Q2 2021 SAGE Therapeutics Inc Earnings Call

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Good morning, welcome to Sage Therapeutics second quarter 2021 financial results Conference call. Currently all participants are in a listen only mode. This call is being webcast live on the investors and media section of sages website at.

Operator: Good morning. Welcome to SAGE Therapeutics' second quarter 2021 financial results conference call. Currently, all participants are in a listen-only mode.

Operator: This call is being webcast live on the Investors and Media section of SAGE's website at sagexrx.com. This call is the property of SAGE Therapeutics, and recording, reproduction, or transmission of this call without the express written consent of SAGE Therapeutics is strictly prohibited. Please note that this call is being recorded.

S. A G E X for X dot com.

This call is the property of Sage Therapeutics and recordings reproduction or transmission of this call without the express written consent of Sage Therapeutics is strictly prohibited.

Please note that this call is being recorded I would now like to introduce Jeff Boyle, Vice President Investor Relations at Sage.

Operator: I would now like to introduce Jeff Boyle, Vice President, Investor Relations at SAGE. Good morning, and thank you for joining SAGE Therapeutics' second quarter 2021 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 a 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.

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Good morning, and thank you for joining Sage Therapeutics second quarter 2021 financial results conference call before we begin I encourage everyone to go to the inverse.

And media section of our website at Sage RF Dot Com, where you can find our press release related to today's call as well as the slides that contain supplemental details.

I would like to point out that we built.

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.

Operator: Please consult the risk factors discussed in today's press release and in our SEC filing for additional details. We will begin the call with Barry Greene, our Chief Executive Officer, who will provide an overview of accomplishments during the quarter and some general content. Barry will be joined by Steve Kaines, our Chief Medical Officer, who will review recent clinical progress, and Kimi Iguchi, our Chief Financial Officer, who will review second quarter financials and discuss financial guidance. So with that, I'll turn the call over to Barry. Barry

Please consult the risk factors discussed in today's press release and in our SEC filings for additional detail.

We will begin the call with Barry Greene, our Chief Executive Officer, who will provide an overview of our accomplishments during the quarter and some general context.

They will be joined by Steve <unk>, Our Chief Medical Officer, who will review recent clinical progress and Kimi Iguchi, Our Chief Financial Officer, who will review second quarter financials and discuss financial guidance.

So with that I'll turn the call over to Barry.

Yes.

Thanks, Jeff and thank you everyone for joining us this morning.

Barry E. Greene: Thanks, Jeff, and thank you, everyone, for joining us this morning. We've made tremendous progress over the first half of the year on our mission to become the leader in brain health at a top-tier biopharmaceutical company by transforming the lives of patients with debilitating disorders of the brain. And with four positive data readouts in the first half of the year and multiple potential catalysts pending in the coming months, we're demonstrating the SAGE methodology is working while executing across all three of our lines of business, Depression, Neuropsych, and Neurology.

We've made tremendous progress over the first half of the year on our mission to become the leader in brain health with a top tier biopharmaceutical company.

Transforming the lives of patients with debilitating disorders of the brain.

With for positive data Readouts in the first half of the year and multiple potential catalysts pending in the coming months, we are demonstrating the sage methodologies working well executed across all 3 of our franchises depression neuroscience and neurology.

Barry E. Greene: Innovation in drug development requires a flexible and thoughtful approach with the intention to provide the best patient impact and experience. SAGE has been innovating since day one with a goal of delivering medicines that matter so people can get better, sooner, and stay better, longer. I'll start the call by reviewing the progress made this quarter and our approach to supporting the millions of patients worldwide with brain health disorders who are in need of innovative medicine.

Innovation in drug development requires a flexible and thoughtful approach with the intention to provide the best patient impact and experience.

<unk> been innovating since day, 1 with a goal of delivering medicines that matter. So people can get better sooner and stay better longer.

I'll start the call by reviewing the progress made this quarter and our approach to supporting the millions of patients worldwide with brain health disorders, who are in need of innovative medicines all day.

Barry E. Greene: I'll then turn the call over to Steve to review the clinical implications and potential importance to patients from our recent data readouts in more detail. Kimi will then provide an update on our financial progress during the quarter.

Then turn the call over to Steve to review the clinical implications on potential importance for patients from a recent data readouts in more detail.

Kidney will then provide an update on our financial progress during the quarter.

In June we announced positive topline data from the phase III waterfall study is around alone in patients with major depressive disorder score M. D D.

Barry E. Greene: In June, we announced positive top-line data from the Phase 3 Waterfall Study of Zoranolone in patients with major depressive disorders, or MDD. The study met its primary endpoint, demonstrating a statistically significant and clinically meaningful reduction in depressive symptoms as measured by HAM-D17 compared to placebo. After the standard two-week treatment, And as we've seen in all studies with Zoranolone, in addition to day 15, a significant reduction in HAMD scores began at the first measurement during treatment, that is, in this case, day 3. And I'll remind you that's after only two doses. Reductions were also seen at day 8 and day 12.

Study met its primary endpoint, demonstrating a statistically significant on clinically meaningful reduction in depressive symptoms as measured by <unk> 17 compared to placebo.

After the standard 2 week treatment regimen and as you've seen in all studies was around alone. In addition to day 15, a significant reduction Ham D scores began at the first measurement dream treatment. That's in this case day, 3 and I'll remind you that's after only 2 doses.

Reductions were also seen at day, 8 and day 12, perhaps just as importantly, we saw clear maintenance of effect through day 42, 4 weeks after treatment was stopped.

Barry E. Greene: Perhaps just as importantly, we saw clear maintenance of effect through day 42, four weeks after treatment was stopped. These data further support our belief in the potential for a differentiated benefit-risk profile for zirconialone as demonstrated in the clinical development program. And, as we believe, the millions of people suffering depression deserve a treatment option with a rapid and sustained reduction in MDD symptoms. Now, thinking about the results from Waterfall in the context of the entire landscape and nest development programs, the RAN alone has shown a remarkably consistent and differentiated profile.

These data further support our belief in the potential for a differentiated benefit risk profile for us around alone as demonstrated in our clinical development program to date.

And as we believe the millions of people suffering depression deserve a treatment option with a rapid and sustained reduction in M. D D symptoms.

I'm thinking about the results from waterfall in the context for the entire landscape of net development programs ran alone has shown a remarkably consistent and differentiated profile.

Barry E. Greene: To date, three of four late-stage pivotal studies with seranilone have been positive, with Ham-D reductions from baseline after two weeks of oral treatment ranging from around 12 to 18 points. These results, in the context of the overall benefit-risk for an oral medication, are unlike anything currently available or in development. And these data give us tremendous confidence in our belief of the regulatory path forward. Notably, in addition to our announcement of the top-line data from the Waterfalls, results from Zoranolone in a positive Phase 3 Robin study and PPD were recently published in JAMA Psychiatry. It's a striking paper that I suggest you read.

To date 3 of 4 late stage pivotal studies was ran alone have been positive with Ham D reductions from baseline after 2 weeks of oral treatment ranging from around 12 to 18 points.

These results in the context of the overall benefit risk for an oral medication are unlike anything currently available or in development.

And these day to give us tremendous confidence in our belief of the regulatory path forward.

Notably in addition to our announcement of the topline data from the waterfall study results from Saran alone the positive phase III Robin study in PPD recently published in Jama Psychiatry is a striking paper that I suggest you read.

With waterfall data on the totality of the landscape for nurse program to date, we and Biogen are planning to discuss the potential NDA package on timing with the FDA.

Barry E. Greene: With the waterfowl data and the totality of the Landscape and Nest program to date, we and Biogen are planning to discuss the potential NDA package and timing with the FDA. As we've said, we believe we have the efficacy data in hand to file the first NDA for xeronal. And our goal is to provide an update later this year, including an update on the potential timing of an NDA filing, if our discussions with the FDA align with our expectations.

As we've said we believe we have the efficacy data in hand to file our first NDA for us around alone and our goal is to provide an update later this year, including an update on potential timing of an NDA file if are discussing for the FDA align with our expectations.

Barry E. Greene: In addition to the ongoing clinical studies, we're also currently running clinical pharmacology studies at the 50 milligram dose needed for an NDA. At this time, after discussions with the agency, we do not believe the Redwood and Rainforest Studies, which were suspended in early 2020, need to be completed for an anticipated NDA filing package. As you may recall, Redwood was designed to study fixed-schedule intramuscular dosing of zaranolone throughout the course of a year. We believe data from the Shoreline Study address this question.

In addition to the ongoing clinical studies. We're also currently running clinical pharmacology studies at the 50 milligram dose needed for in India.

At this time after discussions with the agency, we do not believe the Redwood and rainforest studies, which were suspended in early 2020 needs to be completed for an anticipated NDA filing package.

As you May recall Redwood was designed study fixed schedule intermittent dosing arms around alone throughout the course of the year.

We believe data from the shoreline study address this question rainfall.

Barry E. Greene: Rainforest was designed to investigate the efficacy and safety of Zoranolone in comorbid MDD and insomnia. While Zoranolone has consistently improved sleep across clinical studies as measured by the sleep component of the HAMD scale, we do not believe Rainforest is required for initial trials. Real innovation has been abstinence treatments for depression for decades. There have been more than 35 treatments approved over the last 30 years. But the benefit-risk profile and approach to treatment have been largely unchanged, and rates of depression continue to rise steeply.

Rainforest was designed to investigate the efficacy safety observed on alone and comorbid MVD and insomnia was around alone has consistently improved sleep across clinical studies as measured by sleep component of the Ham D scale, we do not believe rainforest as required for initial filings.

Real innovation has been absent treatment for depression for decades, there have been more than 35 treatments approved over the last 30 years, but the benefit risk profile and approach the treatment had been largely unchanged and rates of depression continue to rise steeply.

Might be available treatments, there are still more than 19 million adults, who experienced at least 1 major depressive episode each year in the U S alone.

Cases are increasing every year.

Additionally, there has been as high as a fourfold increase in depressive symptoms. During the COVID-19 pandemic. We firmly believes around alone has the potential to offer a unique and compelling profile if approved with clinical data to date, showing clinically meaningful reductions in depressive symptoms with consistent improvements in mood anxiety.

Barry E. Greene: Despite the available treatments, there are still more than 19 million adults who experience at least one major depressive episode each year in the U.S. alone, with cases increasing every year. Additionally, there has been as high as a 4-fold increase in depressive symptoms during the COVID-19 pandemic. We firmly believe Xeranolone has the potential to offer a unique and compelling profile if approved, with clinical data to date showing clinically meaningful reductions in depressive symptoms with consistent improvements in mood, anxiety, and sleep.

And sleep.

Rapid onset a 2 week treatment regimen that offers the potential to treat as needed with maintenance of response after treatment completed and a well tolerated safety profile with no evidence of weight gain sexual dysfunction, euphoria Gi upset or sleep disruption symptoms that are typically the cause of treatment discontinuation with standard.

Barry E. Greene: Rapid Onset, a two-week treatment regimen that offers the potential to treat as needed with maintenance of response after treatment is completed, and a well-tolerated safety profile with no evidence of weight gain, sexual dysfunction, euphoria, GI upset, or sleep disruption, symptoms that are typically the cause of treatment discontinuation with standard of care antidepressant drugs. Together with Viagra

A cure anti depressant drugs.

Together with Biogen.

We're now taking the steps in building a best in class commercialization program for us around alone to meet the needs of patients with depression, Hcp's and Payors.

And if we're successful on our efforts to gain approval. We've illustrated this on slides 19 and 20.

As we focus on our goal to brings around to market. Our commercialization work is imperative, we intend to revolutionize the way depression, just thought about and treated.

Barry E. Greene: We're now taking the steps to build a best-in-class commercialization program for xeronalone to meet the needs of patients with depression, HCPs, and payers. And if we're successful in our efforts to gain approval, we've illustrated this on slides 19 and 20. As we focus on our goal to bring Zaranulim to market, our commercialization work is imperative. We intend to revolutionize the way depression is thought about and treated. Current standard of care treatments for MDD can be slow for patients to experience response, and if any, are chronic, with most patients staying on some form of chronic treatment for at least two years, and are often accompanied by burdensome side effects causing adherence issues and drug regimen changes.

Current standard of care treatments for M. D. D can be slow for patients to experience response, if any are chronic with most patients staying on some form of chronic treatment for at least 2 years and are often accompanied by burdensome side effects, causing adherence issues and drug regimen chambers.

We believe the target profile offers around alone with clinical trial data to date, showing a rapid clinically meaningful reduction in depressive symptoms time limited treatment regimen, and well tolerated safety profile will be welcomed by patients living with depression.

The work to create a paradigm shift in the treatment of depression has started.

We look forward to sharing more on our approach to engaging and educating key stakeholders as you ramp up our disease education and launch planning efforts for us around alone.

Now, let me remind you that sage has a deep pipeline of programs investing in house and we've made great progress in expanding and accelerating our pipeline during the quarter.

Our neurology franchise is led by Sage 3.2 for.

Barry E. Greene: We believe the target profile for xeronal... Clinical trial data to date showing a rapid, clinically meaningful reduction in depressive symptoms, a time-limited treatment regimen, and a Well-Tolerated Safety Profile will be welcomed by patients living with depression. The work to create a paradigm shift in the treatment of depression has begun. We look forward to sharing more on our approach to engaging and educating key stakeholders as we ramp up our disease education and launch planning efforts for Zoraniline. Now, let me remind you that SAGE has a deep pipeline of programs invented in-house, and we've made great progress in expanding and accelerating our pipeline during the quarter.

Which is also part of our collaboration with budget and in April we announced positive data from our phase II study in essential tremor.

In this study Sage 3.2 for met the primary endpoint of demonstrating a statistically significant reduction from baseline and the tetris item for upper limb tremor score at day 29, and the total study population compared to placebo.

We also saw a statistically significant correlation between tetra scores and activities of daily living at every time point.

These observations are important as they may help provide future regulatory flexibility.

For patients.

Central tremor can affect nearly every aspect of day to day living and can make the simplest task difficult if not impossible.

We believe the pharmacologic characteristics of Sage 3 to 4 are well suited to address unmet needs for these patients we.

Barry E. Greene: Our neurology franchise is led by SAGE 324, which is also part of our collaboration with Biogen. And in April, we announced positive data from our phase two kinetic study in essential tremors. In the study, SAGE 324 met the primary endpoint by demonstrating a statistically significant reduction from baseline in the Tetris item 4 upper limb tremor score at day 29 in the total study population compared to placebo. We also saw a statistically significant correlation between TETRA scores and activities of daily living at every time frame. These observations are important as they may help provide future regulatory flexibility. For patients, a central tremor can affect nearly every aspect of day-to-day living and can make the simplest tasks difficult, if not impossible.

We are progressing this program and expect to initiate the phase II dose ranging study in late 2021 with the goal of optimizing the dosing frequency with a good tolerability profile and dosing schedule to maintain plasma concentrations that translate into sustained tremor symptom control.

Turning to our neuro Psych franchise, we are evaluating Sage 718, our wholly owned first in class NMDA receptor Pam as a potential oral therapy for cognitive disorders associated with NMDA receptor dysfunction.

In May we announced positive data from part a of the paradigm study on Sage 718 in Parkinson's disease cognitive dysfunction and I'm pleased to report for the first patient has been dosed in part B of that study.

We believe that this 4 week dosing arm will provide additional information about sage 718 to inform the development path forward.

Additionally, the luminary study with Sage 718 in Alzheimer's disease cognitive dysfunction remains on track to read out later this year and also later this year, we intend to initiate a randomized placebo controlled phase II study in Huntington's disease, which are positive we expect will bring us 1 step closer and pursuing an initial regulatory.

Barry E. Greene: We believe the pharmacologic characteristics of SAGE 324 are well suited to address unmet needs in these patients. We are progressing this program and expect to initiate a Phase II dose-ranging study in late 2021 with a goal of optimizing the dose and frequency with a good tolerability profile and a dosing schedule to maintain plasma concentrations that translate into sustained tremor symptom control. Turning to our neuropsych franchise, we are evaluating SAGE 718, our wholly owned, first-in-class NMDA receptor PAM, as a potential oral therapy for cognitive disorders associated with NMDA receptor dysfunction. In May, we announced positive data from Part A of the Paradigms study on SAGE 718 in Parkinson's Disease Cognitive Dysfunction.

<unk> for Sage 718.

As you can see so far in 2021, we've executed on the promised expansion and acceleration across our growing portfolio.

We look forward to providing more updates, including additional analysis of previously reported data to allow key stakeholders and opportunity to further assess the data in detail.

It's all going to come in the second half of this year and we expect to do a lot of education around those data.

With that I'll turn the call over to Steve for more detail on the data we reported this quarter as well as our additional ongoing clinical programs Steve.

Thanks, Barry and good morning, everyone.

I'm thrilled with the data we've generated to date and the progress across all 3 franchises throughout 2021.

Starting with our depression franchise led by Iran alone. Our next generation positive allosteric modulator of Gaba a receptors, we've seen remarkably consistent and differentiated data with saran alone throughout the landscape of Nash clinical development programs that was further supported most recently by the positive outcome in the pivotal water.

Steve Kaines: And I'm pleased to report that the first patient has been dosed in Part B of that study. We believe that this four-week dosing arm will provide additional information about SAGE 718 to inform the development path forward. Additionally, the Luminary Study with SAGE 718 in Alzheimer's Disease Cognitive Dysfunction remains on track to read out later this year. And also later this year, we intend to initiate a randomized placebo-controlled phase 2 study in Huntington's disease, which, if positive, we expect will bring us one step closer to pursuing an initial regulatory indication for SAGE 718.

Paul study.

And as Barry mentioned, we believe the data we've generated to date, along with the ongoing pharmacology studies and safety data from coral supported but I'd, rather not submit anything.

It means just like getting really for share.

Damages, specifically discussed these data on the regulatory NDA filing pathway.

And the waterfall study for the rental and met the primary endpoint, demonstrating a statistically significant and clinically meaningful improvement compared to placebo in Ham D scores at the end of the 2 week dosing period.

Steve Kaines: As you can see, so far in 2021, we've executed on the promised expansion and acceleration across our growing portfolio. We look forward to providing more updates, including additional analysis of previously reported data, to allow key stakeholders an opportunity to further assess the data in detail. That's all going to come in the second half of this year, and we expect to do a lot of education around that data. With that, I'll turn the call over to Steve for more detail on the data we reported this quarter, as well as our additional ongoing clinical programs. Steve?

We also saw a rapid onset of activity beginning at day 3 earliest time point measured.

As a group of patients who responded to the ran alone. After 2 weeks of treatment retained on average more than 85% of their improvement through the end of the trial. In this case are for 30 days after the last dose of medication with the majority of these patients maintaining most if not all of the improvement.

As we continue to analyze the data from this study on the entire landscape program. We look forward to presenting additional data pertaining to the overall profile odds around loans, along with the patient reported outcomes speak to the potentially paradigm changing profile. That's around low may present for patients that were successful what I can say is that the data to date tell us that.

Steve Kaines: Thanks, Barry, and good morning, everyone. I'm thrilled with the data we've generated to date and the progress across all three franchises throughout 2021. Starting with our depression franchise led by Zoranolone, our next generation positive allosteric modulator of the GABA A receptor, we've seen remarkably consistent and differentiated data with seranolone throughout the landscape and NEST clinical development programs, and this was further supported most recently by the positive outcome in the Pivotal Waterfall Study. And, as Barry mentioned, we believe the data we've generated to date, along with the ongoing pharmacology studies and safety data from CORAL, support an NDA filing... I'd rather not submit anything.

<unk> has shown rapid onset.

Large improvements in overall depressive symptoms prolonged benefit after completing the 2 week treatment regimen, and a well tolerated safety profile.

For example in the shoreline study the largest naturalistic study conducted in an M. D. D development program, we've observed that nearly 50% of patients who responded to 30 milligrams only required 1 treatment in a 12 month period and roughly 70 percentage of patients responded to 30 milligrams required no more than 2.

2 week treatments throughout the year.

And as a psychiatrist I believe patients are looking for rapid and sustained reductions in net depressive symptoms with a confidence that they can use a treatment only when needed.

The safety profile as railroads has now been characterized in more than 3500 patients and the data from the waterfall study is consistent with this large and growing safety database.

For example on the waterfall study the vast majority of adverse events were mild to moderate in severity or most importantly, there were no deaths or on a loss of consciousness.

Steve Kaines: We intend to meet with the FDA as soon as possible to specifically discuss these data and the regulatory NDA filing path. In the Waterfall Study, Xeranilin met the primary endpoint, demonstrating a statistically significant and clinically meaningful improvement compared to placebo and Han-B scores at the end of the two-week dosing period. We also saw a rapid onset of activity beginning at day three, the earliest time point measure.

No reports of wiki sexual dysfunction that euphoria, all of which can be associated with current standard of care anti depressants and can lead to discontinuation.

To that end up quickly very few patients discontinued from the study because of adverse events for 3.4 per cent of those receiving saran alone and 1.5% on placebo discontinuing because they use.

There were only 2 serious adverse events and as revenue and 2 in the placebo group.

Steve Kaines: As a group, patients who responded to Zoranolone after two weeks of treatment retained, on average, more than 85% of their improvement through the end of the trial, in this case, a full 30 days after the last dose of medication, with the majority of these patients maintaining most, if not all, of the improvement. As we continue to analyze the data from this study and the entire LANDSCAPE program, we look forward to presenting additional data pertaining to the overall profile of zaranulone, along with patient-reported outcomes to speak to the potentially paradigm-changing profile that zaranulone may present for patients if we're successful. What I can say is that the data to date tell us that ziranolin has shown a rapid onset. LARGE IMPROVEMENTS IN OVERALL DEPRESSIVE SYMPTOMS.

As we continue to review the substantial amount of data from the waterfall study and the rest of the landscape program. We're also committed to sharing data at per year scientific forums as quickly as possible.

Slide 14, and our corporate presentation provides details on the types of data we plan to present at upcoming Congresses, including patient reported outcomes, which we believe will be very insightful.

The totality of the data seen with Saran links day supports our view of its target profile is a rapid durable and use as needed or episodic treatment that we believe has the potential to be meaningful for patients and our health care system. Overall recent health economics and outcomes research conducted by Sage and published in the peer reviewed journal pharmacodynamics.

That the economic burden of MPD treatment with multiple lines of treatment for depression was much higher compared to a single on a treat Richard depression. In fact, there was an increased economic burden associated with delay of depressive episode resolution as early as the second line compared to the first line N V D. It's clear that a rapid.

Steve Kaines: For example, in the Shoreline study, the largest naturalistic study conducted in an MDD development program, we observed that nearly 50% of patients who responded to 30 milligrams only required one treatment in a 12-month period, and roughly 70% of patients who responded to 30 milligrams required no more than two two-week treatments throughout the year. And as a psychiatrist, I believe patients are looking for rapid and sustained reductions in their depressive symptoms with the confidence that they can use treatment only when needed.

<unk> well tolerated episodic treatment for depression as needed and we believe <unk> has the potential to fill that void in the market.

Turning to the 3 additional ongoing phase III studies with Zara Antelope.

<unk> and shoreline studies are on track to read out with data in late 2021.

Coral is investigating the efficacy and safety of <unk> 50 milligrams when co initiated with new open label SSRI in patients with M. D D.

Positive results from the waterfall study, we believe have sufficient efficacy data to support our first FDA filing for us around alone although consistent safety profile remains an important aspect of coral that said of course, we expect to see consistent efficacy profile supporting with differentiated benefit risk was around alone in this trial, including rapid onset of effect.

Steve Kaines: The safety profile has now been characterized in more than 3,500 patients, and the data from the Waterfall Study is consistent with this large and growing safety database. For example, in the Waterfall Study, the vast majority of adverse events were mild to moderate in severity, but most importantly, there were no deaths or loss of consciousness.

Shoreline is designed as a naturalistic open label safety and Tolerability study to investigate as needed repeat treatment with <unk> alone over a 1 year period from patients with MVD.

We expect to reported top line data cut from the 15 milligram, 1 year cohort and shoreline in late 2021.

We're also continuing to enroll patients in the study following our announcement last quarter that we expanded the target enrollment for 500 patients and we're offering patients from the coral study the ability to rollover into shoreline. Following the completion of the coral study.

Steve Kaines: There were also no reports of weight gain, sexual dysfunction, or euphoria, all of which can be associated with current standard of care antidepressants and can lead to discontinuation. To that end, importantly, very few patients discontinued from the study because of adverse events, with 3.4% of those receiving xeranilone and 1.5% on placebo discontinuing because of AEs. There were only two serious adverse events in the Zaranului group and two in the placebo group.

The other ongoing phase III study of <unk> as a skylark study in postpartum depression.

Updating our guidance on the Skylake study, which is now expected to readout in mid 2022, as a result of a slower than anticipated pace of enrollment in the study due to a dramatically and unfortunate lower level for women diagnosed with PPD during the pandemic, possibly preventing women from accessing appropriate screening and diagnosis.

Also on our depression franchise today, we announced topline data from the Chickadee study evaluating the safety and Tolerability and pharmacokinetics of Zalviso and adolescent females is 15% to 17 with postpartum depression.

Steve Kaines: As we continue to review the substantial amount of data from the Waterfall Study and the rest of the Landscape Program, we're also committed to sharing data at premier scientific forums as quickly as possible. Slide 14 in our corporate presentation provides details on the types of data we plan to present at upcoming Congresses, including patient-reported outcomes, which we believe will be very insightful. The totality of the data seen with Zaranulin to date supports our view of its target profile as a rapid, durable, and use-as-needed or episodic treatment that we believe has the potential to be meaningful for patients and our healthcare system overall.

The study was conducted as a post marketing requirement to investigate the Russell and adolescent females with PPD.

The data showed that the safety and pharmacokinetic profile for US Russia and this population was consistent with prior studies in adults and the FDA approved product label importantly, the efficacy seen in the Chickadee study is consistent with what we've seen in the clinical program in adults.

We plan on working with FDA to potentially add this broader age groups for the label.

Moving to our neurology franchise, which is led by Sage 320 for a novel treatment that we believe has incredible potential in the treatment of essential tremor.

Data, we announced in April for the kinetics study.

Steve Kaines: Recent health economics and outcomes research conducted by SAGE and published in the peer-reviewed journal PharmacoEconomics showed that the economic burden of MDD treatment with multiple lines of treatment for depression was much higher compared to a single line of treatment for depression. In fact, there was an increased economic burden associated with delay of depressive episode resolution as early as the second line compared to the first line in MDD.

<unk> 36 per cent reduction in upper limb tremor amplitude from baseline to day 29, and the total study population seen with Sage 324 with adverse events that were generally consistent with the safety profile of $3.20 for seeing previously are supportive of further development and the target product profile for $3.20 for may potentially be very meaningful for patients.

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To that end, we plan to initiate a dose ranging phase II clinical trial with Sage 324 in our central tremor in late 2021, we also look forward to working with our collaborators at Biogen to optimize next steps for the continued development for Sage 320, <unk> to identify the profile, we expect to move into pivotal trials as a reminder at this.

Steve Kaines: It's clear that a rapid-acting, well-tolerated episodic treatment for depression is needed, and we believe Zaranulin has the potential to fill that void in the market. Turning to the three additional ongoing Phase 3 studies with Zoranil, the Coral and Shoreline studies are on track to read out with data in late 2021.

Time, we don't believe additional formulation work is necessary for Sage 324 for <unk>.

Confidence our proposed phase 2 B trial will result in a dose and frequency designed to optimize benefit risk as we continue to develop this novel product candidate for central tremor.

Steve Kaines: Coral is investigating the efficacy and safety of Zaranolone 50 mg when co-initiated with new open-label SSRIs in patients with MDD. The positive results from the Waterfall Study, we believe, have sufficient efficacy data to support our first FDA filing for xeranolone, although a consistent safety profile remains an important aspect of CORAL. That said, of course, we expect to see consistent efficacy profiles supporting the differentiated benefit-risk of xeranolone in this trial, including rapid onset of the virus. Shoreline is designed as a naturalistic, open-label, safety, and tolerability study to investigate as-needed repeat treatment of xeronalone over a one-year period in patients with MDD.

Beyond Sage 320 for our neurology franchise includes Sage 689, a potent product candidate with rapid teekay and solid formulation flexibility with potential in areas of high unmet need including acute agitation mania or migraine.

I'm pleased to share the first patient has been dosed in the phase 1 program for Sage 69, and we're on track to complete the phase 1 study in late 2021. Additionally.

Additionally, I'm pleased to share that our IND, enabling preclinical work is underway for Sage 319, and oral extra synaptic Gaba a receptor preferring Pam <unk>.

The advancements of the Sage 69, and Sage 309 programs represents meaningful expansion and acceleration of our sage developed wholly owned pipeline.

Steve Kaines: We expect to report a top-line data cut from the 50-mg one-year cohort in Shoreline in late 2021. We're also continuing to enroll patients in the study following our announcement last quarter that we expanded the target enrollment to 500 patients, and we're offering patients from the choral study the ability to roll over into Shoreline following the completion of the choral study. The other ongoing phase 3 study of zirandalin is a Skylark study in postpartum depression.

Turning to our neuropsychiatry franchise, where we are continuing to develop sage 7 money, our NMDA receptor Pam and development as a potential oral therapy for disorders, where cognition is 1 of the main drivers of disability.

Consistent with the data seen in Huntington's disease patients in our phase 1 studies.

Patients with Parkinson's disease Sage 708, as shown in an open label Phase 2 trial. The paradigm study a positive impact on multiple domains of cognition, including executive function and learning and memory, while not altering simple attention or reaction time.

Steve Kaines: We're updating our guidance on the SCARLEC study, which is now expected to read out in mid-2022 as a result of a slower than anticipated pace of enrollment in the study due to a dramatically and unfortunate lower level of women diagnosed with BPD during the pandemic, possibly preventing women from accessing appropriate screening and diagnosis. Also in our depression franchise, today we announced top-line data from the Chickadee study evaluating the safety and tolerability and pharmacokinetics of Zolresso in adolescent females aged 15 to 17 with postpartum depression. This study was conducted as a post-marketing requirement to investigate Xeroso in adolescent females with PPV.

On the study patients is 50 to 75 years old with mild cognitive impairment due to Parkinson's disease free.

Sage 7183 milligrams daily for 2 weeks demonstrated improved performance from baseline on multiple tests of executive functioning over 14 days of treatment.

For knowledge there is nothing in clinical development that has generated data, suggesting this kind of profile for potential ability to augment key cognitive domains without the challenges often associated with other approaches.

Within the safety data available the rates of adverse events reported have been low, but the most frequently reported AE being headache, no serious adverse events have been recorded to date for.

We're confident in the potential of Sage 718, and today announced that we have dosed. The first patient in a 4 week dosing arm in the paradigm study together additional data and the PD patient population and inform next steps.

Steve Kaines: The data showed that the safety and pharmacokinetic profile of Xeroso in this population was consistent with prior studies in adults and the FDA-approved product label. Importantly, the efficacy seen in the Chikiti study is consistent with what will be seen in the clinical program in adults. We plan on working with FDA to potentially add this broader age group to the label. Moving to our neurology franchise, which is led by SAGE 324, a novel treatment that we believe has incredible potential for the treatment of essential tremors. The data we announced in April for the Kinetic Study.

As we previously announced we are planning to initiate a double blind placebo controlled phase 2 study of Sage 7 money and Huntington's disease. Later this year and are on track to report topline data from the Luminary study evaluating sage 718 in patients with a D mild cognitive impairment and mild dementia later this year as well.

In addition to Sage 718, our neuroscience franchise also includes Sage 900 for an NMDA receptor Pam product candidate being evaluated as a potential oral therapy for other disorders associated with NMDA Hypofunction. We are on track to complete set of NAV studies in late 2021.

Steve Kaines: A 36% reduction in upper limb tremor amplitude from baseline at day 29 in the total study population seen with SAGE 324, with adverse events that were generally consistent with the safety profile of 324 seen previously, are supportive of further development, and the target product profile for 324 may potentially be very meaningful for patients. To that end, we plan to initiate a dose-ranging Phase 2 clinical trial with SAGE 324 and essential tremor in late 2021.

Our neuroscience franchise also includes sage for 'twenty, 1 and oral NMDA, Pam being evaluated for potential use for neurodevelopmental disorders, and cognitive recovery and rehabilitation, which we expect to advance to preclinical studies this year.

Lastly, today, we announced that we're terminating our phase III study evaluating breaks antelope, and COVID-19 related acute respiratory distress syndrome or ards.

The study did not meet enrollment expectations and was closed to further enrollment this quarter. We will report the data collected to date after full analysis of the results.

This was an important quarter for sage marked by advancements across our pipeline and we're excited about the second half of the year with several potential value, creating catalysts expected. We believe our significant progress this quarter leaves us well positioned to build on our momentum and to advance our mission of making medicines that matter on.

Steve Kaines: We also look forward to working with our collaborators at Biogen to optimize next steps for the continued development of SAGE 324 to identify the profile we expect to move into pivotal trials. As a reminder, at this time, we don't believe additional formulation work is necessary for SAGE 324.

I'll now turn the call over to Kimi for a review of the financials Kimi.

Thanks, Steve and you heard from Stephen Berry, we're executing well in 2021 and making decisions based on data that we believe will ultimately help us deliver medicines and positively impact patients.

Steve Kaines: We are confident our proposed Phase IIb trial will result in a dose and frequency design to optimize benefit-risk as we continue to develop this novel product candidate for essential trauma. Beyond SAGE 324, our neurology franchise includes SAGE 689, a potent product candidate with rapid PK and solid formulation flexibility with potential in areas of high unmet need, including acute agitation, mania, or migraines. I'm pleased to share that the first patient has been dosed in the Phase 1 program for SAGE 69, and we're on track to complete the Phase 1 SAD Study in late 2021.

It's an exciting time for sales and we're expanding in moving our pipeline forward.

On a strength underpinned by a strong financial position.

Let me start with the highlights from our second quarter financials.

Then close with some commentary on our financial guidance.

We recorded $1.6 million and net revenue on a second quarter from the sales of the wrap up.

That compares to $1.1 million of revenue from sales of interest for the same period in 2020.

We remain committed to them on their families and all of those impacted by PPD.

Our targeted commercial efforts, including an integrated approach to engaging key stakeholders on.

Handheld minds with PPD, who may benefit from treatment with the rest of gain assets.

Selling general and administrative expenses were $43.3 million in the second quarter compared to $38.2 million for the same period of 2020.

This includes an increase in expenses on the $8.6 million and a reduction in expenses of $3.5 million due to reimbursement from Biogen as part of our collaboration.

Steve Kaines: Additionally, I'm pleased to share that IND-enabling preclinical work is underway for SAGE 319, an oral extrasynaptic GABA-A receptor-preferring PAM. The advancement of the SAGE 69 and SAGE 319 programs represents meaningful expansion and acceleration of our SAGE-developed, wholly-owned pipeline, training to our neuropsychiatry franchise, where we are continuing to develop SAGE 718, our NMDA receptor PAM, in development as a potential oral therapy for disorders where cognition is one of the main drivers of disability.

The increase in expenses was driven by an increase in activities focused on taking the awareness increased launch readiness activities for a potential product launch if either at or on development efforts are successful.

Noncash stock based compensation expense from the achievement on milestone for certain outstanding performance risk assets back in.

Research and development expenses were $66.2 million on the second quarter.

That was compared to $73.3 million for the same period of 2020 net.

This reflects an increase in expenses of $13 million and a reduction in expenses of $21 million due to reimbursement from Biogen is probably on our collaboration.

The increase in expenses was driven by clinical pharmacology studies that began in 2021 and noncash stock based compensation expense for the achievement of milestones for certain outstanding performance restricted stock units.

Steve Kaines: Consistent with the data seen in Huntington's disease patients in our Phase I studies, in patients with Parkinson's disease, SAGE 718 has shown, in an open-label Phase II trial of a paradigm study, a positive impact on multiple domains of cognition, including executive function and learning and memory, while not altering simple attention or reaction. In the study, patients aged 50 to 75 years old with mild cognitive impairment due to Parkinson's disease To our knowledge, there is nothing in clinical development that has generated data suggesting this kind of profile and the potential ability to augment key cognitive domains without the challenges often associated with other approaches. Within the safety data available, the rates of adverse events reported have been low, with the most frequently reported AE being headache. No serious adverse events have been recorded to date.

Additionally, we had no restructuring expenses in the second quarter of 2021 compared to $28.4 million in the second quarter of 2020.

We reported a net loss of $107.2 million for the second quarter.

That was compared to a net loss on $136.3 million for the comparable period of 2020.

I'd like to highlight the components that we expect will continue to support and build our financial strength for the remainder of 2021 and beyond.

Specifically there are 3 areas that give me confidence in our financial strength and our potential to create value.

First we expect our cash on hand, and $1.9 billion plus ongoing funding and resources from the Biogen collaboration.

Provide the financial flexibility to allow us to continue to make sound and strategic decisions designed to improve our profitability at 6 months.

The Biogen collaboration provides ongoing caution for R&D and SG&A expenses for agreed upon activities related to that ran on a sage can return it for <unk>.

And we have the potential for up to 1.6 billion, if we make development and commercial milestones.

Second our thoughtful and flexible R&D approach.

Combined with our strategy for investing in the near mid and long term.

Has led to a portfolio of multiple programs across 3 franchises.

All of which have shown promising signs of long term value potential for <unk>.

Patients and shareholders.

And third we're working to build a best in class commercialization program designed to help us attract patients HCP and pairs. If our products are approved and with the potential if we're successful to deliver significant shareholder value.

Secondly, we are reiterating our prior financial guidance that we expected on the cash balance of more than $1.7 billion at the end of 2021 and as a reminder, we did not expect to receive any milestone payments from collaborations for the remainder of 2021.

Steve Kaines: We are confident in the potential of SAGE 718 and today announced that we have dosed the first patient in a four-week dosing arm of the paradigm study to gather additional data in the PD patient population and inform next steps. As we previously announced, we are planning to initiate a double-blind, placebo-controlled Phase 2 study of SAGE 718 in Huntington's disease later this year, and we are on track to report top-line data from the Luminary Study evaluating SAGE 718 in patients with AD, mild cognitive impairment, and mild dementia later this year as well.

It's sterling to see what's been achieved to date and we're just getting started I am confident that our strong financial position and flexibility will allow us to continue to drive the portfolio expansion as we work to develop innovative treatments with the potential to impact millions of lives.

I'll now turn it over to Jeff to handle Q&A with the operator, Jeff.

Thanks, Jay before I turn it over for the operator I'll ask that you limit yourself to 1 question. If you have an additional question feel free to return to the queue now I'll turn it over for the operator operator.

Ladies and gentlemen, if you have a question or comment at this time. Please press Star then 1 on your telephone keypad. If for your question has been answered or you wish to remove yourself from the queue simply press the pound key.

Steve Kaines: In addition to SAGE 718, our neuropsych franchise also includes SAGE 904, an NMDA receptor PAM product candidate being evaluated as a potential oral therapy for other disorders associated with NMDA hypofunction. We're on track to complete SAD and MAD studies in late 2021. Our Neuropsych franchise also includes SAGE 421, an oral NMDA-PAM being evaluated for potential use in neurodevelopmental disorders and cognitive recovery and rehabilitation, which we expect to advance to preclinical studies this year. Lastly, today we announce that we're terminating our Phase 3 study evaluating Brixanilone and COVID-19-related acute respiratory distress syndrome or ARD. This study did not meet enrollment expectations and was closed to further enrollment this quarter.

Again, if you have a question or comment at this time. Please press Star then 1 on your telephone keypad.

Our first question or comment comes from the line of Ritu <unk> from Cowen Your line is open.

Hi, Good morning. This is my along for 2 thank you for taking the question and congrats on a corner and he just to go back to the regulatory strategy and just to clarify.

E D corner to be successful for filing N D. D. And then the decision to terminate Redwood and rainforest does that mean getting indicated that short language Tonight proficient free treatment data for other finally, thank you.

Yeah. Thanks, Thanks for the question so as we said on the call.

We have sufficient efficacy data for filing and we take a step back.

Which studies around alone and over 3500 patients and subjects to date and the profile of is around alone has been consistent which is rapid onset.

Of action.

Efficacy as early as the first measured time points day, 3 that's been consistent with day 12.

And 15.

Good clinically meaningful results. So we believe the totality of the efficacy data.

Steve Kaines: We will report the data collected to date after full analysis of the results. This was an important quarter for SAGE marked by advancements across our pipeline, and we're excited about the second half of the year with several potential value-creating catalysts expected. We believe our significant progress this quarter leaves us well-positioned to build on our momentum and to advance our mission of making medicines that matter. I'll now turn the call over to Kimi for a review of the financials. Kimi?

As far as.

As we mentioned on the call with ongoing Pharmacology studies, which also needs to be complete and then we believe we need to confirm this definitively on the agency that will take a snapshot of the safety data from our ongoing other clinical stops studies, including coral.

Packaging totality will be sufficient for filing.

We did and we had breakthrough status were in ongoing dialogue and we were able to confirm redwood and rainforest would not be required for this filing and then to your specific question with shoreline.

Kimi E. Iguchi: Thanks, Steve. As you heard from Steve and Barry, we're executing well in 2021. We're making decisions based on data that we believe will ultimately help us deliver medicines that positively impact patients. It's an exciting time for SAGE, and we're expanding and moving our pipeline forward from a position of strength underpinned by our strong financial position. Let me start with the highlights from our second quarter financials and then close with some commentary on our financial guidance.

So really important data with Shaw as Steve mentioned on the call for.

50% of the patients from shoreline and that was the 30 milligram dose required 1.2 week treatment and the entire course of the year and 70% of patients only reported 1 or 2 treatments for the entire course of this year.

And then about 10% required 3.4% and 10.5 so even at the most frequent studied dose.

Kimi E. Iguchi: We recorded $1.6 million in net revenue in the second quarter from the sales of the rest. That compares to $1.1 million of revenue from sales of Xeresso for the same period in 2020. We remain committed to our moms, their families, and all those impacted by PPD. Our targeted commercial efforts, including an integrated approach to engaging key stakeholders, are aimed to help moms with PPD who may benefit from treatment with Zoretso gain access. Selling general and administrative expenses were $43.3 million in the second quarter compared to $38.2 million for the same period in 2020.

5.2 treatments, we're talking about 10 weeks of drug versus 52 weeks with current.

Anti depressant. So we believe that those data are sufficient to provide the re treatment evidence Steve anything to add.

Steve you might be on mute.

Yeah, no the only thing I'd say is with.

A big a big important factor of all of these for filing is taking share of an appropriate safety database and now with <unk>.

More than 3500 individuals dosed and handed a very clean safety profile, along with 3 positive trials, which includes.

Waterfall, we believe.

But we definitely have the efficacy as well as the safety information necessary for a file it as far as it will we'll confirm that with our next meeting with the agency.

Got it. Thank you for your debt to help for calling in thank.

Kimi E. Iguchi: This includes an increase in expenses of $8.6 million and a reduction in expenses of $3.5 million due to reimbursement from Biogen as part of our COLEVR. The increase in expenses was driven by an increase in activities focused on disease awareness, increased launch readiness activities for a potential product launch if our xeratin development efforts are successful, and non-cash stock-based compensation expense from the achievement of a milestone for certain outstanding performance-restricted Research and development expenses were $66.2 million in the second quarter. That was compared to $73.3 million for the same period in 2020.

Thank you.

Thank you. Our next question or comment comes from the line of solving Richter from Goldman Sachs. Your line is open.

Hey, good morning, and thank you for taking our question. This is Elizabeth on for <unk> I'm, just wondering if there any additional steps that need to be taken ahead of the phase 2 dose ranging study for 3 to 4 thank you.

Yeah listen thanks, Thank you and I'm really important that you mentioned that so taking a step back we started the year articulated to everybody that our intention is here based upon on our strengthened balance sheet is from expands and accelerates the pipe.

And the positive kinetic data we were asked where we were asking the question can we treat essential tremor patients throughout the course of 30 days and see consistent reduction of central tremor with a favorable safety profile without any kind of tachyphylaxis or untoward safety and that's exactly the results from.

Kimi E. Iguchi: This reflects an increase in expenses of $13 million and a reduction in expenses of $20.1 million due to reimbursement from Biogen as part of our collaboration. The increase in expenses was driven by clinical pharmacology studies that began in 2021 and non-cash stock-based compensation expense from the achievement of milestones for certain outstanding performance-restricted stocking. Additionally, we had no restructuring expenses in the second quarter of 2021 compared to $28.4 million in the second quarter of 2020. We reported a net loss of $107.2 million for the second quarter.

<unk>, which gives us confidence to move into a longer term studies extensive tremor, so together with our partners advising.

Joining that.

Next step dose frequency study, where we hope to come out with a dose and frequency debt.

Provides a profile to move into phase 3 so all this news is we've agreed with Biogen now is to work with the agency to make sure that we have the right.

Gross.

And we plan on issuing debt later this year and we will provide guidance and.

Design details once we've initiated that study.

We're moving forward rapidly.

Thank you for our next question or comment comes from the line of Cory cash them off from J P. Morgan Your line is open.

Hi, This is gavin on for Cory. Thanks for taking my question I was just curious about investor feedback.

Kimi E. Iguchi: That was compared to a net loss of $136.3 million for the comparable period of 2020. I'd like to highlight the components that we expect will continue to support and build our financial strength for the remainder of 2021 and beyond. Specifically, there are three areas that give me confidence in our financial strength and our potential to create value. First, we expect our cash on hand to reach $1.9 billion, plus ongoing funding and resources from the Biogen Collaboration, will provide the financial flexibility to allow us to continue to make sound and strategic decisions designed to improve our probability of success. The Biogen collaboration provides ongoing cost sharing for R&D and SG&A expenses for agreed-upon activities related to Zoranerone and SAGE 324.

That you've gathered since the topline waterfall readout on what aspects of the data if any really stand out to to the kols. Thank you.

Yeah. Thanks answer that question so.

Since since we've had the waterfall readout, we've integrated that with the totality of data.

Add great discussions with various investigators and Kols and I think what's what everybody is seeing.

<unk> is really a paradigm shift here.

When we think about the last 35% to 50 years of antidepressants, when we think about what's in development today.

Including.

Some later stage programs nobody has seen an oral medicine that works after 1 or 2 doses and as you know we've seen statistical significance at day 3.

With continued efficacy and I'll ask Steve to talk about the totality of data on what we see shoreline helped emphasize that point.

Yes.

The profile itself is really unique and you talked a lot about the paradigm shifts, but I'll just remind everybody debt.

Kimi E. Iguchi: And we have the potential for up to $1.6 billion if we meet development and commercial milestones. Second, our thoughtful and flexible R&D approach. Combined with our strategy to invest in the near, mid, and long-term, this has led to a portfolio of multiple programs across three franchises, all of which have shown promising signs of long-term value potential for patients and shareholders. And third, we're working to build a best-in-class commercialization program designed to help us reach patients, HCPs, and payers if our products are approved, and with the potential, if we're successful, to deliver significant shareholder value.

What we mean is something really substantial for patients with.

On the typical treatment duration for a first episode for depression 6 months typically people are on their antidepressants for years.

And what we're offering for successful is a time limited treatment for 14 days to weeks for therapy to treat a major depressive episode that is a real revolution is something that patients as well as physicians.

We're looking for you know.

Other kinds of things that we're now working with is really integrating the data to be able to illustrate the overall benefit risk profile and working specifically with <unk>.

With all of the Kols that were in touch with too.

Both.

I mean sure they understand exactly what we're trying to do and then getting their feedback about how best to articulate that benefit risk profile, what we've seen so far.

Kimi E. Iguchi: Separately, we are reiterating our prior financial guidance that we expect to have a cash balance of more than $1.7 billion at the end of 2021. And as a reminder, we do not expect to receive any milestone payments from collaborations for the remainder of 2021.

Most patients are requiring no more than 2 treatments over the course of a year that's for weeks at a.

We were 48 weeks in a year theyre not taking medication a real revolution in the treatment of depression on when those patients themselves are really quite interested in so the kinds of things we'll be looking to go more deeply into our 1 of a patient's views of this treatment how does that reflected on the overall outcome is something that's very important in demonstrating clinical meaningfulness.

Kimi E. Iguchi: It's thrilling to see what's been achieved to date, and we're just getting started. I'm confident that our strong financial position and flexibility will allow us to continue to drive the portfolio expansion as we work to develop innovative treatments with the potential to impact millions of lives. I'll now turn it over to Jeff to handle Q&A with the operator.

And using that with our with Kols and everybody else to really help everyone understand.

How this may be used in the treatment paradigm, it's going to be a book.

Very well could be tool for proof.

And how best to then introduce it into clinical practice.

Jeff Boyle: Thanks, Kimi. Before I turn it over to the operator, I'll ask that you limit yourself to one question. If you have an additional question, feel free to return to the queue. Now, I'll turn it over to the operator. Operator? Ladies and gentlemen, if you have a question or comment at this time, please press star then 1 on your telephone keypad. If your question has been answered or you wish to remove yourself from the queue, simply press the pound key.

It's exciting for me because im assuming thats entirely new you know if I and I haven't seen the data for years now if ive had this medicine in my arm <unk> when I was a practice that would've use it on everybody.

Finding ways to to.

Sort of educate and then ultimately change practices is kind of where we are right now and it's a really exciting opportunity.

Great. Thank you.

Thanks for the question.

Thank you. Our next question or comment comes from the line of polymer piece from Stifel. Your line is open.

Hey, thanks, so much for taking the question.

Hey, I just wanted to clarify 1 thing and then ask 1 quick question after that but on your comments Barry is there a scenario here, where you could initiate and complete an NDA filing for us or analog before we ever get the oral data just trying to understand if that's 1 of the possible for mutations and then can you.

Jeff Boyle: Again, if you have a question or comment at this time, please press star then 1 on your telephone keypad. Our first question or comment comes from the line of Ritu Baral from Collins. Your line is open.

Just remind us where you are on abuse liability work for us or add alone and kind of what your operating expectation is as you approach a regulatory review thanks, so much.

Yes, Paul.

Thanks for the question and I'll.

Operator: Hi, good morning. This is Wylan Furutu.

Let me provide context on that Steve to fill it and so what we said as the assets.

Operator: Thank you for taking the question and congratulations on the quarter. And maybe just to go back to the regulatory strategy, just to clarify, do you need coral to be successful to file an MDD? And in the decision to terminate Redwood and Rainforest, does that mean the FDA had indicated that Shoreline would provide sufficient retreatment data for the filing? Thank you.

The efficacy data we have the day 3 out of for phase III, including the data from shoreline.

Sufficient for an efficacy filing we have ongoing to your point with ongoing pharmacology studies, we did run the pharmacology studies at 30 milligrams, but.

Changing to now the 50 milligram data from earlier phase II learnings for rewriting millions of pharmacology studies, including abuse.

As you have in those will be completed later this year.

Barry E. Greene: Yeah, thanks for the question. As we said on the call, we have sufficient efficacy data for filing. If we take a step back, we've studied Zoranolone in over 3,500 patients and subjects to date, and the profile of Zoranolone has been consistent, reaching a rapid onset of action, and efficacy as early as the first measured time point of day 3, that's been consistent with day 8, 12, and 15, significantly significant clinical results.

Those data will be part of the the filings in terms of other studies coral Skyler, we believe and we need to confirm this with you need to see that on a blinded snapshot of the safety data.

We'll be required to file so it is conceivable that were filed on the regulatory path for other phase III readout, but that's simply a matter of timing.

Steve anything to add.

Barry E. Greene: So we believe the totality of the efficacy data is viable. As we mentioned on the call, we have ongoing pharmacology studies, which also need to be complete, and then we believe, and we need to confirm this definitively with the agency, that we'll take a snapshot of the safety data from all ongoing other clinical studies, including CORAL, and that package, in totality, will be sufficient for filing. We did, and we had breakthrough status, so we're in an ongoing dialogue, and we were able to confirm redwood and rainforest would not be required for this filing.

No the assets, specifically about whether or not the clean pharm package is complete and there are some ongoing sales as various surface at 50 milligrams, obviously for any drug that gets into the CNS theres an abuse liability package that you do.

We will certainly have it in time for the filing and there's nothing there that is giving us pause.

We expect that we will have all of the day that we need to file for it.

At the time of completion after operating under our views with the FDA as Barry said with the.

Barry E. Greene: And then to your specific question about Shoreline, we saw really important data with Shoreline. As Steve mentioned on the call, 50% of the patients on Shoreline, and that was the 30 milligram dose, required one and two-week treatment over the entire course of the year. And 70% of patients only required one or two treatments in the entire course of the year. And then about 10% required three, 10 to four, and 10 to five.

Efficacy data as well as the safety data, it's really just a matter of the technical aspects of what goes into a filing.

Sort of agree on.

Okay. Thanks.

Thank you.

Our next question or comment comes from the line of <unk> Ahmad from Bank of America. Your line is open.

Mr. Ahmad you maybe on mute your phone.

Okay.

Sorry about that can you hear me now.

No.

Yes, yes, okay.

Okay, great. Thanks.

Thanks for taking my question on good morning, 1 question that I have about the discontinued rainforest study 1 thing that was being studied there of course with this co morbid insomnia and for the time that we've looked at this drove 1 of the major benefits that physician checks have given us is that.

Barry E. Greene: So even at the most frequently studied dose of five two-week treatments, we're talking about 10 weeks of drug versus 52 weeks of current antidepressants. So we believe that those data are sufficient to provide the retreatment evidence. Steve, anything to add? Keep it up. Keep it up. Keep it up! Hey, yeah, no, the only thing I'd say is, you know, a big, very important factor of all of these for filing is making sure you have an appropriate safety database.

Already have patients to be able to sleep better at night with D. A.

Inc. I'm positive and on would increase their desire to want to prescribe saran alone and so now that you've discontinued the study I'm just curious.

How would we get a little bit more color on on the if somebody said how sleep stress Sharon is that still something that you would want to have language in an ultimate label. Thank you.

Barry E. Greene: And now, with more than 3,500 individuals dosed in hand with a very clear safety profile, along with three positive trials, including Waterfall, we believe that we definitely have the efficacy as well as the safety information necessary for a file. And as Barry said, we'll confirm that with our next meeting with the agency.

Debt to the net.

That's a great question, so I will remind you that.

Through the M D scores and the patient reported outcomes in the completed clinical studies, we have insight into not only a mood and anxiety, but sleep and sleep architecture, and we believe that we have data sufficient.

Steve Kaines: Got it. Thank you for the helpful advice.

Operator: Thank you. Our next question or comment comes from the line of Salveen Richter from Goldman Sachs.

And understanding that patients sleep patterns have been improved.

Now obviously label negotiations on exactly whats in the label as a matter of F. D. A negotiation, but we believe that we have we have those data if we believe.

Operator: This is Elizabeth on behalf of Salveen. I'm just wondering if there are any additional steps that need to be taken ahead of time.

Yes, we get the label that ongoing studies required to make more definitive statements. We certainly can do.

Barry E. Greene: Yeah Elizabeth, thank you. And it's really important that you mention that. So, you know, taking a step back, we started the year articulating to everybody that our intention this year, based upon our strengths and balance sheet, is to expand and accelerate the pipeline. And the positive kinetic data, where we asked the question, can we treat essential tremor patients throughout the course of 30 days and see consistent reduction in essential tremor with a favorable safety profile without any kind of tachyphylaxis or unto And that's exactly the result we had, which gives us confidence to move into a longer-term study of essential tremor. So, together with our partners at Bison, we're designing that.

Studies, but we think we've got data in hand that helps us understand that patients are in fact in many of these patients as you know on sleep in patients arent back sleeping better delayed demand.

Yes.

Like you we remain interested on the potential benefits of sleep.

And how to get at that is something that we'll be looking into certainly we've seen consistently when we look at the individual factors.

That fleet there has improved not only sleep of course, we're seeing improvements in the core symptoms of depression and so forth.

Which is what you need to VNS depression, but sleep is certainly a factor there and 1 that we think theres going to be important as a benefit for patients.

How we how we get to that first focus on depression get the drug approved something that's absolutely important during a screen health pandemic, where the rates of depression going up through the roof and.

As we become successful we will be able to take another look at that but certainly from.

Barry E. Greene: Next Step Dose Frequency Study, where we hope to come out with a dose and frequency that provides the profile to move into Phase 3. So all we have to do is, we've agreed with VIAGE, and now we have to work with the agency to make sure that we have the right dose and frequency. And we plan on initiating that later this year, and we will provide guidance and design details once we've initiated that study. We're moving forward. Thank you. The next question or comment comes from the line of Corey Casimoff from JP Morgan. Your line is open. This is Gavin on behalf of Corey.

From a scientific data data communication will be able to say, where it's about that obviously, we've done a lot of sleep work already.

And then through the individual factors from our trials will be able to articulate those benefits.

And those are some other things that were planning on doing near term how we address that long term is something that obviously, we're working on with Biogen is moving forward.

Okay. Thank you.

Thank you.

Thank you. Our next question or comment comes from the line of you asked me Rahimi from Piper Sandler Your line is open.

Hi team. Thank you for taking my questions and thank you for all the updates I have questions on shoreline. The first 1 is can you tell me how many patients on the 50 milligram dose for we'll have for 1 year complete it for the day that it's late this year and then 2 when you look so far is the rate of.

Operator: Thanks for taking our question. We're just curious about investor feedback that you've gathered since the top line waterfall readout and what aspects of the data, if any, really stand out to the KOLs. Thank you. Yeah, thanks for that question.

Re core started eating a second dose the same and the 50 milligram versus a 30 milligram dose that you have reported at Inc.

Yeah, Yeah. Thanks for the question and thanks for asking about Caroline. This is a really important study that helps us understand the incredible durability that we're seeing in patients and keep in mind that and people have to reflect on it patients are taking drug for 2 weeks and as we've seen in our phase.

Barry E. Greene: So, since we've had the Waterfall readout, we've integrated that with the totality of data, and we've had great discussions with various investigators and key opinion leaders, and I think what everybody is seeing is really a paradigm shift. When we think about the last 35 to 50 years of antidepressants, when we think about what's in development today, including some later stage programs, nobody is seeing an oral medicine that works after one or two doses, and as you know, we've seen statistical significance at day three with continued efficacy.

<unk> for weeks or more after dose patients are still reporting that they are enormous and stays in shoreline. Further reflects the durability of the drug I'm going to turn over to Steve to get into the into the details for the tranche very important in the context around on.

Yes, yes.

The short answer of course is we'll know the actual number.

When when the study is completed and so we're following that and then they go on to have as many patients as we can at the end of the study as you continue to roll on patients in fact were relocations for the coral study into the trial and what you do with it long term trials like this is take data cuts along the way, but I can tell you is we're seeing very remarkable.

Barry E. Greene: And I'll ask Steve to talk about the totality of data and what we've seen in Shoreline to help emphasize that point. Yeah, the profile itself is really unique. We talk a lot about the paradigm shift, but I'll just remind everybody that what we mean is something really substantial for patients. The typical treatment duration for a first episode of depression is six months.

Our results in terms of response and remission in the shoreline study during those initial 50 milligram doses and that's been true since the earliest cuts so and our estimates now are that 80% plus of patients of sugar response, meaning 50% reduction.

Steve Kaines: Typically, people are on their antidepressants for years, and what we're offering for successful is a time-limited treatment, 14 days, two weeks of therapy to treat a major depressive episode. That is a real revolution.

And about 43 per cent a little bit more are showing full remission and those loans have been rock solid since the earliest days of our program, they're not only higher than what we saw at 30 milligrams, but at the same general range. So so we're seeing really good response, that's been continuing both.

Steve Kaines: It's something that patients as well as physicians are looking for. You know, the kinds of things that we're now working on are really integrating the data to be able to illustrate the overall benefit-risk profile and working specifically with all of the KOLs that we're in touch with to both make sure they understand exactly what we're trying to do and then get their feedback about how best to articulate that benefit-risk profile.

For for first the 30 milligrams and now throughout the 50 milligram dose they will have the actual member metrics and numbers.

For the study when the study completes.

Thank you Steve are you able to agree on and on.

As of right now the size of shoreline just like how many patients are currently in shoreline.

I can say that this is the last data cut there was more than 500 patients enrolled in the trial and this would be the equivalent of a long term safety study, where we expect attrition throughout the year people are getting better they're going about their business. They don't necessarily are interested, especially if they're feeling well to continue to check in so even the low.

Steve Kaines: You know, what we've seen so far is that most patients require no more than two treatments over the course of a year. That's four weeks at a time when there are 48 weeks in a year they're not taking medication.

Steve Kaines: A real revolution in the treatment of depression, one that patients themselves are really quite interested in. So the kinds of things we'll be looking to go more deeply into are what are the patient's views of this treatment, how does that reflect on the overall outcome, something that's very important in demonstrating clinical meaningfulness, and using that with KOLs and everybody else to really help everyone understand how this may be used in the treatment paradigm.

The rates of attrition in the trial are things that we look at but what we're seeing is very high levels of retention.

1 other point, we'd like to make is is not only in shorelines are patients getting better, but only a small number of them are requiring additional re treatments. This is this would be the equivalent of a reverse placebo effect, meaning interest no theyre not on therapy.

Only a fraction of them require additional treatments and so among other things we get we start to understand what treatment in the real world would look like with our medicine.

Steve Kaines: It's going to be a very welcome new tool approved, and how best to then introduce it into clinical practice. So, you know, it's exciting for me because this is something that's entirely new. You know, if I, and I've been seeing the data for years now, if I had this medicine in my arsenal when I was in practice, I would have used it on everybody. And finding ways to sort of educate and then ultimately change practices is kind of where we are right now.

And 1 treatment, but half of all patients only required that index treatment another 20% required in the <unk>.

More treatment in the course of a year, that's fundamental day, you're not gonna find out of the literature of and this is part of what we're doing creating.

Both our new approach to treatment as well as the foundational data that is necessary in order to make wise treatment choices. So that's why shoreline is so important.

Steve Kaines: It's a really exciting opportunity. Great, thank you. Thanks for the questions. Thank you. Our next question or comment comes from the line of Paul Matteis from Stifle. Your line is open.

And you know Theres a.

There's a lot there, but those are from from my perspective. Those are the things that are really most important as this program progresses.

Operator: Hey, thanks so much for taking the question. Hey, I just wanted to clarify one thing and then ask one quick question after that. Based on your comments, Barry, is there a scenario here where you could initiate and complete an NDA filing for xeranilone before we ever get the coral data? Just trying to understand if that's one of the possible permutations.

Thank you Sam.

Yep.

Yes.

Our next question or comment comes from a lot of Andrew Tsai from Jefferies. Your line is open.

Hi, good morning, and thanks for having me. So my question is on coral.

As investors start to think about the likelihood of success and what the study could show at day 15 is it fair for us to assume the comparator arm, which as you know.

The typical SSRI.

Operator: And then can you just remind us where you are on the abuse liability work for xeranilone and kind of what your operating expectation is as you approach a regulatory review? Thanks so much. Yeah, Paul, thanks for the question. And I'll, let me provide context for that, Steve, to fill it in.

Essentially be viewed as a traditional placebo arm since ssris takes 6 to 8 weeks to work or does co initiating with an SSRI or still somehow change the calculus and then I.

A corollary to that is it.

You know as we think about day 42 could both arms improve on on Ham D. Oh.

Barry E. Greene: So what we said is that the efficacy data we have to date, three out of four positive phase 3s, the data from Shoreline are sufficient for an efficacy phylan. We have ongoing pharmacology studies. We did run the pharmacology studies at 30 milligrams, but now changing to the 50 milligram data from earlier phase 3 learnings, we're rerunning many of the pharmacology studies, including abuse studies, as you have, and those will be completed later this year. So those data will be part of the phylan.

Sorry, I start to kick in for some patients. Thanks.

Yeah, Andrew Thanks for that question.

I'm going to ask Steve to talk about our.

The rest of the experience for us.

Uh huh.

Jeff dose events for that question for an approved drug, but let me say that our coral as you highlighted is that from an important question what happens when we co administered anti depressant.

Barry E. Greene: In terms of other studies, Coral Skylark, we believe, and we need to confirm this with the agency, that a blinded snapshot of the safety data will be required for filing. So it's conceivable that we're filing a regulatory package before other phase 3s come out, but that's simply a matter of timing. Steve, anything to add? No, you asked specifically about whether or not the ClinFarm package is complete, and there are some ongoing studies, as Barry said, that say 50 milligrams.

With patience wins around on the data we have today.

Have patients on.

So for them because these are not patients that you assume experienced some of the horrific side effects that you might like.

Anti depressant, so we're absolutely different question and you should learn.

From Coral now I'll also say that as basis on each and every time.

We conduct clinical studies, we learn from those clinical studies and we make adjustments for future studies based upon those learnings. So if there's adjustments to be made.

<unk>, we will make those adjustments and work on the agency on any necessary adjustments.

Barry E. Greene: Obviously, for any drug that gets into the CNS, there's an abuse liability package that you do. We'll certainly have time for the filing, and there's nothing there that's giving us pause. We expect that we'll have all of the data that we need to file at the time of completion, after our meetings with the FDA. As Barry said, with the efficacy data as well as the safety data, it's really just a matter of the technical aspects of what goes into a filing that we need to sort of agree on.

To your specific point, you're right, we do not expect debt the antidepressant alone will confer any beneficial.

Any any benefits for 4 to 6 weeks, but we may in fact, the side effects earlier and that will be very interesting to date, because as Steve highlighted earlier.

While we have seen somnolence and sleepiness was around alone we have not seen things like weight gain sexual dysfunction Gi upset some of the other side effects you see with.

Steve Kaines: Okay, thanks. Thank you. Our next question or comment comes from the line of Tazeen Ahmad from Bank of America. Your line is open. Mr. Ahmad, you may need to unmute your phone.

With antidepressants.

Hopefully that's helpful. And then maybe you could talk about how you know arms might come together multiple weeks of dosing limitations on cash.

Operator: Sorry about that. Can you hear me now? Yeah. Okay, great. Thanks for taking my question and good morning. One question that I have about the discontinued rainforest study, one thing that was being studied there, of course, was comorbid insomnia. And for the time that we've looked at this drug, one of the major benefits that physicians have seen is that, for the time that we've looked at this drug, one of the major benefits that physicians have seen

In other drugs.

Oh absolutely.

<unk>.

We we don't contested anti depressants when given over the course of several weeks may actually demonstrate benefit and just like in our other clinical trials.

No the patients over time, they may improve even in the placebo arm. So we're not looking as we haven't for placebo.

Drug differences out to day 42, especially not in coral recall.

This study is looking to address a very particular use case, which is how do you jump start therapy. When you co initiate an anti depressant with low.

Operator: Thank you so much for joining us today. One of the things that you have given us is that the ability of patients to be able to sleep better at night would be a big positive and would increase their desire to want to prescribe seranolone. And so now that you've discontinued that study, I'm just curious, how would we get a little bit more color on the ability to help sleep structure?

Sage Sage 2 and 7 is our antelope with an anti depressant.

College or they call that induction with maintenance, how do you start people to get better more quickly.

And so we're looking at this early time point for they've shown consistent differentiation from placebo or any other drug that's available at day 3 to 8 a 12 day 15, you know really early on.

Barry E. Greene: Yes, Tazeen, that's a great question. So I will remind you that through the MD scores and the patient-reported outcomes in the completed clinical studies, we have insight into not only mood and anxiety but sleep and sleep architecture, and we believe that we have data sufficient to understand that patients' sleep patterns have been improved. Now, obviously, label negotiations and exactly what's in the label are a matter of FDA negotiation, but we believe that we have those data.

Are there non specific effects that many things of course, I mean, we do that through the powering we do that through.

The contract for the trial and so forth, but we do think that if the study is successful adjusted.

Yet another use case, where patients may or physicians may want to choose this as a treatment option.

Barry E. Greene: If we believe, after we get the label, that ongoing studies are required to make more definitive statements, we certainly can do studies, but we think we've got data in hand that helps us understand that patients are, in fact, and many of these patients, as you know, aren't sleeping. Steve Aikman, Yeah, you know, Tazeen, like you, we remain interested in the potential benefits of sleep, you know, and how to get at Certainly, we've seen consistently that when we look at the individual factors, that sleep is improved.

And you know the technicalities of it.

Obviously, we plan for success on inventory that the powering is adequate to show those differences.

Very helpful color. Thank you guys.

Yep.

Thank you. Our next question or comment comes from non of Laura Chico from Wedbush. Your line is open.

Hi, Good morning. Thank you very much for taking the question I have 1 on Saran alone M. P. P. D. So the phase III Jama paper shows a higher proportion of patients with symptom onset during the third trimester vs. <unk> studies and it seems like a bit of a shift in diagnosis, but not much time elapsed between when the.

Barry E. Greene: Not only sleep, of course; we're seeing improvements in the core symptoms of depression and so forth, which is what you need to be an antidepressant. But sleep is certainly a factor there and one that we think is going to be important as a benefit for patients. You know, how we get to that first, focus on depression, get the drug approved, something that's absolutely important during a brain health pandemic where the rates of depression are going up through the roof.

Does the Randall on PPD until restaurant PPD studies were conducted so with skylark pushing back I'm. Just wondering if you can comment on whether you think these are more permanent changes in the PPD landscape.

It's interesting because you're seeing elevated depression rates elsewhere, but not in postpartum depression. So I guess the question here is how does this impact 1 on your P. P. D submission strategy, but then also how do you see this playing out in a commercial environment in terms of maybe who might be the primary point of care for Saran alone.

Steve Kaines: And, you know, as we become successful, we'll be able to take another look at that. But certainly, from scientific data, data communication, we'll be able to say something about that. Obviously, we've done a lot of sleep work already. And then, through the individual factors from our trials, we'll be able to articulate those benefits. And those are some of the things that we're planning to do near term. How we address that long term is something that, obviously, we're working on with Biogen as we move forward.

Yeah, Laura Thank you.

A few different questions from there so let me try to unwind it.

Steve here. So thank you for highlighting the paper, we're really proud of the Robin study and as I highlighted in my prepared remarks, just a beautiful paper Inc.

And on paper that really reflects just how well is around on works in these moms with PPD.

Let me start with the kind of the commercial landscape. So if we're fortunate.

With our successful waterfall for file as we expect for the agency and get an indication for both <unk> and PPD, which is which is what we expect.

Operator: Okay, thank you. Thank you. Thank you. Our next question or comment comes from the line of Yasmeen Rahimi from Piper Sandler. Your line is open. Hi team, thank you for taking my questions and thank you for all the updates. I have questions about shorelines. The first one is, can you tell me how many patients there are?

We will be reaching out.

And making sure that all moms, particularly those with risk factors haven't planned on every mom as you know as it plans for when her water breaks you knows where her bag is who's taking share and who are positioned is gonna be where she's giving birth, but almost no moms have a plan for being suppressed.

2 months 3 months after the babies born so we're going to make sure that we work with patient advocacy work with obgyn, who work in the psychiatry community to ensure that they don't moms have plan. After after giving birth net debt is probably broader than just the.

Operator: on the 50 milligram dose group will have one year completed.

Operator: The rate of... Recourse or needing a second dose was the same in the 50 milligram versus a

Operator: versus the 30 mg dose that you have reported. Thank you.

Since the news other.

Barry E. Greene: Yeah, yeah, thanks for the question, and thanks for asking about Shorline. This is a really important study that helps us understand the incredible durability that we're seeing in patients. And keep in mind that, and people have to reflect on this, patients are taking drugs for two weeks. And as we've seen in our phase threes, the four weeks or more after the dose, patients are still reporting that they're in a normative state. And Shorline further reflects the durability of the drug. I'm going to turn it over to Steve to get into the details. But Shorline is very important in the context of Serano.

There's other health concerns of moms have after after giving birth. So we will be aggressive in ensuring that that moms with depression.

Access to zero on we've heard from some kols that can say that.

With certain with certain other risk factors they intend for those moms, so actually leave the hospital with a scripted handling cases depressive symptoms come up so I think we'll be well prepared there Steve you want to talk about the timing differences debt that Laura highlighted.

Oh sure so Laura.

I'm glad you did the close reading a we've always included on page.

So I had an answer for investors. So we think there are a few things that are going on 1 of them is with the approval of Zalviso. There's a heightened awareness among treaters, both identify and diagnose patients and that I believe is being reflected in the ability to at least identify patients prior to being treated.

Steve Kaines: The short answer, of course, is we'll know the actual number when the study is completed, and so we're following that. And the goal is to have as many patients as we can at the end of the study and to continue to roll in patients. In fact, we're rolling patients from the choral study into that trial. And what you do with long-term trials like this is take data cuts along the way.

Importantly, we are not enrolling patients in the study despite when their diagnosis was made until a full month. After the delivery that's to ensure that we're not medicalizing sort of the normal changes in mood.

Steve Kaines: What I can tell you is we're seeing very remarkable results in terms of response and remission in the shoreline study during those initial 50-milligram doses, and that's been true since the earliest cuts. So our estimates now are that 80% plus of patients are showing a response, meaning a 50% reduction, and about 43%, a little bit more, are showing full remission. And those have been rock solid since the earliest days of our program.

Immediately after delivery mean people have to have the onset of symptoms and they have to be maintained for several weeks 4 weeks plus for them to really be appropriate for a diagnosis of M. D D in and Thats really important for us I mean, unless other symptoms remain theyre not M. D. D. So we think there is.

There's awareness screening attention and a bit of know how on how to how to identify these patients and thats important with regard to the epidemiology well, we know a few things 1 rates of depression. If you just ask people their way up.

Steve Kaines: They're nominally higher than what we saw in 30 milligrams, but in the same general range. So we're seeing really good response that's been continuing both for first the 30 milligrams and now throughout the 50-milligram doses. We'll have the actual metrics and numbers when the study completes.

The other births are down and we also surmise based on discussions with with investigators and Kols that new moms are much more reluctant to come into into care during the pandemic. So.

All of those factors taken together speak to 1 the importance of.

Operator: Thank you, Steve. Are you able to comment on, as of right now, the size...

Affordable treatment for modern treatment time limited treatment that doesn't require people coming into our center.

Operator: I'm working on, as of right now, the size of Shoreline, just like how many patients are currently in Shoreline. You know, I can say that as of the last data cut, there were more than 500 patients enrolled in the trial. And this would be the equivalent of a long-term safety study where we expect attrition throughout the year. People are getting better. They're going about their business.

As well as the ongoing work related to the Skylark study. So you know as much as it's disappointing to change the timeline for the importance of the work remains and we are really looking forward to getting that study over the finish line I would also add debt as part of our as part of our filing strategy, we do intend to discuss the utility of our <unk>.

Steve Kaines: They don't necessarily have to be interested, especially if they're feeling well, to continue to check in. So even, you know, the rates of attrition in the trial are things that we look at. But what we're seeing is very high levels of retention. One of the points we like to make is not only are patients in Shoreline getting better, but only a small number of them are requiring additional retreatments. This would be the equivalent of a reverse placebo effect, meaning patients know they're not on therapy and only a fraction of them require additional treatments. And so, you know, among other things, we get it.

Current package for getting both at M. D. D N. A P. P. D label. So all of that is part of our current approach based on the outcomes from from the Jama Psychiatry paper.

Thanks, guys.

Thanks for.

Thank you. Our next question or comment comes from the line of Jay Olson from Oppenheimer. Your line is open.

Thank you for taking the questions I appreciate the importance of a rapid response and M. D. D, which you described earlier can you talk about how on early response correlates with positive longer term outcomes and M. D. D and also comment on how the onset of response for Saran alone compares to other novel.

Depressing such as ketamine. Thank you.

Steve Kaines: We start to understand what treatment in the real world would look like with our medicine. And, you know, one treatment, half of all patients only require that index treatment. Another 20 percent require, you know, one more treatment in the course of a year. That's fundamental data. You're not going to find that in literature.

Yeah, Jason Thanks for the question.

Thank you for highlighting a really important point, so what we know about MTBE and there's been many studies from us and others is that the earlier you diagnose and more rapidly.

You get people better bet.

Over the longer term outcomes for depression, and other comorbidities, such as cardiovascular disease, and diabetes and Theres literature from for many let's talk about the downstream effects of not treating of person with depression rapidly get them better.

Steve Kaines: And this is part of what we're doing, creating both a new approach to treatment as well as the foundational data that's necessary in order to make wise treatment choices. So that's why Shoreline is so important. And, you know, there's a lot there. Those are, from my perspective, those are the things that are really most important for this program to progress. Thank you. See you.

<unk>.

Let's talk about the scatter meeting some of the health economic data.

Data that's out there about.

Not putting people on black benefits of treating people early and getting a better faster.

Operator: Thank you, guys. Thank you. Our next question or comment comes from the line of Andrew Tsai from Jeffries. Your line is open.

I mean, the most important I mean, let's start with patients first everyone wants to get better quickly that's kind of the goal of all medicine Theres a few things we know with depression, though which is the more quickly someone gets better the more likely they are to maintain those benefits regardless of what their treatment. So when we lean into getting patients better within a 2 week course of therapy that is very much.

Operator: Hi, good morning, and thanks for having me. So, my question is on coral. You know, as investors start to think about the likelihood of success and what the study could show at day 15, is it fair for us to assume the comparator arm, which is, you know, the typical SSRI, could essentially be viewed as a traditional placebo arm since, you know, SSRIs take six to eight weeks to work? Or does co-initiating with an SSRI still somehow change the calculus? And then, I, a corollary to that is, can, you know, as we think about day 42, could both arms improve on AMD as SSRIs start to kick in for some patients? Thanks.

Built on a well described phenomenon, which is get people better quickly and we know that we're gonna be able to get them back into their life their role functioning and be able to begin that.

Journey of of a true recovery right I mean, if there's 1 thing to have symptomatic improvement. It's another to have improvement in your role functioning and really looking at what that looks like for patients and from patient reported outcomes for something that's really important for.

For us.

No.

Operator: Andrew, thanks for that question. I'm going to ask Steve to talk about our, The rest of the experience is out to multiple step dosing, so I'll answer that question for an improved drug. But let me say this, Coral, as you highlighted, is asking an important question. What happens when we co-administer an antidepressant with patients who have geranium?

Those impacts are ones that we're really looking we're willing to to get out into the real world. Both from the waterfall study, but more importantly from landscape with regard to.

With regard to other drugs, including.

Academy.

Well there are reports of very early onset.

Statistical significance on differences in this drug is really after multiple multiple treatments.

Barry E. Greene: And the data we have today are patients on some of the safest doses of antidepressants. These are not patients that you assume experience some of the horrific side effects that you might get from antidepressants. So we're asked a different question, and we should learn from Coral.

I would also pointed out that debt and to provide O. S. Ketamine. They are studying it very different patient population is important 1 wishes treatment resistant depression.

Our program is focusing on what I would what I would sometimes referred to as garden variety of depression patients, who don't necessarily have multiple multiple and very severe episodes, but still deserve the opportunity to get better and get back and get back on with their lives. So we're seeing faster onset as early as day 3.

Barry E. Greene: Now, I also say that, as SAGE has done each and every time, when we conduct clinical studies, we learn from those clinical studies, and we make adjustments to future studies based upon those lessons. So if there are adjustments to be made to Coral, we will make those adjustments and work with the agency on any necessary adjustments. But to your specific point, you're right. We do not expect that the antidepressant alone will confer any benefit for four to six weeks, but we may, in fact, see side effects earlier.

We're seeing for.

<unk> maintained benefit after a time limited therapy, 2 weeks and a really really positive benefit risk profile. We think this is something that when it's approved for really revolutionized the treatment for many people I'd only add debt with greater than 30 drugs approved in the United States for M. D D.

Barry E. Greene: And that will be very interesting to date because, as Steve highlighted earlier, while we've seen somnolence and sleepiness, which are analogs, we have not seen things like weight gain, sexual dysfunction, GI upset, and some of the other side effects you see with antidepressants.

There are still upwards of 19 million people a year that have major depressive episodes. So.

As much as people view this as something that's relatively straightforward to treat the unmet need is enormous and we think everybody deserves to get better quickly and get back on it and get back on their feet.

Steve Kaines: So hopefully that's helpful, and Steve, maybe you could talk about how, you know, arms might come together in multiple weeks after similar patients on another drug. Oh, absolutely. We don't contest that antidepressants, when given over the course of several weeks, may actually demonstrate benefit. And just like in our other clinical trials, we do know that patients, over time, may improve even in the placebo arm. So we're not looking, as we haven't, for placebo drug differences out through day 42, especially not in coral.

Alright.

Thank you Jay and that all the data out there support.

Steve just said we know that.

Patients debt.

Have recurring depression that are treated on multiple medicines and stay depressed for long periods of time go on to develop diabetes go on for adult cardiovascular disease, and other comorbidities, which.

Not only hurt that individual but.

And cost of the whole health care system.

We were listening to.

Steve Kaines: Recall, this study is looking to address a very particular use case, which is, how do you jump-start therapy when you co-initiate an antidepressant with SAGE 217s or antelope with an antidepressant? In oncology, they call that induction with maintenance. How do you get people to get better more quickly?

1 of the Wall Street analysts on a on a panel sales were kols that these data are remarkable on when you give them for my patients where they need to get better faster.

And when asked well, which patients don't need to get better faster.

That physicians have been dumped on it so everybody deserves to get better faster.

Super helpful. Thank you very much.

Thank you next question or comment comes from the line of <unk> Kulkarni from Canaccord. Your line is open.

Steve Kaines: And so we're looking at those early time points that have shown consistent differentiation from placebo or any other drug that's available at day 3, day 8, day 12, day 15, you know, really early on. You know, are there nonspecific effects that we need to take into account? Of course. I mean, we do that through the powering. We do that through the conduct of the trial and so forth. But we do think that if the study is successful, it'll add just yet another use case where patients may or physicians may want to choose this as a treatment option.

Good morning, Thanks for taking my question, we've seen the durability and response data within potential real world use of different antelope, there anything, particularly from a safety perspective that might limit. The immediate second 14 day course of therapy. That's required I guess asked another way. This goes back to why a 14 day period was chosen as the first place and what's the longest continuous Cpus.

Net personnel on might be from us I can nitpick perspective.

Yeah, Let me, let me start and.

And then ask Steve to comment so.

The science behind is around alone was a beliefs that debt.

Steve Kaines: And, you know, the technicalities of it are obvious. We plan for success, and we ensure that the powering is adequate to show this difference. Very helpful caller, thank you guys. Thank you. Our next question or comment comes from the line of Laura Chico from Wedbush. Your line is open.

In depression.

We can buy targeting positive.

Allosteric modulator Gaba a debt, we can reset patients to kind of an enormous of state kind of rewire. The brain architecture. So at least from going on because it was going to be of short duration therapy, not a chronic therapy that's from paradigm shifts.

Operator: Good morning. Thank you very much for taking the time to answer my question. I have one on Zoranolone and PPD. So the Phase 3 JAMA paper shows a higher proportion of patients with symptom onset during the third trimester versus the Zolreso studies. And it seems like a bit of a shift in diagnosis, but not much time has elapsed between when the Zoranolone PPD and Zolreso PPD studies were conducted. So with Skylark pushing back, I'm just wondering if you can comment on whether you think these are more permanent changes in the PPD landscape.

We're talking about here. So what we've seen now are patients treated for 2 weeks to get better faster and the shoreline data for <unk>. Thus.

Thus far about how often recruitment is required so.

We have top studies that have.

No animals on for longer term without other military respect but.

The adverse event profile has been consistent in fact improves over time as patients are retreated. So we think of this as kind of a.

Treat as needed therapy.

Operator: It's interesting because you're seeing elevated depression rates elsewhere but not in postpartum depression. So I guess the question here is, how does this impact, one, on your PPD submission strategy? But then also, how do you see this playing out in a commercial environment in terms of maybe who might be the primary point of care for Zoranolone? Thanks.

And Steve mentioned this earlier on the call. This is very important.

When.

When patients often go off anti depressants.

Typical anti depressants and they're off drug they know they're off drug on the ultimate.

Seek to get back on growth.

Shoreline data with patients off drug and C pilot and it's earlier.

And they stayed debt so they're not seeking to get back on drug even though they're they're they're off drugs. So we believe that.

Operator: Yeah, Laura, thank you. There are a few different questions in there.

As patients need a 2 week therapy to be able to get additional 2 weeks therapies kind of in the real world.

Barry E. Greene: So let me try to unwind it and get some help from Steve here. So, you know, thank you for highlighting the paper. We're really proud of the Robbins study. And as I highlighted in my prepared remarks, it's just a beautiful paper and a paper that really reflects just how well xeraniline works in these moms with PPD. Let me start with the commercial landscape.

Steve anything to add.

Just just to speak specifically to your question there is.

I can't obviously, we don't on the label yet we've been starting to make therapy, because when we do the modeling and I know we've talked about this before most of the improvement happens within the first week bye.

By the end of 2 weeks were really starting to show.

Some incremental improvements, but you know really if patients are doing well on and of course.

Barry E. Greene: So if we're fortunate with our successful waterfall profile, as we expect for the agency, and we get an indication for both MDD and PPD, which is what we expect, we will be reaching out and making sure that all moms, particularly those with risk factors, have a plan. And every mom, as you know, has a plan for when her water breaks; she knows where her bag is, who's taking her in, who her physician's going to be, where she's giving birth.

These are really I just wanted to point this out and you guys can do.

And it can go into your research, but these are remarkable data, we're seeing 80% responses.

Somewhere between 40, and 50% for emissions, you're not seeing that.

With any drug let alone after of course for a limited course of therapy and so.

For Us this is really transformative and part of what was so exciting about the program. When we're getting started is the opportunity to then use these data to think differently about the treatment paradigm.

Barry E. Greene: But almost no moms have a plan for being depressed, you know, a week, two months, three months after the baby is born. So we're going to make sure that we work with patient advocates, we work with OBGYNs, we work with the psychiatry community to ensure that all moms have a plan after giving birth. That is probably broader than just depression symptoms. There are other health concerns that moms have after

[noise] addresses patients' needs and wants to get better and not necessarily keep taking medication forever. So.

Assuming the drug is approved.

We could potentially think about other kinds of dosing schemes. This already is is a really important and we've seen it.

Very consistent in terms of actually very consistent in terms of safety in study after study after study.

And quite frankly, the time limited aspect of this is what got the FDA is Texas, while we have breakthrough in the first place. Its a concept that I think will really add something unique to the to the.

Barry E. Greene: So we will be aggressive in ensuring that moms with depression have access to Ritalin. We've heard some KOLs actually say that with certain mothers with risk factors, they intend for those moms to actually leave the hospital with a scripted hand in case depressive symptoms come up. So I think we'll be well prepared there.

Treatment toolbox for patients with depression.

Got it thanks.

Yes.

Thank you.

Time for 1 final question. Our final question comes from the line of Gary Nachman from BMO capital markets. Your line is open.

Hi, Thanks for taking my questions Evan Clark on them for a gain margin I just had a quick question. So for Sage 689 in space and on are for programs are there any specific or potential indications you would be looking to target some color around that would be great price.

Steve Kaines: Steve, you want to talk about the honeymoon differences that Laura highlighted? Oh, sure. So, Laura, you know, I'm glad you did the close reading. We've always included patients that had an onset during the third trimester.

Yes, thanks for the question.

Steve you want to take that.

Sure core Fernanda for where obviously you know we usually start at the highest level you look for disorders, where there's known or suspected EBITDA.

Steve Kaines: So we think there are a few things that are going on. One of them is that with the approval of Zolresto, there's been a heightened awareness among treaters both to identify and diagnose patients. And that, I believe, is being reflected in the ability to at least identify patients prior to being treated. Importantly, we are not enrolling patients in the study despite when their diagnosis was made until a full month after delivery.

Hypofunction and for 71.8 were looking at neuro degenerative disorders. Fernando for we think this may very well be beneficial for their developmental disorders, whether that'd be.

Autism or schizophrenia, or other places for other disorders, where theres cognitive.

Where there's cognitive impairments and executive function does it a little bit different from.

From neuro degeneration, so that.

Those are areas that we're looking at it as we understand more about the drug will be more specific.

Steve Kaines: That's to ensure that we're not medicalizing sort of the normal changes in mood immediately after delivery. I mean, people have to have their onset of symptoms, and they have to be maintained for several weeks, four weeks plus, for them to really be appropriate for a diagnosis of MDD. And that's really important for us.

For 69, just a rapid onset parenteral drug injectable now it could be it could be formulated in lots of ways. So we're looking at places where rapid onset of Gaba positive modulation may very well be helpful. So the kinds of things we've talked about RSA agitation, where we know there remains an unmet need whether it would be an emergency.

Steve Kaines: I mean, unless those symptoms remain, they're not MDD. So we think there's awareness, screening, attention, and a bit of know-how on how to identify these patients. And that's important.

Things are for people with severe dementia. Likewise, there is a potential interest in areas like severe migraine or other places where people may come in for a.

Steve Kaines: With regard to the epidemiology, well, we know a few things. One, rates of depression are way up. We also know that births are down. And we also surmise, based on discussions with investigators and key opinion leaders, that new moms are much more reluctant to come into care during the pandemic.

Very rapid.

On responses, so lots can be driven by the by the results for the phase 1 and where we are in terms of other benefit risk, but we're looking to identify differentiated molecules and then develop them in very different ways to look for the molecules we have already.

Thanks, Steve.

Thank you at this time I'd like to turn the conference back over to Mr. Barry Greene for any closing remarks.

Thank you and thanks, everyone for joining us this morning, I'm thrilled for the substantial progress we've made in the first half of 2021 with several milestones achieved on our mission to become the leader in brand now.

Steve Kaines: So all of those factors taken together speak to, one, the importance of a portable treatment, a modern treatment, a time-limited treatment that doesn't require people coming into a center, as well as the ongoing work related to the Skylar study. So, you know, as much as it's disappointing to change the timeline, the importance of the work remains, and we're really looking forward to getting that study over the finish line. I would also add that as part of our following strategy, we do intend to discuss the utility of our current package for getting both an MDD and a PPD label. So all of that is part of our current approach based on the outcomes from the JAMA psychiatry paper. Thanks, Chris.

As shown on the serious business for example, a recent study noted that up to 31% of people with MVD have attempted suicides and.

In our depression, neurology and neuropsychiatry franchises from potential helped millions we're taking on diseases that have massive impacts on people families society and generations and were committed to getting it right even in the face of Maine.

A major paradigm shift and major expectation changes and let me just put this out there many of US are getting prepared to send kids back to college and on certain times. If you have a daughter and fingers sophomore year and you discover that she hasn't left room for a couple of weeks and you're fortunate enough to get her health and she gets a diagnosis.

Steve Kaines: Thanks for watching. Thank you. Our next question or comment comes from the line of Jay Olson from Oppenheimer. Your line is open.

Major depressive disorder would you honor on a typical antidepressants that might be for 6 weeks to work with unknown side effects potentially losing per semester per year for potentially for whole college career would you rather have run on drugs is a better after 1 or 2 doses back in classes.

Operator: Thank you for taking the questions. We appreciate the importance of a rapid response in MDD, which you described earlier. Can you talk about how an early response correlates with positive longer-term outcomes in MDD and also comment on how the onset of response for zaranolone compares to other novel antidepressants such as esketamine? Thank you. Yeah, Jay, thanks for the question and really thank you for highlighting a really important point.

Which 1 I would say so that's what we're focused on despite some of the feedback we're hearing initially.

<unk> of the Sage seamless year assets up for several potential near mid and long term sales the rest of the year and into 2022.

Barry E. Greene: So what we know about MDD, and there have been many studies from us and others, is that the earlier you diagnose and the more rapidly you get people better, the better their longer-term outcomes for depression and other comorbidities such as cardiovascular disease and diabetes. And there's literature from many that talk about the downstream effects of not treating a person with depression quickly to get them better faster. Let's talk about ascetamines and some of the health economic data that's out there about not treating people, or, in fact, the benefits of treating people early and getting them better faster.

Safety will continue to work tirelessly to deliver on our vision of bringing medicines that matter for patients so they get better sooner and stay better longer.

Again and have a great day everyone.

Ladies and gentlemen, thank you for participating on today's conference. This concludes the program you may now disconnect everyone have a wonderful day.

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Barry E. Greene: Yeah, I mean, the most important thing is that let's start with patients first. Everyone wants to get better quickly. That's kind of the goal of all medicine. There are a few things we know with depression, though, which is the more quickly someone gets better, the more likely they are to maintain those benefits, regardless of what their treatment is. So when we lean into getting patients better within a two-week course of therapy, that very much builds on a well-described phenomenon, which is getting people better quickly.

Barry E. Greene: And we know that we're going to be able to get them back into their life, their role functioning, and be able to begin that journey of true recovery, right? I mean, there's one thing to have symptomatic improvement; it's another to have improvement in your role functioning. And really looking at what that looks like for patients and from patient reported outcomes is something that's really important for us. You know, so those impacts are ones that, you know, we're really looking to get out into the real world, both from the waterfall study and, more importantly, from landscape.

Steve Kaines: With regard to, you know, with regard to other drugs, including esketamine, while there are reports of very early onset, you know, the real statistical significance, you know, differences in this drug are really after multiple, multiple treatments. I would also point out that in Spravato esketamine, they're studying a very different patient population, an important one, which is treatment-resistant depression. You know, our program is focusing on what I would sometimes refer to as garden-variety depression patients who don't necessarily have multiple, multiple, and very severe episodes but still deserve the opportunity to get better and get back on with their lives. So, we're seeing faster onset as early as day three.

Steve Kaines: We're seeing, you know, maintained benefit after a time-limited therapy, two weeks, and a really, really positive benefit-risk profile. We think this is something that, when it's approved, will really revolutionize treatment for many people. I'd only add that, you know, with more than 30 drugs approved in the United States for MDD, there are still upwards of 19 million people a year that have major depressive episodes. So, you know, as much as people view this as something that's relatively straightforward to treat, the unmet need is enormous, and we think everybody deserves to get better quickly and get back on their feet. Thank you. And Jay, all the data out there support what Steve just said.

[music].

Barry E. Greene: We know that patients that have recurring depression, that are treated with multiple medicines and stay depressed for long periods of time, go on to develop diabetes, go on to develop cardiovascular disease, and other comorbidities, which not only hurt that individual but add cost to the whole healthcare system. And we were listening to one of the Wall Street analysts on a panel of CLLs where KLL said, these data are remarkable. I'm going to give them to my patients that I need to get better faster. And when asked, well, which patients don't need to get better faster? That physician was a bit dumbfounded.

Steve Kaines: So everybody deserves to get better faster. Very helpful. Thank you very much.

Operator: Thank you. Our next question or comment comes from the line of Sumant Kulkarni from Canaccord. Your line is open.

Operator: Good morning. Thanks for taking my question. We've seen the durability and response data, but in potential real-world usage of Zoranolone, is there anything, particularly from a safety perspective, that might limit an immediate second 14-day course of therapy if that's required? I guess, asked another way, this goes back to why a 14-day period was chosen in the first place and what the longest continuous safe use period for Zoranolone might be from a regulatory perspective.

Barry E. Greene: Yeah, let me start and then ask Steve about the comments. So the science behind Zoranolol was a belief set that in depression, we can, by targeting positive and allosteric receptiveness with modulating GABA-A, we can reset patients to kind of a normative state, kind of rewire the brain architecture. So the belief that was going on was that it was going to be a short-duration therapy and not a chronic therapy. That's the paradigm shift.

Barry E. Greene: So, what we've seen now are patients treated for two weeks; they get better faster, and the Shoreline data provides evidence thus far about how often retreatment is required. We have top studies that have animals on for longer terms without other deleterious effects, but the adverse event profile has been consistent, in fact, improved over time as patients are retreated. So, we think of this as a treat as needed therapy, and Steve mentioned this earlier on the call, and this is very important because when patients often go off antidepressants. We believe that as patients need the two-week therapy, they'll be able to get additional two-week therapy in the real world. Need anything to add?

Steve Kaines: Yeah, just to speak specifically to your question, you know, there is, you know, I can't, obviously, we don't have a label yet. We've been studying two weeks of therapy because when we do the modeling, and we've talked about this before, most of the improvement happens within the first week. By the end of two weeks, we're really starting to show, you know, some incremental improvements, but, you know, really, patients are doing well. And, and, of course, I just want to point this out, and you guys can, you know, can go and do your research, but these are remarkable data. You know, we're seeing 80% responses and, you know, somewhere between 40 and 50% remissions. You don't see that with any drug, let alone after a limited course of therapy.

Steve Kaines: And so, you know, for us, this is really transformative. And part of what was so exciting about the program when we were getting started is the opportunity to then use these data to think differently about a treatment paradigm that addresses patients' needs and wants them to get better and not necessarily keep taking medication forever. So, you know, assuming the drug is approved, we'll, we can potentially think about other kinds of dosing schemes. This already is really important, and we've seen it, you know, very consistent in terms of actually very consistent in terms of safety and study after study after study.

Steve Kaines: And quite frankly, the time-limited aspect of this is what got the FDA's attention and why we have breakthrough in the first place. It's a concept that I think will really add something unique to the treatment toolbox for patients with depression. Got it, thanks.

Operator: Thank you. Thank you. We have time for one final question. Our final question comes from the line of Gary Machman from BMO Capital Markets. Your line is open. Hi, thanks for taking my questions. This is Edmond Hua filling in for...

[music].

Operator: I just had a quick question. So for the SAGE 689 and SAGE 904 programs, are there any specific or potential indications you would be looking to target? Some color around that would be great.

Steve Kaines: Yeah, thanks for the question. Steve, do you want to take that? Sure. For 904, you know, we're obviously, you know, we usually start at the highest level. We look for disorders where there's known or suspected NMDA hypofunction. And for 718, we're looking at neurodegenerative disorders. For 904, we think this may very well be beneficial for neurodevelopmental disorders, whether that be autism or schizophrenia or other places or other disorders where there's cognitive impairment and executive function deficits, a little bit different from neurodegeneration. So those are areas that we're looking at. And, you know, as we understand more about the drug, we'll be more specific. For 689, this is a rapid-onset parenteral drug. It's injectable now.

Steve Kaines: It could be formulated in lots of ways. So we're looking at places where rapid onset of GABA positive modulation may very well be helpful. So the kinds of things we've talked about are, say, education, where we know there remains an unmet need, whether it be in emergency settings or for people with severe dementia. Likewise, there is a potential interest in areas like severe migraine or other places where people may come in for and need very rapid responses.

Steve Kaines: So a lot can be driven by the results of phase one and where we are in terms of our benefit risk, but we're looking to identify differentiated molecules and then develop them in very different ways than the molecules we have already.

Barry E. Greene: Thank you. This time I'd like to turn the conference back over to Mr. Barry Greene for any closing remarks. Thank you and thank you to everyone for joining us this morning. I'm thrilled with the substantial progress we've made in the first half of 2021, with several milestones achieved on our mission to become a leader in brain health. As you all know, this is serious business. For example, a recent study noted that up to 31% of people with MDD have attempted suicide, and our depression, neurology, and neuropsych franchises have potentially helped millions.

Barry E. Greene: We're taking on diseases that have massive impacts on people, families, society, and generations. And we're committed to getting it right, even in the face of... major paradigm shifts and major expectation changes. And let me just put this out there. Many of us are getting prepared to send kids back to college in uncertain times. If you have a daughter entering her sophomore year and you discover that she hasn't left the room for a couple weeks, and you're fortunate enough to get her help, and she gets a diagnosis of major depressive disorder, would you want her on a typical antidepressant that might take four to six weeks to work with unknown side effects, potentially losing her semester, her year, or potentially her whole college career? Would you rather have her on a I know which one I would choose.

Barry E. Greene: So that's what we're focused on, despite some of the feedback we're hearing initially. The achievements of the SAGE team this year have set us up for several potential near, mid, and long-term catalysts throughout the rest of the year and into 2022. The SAGE team will continue to work tirelessly to deliver on our vision of bringing medicines that matter to patients so they can get better sooner and stay better longer.

Barry E. Greene: Thanks again, and have a great day, everyone. Bye. Ladies and gentlemen, thank you for participating in today's conference. This concludes the program. You may now disconnect. Everyone, have a wonderful day!

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