline.

Right now we still have to have some.

Larger study or some study like like the longer term analysis, but when we see waterfall one of the things were going to have to take a hard look at is.

Based on the six month data, we're not seeing a lot of relapses. If you think about patients getting the drug treatments and youre thinking about 75% of patients maintaining their effect, regardless of background therapy or no background therapy, yes, that's something we'll have we'll need to take up of the agency. Because initially we had looked at we had only a follow up data out.

Good day, 42, and we had assumed that people would need sort of.

The current treatment I think that assumption, so far as being challenged by the six month data.

And we'll have to take a look hard I look at shoreline and shoreline, which we're optimistic about now based on the six month data gives us something like that will weaken well revisit what what the what long term dated we might need.

If if we're.

At waterfall up reports out positively on Steve our Jim you want to anything to that.

Steve Kames: Yeah, I'll just say a few things. First of all, just to remind everyone, this is a program that's proceeding under breakthrough therapy designation, which gives us an opportunity to have interactions across the board. And so, as the data unfolds, we're able to interact with the FDA and talk about what the potential pathways forward are as breakthroughs because we share our understanding of the urgency of developing an entirely new therapy, and that's what this whole program has been designed to do. So yeah, when we have data, we'll do what we always do, which is go back to the agency. So that's a lot of words to say.

Yeah, I was just say a few things I mean first of all just to remind everyone. This is a program that's proceeding under breakthrough therapy designation, which gives us an opportunity to have interactions across the board.

And so as we as the data unfold, we're able to interact with with the FDA and talk about what the potential pathways forward our.

Breakthrough because we share our understanding of the urgency for developing an entirely new therapy and that's what this whole program.

And designed to do so yeah, when we have data.

We'll do we always it was just go back to the agency remember, it's not just the clinical efficacy data. It's also farm data and everything else that we've been consistently showing across the board now with more than 2500 patients that have been exposed to the drug we have a very clear idea on the.

Corey Kasimov: As the data unfolds, we'll have those discussions and identify the most efficient path forward for patients. Thank you. Your next question comes from Corey Kasimov with J.P. Morgan. Your line is open.

With the overall adverse event profile safety profile is so a lot of information comes through all of which will lead to.

The most efficient regulatory strategy forward so.

Jeff Jonas: Hey, good morning, guys. Thanks for fitting me in. So for the RRT study that's on tap to begin in the second half, do you plan to piggyback on top of your existing MDD sites, or will they be separate? I guess I'm just curious how fast this can go, since it sounds like this would represent the initial MDD filing. Thank you. There will be a combination of sites. Waterfall is moving quickly.

There's a lot of words to say as the data unfolds, we'll have those discussions and identify that most efficient path forward for patients.

Thank you. Our next question comes from Cory Kasimov from Jpmorgan. Your line is okay.

Hey, good morning, guys. Thanks for fitting me in so for the Archie study that's on top to begin in the second half do you plan to piggyback on top of your existing MDD sites will they be separate I guess Im just curious how fast. This can go since it sounds like this would represent the initial MDD filings. Thank you.

Jeff Jonas: We have a lot of really well-performing sites, and I think that we'll continue to try to go quickly. I think that one of the lessons of waterfall and of this year has been our ability to leverage our infrastructure that we've developed over time and the team's ability to move quickly from protocol to protocol. We'll be doing that as well. We do think the design of these studies; we design the studies to be, for want of a better word, palatable, to the investigators and sites. And one of the advantages of Zoranolone in general has been that a two-week course of therapy, potential patient benefit quickly, has been greeted with a lot of enthusiasm by treating clinicians. So that's one of the encouraging things that we've seen throughout all of this. Jim, I don't know if you want to add anything to that.

Yes, so well there'll be a combination of site that mean waterfalls moving quit we have a lot of really well by well.

Well performing sites I think for water.

So that I think that we'll we'll continue to try to actually go quickly I think that one of the lessons of waterfall in the lessons of this whole of this year has been that our ability to leverage.

Our infrastructure that we've developed over time in the team's ability to move quickly from protocol to protocol. So we'll be doing that as well. We do think the design of these studies, we do design studies to be.

I want to have a better word palatable.

To the investigators insights and one of the advantages of is around alone and general has been that two week course of therapy patient potential patient benefit quickly has been very X has been agreed with a lot of enthusiasm.

Jim Doherty: Yeah, I would just add, Jeff, that we have a pretty large network of sites, and so we're confident that we're going to be able to run all the studies and keep ourselves on track for all of them. Thank you. Our next question comes from Laura Chico with White Bush Security.

By treating clinicians so were that's one of the encouraging things that we've seen throughout all of this.

Jim I don't know if you want to anything to that.

Yes, I would just add Jeff that we'd have a pretty large network of sites and so we're confident that we're going to run all the studies.

Laura Kathryn Chico: Your line is open. Hi, this is Kenneth on behalf of Laura. Thanks for taking the question. So, on Skylark.

And keep ourselves on track for all.

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

Jim Doherty: The Lorosso cells were clearly impacted by COVID, and while the extent of disruptions appears to have stabilized since this spring, what are your expectations around recruitment dates? And with data in 2021, how should we be thinking about the number of sites that will be necessary for recruitment, and will this be fully outpatient? Sure, thanks for the question. This is Jim.

Hi, This is kind of gone for Laura Thanks for taking the question.

So on Skylark.

Ross ourselves, we're clearly impacted by Covidien, while the extended disruptions appear to have stabilized since this spring.

Your expectations around liquidity case, and with data in 2021, how should we be thinking about the number of sites that will be necessary for a small this before we outpatient thank you.

Sure. Thanks for the questions as Jim Yes, I think the important thing to remember we're skylark is that with surround alone. What we're talking about is an outpatient therapy and so that's just a different opportunity than what's with so wrestle, but certainly from a recruiting perspective, we're anticipating that we're going to be able to recruit for this.

Jim Doherty: Yeah, I think the important thing to remember for Skylark is that with Soranolone, what we're talking about is an outpatient therapy, and so that's just a different opportunity than with Soresso, but certainly from a recruiting perspective, we're anticipating that we're going to be able to recruit for the Skylark study in a comparable way to what we're seeing in our other studies with Soranol It's a smaller patient population, and so, of course, there'll be an impact there. But I think probably the most important thing is that with an oral drug in an outpatient setting, it's just going to be a little bit different. Steve, did you want to add anything?

I would like study.

Comparable way to what we're seeing on.

Our other studies with is around alone.

It's a smaller patient population and so of course there'll be an impact there.

But I think the probably the most important thing is that with an oral drug in an outpatient setting is those situations, Steve as you want to add anything.

Steve Kames: Yeah, I was just saying, you know, with COVID, Mike referred to that as impacting patients, sort of being able to be admitted to the hospital for treatment. On the other side of that, of course, is that there's enormous unmet need, and that's only growing. With increased isolation of women in the face of being delivered without significant others in the living room and having to go home without the support of family members and so forth.

Yeah, I was just say either with with Covance, Mike referred to that is impacting patients.

Sort of being able to be admitted to hospital for treatment.

On the other side of that of course is that theres enormous unmet need and thats only growing with increased isolation of women in the face of being delivering without significant others living room, and having to go and without the support of.

Family members, and so forth the rates and and potential interest in postpartum depression is only growing so as as Jim said you know the the trial itself is now patient trial. It gets around some of those logistical challenges and just based on her experience with execution, we anticipate being able to enroll that.

Steve Kames: The rates and potential interest in, you know, postpartum depression are only growing. So, as Jim said, the trial itself is an outpatient trial. It gets around some of those logistical challenges.

Mike Clunan: And just based on our experience with execution, we anticipate being able to enroll that in a very similar way as we have with waterfall. It's an important issue. It's an important disorder and one that we've been committed to for a long time. Yeah, and I'll just come in. This is Mike as well. I think it's important for a couple of points.

In a very similar way as we have with waterfall up to an important issue. It's an important disorder and one that we've been committed to for a long time.

Yes ill just coming this is Mike as well I think just it's important for a couple of points. One is as we said we have those distinct pass now offers around a lot. We have the TV path with Skylark right. One study will be able to seek approval. There we have the two paths with MDD, both the our t. indication and the episodic and the one point I'll also making come in combination with saying.

Mike Clunan: One is, as we've said, we have those distinct paths now for Zoranolone. We have the PPD path with Skylark, right, one study, and we'll be able to seek approval there. We have the two paths with NDD, both the RRT indication and the episodic.

Mike Clunan: And the one point I'll also make, in combination with what's being said, very different profiles, right, on the PPD side between Zoraso and Zoranolone, right? The rapid-acting nature is still there, but an oral therapy that patients aren't gonna have to go into a hospital to receive the 60-hour infusion. We're still very excited about the PPD market and what we think Zoran Okay, thanks so much.

Very different profiles, writing on the TV side between zero Russow and Saran long right. The rapid acting nature is still there was an oral therapy that patients are going out to go into a hospital to receive the 60 on fusion might we're still very excited about the tpd market and what we things around along can do there.

Okay. Thanks, so much.

Jay Olson: Thank you. And our last question is from Jay Olson with Oppenheimer. Your line is open.

Okay.

Thank you and your last question is from Jay Olson with Oppenheimer. Your line is open.

Jeff Jonas: Thanks for taking the question. Were you surprised by the durability of xeranilone in the six-month Mountain follow-up? How do you plan to leverage that finding with regard to your filing strategy and, ultimately, your target product profile for xeranilone? This is Jeff.

Oh, hi, thanks for taking the question.

Were you surprised by the durability is there anyone in the six month mountain follow up and how do you plan to leverage the that finding a with regards to your filing strategy and ultimately your target product profile for is around.

Jeff Jonas: Thanks for that question. You know, I don't want to use the word surprise. I guess I'd say we were gratified that the data that we've acquired to date over all of our studies can now be extended out to six months. We're aware, and as I said in my opening remarks, that this is really counter to the narrative about depression, that you enlist, that patients enlist themselves as chronic mental health patients for the rest of their lives, that they're so delicate that they have to stay on treatment for years and And, and, and those of us who treat these patients, you know, we've always wanted something better. And we wanted something different.

Hi, This is Jeff thanks for that question.

You know I don't want to use the word surprised I guess I'd say, we were gratified that the data that we've acquired to date over all of our studies.

Can be now be extended out to six months.

Yes.

We are aware and I said in my opening remarks. This is really counter to the narrative about depression.

That you and list that patients in list themselves as chronic mental health patients for the rest of their lives that they're so delicate that they have to stay on on treatment for years and years and and and those of US who are treated these patients we've always wanted something better.

And we want that something different and so I think we've been gratified by it.

Jeff Jonas: And so I think we've been gratified by it. I do think that the data really do, I wouldn't say surprise, but the data really, you know, don't run counter to, I think Steve and I are both psychiatrists, don't run counter to our personal experiences and how we used to treat patients. But it really does, it is surprisingly inconsistent with the pharmacomythology about how to treat patients.

I do think that.

The data really do I wouldn't say surprised with the data we don't run counted like I think Steve and I about Skijus don't run counter to our personal experience isn't how used to treat patients, but it really does it is surprisingly inconsistent with the pharmaco mythology about how to treat depression and so we do think that.

Jeff Jonas: And so we do think that these data, we continue to, this is just another step, and we do think that these data, though, do inform what might come from Shoreline. And if we can sustain this, you know, we think the profile of the drug will be unique. We think that, you know, the ability to get patients better more rapidly, to have a tolerable side effect profile, and to eliminate the necessity for automatic chronic pharmacotherapy will be a really important treatment option for patients that otherwise would be looking at years, potentially years, of SSRI therapy. So we're very encouraged by it, and we intend to think about how we could disrupt the treatment paradigm, and that will be, of course, Mike's job once we have the data.

Use data we continue to this is just another step.

And we do think that these data, though do inform what might come from shoreline and if we can sustain this we think the profile the drug will be unique.

We think that the ability to get patients better more rapidly.

How about tolerable side effect profile add it to.

Eliminate the necessity for automatic chronic pharmacotherapy will be in a really important treatment option for patients that otherwise are looking at years potentially years of Sri therapy. So we're very encouraged by and we would we intend to think about how we could disrupt the tree.

My paradigm and that will be of course mikes job once we have the data.

Jeff Jonas: But we do think these data are an important next step, where you're not seeing rebound, you're not seeing withdrawal, you're not seeing any signs, you're seeing really good durability. Now, the other thing I'd point out, though, is we said early on that the thesis behind these drugs and the mechanism behind some of the neurosteroids is the ability to alter post-synaptic receptor trafficking. And we've always thought about restoring normal homeostatic mechanisms in the brain. And in that respect, we've always believed that seranolone is a distinct molecule. It's not really what other people call an antidepressant. It's something different.

But we do think these data are an important next step where you're not seeing rebound you're not seeing withdraw are you seeing very good you're not seeing any sign.

We're seeing really good durability now the other thing I point out, though as we set early on that the thesis behind these drugs and the mechanism behind some of the nervous storage is the ability to alter post synaptic receptor trafficking and we've always thought about restoring normal homeostatic mechanisms and the brain and in that respect we've always the.

I believe thats around alone is a distinct.

It's not really what other people call an anti depressants.

It's something different it's something that normalizes mood potentially normalizes neural circuitry and potentially offers a reset of mood function. So we think the six month data really represent this sort of paradigm shift and how one can think about major depressive disorder. So we add so we do think we were that we're on the way to doing it.

Jeff Jonas: It's something that normalizes mood, potentially normalizes neural circuitry, and potentially offers a reset of mood function. So we think the six-month data really represent this sort of paradigm shift in how one can think about major depressive disorder. We do think that we're on the way to doing it. We think that this will be an important treatment option for patients, and it's one we intend to continue to pursue. That's super helpful.

We think that this will be an important treatment option for patients and it's one we intend to continue to pursue.

Super helpful. Thanks for taking the questions.

Thanks for taking the question. Thank you, and now I'd like to turn the call back over to Jeff Jonas for closing remarks. Well, again, thank you everyone for joining us this morning. I know you're all busy, and I hope everyone's healthy and your families are healthy. To close, I just want to reiterate three important points. The team at SAGE has done a great job executing on our clinical programs, all of which remain on track or ahead. As you've heard today, we have numerous catalysts over the next 18 months, and SAGE is really proud of our Discovery Medicinal Chemistry Group for developing this really, what makes us unique, a rich pipeline of novel and internally developed clinical assets, which we believe have the potential to help literally millions of people. So with that, I'm looking forward to updating all of you in the future with all of our milestones, and I hope all of you stay well. Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.

Thank you I'd now like you turn the call back over to Jeff Jones for closing remarks.

Well again, thanks, everyone for joining us this morning, I know, you're all bid and hope everyone has had a healthy and your families are helping to.

To close I, just want to reiterate three important points.

The team at stage has done a great job executing on our clinical programs all of which remain on track or ahead of schedule.

As you've heard today, we have numerous catalyst over the next 18 months and Sage is really proud of our discovery made additional chemistry group, they're developing this really what makes us unique our rich pipeline of novel in internally that certainly develop clinical assets with which we believe have the potential to help literally millions of people so with that.

Forward to updating all of you in the future with all of our milestones and help all of you stay well and have a great day.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating as you may now disconnect.