Q2 2022 SAGE Therapeutics Inc Earnings Call

August 2, 2022

The conference will begin shortly to raise your hand during Q&A you can dial star one one.

The conference will begin shortly.

[music].

Okay.

Good morning, welcome to Sage Therapeutics second quarter 2022 financial results Conference call.

Currently all participants are in listen only mode.

To raise your hand during Q&A, you can dial star 11.

This call is being webcast live on the investors and media section of Sage's website, its age Rx 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'd now like to introduce Helena Rubinstein director of Investor Relations at Sage.

To raise your hand during Q&A, you can dial star 1 1.

Thank you for participating.

Good morning, and thank you for joining Sage Therapeutics second quarter 2020 financial results conference call before we begin I encourage everyone to go to the investors and media section of our website.

<unk> Com, where you can find the press release related to today's call as well as the slides.

Supplemental detail.

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

Statements are subject to certain risks and uncertainties and our actual results may differ materially. Please consult the risk factors discussed in today's press release and in our SEC filings for additional detail.

We will begin the call with prepared remarks by Barry Greene, Our Chief Executive Officer, who will provide an overview of our progress during the second quarter.

We will also be joined by Al Robichaud, Our Chief Scientific Officer, who will review recent progress and development activities across our program.

Christopher <unk>, our Chief business Officer, who will provide an update on our progress preparing for the launch of the ran on an entity in CPD, if approved and Kimi Iguchi, Our Chief Financial Officer will review the financial results from the quarter with that I'll now turn the call over to Barry.

Good morning.

វាសនានិត្រ្រ្រាប់។ វាស់ប្រាប់។ ...

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

Good morning.

The first half of 2022 was important for Sage as we continued our focused execution across our pipeline.

We started the year by meeting our goals and achieving expected milestones on or ahead of plan timelines.

We have a tremendous sense of urgency to create innovation and meaningful medicines for people, who currently lack adequate treatment options.

Our goal is to decrease disability and suffering while improving the health and productivity of people their families and health care system.

We're making progress across the entire company as we work to further establish stage as a leader in brain health and a top tier biopharmaceutical company.

I'd like to now take a moment to review our progress in the second quarter and offer some context as to how we are thinking about the future of sage.

Welcome to Sage Therapeutics' second quarter 2022 financial results conference call. Currently, all participants are in listen-only mode.

This call is being webcast live on the Investors and Media section of Sage's website at sagerx.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.

I'd now like to introduce Helen Rubenstein, Director of Investor Relations at Sage.

Good morning, and thank you for joining Sage Therapeutics' second quarter 2022 financial results conference call.

Before we begin, I encourage everyone to go to the Investors and Media section of our website at sagerx.com, where you can find the press release related to today's call, as well as the slides that contain supplemental details.

Starting with the depression franchise, we and Biogen recently announced positive results from the phase III Skylark studies evaluating <unk> alone and women with postpartum depression or PPD.

Chris Binecki, our Chief Business Officer, will provide an update on our progress preparing for the launch of the RAN alone in MDD and PPD, if approved.

I'd like to point out that we will be making forward-looking statements, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. Please consult the risk factors discussed in today's press release and in our SEC filings for additional details.

We believe the totality of the data generated with <unk> alone support the potential of <unk> alone as a rapidly acting.

Generally well tolerated oral therapeutic to treat major depressive disorder, or <unk> as well as PPD with sustained effect.

People with depression deserve new treatment options. We believe is around alone has the potential to deliver that important new options.

With the placebo controlled studies of <unk> alone and <unk> reported.

We will begin the call with prepared remarks by Barry Green, our Chief Executive Officer, who will provide an overview of our progress during the second quarter.

We are focused on completing the NDA filing for <unk> alone, which you announced the start of in May as a rolling submission.

We will also be joined by Al Robichaud, our Chief Scientific Officer, who will review recent progress in development activities across our program.

As we've shared our NDA will include both MVD MPD and one filing.

And we believe this is an exciting opportunity to accelerate our planned submission in PPD, providing the opportunity to brings around alone to people with mbd in PPD as efficiently as possible.

Our planned filing timeline.

If we received priority review provides us a possible <unk> date for <unk> in the third quarter of 2023.

Work is well underway and on track for the potential launch of is around alone in MTBE in PPD.

Chris Benneke, our Chief Business Officer, will provide an update on our progress preparing for the launch of the RAN alone in MDD and PPD, if approved.

And Kimi Iguchi, our Chief Financial Officer, will review the financial results from the quarter.

With that, I'll now turn the call over to Barry.

Strategically, we're thinking big about the opportunity in both <unk> and PPD as we develop a focused launch plan, which we expect to scale with success.

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

The first half of 2022 was important for Sage as we continued our focused execution across our pipeline. We started the year by meeting our goals and achieving expected milestones on or ahead of planned timelines.

<unk> successfully will need to continue to deepen our engagement with key stakeholders around the profound unmet need that exists for those living with <unk> and PPD.

We have a tremendous sense of urgency to create innovation and meaningful medicines for people who currently lack adequate treatment options. Our goal is to decrease disability and suffering while improving the health and productivity of people, their families, and the health care system.

We're making progress across the entire company as we work to further establish Sage as a leader in brain health and a top-tier biopharmaceutical company.

We plan to educate payers on the <unk> value proposition, which is supported by the weight of the clinical evidence from the landscape in this program.

Lastly, we expect to further build internal capabilities intended to enable strong launch execution.

We believe that if we continue to successfully act on these items and execute on our launch plans.

Clinicians will prescribes ran alone and <unk> and PPD with the sense of urgency.

Patients with <unk>, and PPD will astra's around alone and payers will enable access to this critically needed treatment. All of this is important to both indications are approved.

To further support these preparations we announced this morning that CRISPR Nike has been promoted to Chief business Officer, Chris.

I'd like to now take a moment to review our progress in the second quarter and offer some context as to how we are thinking about the future of Sage.

Chris will provide more details on our ongoing commercialization preparation efforts later in the call.

Additionally, we made progress during the quarter in our neuroscience franchise led by Sage 718.

Wholly owned first in class NMDA Pam.

As you know Sage 718 is being developed as a potential oral therapy for certain cognitive disorders, starting with Neurodegenerative diseases, specifically, huntington's disease, Parkinson's disease, and Alzheimer's disease.

Impaired cognition is a significant morbidity of these diseases and you can have a dramatic impact on people's ability to live life independently and to thrive.

We're committed to advancing the <unk> program with the goal of further demonstrating its therapeutic potential and novel approach.

Our neurology franchise led by Sage three to four is being evaluated as a potential treatment for people suffering from a central tremor and other neurological disorders.

Movement disorders can make the simplest activities of daily life difficult if not impossible.

We enter collaboration partner Biogen believe based on the data seen to date with the potential to make a meaningful impact on the ability of those living with the central tremor to fulfill activities of daily living.

We have made encouraging progress across all our therapeutic areas in the second quarter and to date.

Closer to delivering our science to patients and creating value for society.

Ultimately advancing our mission to Fearless would lead the way to create a world with better brain health. So every person can thrive.

I want to thank the entire sales team the patients in our clinical studies and their families. All of those involved in running clinical studies and our collaborators for the hard work and dedication.

The next 18 months will be pivotal for us as we continue to execute on our <unk> program and across our broader pipeline.

And we're excited for the journey ahead.

Even in these extraordinary times I'm confident we can deliver the next chapter in our success.

And Kimi Iguchi, our Chief Financial Officer, will review the financial results from the quarter.

With that I'll turn the call over to al for more detailed discussion of our portfolio progress and current clinical expectations.

With that, I'll now turn the call over to Barry.

<unk>.

Thanks, Barry and good morning, everyone.

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

As Barry mentioned, we made important pipeline progress during the second quarter I am pleased to detail our advances as well as comment on our early development programs.

The first half of 2022 was important for SAGE as we continued our focused execution across our pipeline. We started the year by meeting our goals and achieving expected milestones on or ahead of planned timelines.

We're making progress across the entire company as we work to further establish SAGE as a leader in brain health and a top-tier biopharmaceutical company.

Starting with our depression franchise, we announced in early June that the Skylark study of Zarate alone 50 milligrams and postpartum depression met its primary endpoint of change from baseline in AMD 17 total score at day 15, compared to placebo and all key secondary endpoints changed from baseline in <unk> 17 total score phase III.

I'd like to now take a moment to review our progress in the second quarter and offer some context as to how we are thinking about the future of SAGE. Starting with the depression franchise, we in Biogen recently announced positive results from the Phase 3 Skylark study evaluating xeronalone in women with postpartum depression or PPD. We believe the totality of the data generated with xeranolone support the potential of xeranolone, as a rapidly acting, generally well-tolerated oral therapeutic to treat major depressive disorder, or MDD, as well as PPD, with sustained effect.

Starting with the depression franchise, we in Biogen recently announced positive results from the Phase 3 Skylark study evaluating xeronalone in women with postpartum depression, or PPD. We believe the totality of the data generated with xeronalone support the potential of xeronalone as a rapidly acting, generally well-tolerated oral therapeutic to treat major depressive disorder, or MDD, as well as PPD, with sustained effects. People with depression deserve new treatment options. We believe xeronalone has the potential to deliver that important new option, to date.

We're closer to delivering our science to patients and creating value for society, ultimately advancing our mission to fearlessly lead the way to create a world with better brain health so every person can thrive.

I want to thank the entire SAGE team, the patients in our clinical studies, their families, all those involved in running clinical studies and our collaborators for the hard work and dedication.

The next 18 months will be pivotal for us as we continue to execute on our Xeranlin program and across our broader pipeline, and we're excited for the journey ahead.

Even in these extraordinary times, I'm confident we can deliver the next chapter in our success.

People with depression deserve new treatment options. We believe xeranolone has the potential to deliver that important new option.

With that, I'll turn the call over to Al for a more detailed discussion of our portfolio progress and current clinical expectations.

With the placebo-controlled studies of xeranolone in MDD and PPD reported, we are focused on, completing the NDA filing for xeranolone, which we announced the start of in May as a rolling submission. As we've shared, our NDA will include both MDD and PPD in one filing, and we believe, this is an exciting opportunity to accelerate our planned submission of PPD, providing the opportunity to bring xeranolone to people with MDD and PPD as efficiently as possible.

Al?

Our planned filing timeline, if we receive priority review, provides us a possible PDUFA, date for xeranolone in the third quarter of 2023. Work is well underway and on track for the potential launch of xeranolone in MDD and, PPD.

Strategically, we're thinking big about the opportunity in both MDD and PPD as we develop, a focused launch plan, which we expect to scale with success.

To launch successfully, we'll need to continue to deepen our engagement with key stakeholders, around the profound unmet need that exists for those living with MDD and PPD.

28% to <unk> 45, compared to placebo as well as change from baseline in the CGI S score at day 15.

We plan to educate payers on the xeranolone value proposition, which is supported by the, weight of the clinical evidence from the Landscape and NEST programs.

Lastly, we expect to further build internal capabilities intended to enable strong launch, execution.

Notably <unk> 50 milligrams demonstrated a statistically significant and clinically meaningful reduction in depressive symptoms compared to placebo as measured by change from baseline <unk> 17 at day 15 of four points and a corresponding P value of zero.

We believe that if we continue to successfully act on these items and execute on our launch, plans, clinicians will prescribe xeranolone in MDD and PPD with a sense of urgency, patients with MDD and PPD will ask for xeranolone, and payers will enable access to this critically needed treatment. All of this is important if both indications are approved.

To further support these preparations, we announced this morning that Chris Bennecke, has been promoted to Chief Business Officer.

Chris will provide more details on our ongoing commercialization preparation efforts later, in the call.

007.

These results are remarkable and reinforced the data observed across is around our own clinical development program in which treatment with <unk> resulted in a rapid reduction in depressive symptoms that was sustained throughout the follow up period with a generally will color the safety profile.

Skylark study underscores the potential was around alone to be an important differentiated therapy, if approved and completed the placebo controlled trials in both our landscape and this programs and NPD in PPD.

We also presented data from our human abuse potential study with <unk> alone in the second quarter and this study is around 130 milligram and 60 milligram doses in the therapeutic range demonstrated lower abuse potential compared with alprazolam, one five milligrams and three milligrams and 90 milligrams is around alone was.

Comparable to alprazolam these.

These data all of our clinical data support viable medical use and lower like ability and abuse potential was around alone.

We do expect that's around the world will be a schedule for drug if approved findings from our market research has shown that clinicians are both experienced and comfortable prescribing scheduled for growth.

Thanks, Barry, and good morning, everyone.

I'd also like to highlight that we announced in early June that enrollment is complete and the shoreline study it was around and MDT shoreline is the largest naturalistic study done to date in depression and is examining as needed intermittent dosing over the course of one year.

As Barry mentioned, we've made important pipeline, progress during the second quarter.

I'm pleased to detail our advancements as well as comment on our early development programs. Starting with our depression franchise, we announced in early June that the Skylark study of Xeranlin 50 milligrams in postpartum depression met its primary endpoint, a change from baseline in HAMD 17, total score at day 15 compared to placebo, and all key secondary endpoints changed from baseline in HAMD 17, total score at days 3, 28, and 45 compared to placebo, as well as change from baseline in the CGIS score at day 15.

Notably, Xeranlin 50 milligrams demonstrated a statistically significant and clinically meaningful reduction in depressive symptoms compared to placebo as measured by change from baseline in HAMD 17 at day 15 of four points and a corresponding P value of 0.0007.

We recently presented data from the previous reported cohort of the choice study at the American Society of clinical Psychopharmacology annual meeting as.

These results are remarkable and reinforce the data observed across the Xeranlin clinical development program in which treatment with Xeranlin resulted in a rapid reduction in depressive symptoms that was sustained throughout the follow-up period with a generally well-tolerated safety profile.

The Skylark study underscores the potential for Xeranlin to be an important and differentiated therapy, if approved, and completes the placebo-controlled trials in both our Landscape and NIST programs in NDD and PPD.

We also presented data from a human abuse potential study with Xeranlin in the second quarter. In this study, Xeranlin 30 milligrams and 60 milligrams, both doses in the therapeutic range, demonstrated lower abuse potential compared with Alprazolam 1.5 milligrams and 3 milligrams, and 90 milligrams of Xeranlin was comparable to Alprazolam.

These data, along with our clinical data, support viable medical use and lower likability and abuse potential for Xeranlin.

We do expect that Xeranlin will be a Schedule IV drug, if approved. Findings from our market research have shown that clinicians are, both experienced and comfortable prescribing Schedule IV drugs.

As a reminder, in the 50 milligram cohort of the shoreline study, 80% of patients who responded to the initial two week treatment with Sorel and 50 milligrams only received one or two courses during their time in this year long study with a median time the second fleet recourse of 249 days.

I'd also like to highlight that we announced in early June that enrollment is complete in the Shoreline study of Xeranlin and MDD. Shoreline is the largest naturalistic study done to date in depression and is examining as-needed intermittent dosing over the course of one year. We recently presented data from the previously reported cohort of the Shoreline study at the American Society of Clinical Psychopharmacology annual meeting.

As a reminder, in the 50 milligram cohort of the Shoreline study, 80% of patients who responded to the initial two-week treatment with Xeranlin 50 milligrams only received one or two treatment courses during their time in this year-long study, with a median time for the second treatment course of 249 days.

These data support our belief that Zoranolone can have remarkable durability.

These data support our belief that surround alone can have remarkable durability. We look forward to sharing more data from <unk> clinical development program and key scientific forums over the next several quarters highlights specifically our upcoming data presentations at the 2022 Psych Congress in September .

We look forward to sharing more data from the Zoranolone Clinical Development Program, in key scientific forums over the next several quarters.

I'll highlight specifically our upcoming data presentations at the 2022 Psych Congress in, September.

In addition, we are sharing an update on both the rainforest and Redwood studies today as a reminder, the rainforest study was designed to investigate the efficacy and safety of 30 milligrams was railroad sleep architecture and MPD. The same objective primary endpoint measured in trials of insomnia disorders.

In addition, we are sharing an update on both the Rainforest and Redwood studies today.

As a reminder, the Rainforest study was designed to investigate the efficacy and safety of, 30 milligrams of Zoranolone on sleep architecture and MDD, the same objective primary endpoint measured in trials of insomnia disorders.

The Redwood study was designed to examine fixed-schedule intermittent dosing of 30 milligrams, of Zoranolone throughout the course of a year. This study was also designed to complement the Shoreline study, which examined the as-needed, intermittent dosing of Zoranolone.

Study was designed to examine fixed schedule intermittent dosing of 30 milligram of.

Zorana alone throughout the course of the year.

This study was also designed to complement the shoreline study, which examined the as needed intermittent dosing of <unk> base.

Based on our discussions with the FDA at the time, we suspended both the rainforest and Redwood studies in early 2020 before they were completed.

Based on our discussions with the FDA at the time, we suspended both the Rainforest and, Redwood studies in early 2020 before they were completed. These decisions were based on our plans to advance the program with a 50 milligram dose, of Zoranolone.

These decisions were based on our plans to advance the program with the 50 milligram dose of <unk>.

Furthermore, we believe and confirmed with the agency that neither study is needed to, support our NDA filing.

Furthermore, we believe and confirmed with the agency. Neither study is needed to support our NDA filing that said I'd like to share some high level findings from these studies.

That said, I'd like to share some high-level findings from these studies. Starting with the Rainforest study, although terminated early, the study provides important, insights on the potential effect of Zoranolone in the improvement of sleep parameters in patients with MDD. The study was not fully enrolled, with only 87 patients randomized. The rationality of the improvement in sleep architecture was clear, with Zoranolone 30, milligrams showing numerical advantage over placebo in objective measures of quality of sleep, including wake after sleep onset, total sleep time, latency to persistent sleep, median number of wakenings, median duration of wakenings, and endpoints involving REM sleep.

Starting with the rainforest study although terminated early.

<unk> provides important insights on the potential effect of the railroad and the improvement of sleep parameters in patients with <unk>.

The study was not fully enroll with only 87 patients randomized.

The rationality of the improvement in sleep architecture was clear with the railroad 30 milligrams showing numerical advantage over placebo and objective measures of quality asleep, including wake after sleep onset total sleep time.

Latency to persistently median number of awakenings medium duration of weakening and endpoints involving Rem sleep.

Insomnia is one of the most common symptoms associated with depression, and disturbances, of sleep are associated with decline in quality of life. It's very clear that improving sleep in depression is associated with better outcomes, making, the findings from our Rainforest study encouraging, as they suggest that Zoranolone may provide a sleep benefit to patients suffering with MDD.

It's on me as one of the most common symptoms associated with depression and disturbances asleep associated with the decline in quality of life.

It's very clear that improving sleep in depression is associated with better outcomes, making the findings from our rainforest study encouraging as they suggest that <unk> may provide a steep benefit to patients suffering with mbd.

If many antidepressants can negatively impact sleep architecture, this would be an exceptional, potential benefit of Zoranolone treatment.

As many of the process can negatively impact sleep architecture. This would be an exceptional potential benefit of Dorado and treatment.

We believe that data across the Zoranolone clinical development program, along with the, directional learnings from the Rainforest study, reinforce that Zoranolone's mechanism of action may address multiple aspects of depression, including the core depressive symptoms, as well as symptoms of anxiety and insomnia.

We believe that data across is that our own clinical development program all of the directional learnings from the rainforest study reinforce that <unk> mechanism of action may address multiple aspects of depression, including the core depressive symptoms as well as symptoms of anxiety and insomnia.

Turning now to the Redwood study the fixed schedule intermittent dosing of 30 milligrams of <unk>.

Turning now to the Redwood study, the fixed schedule intermittent dosing of 30 milligrams, of Zoranolone, 53 patients with MDD were enrolled in the open-label phase of the study, and two patients proceeded to the randomized phase before it was terminated.

53 patients with MTB were enrolled in the open label Phase of the study and two patients proceed into the randomized phase before it was terminated.

Given the low number of patients randomized, there isn't enough data from the Redwood study, to identify any trends.

Given the low number of patients random randomized.

Data from the Redwood study to identify any trends will.

What we can say is that no additional safety findings were reported.

But we can say is that no additional safety findings were reported.

In terms of re treatment, we do have data from another study in the clinical development program. The open label shoreline study and MTV that I mentioned earlier.

In terms of re-treatment, we do have data from another study in the clinical development, program, the open-label Shoreline study in MDD that I mentioned earlier.

We believe these data afford the closest real-world evidence we have to date on the, potential of Zoranolone therapy in the treatment of MDD may help guide patients and healthcare providers in treatment choices if Zoranolone is approved.

We believe these data afford the closest real world evidence evidence we have to date on the potential of <unk> therapy in the treatment of Mbd May help guide patients and health care providers and treatment choices.

<unk> is approved.

Additionally, in the shoreline study for those patients who use one or more re treatments efficacy and safety outcomes are similar to those observed in the initial treatment course.

Additionally, in this shoreline study, for those patients who used one or more re-treatments, efficacy and safety outcomes were similar to those observed in the initial treatment course.

We look forward to sharing the data collected from the Rainforest Study, as well as additional, data across the entire clinical development program at upcoming conferences.

We look forward to sharing the data collected from the rainforest study as well as additional data across the entire clinical development program at upcoming conferences.

Now I'd like to turn to our neuropsychiatric franchise led by Sage 701, eight our lead NMDA receptor positive allosteric modulator that is an investigational oral therapy being developed for certain disorders, where impairment of cognition is one of the main drivers of disability.

Additionally, we made progress during the quarter in our Neuropsych franchise led by, SAGE 718, a wholly owned, first-in-class NMDA PAM. As you know, SAGE 718 is being developed as a potential oral therapy for certain cognitive, disorders starting with neurodegenerative diseases, specifically Huntington's disease, Parkinson's disease, and Alzheimer's disease. Impaired cognition is a significant morbidity of these diseases and can have a dramatic, impact on people's ability to live life independently and to thrive.

Now I'd like to turn to our neuropsychiatric franchise, led by SAGE 718, our lead NMDA, receptor positive allosteric modulator that is an investigational oral therapy being developed for certain disorders where impairment of cognition is one of the main drivers of disability. SAGE 718 is one of our wholly-owned programs and was granted a Fast-Track designation by, the FDA as a potential treatment for cognitive impairment in Huntington's disease, or HD.

We're committed to advancing the SAGE 718 program with the goal of further demonstrating, its therapeutic potential and novel approach.

<unk> is one of our wholly owned programs and was granted fast track designation by the FDA as a potential treatment for cognitive impairment and huntington's disease or HD.

We also investigated SAGE 718 in people with mild cognitive impairment due to Parkinson's, disease, or PD, and people with mild cognitive impairment and mild dementia due to Alzheimer's disease, or AD. SAGE 718 data have been consistent in demonstrative improvement on important tests of executive, function across multiple open-label studies to date, including the paradigm and luminary studies in people with mild cognitive impairment due to PD and people with mild cognitive impairment and mild dementia due to AD, respectively. Additionally, in the placebo-controlled ketamine exposure study, subjects treated with SAGE, 718 demonstrated statistically significant improvement on several cognitive tests, including the two-back test compared to those treated with placebo at multiple time points.

We also investigated sage $700000 in people with mild cognitive impairment due to Parkinson's disease, or PD and people with mild cognitive impairment and mild dementia due to Alzheimer's disease or <unk>.

Phase <unk> data have been consistent and demonstrated improvement an important test of executive function across multiple open label studies to date, including the paradigm luminary studies in people with mild cognitive impairment due to PD and people with mild cognitive impairment and mild dementia due to 80, respectively.

Additionally, placebo controlled ketamine exposure study subjects treated with Sage 708 demonstrated a statistically significant improvement with several cognitive tests, including the two back test compared to those treated with placebo multiple time points.

And our HD clinical studies, we are making progress enrolling the phase II dementia study and the phase II surveyor study with people with HD cognitive impairment.

In our HD clinical studies, we are making progress in enrolling the Phase II dementia, study and the Phase II surveyor study in people with HD cognitive impairment. We believe the complementarity of these two studies will help us understand the potential, benefits of SAGE 718 in HD. The dementia study will evaluate the difference between treatment with SAGE 718 and placebo, on cognitive performance in Huntington's disease, and the surveyor study, on the other hand, will help us interpret the clinical meaningfulness of the cognitive effects observed in the dementia study.

We believe the complementarity of these two studies will help us understand the potential benefits of saved 708, an HD.

This study will evaluate the difference between treatment with Sage 708, and placebo on cognitive performance in Huntington's disease with severe study on the other hand will help us interpret the clinical meaningfulness of the cognitive effects observed in dementia study.

Basically, the surveyor study will help us to answer the so what question, as in, so, what do these cognitive effects mean for patients and activities of daily living, and what impact does SAGE 718 have on their everyday lives?

Basically the Sophia study will help us to answer the <unk> question. So what do these cognitive effects medium for patients and activities of daily living and what impact with Sage 708 have on their everyday lives.

Based on the results of the dementia and surveyor studies, we will consider opportunities to, engage with regulators with the goal, if our studies are successful, to bring SAGE 718 to people with HD cognitive impairment as quickly as possible, as there are no current therapies available today.

Based on the results of the dementia and surveyor studies, we will consider opportunities to engage with regulators with the goal. If our studies are successful to bring saved 708 to people with HD cognitive impairment as quickly as possible as there are no current therapies available today.

Turning to our other clinical programs and Neurodegenerative diseases enrollment and the precedent study a phase II placebo controlled study of Sage 718 people with mild cognitive impairment due to PD is going very well. We also remain on track to initiate a placebo controlled phase III study with <unk> 708, and people with mild cognitive impairment and mild.

Turning to our other clinical programs in neurodegenerative diseases, enrollment in, the precedent study, a Phase II placebo-controlled study of SAGE 718 in people with mild cognitive impairment due to PD, is going very well.

We also remain on track to initiate a placebo-controlled Phase II study with SAGE 718 in people with, mild cognitive impairment and mild dementia due to AD, planned to begin in late 2022.

Dementia due to a.

Planned to begin in late 2022.

We look forward to sharing data from studies complete with SAGE 718 to date at the upcoming, European College of Neuropsychopharmacology and American College of Neuropsychopharmacology annual meetings later this year.

We look forward to sharing data from studies complete with Sage 708 to date at the upcoming European College of Neuropsychopharmacology and American College of Neuropsychopharmacology annual meetings later this year.

Our neurology franchise, led by SAGE 324, is being evaluated as a potential treatment, for people suffering from essential tremor and other neurological disorders.

Lastly, I'd also like to highlight recent advancement in our neurology franchise led, by SAGE 324, a next-generation positive-alloceric modulator of GABA-A receptors, which we believe holds significant potential in the treatment of neurological conditions like essential tremor, or ET, a disease that has limited treatment options for patients and has had no innovation for over 50 years.

Lastly, I would also like to highlight recent advancements in our neurology franchise led by Phase III two four and next generation positive allosteric modulator of Gaba a receptors, which we believe hold significant potential in the treatment of neurological conditions like essential tremor, where ETE.

Disorders.

Movement disorders can make the simplest activities of daily life difficult, if not impossible. We and our collaboration partner, Biogen, believe, based on the data seen to date, we have the potential to make a meaningful impact on the ability of those living with essential tremor to fulfill activities of daily living.

We've made encouraging progress across all our therapeutic areas in the second quarter and to date. We're closer to delivering our science to patients and creating value for society, ultimately advancing our mission to fearlessly lead the way to create a world with better brain health so every person can thrive.

A disease that has limited treatment options for patients that had no innovation for over 50 years.

I want to thank the entire SAGE team, the patients in our clinical studies, their families, all those involved in running clinical studies, and our collaborators for the hard work and dedication.

We are pleased to announce that we have initiated our Phase 2 Long-Term Open Label Safety Study, with Phase 324 in ET. The aim of the study is to assess the long-term safety and tolerability of Phase 324 over, a multi-year period with the incidence of treatment emergent adverse events as a primary endpoint.

We are pleased to announce that we have initiated our phase two long term open label safety study with phase III two four in.

The aim of this study is to assess the long term safety and Tolerability of phase III two for over a multiyear period that the incidence of treatment emergent adverse events as a primary endpoint.

In addition, we are continuing to enroll in our phase <unk> kinetic two dose ranging study evaluating phase III for <unk> to optimize the dose and frequency and continue to expect enrollment completion to occur in late 2022.

In addition, we are continuing to enroll in our Phase 2B Kinetic Tube Dose Ranging Study, evaluating Phase 324 in ET to optimize the dose and frequency and continue to expect enrollment completion to occur in late 2022.

As with our other franchises, we look forward to sharing data from previously completed studies with phase III two four in the coming months, including our upcoming presentation at the international Parkinson and movement disorder Society annual meeting.

As with our other franchises, we look forward to sharing data from previously completed, studies with Phase 324 in the coming months, including in our upcoming presentation at the International Parkinson and Movement Disorder Society Annual Meeting.

To close for me, it's been a rewarding journey over the last decade and are proud of the team was moved this dynamic pipeline forward. We're excited about what's to come in the next 18 months and believe our organization is poised to continue building momentum generated in the first half of the year is one of the leaders in brain health.

To close, for me, it's been a rewarding journey of the last decade, and I'm proud of the team, who has moved this dynamic pipeline forward.

The next 18 months will be pivotal for us as we continue to execute on our Xeranlin program and across our broader pipeline, and we're excited for the journey ahead.

We're excited about what's to come in the next 18 months and believe our organization, is poised to continue building on the momentum generated from the first half of the year as one of the leaders in brain health.

Now I'll turn the call over to Chris to provide additional context on our planned approach, as we prepare for the potential commercialization of seranolone in MDD and PPD.

Now I'll turn the call over to Chris to provide additional context on our planned approach as you prepare for the potential commercialization of surround alone and Mgd and PPD Chris.

Chris?

Thanks, Al.

Thanks Al I am pleased to be with you. All this morning to share updates on our commercialization preparations for <unk> alone.

Even in these extraordinary times, I'm confident we can deliver the next chapter in our success.

I'm pleased to be with you all this morning to share updates on our commercialization, preparations for seranolone.

With that, I'll turn the call over to Al for more detailed discussion of our portfolio progress, and current clinical expectations.

Patients with depression urgently need new treatment options that are safe, we're quickly and offer lasting effects.

Al?

Adults with depression urgently need new treatment options that are safe, work quickly, and offer lasting effects.

Thanks, Barry, and good morning, everyone.

As Barry mentioned, we've made important pipeline progress during the second quarter.

An increase in the global prevalence of depression has been consistently reported since 1990, and approximately one in five adults in the United States will experience MDD at some point in their life. Current treatments for MDD and PPD are often not adequate to address the profound challenges, of treating depression.

An increase in the global prevalence of depression has been consistently reported since 19, 90% and approximately one in five adults in the United States will experience mbd at some point in their lives.

Current treatment through MVD and PPD are often not adequate to address the profound challenges of treating depression.

This, on top of more people seeking treatment for depression, a healthcare system that fails, to appropriately screen and assess, and a significant portion of the population failing to receive care. To put it simply, the current treatment paradigm relies on a try-and-fail approach that does, not meet the needs of many people with MDD and PPD.

On top of more people seeking treatment for depression, a healthcare system that fails to appropriately screen in SaaS and a significant portion of the population failing to receive care.

Put it simply the current treatment paradigm relies on a try and fail approach that does not meet the needs of many people with MD in PPD.

Something much change because those who suffer from depression, many of whom are family and friends deserve better.

Something must change, because those who suffer from depression, many of whom are family and, friends, deserve better.

Stages prepared to be at the forefront of that solution with our plans for a single NDA filing for <unk> alone that will include both <unk> and PPD indication, we have a clear commercialization strategy, which prioritizes stakeholder engagement leverages disease state awareness and builds capabilities that we believe will enable us to execute at a high level in <unk>.

I'm pleased to detail our advancements as well as comment on our early development programs.

SAGE is prepared to be at the forefront of that solution.

Starting with our depression franchise, we announced in early June that the Skylark study of Xeranlin 50 milligrams in postpartum depression met its primary endpoint, a change from baseline in HAMD 17, total score at day 15 compared to placebo, and all key secondary endpoints, change from baseline in HAMD 17, total score at days 3, 28, and 45 compared to placebo, as well as change from baseline in the CGIS score at day 15. Notably, Xeranlin 50 milligrams demonstrated a statistically significant and clinically meaningful reduction in depressive symptoms compared to placebo, as measured by change from baseline in HAMD 17 at day 15 of four points and a corresponding P value of 0.0007.

With our plans for a single NDA filing for seranolone that will include both MDD and, PPD indications, we have a clear commercialization strategy which prioritizes stakeholder engagement, leverages disease state awareness, and builds capabilities that we believe will enable us to execute at a high level and scale with success.

Scale with success.

To rapidly and effectively reach clinicians and patients with MDD and PPD at launch, if, seranolone is approved, we're working with our collaboration partner Biogen on an omni-channel approach that prioritizes digital channels right from the outset.

To rapidly and effectively reach clinicians and patients with <unk> and PPD at launch. It's a rent alone is approved we're working with our collaboration partner Biogen on an omnichannel approach that prioritizes digital channels right from the outset.

I'd also like to provide some high-level thoughts on our approach to market access. Payers are telling us that the unmet need for patients with MDD and PPD is clear.

I'd also like to provide some high level thoughts on our approach to market access.

Payers are telling us that the unmet need for patients with <unk> and PPD is clear.

The prevalence of depression continues to rise despite available treatments, and new, treatment options that work quickly are desperately needed.

The prevalence of depression continues to rise despite available treatments and new treatment options that were quickly are desperately needed.

In our early engagements with payers. We have also heard that they believe zarin alone has the potential to be a promising new option for the treatment of both <unk> and PPD with the new MLA in with clinical data, suggesting the potential to provide rapid and sustained relief in depressive symptoms for patients and a generally well tolerated safety profile.

In our early engagements with payers, we have also heard that they believe seranolone has, the potential to be a promising new option for the treatment of both MDD and PPD, with a new MOA and with clinical data suggesting the potential to provide rapid and sustained relief in depressive symptoms for patients and a generally well-tolerated safety profile, for Health Care and the Health Profile.

These results are remarkable and reinforce the data observed across the Xeranlin clinical development program in which treatment with Xeranlin resulted in a rapid reduction in depressive symptoms that was sustained throughout, the follow-up period with a generally well-tolerated safety profile.

To that end, we are thinking strategically about pricing and access and working to design, an approach that considers the needs of payers, healthcare professionals, and most importantly patients and their families.

To that end, we are thinking strategically about pricing and access and working to design an approach that considers the needs of payers and health care professionals, and most importantly patients and their families. Our overall goal with Saran alone. It gets approved is to ensure that appropriate patients with MDM PPD, who are prescribed saran alone can quickly receive it.

Our overall goal with Sorentolone, if approved, is to ensure that appropriate patients with, MDD and PPD who are prescribed Sorentolone can quickly receive it.

As such we believe that it's essential that we work with payers to try to minimize barriers that can impact the health care professionals, the ability to prescribe saran alone to treat emdeon PPD. So their patients have the potential to obtain rapid and sustained relief of their depressive symptoms we.

As such, we believe that it's essential that we work with payers to try to minimize barriers, that can impact the healthcare professional's ability to prescribe Sorentolone to treat MDD and PPD so their patients have the potential to obtain rapid and sustained relief of their, depressive symptoms.

We look forward to sharing more details regarding our efforts to lay the foundation for the, successful commercialization of Sorentolone at an upcoming Commercial Spotlight event which we plan to host later this year.

We look forward to sharing more details regarding our efforts to lay the foundation for the successful commercialization of <unk> alone and an upcoming commercial spotlight event, which we plan to host later this year.

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

Now I'll turn the call over to Kimmy for a review of our financials.

Kimmy?

Thanks, Chris.

These data, along with our clinical data, support viable medical use and lower likability and abuse potential for Xeranlin.

Our financial results for the second quarter of 2022 are detailed in our press release, issued this morning.

We do expect that Xeranlin will be a Schedule 4 drug, if approved. Findings from our market, research have shown that clinicians are both experienced and comfortable prescribing Schedule, 4 drugs.

Actual results for the second quarter of 2022 are detailed in our press release issued this morning.

I'd also like to highlight that we announced in early June that enrollment is complete, in the SHORELINE study of Zaranon and MDD. SHORELINE is the largest naturalistic study done to date in depression and is examining as-needed intermittent dosing over the course of one year. We recently presented data from the previously reported cohort of the SHORELINE study at the American Society of Clinical Psychopharmacology annual meeting.

I'd like to take a moment to provide some context and highlight a few key points. At the end of the second quarter, we continue to be in a strong cash position that we believe, will provide our organization with the flexibility to make strategic investments across our franchises and support the launch of Sorentolone if approved by the agency. Our net loss for the second quarter of 2022 was $126.3 million, and we ended the quarter, with cash, cash equivalents, and marketable securities of $1.5 billion.

As a reminder, in the 50-milligram cohort of the SHORELINE study, 80% of patients who responded to the initial two-week treatment with Zaranolone 50 milligrams only received one or two treatment courses during their time in this year-long study, with the median time to the second treatment course of 249 days.

Like to take a moment to provide some context and highlight a few key points.

These data support our belief that Zaranolone can have remarkable durability.

We look forward to sharing more data from the Zaranolone Clinical Development Program in key scientific forums over the next several quarters.

At the end of the second quarter, we continued to be honest John cash position that we believe will provide our organization with the flexibility to make strategic investments across our franchises.

I'll highlight specifically our upcoming data presentations at the 2022 Psych Congress in September.

In addition, we are sharing an update on both the Rainforest and Redwood studies today.

As a reminder, the Rainforest study was designed to investigate the efficacy and safety of 30 milligrams of, Zaranolone on sleep architecture and MDD, the same objective primary endpoint measured in trials of insomnia disorders.

The Redwood study was designed to examine fixed-schedule intermittent dosing of 30 milligrams of Zaranolone throughout the course of a year.

This study was also designed to complement the SHORELINE study, which examined the as-needed, intermittent dosing of Zaranolone.

Port the launches are analog accrued by the agency.

Our net loss for the second quarter of 2022, with a $126 3 million and we.

Ended the quarter with cash cash equivalents and marketable securities of $1 5 billion.

Turning to operating expenses R&D expenses increased to $77 3 million in the second quarter of 2022 compared to $66 2 million to the same period in 2021.

Turning to operating expenses, R&D expenses increased to $77.3 million in the second quarter, of 2022 compared to $66.2 million for the same period in 2021. The increase in spend was primarily related to spending on Phase 324 and our wholly owned, pipeline, which includes Phase 718.

The increase in spend was primarily related to spending on page $3 24, and our wholly owned pipeline with.

Sage 718.

Looking forward, we expect R&D spend to continue to increase in the coming quarters as we advanced the six planned and ongoing phase II study for Sage 718, <unk> hundred 24 that al mentioned earlier.

Looking forward, we expect R&D spend to continue to increase in the coming quarters as we advance, the six planned and ongoing Phase 2 studies with Phase 718 and Phase 324 that Al mentioned earlier.

Importantly, the flexibility provided by our strong cash position allows us to invest in, our wholly owned pipeline where our confidence is demonstrated by our advancement of three potential indications for Phase 17 and continued work across Phase 689, Phase 319, and Phase 421.

Importantly, the flexibility provided by our strong cash position allows us to invest in our wholly owned pipeline, where our confidence is demonstrated by our advanced they are three potential indications for <unk> 17, and continued work on our cost Sage 689, <unk> thousand 19 on page $4 21.

SG&A expenses increased to $52.4 million in the second quarter of 2022 compared to $43.3 million, for the same period of 2021. The increase is primarily related to hiring employees to support ongoing activities in, anticipation of potential future product launches of our product candidates. As you heard from Barry, we are preparing for the potential launch of Xeranolone, and, we expect that SG&A expenses will increase as we continue commercial preparation.

SG&A expenses increased to $52 4 million in the second quarter of 2022.

Care to $43 3 million for the same period of 2021.

The increase is primarily related to hiring employees to support ongoing activities in anticipation of potential future product launches of our product candidates.

As you heard from Barry we are preparing for the potential launches they ran alone and.

We expect that SG&A expenses will increase as we continue commercial preparation.

As part of our collaboration with Biogen, we're jointly developing Xeranolone and Phase, with a 50-50 cost sharing in the United States. During the second quarter, we recorded $23.8 million in reimbursement from Biogen related, to our collaboration and license agreement.

As part of our collaboration with Biogen.

Currently developing Duran alone Sage 324, with a 50 50 cost sharing in the United States.

During the second quarter, we recorded $23 8 million in reimbursement from Biogen related to our collaboration and license agreement.

We believe that the work we're doing to prepare for commercialization now who will provide an important foundation for our organization going forward, including potential future launches with our wholly owned programs. If we're successful.

We believe that the work we're doing to prepare for commercialization now will provide an, important foundation for our organization going forward, including potential future launches with our wholly owned programs if we're successful.

Looking ahead into the rest of 2022, we're reaffirming the financial guidance that we provided earlier this year we.

Looking ahead into the rest of 2022, we're reaffirming the financial guidance that we, provided earlier this year. We anticipate having cash, cash equivalents, and marketable securities of approximately, $1.3 billion at the end of 2022.

We anticipate having cash cash equivalents and marketable securities.

Approximately $1 3 billion at the end of 2022.

We cannot anticipate receipt of any milestone payments from collaborations in 2022.

We do not anticipate receipt of any milestone payments from collaborations in 2022. We believe that our current cash, cash equivalents, anticipated funding from our ongoing, collaboration, and potential revenue will support operations into 2025.

We believe that our current cash cash equivalents and anticipated funding from our ongoing collaboration and potential revenue will support operations into 2025.

Despite the uncertain market environment, we all face Sage continues to act from a position of strength.

Despite the uncertain market environment we all face, SAGE continues to act from a position, of strength.

I'm confident that we'll continue to execute throughout the remainder of 2022 in our pursuit, to deliver life-changing brain health medicines so every person can thrive.

I'm confident that we will continue to execute throughout the remainder of 2022 and our pursuit to deliver life changing brain out Madison. So every person can thrive.

Moreover, our approach to SAGE enables quick decision-making, facilitating disciplined, investments that we believe will provide value over the long term as we execute our efforts to lead in brain health.

Moreover, our posted stage enables quick decision, making facilitating disciplined investments that we believe will provide value over the long term as we execute our effort to lead in brain health.

While were thinking big about the Dorado, one opportunity, we're very mindful of the capital allocation prior to launch we plan to invest appropriately and be prepared to scale with success.

While we're thinking big about this round one opportunity, we're very mindful of the, capital allocation prior to launch. We plan to invest appropriately and be prepared to scale with success.

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

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

Helen?

Alan.

Thanks, Kimmy.

Thanks, Kimi before I turn it over to the operator I'll ask that you limit yourself to one question. If you have an additional question. Please feel free to return to the queue.

Before I turn it over to the operator, I'll ask that you limit yourself to one question.

If you have an additional question, please feel free to return to the queue.

Now I'll turn it over to the operator to handle Q&A.

Now I'll turn it over to the operator to handle Q&A operator.

Operator?

As a reminder, to ask a question, you will need to press star 1 1 on your telephone.

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

Please stand by while we compile the Q&A roster.

Please standby, while we compile the Q&A roster.

Our first question comes from Savi <unk> with Goldman Sachs. Your line is now open.

Our first question comes from Salveen Richter with Goldman Sachs.

Your line is now open.

Hi, thanks for taking our question.

Hi, Thanks for taking our question. This is Tommy on for Celgene and our question is about rain forest reinforce was terminated are there plans to share the data with the agency is there the possibility that findings from this study could be included on the label in some way and are there plans to restart. These studies with a 50 milligram dose. Thank you.

This is Tommy on for Salveen, and our question is about rainforest.

While rainforest was terminated, are there plans to share the data with the agency?

Is there the possibility that findings from the study could be included on the label in, some way?

Based on our discussions with the FDA at the time, we suspended both the Rainforest and Redwood studies in early 2020 before they were completed. These decisions were based on our plans to advance the program with the 50-milligram dose of, Zaranolone.

And are there plans to restart these studies with the 50 milligram dose?

Thank you.

Yeah, Tommy, thanks for the question.

Yes, Tommy Thanks. Thanks for the question. So we will be presenting data from the rainforest study, which as you mentioned 30 milligram dose.

So we will be presenting data from the rainforest study, which, as you mentioned, the 30 milligram, dose was terminated early. We made that decision in conjunction with the agency.

It was terminated early we made that decision in conjunction with the agency and as a reminder.

Furthermore, we believe and confirmed with the agency that neither study is needed to support our NDA filing.

And as a reminder, neither rainforest or Redwood data are required for the NDA filing.

Neither rainforest or Redwood data are required for the NDA filing of course, those data will be shared.

Of course, those data will be shared.

That said, I'd like to share some high-level findings from these studies. Starting with the Rainforest study, although terminated early, the study provides important, insights on the potential effect of Zaranolone in the improvement of sleep parameters in patients with MDD. The study was not fully enrolled, with only 87 patients randomized. The rationality of improvement in sleep architecture was clear, with Zaranolone 30 milligrams showing numerical advantage over placebo in objective measures of quality of sleep, including wake after sleep onset, total sleep time, latency to persistent sleep, median number of wakenings, median duration of wakenings, and endpoints involving REM sleep.

The data we saw in rainforest was consistent with the totality of data seen to date with, Zaranolone. Reduction in depressive symptoms, reduction in anxiety, and importantly, this is what, specifically being studied, improvement in sleep and sleep architecture.

The data we saw in <unk> for US was consistent with the totality of data seen to date was around alone.

Insomnia is one of the most common symptoms associated with depression, and disturbances of sleep are associated with decline in quality of life. It's very clear that improving sleep in depression is associated with better outcomes, making the findings from our Rainforest study encouraging, as they suggest that Zaranolone may provide a sleep benefit to patients suffering with MDD.

Reduction in depressive symptoms reduction in anxiety and importantly, this is what specifically being studied.

As many antidepressants can negatively impact sleep architecture, this would be an exceptional potential benefit of Zaranolone treatment.

We believe that data across the Zaranolone clinical development program, along with the directional learnings from the Rainforest study, reinforce that Zaranolone's mechanism of action may address multiple aspects of depression, including the core depressive symptoms, as well as symptoms of anxiety and insomnia.

Turning now to the Redwood study, the fixed-schedule intermittent dosing of 30 milligrams of Zaranolone, 53 patients with MDD were enrolled in the open-label phase of the study, and two patients proceeded to the randomized phase, Terminated.

<unk> and sleep and sleep architecture, it's too early to talk about exactly what's in the label or what will be able to use them promotion, but these findings will be important as we commercialized zorana alone Chris anything to add.

Given the low number of patients randomized, there isn't enough data from the Redwood study, to identify any trends.

It's too early to talk about exactly what's in the label or what we'll be able to use, in promotion.

What we can say is that no additional safety findings were reported.

But these findings will be important as we commercialize Zaranolone.

In terms of retreatment, we do have data from another study in the Clinical Development, Program, the Open Label Shoreline study, an MDD that I mentioned earlier.

We believe these data afford the closest real world evidence we have to date on the potential, of serotonin therapy in the treatment of MDD may help guide patients and healthcare providers in treatment choices if serotonin is approved.

Additionally in the Shoreline study, for those patients who use one or more retreatments, efficacy and safety outcomes were similar to those observed in the initial treatment course.

We look forward to sharing the data collected from the Rainforest study as well as additional, data across the entire Clinical Development Program at upcoming conferences.

Now I'd like to turn to our neuropsychiatric franchise led by SAGE 718, our lead NMDA receptor, positive allosteric modulator that is an investigational oral therapy being developed for certain disorders where impairment of cognition is one of the main drivers of disability. SAGE 718 is one of our wholly owned programs and was granted fast track designation by, the FDA as a potential treatment for cognitive impairment in Huntington's disease or HD.

We also investigated SAGE 718 in people with mild cognitive impairment due to Parkinson's, disease or PD and people with mild cognitive impairment and mild dementia due to Alzheimer's disease or AD. SAGE 718 data have been consistent in demonstrated improvement on important tests of executive, function across multiple open label studies to date, including the paradigm and luminary studies in people with mild cognitive impairment due to PD and people with mild cognitive impairment and mild dementia due to AD respectively. Additionally, in the placebo controlled ketamine exposure study, subjects treated with SAGE, 718 demonstrated statistically significant improvement on several cognitive tests, including the two back test compared to those treated with placebo at multiple time points.

In our HD clinical studies, we are making progress in enrolling the phase two dementia, study and the phase two surveyor study in people with HD cognitive impairment. We believe the complementarity of these two studies will help us understand the potential, benefits of SAGE 718 in HD. The dementia study will evaluate the difference between treatment with SAGE 718 and placebo, on cognitive performance in Huntington's disease and the surveyor study on the other hand will help us interpret the clinical meaningfulness of the cognitive effects observed in the dementia study.

Basically, the surveyor study will help us to answer the so what question, as in, so, what do these cognitive effects mean for patients and activities of daily living and what impact does SAGE 718 have on their everyday lives?

Based on the results of the dementia and surveyor studies, we will consider opportunities to, engage with regulators with the goal, if our studies are successful, to bring SAGE 718 to people with HD cognitive impairment as quickly as possible as there are no current therapies available today.

According to our other clinical programs in neurodegenerative diseases, enrollment, in the precedent study, a phase two placebo-controlled study of SAGE 718 in people with mild cognitive impairment due to PD is going very well.

No very well.

We also remain on track to initiate a placebo-controlled phase two study with SAGE 718 in people with, mild cognitive impairment and mild dementia due to AD planned to begin in late 2021.

Cited about the opportunity and we'll continue to see the impact of reinforced as future opportunities moving forward.

We look forward to sharing data from studies complete with SAGE-718 to date at the upcoming, European College of Neuropsychopharmacology and American College of Neuropsychopharmacology annual meetings later this year.

Lastly, I'd also like to highlight recent advancement in our neurology franchise led, by SAGE-324, a next-generation positive-alloceric modulator of GABA-A receptors, which we believe holds significant potential in the treatment of neurological conditions like essential tremor, or ET, a disease that has limited treatment options for patients and has had no innovation for over 50 years. We are pleased to announce that we have initiated our Phase 2 long-term open-label safety study, with SAGE-324 and ET.

The aim of this study is to assess the long-term safety and tolerability of SAGE-324 over a, multi-year period with the incidence of treatment-emergent adverse events as a primary endpoint.

In addition, we are continuing to enroll in our Phase 2b Kinetic Tube Dose Ranging Study, evaluating SAGE-324 and ET to optimize the dose and frequency and continue to expect enrollment completion to occur in late 2022.

As with our other franchises, we look forward to sharing data from previously completed, studies with SAGE-324 in the coming months, including in our upcoming presentation at the International Parkinson and Movement Disorder Society annual meeting.

To close, for me, it's been a rewarding journey over the last decade, and I'm proud of the, team who has moved this dynamic pipeline forward.

We are excited about what's to come in the next 18 months and believe our organization, is poised to continue building on the momentum generated from the first half of the year as one of the leaders in brain health.

Thanks Tommy.

Now I'll turn the call over to Chris to provide additional context on our planned approach, as we prepare for the potential commercialization of serralinolone in NDD and PPD.

Yeah.

Thank you.

Our next question comes from Ritu <unk> with Cowen Your line is now open.

Chris?

Thanks, Al.

Good morning, guys. Thanks for taking the question.

Chris, anything to add?

I wanted to ask about how confident you feel about the regulatory pathway that youre going to be embarking on shortly specifically.

No.

Is there any learnings from the axiom precedent in the ongoing.

Film review.

That you've taken away or that you've gleaned that will better prepare you for what the FDA wants on the outset.

First of all in the process.

Yes. Thank.

I'm pleased to be with you all this morning to share updates on our commercialization, preparations for serralinolone.

No Barry, we're excited about the opportunity and we'll continue to see the impact of Rainforest, as we think about future opportunities moving forward.

Thank you for that question I would I would say, we're highly confident in the interactions we've had with.

With FDA stem.

Stemming back to 2020, when we outline the landscape and nurse programs, we've confirmed multiple times with the agency the totality of the data required for NDA filing we started that rolling submission in may of this year and plan to complete a single filing for both <unk> and PPD by the end of the year.

Can tell you that all modules are are in hand, and going very well.

The non clinical CMC modules as well as the clinical modules are all well on schedule.

Obviously, there are there are things that can happen that are unforeseen, but we feel very good about all of the modules that are in preparation and the interactions with the agency and I believe that.

Patients with depression urgently need new treatment options that are safe, work quickly, and offer lasting effects.

<unk>, a fast acting antidepressant, that's oral and short courses desperately needed in the word world today, and we believe the agencies understand that.

Something must change because those who suffer from depression, many of whom are family and, friends, deserve better.

We're prepared to be at the forefront of that solution.

With our plans for a single NDA filing for serralinolone that will include both MDD and, PPD indications, we have a clear commercialization strategy which prioritizes stakeholder engagement, leverages disease state awareness, and builds capabilities that we believe will enable us to execute at a high level and scale with success.

To rapidly and effectively reach clinicians and patients with MDD and PPD at launch, if, serralinolone is approved, we're working with our collaboration partner, Biogen, on an omni-channel approach that prioritizes digital channels right from the outset.

I'd also like to provide some high-level thoughts on our approach to market access. Payers are telling us that the unmet need for patients with MDD and PPD is clear.

Have the conversation still been interactive relatively real time.

Yes.

I'd say I'd say this regular interaction and updates with the FDA theres, both formal and informal kind of email interactions, but yes. There has been there has been regular interactions and things are going things are going well we anticipate.

The prevalence of depression continues to rise despite available treatments, and new, treatment options that work quickly are desperately needed. In our early engagements with payers, we have also heard that they believe Xeranolone has, the potential to be a promising new option for the treatment of both MDD and PPD. With the new MOA and with clinical data suggesting the potential to provide rapid and sustained, relief in depressive symptoms for patients, and a generally well-tolerated safety profile.

To that end, we are thinking strategically about pricing and access, and working to design, an approach that considers the needs of payers, healthcare professionals, and most importantly, patients and their families.

The filing by the end of the year and as we said on the call. If we get priority review <unk> date in the third quarter of next year and we're excited for the interactions.

Great. Thanks, Thanks for you too.

Thank you.

Our overall goal with Xeranolone, if approved, is to ensure that appropriate patients with, MDD and PPD who are prescribed Xeranolone can quickly receive it.

Thanks, Tommy.

Our next question comes from Paul Matisse with Stifel. Your line is now open.

As such, we believe that it's essential that we work with payers to try to minimize barriers, that can impact the healthcare professional's ability to prescribe Xeranolone to treat MDD and PPD, so their patients have the potential to obtain rapid and sustained relief of their depressive symptoms.

Thank you.

We look forward to sharing more details regarding our efforts to lay the foundation for the, successful commercialization of Xeranolone at an upcoming commercial spotlight event, which we plan to host later this year.

Our next question comes from Ritu Baral with Cowen.

Hey, Thanks, so much following up on Rich's question on the regulatory.

Victorious side can you clarify how are you framing shoreline in the NDA are you framing the study.

The maintenance study or are you framing this as sort of a broader open label safety study with more quality qualitative conclusions and then to that point what are you proposing for.

For re dosing in the real World are you proposing something that is as restricted the shoreline, where you have to wait at least six weeks and we have very specific criteria for monitoring or are you kind of proposing a paradigm, where physicians have a lot more discretion than that thanks. So much.

Now I'll turn the call over to Kimmy for a review of our financials.

Kimmy?

Yes, Thanks, Paul for the question. So let's shoreline is the largest naturalistic study ever run in depression.

Thanks, Chris.

Our financial results for the second quarter of 2022 are detailed in our press release, issued this morning.

I'd like to take a moment to provide some context and highlight a few key points. At the end of the second quarter, we continue to be in a strong cash position that we believe, will provide our organization with the flexibility to make strategic investments across our franchise and support the launch of Xeranolone if approved by the agency. Our net loss for the second quarter of 2022 was $126.3 million, and we ended the quarter, with cash, cash equivalents, and marketable securities of $1.5 billion.

Turning to operating expenses, R&D expenses increased to $77.3 million in the second quarter, of 2022, compared to $66.2 million for the same period in 2021. The increase in spend was primarily related to spending on Phase 324 and our wholly-owned, pipeline, which includes Phase 718.

Looking forward, we expect R&D spend to continue to increase in the coming quarters as we advance, the six planned and ongoing Phase 2 studies with Phase 718 and Phase 324 that Al mentioned earlier.

Importantly, the flexibility provided by our strong cash position allows us to invest in, our wholly-owned pipeline, where our confidence is demonstrated by our advancement of three potential indications for Phase 17 and continued work across Phase 689, Phase 319, and Phase, 421.

SG&A expenses increased to $52.4 million in the second quarter of 2022, compared to $43.3, The increase is primarily related to hiring employees to support ongoing activities in anticipation of potential future product launches of our product candidates. As you heard from Barry, we are preparing for the potential launch of Xeranolone, and, we expect that SG&A expenses will increase as we continue commercial preparation.

It's a study where patients were enrolled.

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

As part of our collaboration with Biogen, we are jointly developing Xeranolone and Stage, 4 with a 50-50 cost sharing in the United States.

During the second quarter, we recorded $23.8 million in reimbursement from Biogen related, to our collaboration and license agreement.

And then asked every other every two weeks how they were doing.

We do not anticipate receipt of any milestone payments from collaborations in 2022. We believe that our current cash, cash equivalents, anticipated funding from our ongoing collaboration, and potential revenue will support operations into 2025.

Despite the uncertain market environment we all face, SAGE continues to act from a position, of strength.

I'm confident that we'll continue to execute throughout the remainder of 2022 in our pursuit, to deliver life-changing brain health medicines so every person can thrive.

Helen?

Thanks, Kimmy.

While we're thinking big about this Rental One opportunity, we're very mindful of the, capital allocation prior to launch. We plan to invest appropriately and be prepared to scale with success.

Yes.

As Youre aware, 80% of those enrolled in shoreline that responded required only one or two two weeks two.

<unk> of course in the course of the year. So two to four weeks of drug in the course of the year and a majority of those that respond shoreline only needed one course of treatment in the year and of course re treatment for patients.

That responded.

Was consistent and no additive safety issues. So the totality of the shoreline data will be included in the NDA filing. It's a large safety database and we believe it will be instructive to clinicians on when re treatment can be used and I'll ask Chris to comment on how this is a paradigm shift in the <unk>.

Before I turn it over to the operator, I'll ask that you limit yourself to one question.

If you have an additional question, please feel free to return to the queue.

Depression, but not necessarily a paradigm shift in our clinicians practice. So we're going to submit the shoreline as safety data. We believe it will be instructive to re treatment. It's a little early to talk about exactly what will be in the label of the guidelines for re treatment, but I'll remind you that that physicians can use.

Now I'll turn it over to the operator to handle Q&A.

Operator?

As a reminder, to ask a question, you will need to press star 1 1 on your telephone.

General and any other approved drug as they see fit and as they learn more about the opportunities of how to use. These medicines, Chris you want to talk about impact of practice.

Please stand by while we compile the Q&A roster.

Our first question comes from Salveen Richter with Goldman Sachs.

Yes sure. Thanks, Barry so so the profile seen with prominent clinical trials to date in particular the landscape studies.

Your line is now open.

Hi.

Thanks for taking our question.

We have demonstrated that with respect to saran alone, we've seen rapid and sustained reduction in depressive symptoms and a generally well tolerated safety profile with a short 14 day course of treatment.

This is Tommy on for Salveen.

And our question is about rainforest.

While rainforest was terminated, are there plans to share the data with the agency?

Is there the possibility that findings from the study could be included on the label in, some way?

Physicians have prescribed the product so with respect to see the product being used this will enable physicians opportunity to offer patients treatment free periods in between depressive episodes. So the patients don't have to locations on a product basis now what we've heard from key opinion leaders that we've engaged with.

Market research.

This in and of itself is an advancement in treatment functionally with regard to how they've been treating depression. This is a change in the treatment paradigm, but this does not really reflect a change in the way that physicians are actually matters.

What we would expect as that was ran alone that a physician would prescribe the patient a two week course of therapy. They would check in with the patient at the end of that two week period, where they would hero.

The efficacy and the Tolerability profile of the product patients would then go on to experience some free symptom free life and as needed at the six month period.

Backend with the physician with an update now obviously in between that two week period in period, if there were.

One of the hallmark symptoms of depression, if that were to return for the patient. The patient then certainly would reach out back to the clinician and the clinician could prescribe the second two week course, so again as I said this really reflects changing the treatment paradigm not a change in the way that clinicians are actually managing their patients and we're very excited about the opportunity to introduce this.

We hear from clinicians they're waiting for is <unk>.

And are there plans to restart these studies with the 50 milligram dose?

Thank you and I really just trying to clarify on the regulatory side, given the whole back history with Redwood and the utility of that study versus shoreline do you look at shoreline as as a maintenance study with the ability to have maintenance claims for Matt or.

Thank you.

Yeah, Tommy, thanks for the question.

Just trying to get a little more specific there yes, Paul thanks.

So we will be presenting data from the rainforest study, which, as you mentioned, the 30 milligram, dose was terminated early. We made that decision in conjunction with the agency.

And as a reminder, neither rainforest or Redwood data are required for the NDA filing.

So again, we're going to submit shoreline as part of the filing it's a large safety database. We believe it will be instructive to re treatment when we met with the agency.

Of course, those data will be shared.

It's too early to talk about exactly what's in the label or what we'll be able to use, in promotion.

No Barry, we're excited about the opportunity and we'll continue to see the impact of Rainforest, as we think about future opportunities moving forward.

I think it was the fall of last year, we confirm that shoreline.

Would be sufficient as part of the filing and the Redwood study no longer needed to be run because we had sufficient data of re treatments. So we'll we'll provide more as we as we interact with the agency and get into label negotiations.

Okay. Thanks, Kurt Thanks, Paul.

Thanks Tommy.

Your line is now open.

Thank you.

Our next question comes from Amit <unk> with Needham Your line is now open.

Good morning, Thanks for taking my question, maybe just a follow up to the previous question.

Thank you.

Good morning guys.

Do you anticipate.

Our next question comes from Ritu Baral with Cowen.

Thanks for taking the question.

The indication for the product to be.

Treatment of depression or would it be cloud.

Classify that something was supposed to say Chris is acute treatment.

Do you expect the FDA to limit the number of treatments in the year.

And then I'll have a question on the pipeline.

Amit Thanks for the question so in terms of.

I wanted to ask about how confident you feel about the regulatory pathway that you're going to be embarking on shortly.

The specifics of the label again, it's too early to talk about label specifics until we really get into it with the agency. We have said previously and we anticipate an indication statement something like for the treatment of <unk> and PPD, so pretty straightforward.

Specifically, if there are any learnings from the Axiom precedent and the ongoing Axiom review that you've taken away or that you've gleaned, that will better prepare you for what the FDA wants on the outset versus in the process?

Pretty straightforward.

Straightforward indication statement.

As we talked about with Paul's question, we believe shoreline will be instructive for re treatment. We've got data up to five re treatments in the course of the year and.

And we believe that the total data set will be instructive for for a treatment as Chris highlighted the normal course of practice would be to prescribe medicine. In this case, if it's around alone rather than instructing the patient that hanging there. This can take four to eight weeks to work, we believe that patients will.

Patients will be instructed that.

Please take this at night with your dinner you may feel better in two or three days.

The full two course.

Treatment and as normal I'll check back in view in two weeks, if you're dark and mood anxiety increases our sleep disruption occurs again please.

Please check back in otherwise, we'll see in six months, so as Chris highlighted.

In the normal course of practice and if theres a recruitment required we believe that we've got data that instructs on re treatment.

Mhm.

Do you still anticipate AD com or less.

Less clear at this point.

No change in anticipation or not.

Whether an AD com is used or not at the sole discretion of.

The agency there is no regulatory statute for exactly how or when they share with us.

We'll learn more clearly after our NDA filing and again, if we get priority review <unk> date in the third quarter of next year of course, we are preparing for an AD com and we are going to be very well prepared if they choose an AD com if they don't.

On an ad com.

Signal speed of approval that would be great. If they do hold the AD comm, we look forward to that as well because it will allow us to feature the totality of the <unk> data and really put it on display.

Got it.

I guess I've asked.

Roughly 102 questions, but maybe just one quick one on <unk>.

Kevin money.

When do we anticipate data from.

From any of these ongoing studies and.

Did you start to see positive data come through would you anticipate developing all of these three indications on your own or would you consider partnering.

Thank you.

Yes. Thanks, Amie, we're really excited by the Sage 718 program a first in class.

NMDA Pam, we recently announced the initiation of studies for Sage 718 in Huntington's mild cognitive impairment.

And Mci due to Parkinson's disease, and we anticipate starting a placebo controlled Alzheimer's study.

By the end of the year and as Youre, well aware, we presented data from from.

The various studies showing.

Consistent improvement in executive function learning and memory. So as we are.

Get these studies up and running and enrolling will provide further guidance on.

<unk> the timing of data Readouts in terms of phase III is that's something that we will make a determination on once some of the phase II readout clearly the Huntington studies have been designed in a way that.

As positive.

We will meet with the agency to discuss the fastest way of getting Sage 718 to the market.

Okay. Thank you thanks Tommy.

As a reminder, in the interest of time, we ask that you limit yourself to one question and rejoin the queue for any follow ups.

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

Your line is now open.

Good morning guys.

Yeah, Ritu, thank you for that question.

Good morning, Thank you for the update and for taking the question.

Thanks for taking the question.

Can you please remind us the original objectives of the Redwood and rainforest studies, and whether or not you plan to continue pursuing those objectives and whether any of the study results are going to be included in the NDA filing.

I wanted to ask about how confident you feel about the regulatory pathway that you're going to be embarking on shortly.

I would say we're highly confident in the interactions we've had with FDA stemming back to 2020 when we outlined the Landscape and NEST programs.

Thanks for the question Jay.

We've confirmed multiple times with the agency the totality of the data required for NDA filing. We started that rolling submission in May of this year and plan to complete a single filing for both MDD and PPD by the end of the year.

Let me first comment that the.

I can tell you that all modules are in hand and going very well.

The non-clinical CMC modules as well as the clinical modules are all well on schedule.

Obviously, there are things that can happen that are unforeseen, but we feel very good about all the modules that are in preparation and the interactions we have with the agency.

This discussion you led with Greg not only was just outstanding things Youre doing that I think it really highlighted how someone who uses around oil and thinks about.

I believe that a fast-acting antidepressant that's oral and short-course is desperately needed in the world today, and we believe the agencies understand that.

Yeah, Ritu, thank you for that question.

Have the conversations still been interactive, relatively real-time, I guess?

I would say we're highly confident in the interactions we've had with FDA stemming back to 2020 when we outlined the Landscape and NEST programs.

I'd say there's regular interaction and updates with the FDA.

There's both the formal and then informal kind of email interactions, but, yes, there's been regular interactions and things are going well.

It's about that drug that was very instructive not only for us, but I think for many in the community trying to understand the uses around on so thanks for that in terms of in terms of rainforest and Redwood.

We anticipate the filing by the end of the year, and as we said on the call, if we get priority review, a PDUFA date in the third quarter of next year, and we're excited for the interactions.

I can tell you that all modules are in hand and going very well.

The non-clinical CMC modules as well as the clinical modules are all well on schedule.

Obviously, there are things that can happen that are unforeseen, but we feel very good about all the modules that are in preparation and the interactions we have with the agency.

We don't anticipate running a redwood study now or anytime in the future as we've highlighted we believe that the retreat in data and shoreline, which were part of the submission will be instructive not only from a safety database perspective, but in terms of how re treatment can be used in terms of rainforest study MDT.

Those with insomnia Directionally saw very positive results consistent with the totality of this rental and data and that's the study we might run in the future we have more to do with our collaborators biogen through that outline the unmet needs in the phase III before so stay tuned for more on that later.

Great.

Great. Thank you thanks Jay.

Thank you.

Thanks.

Okay.

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

Hi, this is shopping around for unfair yes. Thank you for taking my questions.

Thanks for you, too.

Regarding the shoreline study you mentioned that the median time to the second treatment course was 200 and party 90 days can.

Thank you.

Can you kind of like what's the sharpest and the longest duration before which the patient needed the second dose.

And what's the longest time.

Duration for safety analysis in the short line to date. Thank you.

Our next question comes from Paul Matisse with Stiefel.

Yes, no thanks for the discussion.

So shoreline.

Your line is very instructive study again it was the largest naturalistic study run to date in depression, we've enrolled over 500 patients and it was a one year duration study so.

Your line is now open.

Hey, thanks so much.

The majority of patients that responded in shoreline required only one two week course in the course of the year and the <unk>.

Following up on Ritu's question, on the regular...

80% of patients had one or two of courses in the course of the year. So it really speaks to the effectiveness and durability of shoreline. The fact that the median time to retreat was 249 days I think is demonstrable that the majority of patients first depressive episode was treated in treated well and then.

Can you clarify, how are you framing Shoreline in the NDA?

Potentially another trigger event caused another depressive episode, requiring a re treatment, but again the majority of those responded did not require re treatment and in terms of short and long duration will be providing more data as we prevent shoreline.

We presented a SCP.

More details for sure lying in meetings to come.

Thank you.

Our next question comes from <unk> <unk> with Guggenheim Partners. Your line is now open.

Are you framing this study as a maintenance study, or are you framing this as sort of a broader open-label safety study with more qualitative conclusions?

Thanks for taking my question just a question.

And then to that point, what are you proposing for re-dosing in the real world?

Are you proposing something that is as restricted as Shoreline, where you have to wait at least six weeks and you have very specific criteria for monitoring?

In line.

I mean <unk>.

<unk> seen the S&P study, so just trying to get a sense of some of the DDI work that you might have done can you just comment on that and also showing positive impact on sleep.

Or are you kind of proposing a paradigm where physicians have a lot more discretion than that?

Thanks.

Unknown Speaker Yeah, thanks, Paul, for the question.

Across multiple studies.

So, let's Shoreline is the largest naturalistic study ever run in depression. It's a it's a study where patients were enrolled, and then asked every other every two weeks how they were doing.

And as, as you're aware, 80% of those enrolled in Shoreline that responded, required only one or two, two weeks, of course, a two week course in the course of a year. So two to four weeks of drug in the course of the year, and a majority of those that, respond Shoreline only needed one course of treatment in the year.

Ken.

<unk> combined with some of the sleep AIDS are.

Sedative and <unk> that are out there. So just trying to get a sense of the combo and also if you can characterize some of the driving study that you might have conducted what the key findings. Thanks.

And of course, retreatment for patients that responded was consistent and no additive safety issues.

Yes.

I guess a few questions. There, let me start with half in driving and I'll ask al to comment on the drug to drug interaction studies. So.

Any CNS drug entering the market must be analyzed for abuse potential that Hap studies are one of the standard elements used by the agency when considering abuse potential for CNS active medication.

And as.

As a reminder, there is a 90 day review period following.

If it happens to do for approval. So the Hap study was around was consistent with the FDA guidance on this type of study and we expect the FDA to consider data from the Hap study in the entire development program of <unk> alone for a recommendation to the DEA.

We believe that given what we know and paint brain penetrant.

<unk> is around alone that will be scheduled for a drug which is not an issue.

Prescribing and again we're entirely.

So the totality of the Shoreline data will be included in the NDA filing.

Excited about the totality of zorana alone in both <unk> and PPD.

It's a large safety database, and we believe it will be instructive to clinicians on when retreatment can be used.

Critically meaningful reductions in depressive symptoms with consistent improvements in mood and anxiety the rapid onset of action, which we've talked about as little as two or three days. The two week treatment course, and the well tolerated potential certainly as an oral therapy that.

I believe that a fast-acting antidepressant that's oral and short-course is desperately needed in the world today, and we believe the agencies understand that.

And I'll ask Chris to comment on how this is a paradigm shift in the treatment of depression, but not necessarily a paradigm shift in a clinician's practice.

We clearly believe the world needs in terms of driving studies those are complete and will be part of the submission there.

Have the conversations still been interactive, relatively real-time, I guess?

I'd say there's regular interaction and updates with the FDA.

There's both the formal and then informal kind of email interactions, but yes, there's been regular interactions and things are going well.

I'll call them Checkbox studies that require to be run we anticipate as in many drugs, including over the counter drugs there'll be.

We anticipate the filing by the end of the year, and as we said on the call, if we get priority review, a PDUFA date in the third quarter of next year, and we're excited for the interactions.

Great.

Thanks.

Thanks, Ritu.

Thank you.

A warning in the label something like please don't operate our driver operate heavy machinery until the full use of the drug is known that's consistent with many drugs, even drugs like <unk>, which are use over the counter.

So you want to talk about the DDI DDI studies.

Sure Larry.

Great.

Recall that most of the studies that we've done in the past.

It doesn't pass were many of the patients were on the depressed et cetera, So and what we've seen consistently throughout all of the studies that we have seen no differences in risk.

So the safety profile of those patients on whether they are on it with one another drug or Theyre. Not in addition, you recall call study one Ron can comment with a dose of a.

And we again saw pretty much the same response as well as the safety profile of those molecules not counting.

Side effects associated with <unk> as a person.

Hey.

Data suggest that we don't see any any issues with dosing compound with other anti depressions as I've said and most of all clinical trials had patients in them.

On Stateline depressant so.

It doesn't prohibit the use and we don't see any differences in response rate between those two patient sets.

Our next question comes from Paul Matisse with Stiefel.

Thank you.

Our next question comes from Marc Goodman with SBB Leerink.

Your line is now open.

Yes, hi.

Mentioned above.

About the launch and how youre going to scale appropriately with respect to spend can you give us a little more color. What you mean or are you trying to say that we should not expect.

500 person sales force between the two companies.

Aggressive DTC on the television.

Six months. After launch are you trying to say that it's kind of something different than that or maybe you could just give us a sense of.

What you meant there and then just on dimension and survey or whats. The timeline first timelines you can tell us when you think those phase III readout. Thanks.

Thanks, Mark and I'll ask Chris and actually <unk> to comment as well so what we're what we're saying is we and Biogen are actually thinking very big about the MDT in PPD opportunities and we will use an omnichannel approach.

Leaning in on digital to start, but we're also saying that that we're going to be smart about capital allocation and think about starting at an appropriate size with salesforce with DTC and other omni channel tools and then scale with success I think it's a best practice to.

To put the right capital allocation to launch and as you see uptake with.

With site with primary care to continue scale with an update rather than scale ahead of that uptake.

Lessons learned for many many drug launches that sometimes companies overcapitalized. The launch so we're being very clear that we're going to spend appropriately to launch well and we anticipate success of launch and then we will scale with our success rather than scaling before the success, Chris Kimi anything to add.

Yes, Barry I'll take it first and then I'll pass it over to Kimi. So so with respect to what we've learned from key opinion leaders and clinicians from both market research and scientific exchanges that functionally they want faster relief and they want a therapy that can not only deliver that fast relief, but.

And that relief over a period of time without stigmatising side effects associated with other antidepressants that they've become all too familiar with over the last 30 to 35 years with that said that.

That in and of itself something that we've seen from the ran alone over the course of the landscape of NES studies, So with respect to our go to market approach, it's going to be absolutely important that we get out there quickly with that message with the data that we have to reach those clinicians that you talked about getting to with an omnichannel approach also making sure that.

We're able to reach patients with that message around what is around alone has the potential to deliver it.

I was saying, but I will mention that it's important for us to think about educating and proactively partnering with payers to make sure that they are aware of this around alone at its approval and what it ultimately can deliver as you might imagine we've already had those conversations with Payors and.

We will continue to stay engaged with payers educating and proactively preparing for the launches of rent along with that that important stakeholder group Kevin Yes, So mark I think again your question around.

Scaling is a great one right now, especially in this environment, we're going to be very smart about how we ramp up our costs in the SG&A side and that's part of that scaling that Chris just talked about but we're thinking about that across the entire organization. So even in the R&D space, we're thinking about it.

G&A, we're thinking about it is how to be very smart and disciplined in our investing.

And a good example of that was really the decision we made with Sage 904 to help that program because it didnt meet the criteria that we had set for us and so we're going to continue that.

<unk> balance sheet, but we're still being very disciplined in how we think about investing our capital.

And Mark your question about <unk>.

Sage 718, we highlighted earlier in the call the initiation of <unk>.

<unk> Parkinson's and by the end of the year, the Alzheimers study and as those studies ramp up and sites.

Come online in accrual is clear we will provide updates on when the data will read out.

Thanks.

Hey, thanks so much.

Mark.

Thank you.

Our next question comes from Vikram <unk> with Morgan Stanley . Your line is now open.

Following up on Ritu's question, on the regular...

Can you clarify, how are you framing Shoreline in the NDA?

Good morning. This is Scott on for Vikram. Thank you for taking my question.

Are you framing the study as a maintenance study, or are you framing this as sort of a broader open-label safety study with more qualitative conclusions?

You mentioned in the release that non labor changes post the rest so I expect that based on some bird studies could.

Could you provide a bit more.

Detail on what you observed in the study.

Yeah, guys. Thanks for the question. So the sunbird study was evaluating the safe use administrations of RSO.

And then to that point, what are you proposing for re-dosing in the real world?

In our home <unk> setting.

As you highlighted we don't plan to make any label changes there were no new safety signals related to Zurich Tso identified in this study was kind of.

A human use potential study rather than a placebo controlled efficacy study the study enrolled as expected and recruit on time.

And importantly, the <unk> cellular sage to develop the operational capability to run a virtual or decentralized study model that will leverage in future studies.

We remain committed to providing optionality.

<unk> with PPD, and we're really optimistic that.

With the output of Skylark that zorana alone if approved will significantly improve access for women in need of treatment for PPD.

Okay.

Thank you for the update thanks Kessel.

Thank you.

Our next question comes from Gary Nachman with BMO. Your line is now open.

Thanks, guys good morning.

So in your early payer discussions on Saran alone when you consider pricing.

Will you assume for average number of treatment courses per patient per year based on the shoreline data and how you think that's going to factor into pricing.

Are you proposing something that is as restricted as Shoreline, where you have to wait at least six weeks and you have very specific criteria for monitoring?

So we're going to submit the Shoreline as a safety data, we believe it will be instructive to retreatment.

And how payers are going to do the drug given its profile.

And then just I guess more generally.

What is the market research, telling you about each of the MDT in PPD and opportunities.

And where do you think saran alone they have a bigger impact early on when it's launched.

Both from the payers.

Payer standpoint also in terms of physician and patient.

Desire for the job.

Thanks, Gary Let me turn it over to Chris and I'll loop back at the end.

Yes, thanks, Barry so so with respect to the first question around pricing obviously, it's early to get into discussions specifically on where we're going to be with pricing <unk> Biogen, we'll provide that clarity on pricing in and around the time of approval. If were successful what I can say is that as we think about pricing we're thinking about it.

Or are you kind of proposing a paradigm where physicians have a lot more discretion than that?

It's a little early to talk about exactly what will be in the label or the guidelines for retreatment.

But I'll remind you that that, you know, physicians can use Duranilone or any other approved drug as they see fit, and as they learn more about the opportunities of how to use these medicines.

Thanks.

Chris, you want to talk about impact to practice?

Unknown Speaker Yeah, thanks, Paul, for the question.

Yeah, sure.

Thanks, Barry.

In relation to how it in a place with access at the same time, so with respect to both pricing and access it's critical that we design an approach that considers the needs of payers themselves physicians as well as importantly.

The patients who offer the product now our overall goal. It's around what is approved to ensure that appropriate patients are able to get in saran alone for both <unk> and PPD, maybe you can get it when they need it and the clinicians private the product with out without any sort of mix and in the process now what that means is that we have.

As an organization need to partner with payers to make sure that things like prior authorizations and step edits or mitigated by virtue of the way that we collaborate and think about the contracting process I know historically, we've talked about.

<unk> for us to introduce proactive value based agreements with this important stakeholder audience and that's going to be an important piece of the strategy as we think about how we're going to make sure that the product is ultimately available. So we're leaning in on those VBA conversations that we're having right now in and around conversations around unmet need and the data that we've been able to.

Demonstrate with respect to the landscape of nest around how is the rent alone has the potential to offer.

A distinct opportunity for payers to make the product available for those with both MDI and PPD. So more to come on price, but were thinking the approach holistically and it around pricing and access and again, making sure that we're educating and proactive partnering with payers with a goal of enabling at launch access.

I think the question around some of the opportunities and where we see bigger impact with respect to hcp's payers and patients.

Taking a step back and thinking about the opportunity in the marketplace.

To depression, there are $21 million or so people that experience, one or more depressive episodes in a given year and given that number there's still are 7 million patients.

Who are either new to therapy, adding therapy or switching therapy, what we know from the market research.

Given that there are a number of generic medications that have been available now for 30% to 35 years. There is still as profound unmet need in patients need new therapies with new Msas like Saran alone that offer rapid and lasting relief without the tolerability issues and the Stigmatising side effects that you see with other therapies that they become with all.

So the profile seen with clinical trials to date, in particular, the landscape studies, you know, have demonstrated that with respect to Duranilone, we've seen rapid and sustained reduction in depressive symptoms, and a generally well-tolerated safety profile with a short 14-day course of treatment after the physicians have prescribed the product.

With just a 14 day course of therapy again, I think in MTBE for those patients that are new to therapy, adding therapy or switching it offers a profound opportunity our opportunity there is to really make sure that out of the gate as launches around alone that we are engaged with those clinicians and we demonstrate the opportunity.

So with respect to the product being used, you know, this will enable physicians the, opportunity to offer patients treatment-free periods in between depressive episodes so that patients don't have to take medications on a chronic basis.

Now, what we've heard from key opinion leaders that we've engaged with in market research, you know, this in and of itself is an advancement in treatment.

To introduce our rent alone early in the treatment process, where patients can have the best expected effects with both <unk> and <unk>.

Now with respect to payers I covered all payors and what I think the opportunity there is in and around.

To educate and proactively partner with those payers, so im not going to say.

And last but not least I think patients I think as Barry noted in our in his comments about our go to market approach, it's going to be really important from an omnichannel perspective.

Patients early our awareness around alone and the distinction that surround alone offers relative to perhaps the way that they've experienced other antidepressants in the past with respect to the rapid onset of action and the sustained relief all over just requiring a two week course of therapy. So with that said Barry hand, it back to you to cover off on anything.

You know, functionally, with regard to how they've been treating depression, this is a change in the treatment paradigm.

But this does not really reflect a change in the way that physicians are actually managing patients. What we would expect is that with Duranilone, that a physician would prescribe the patient, a two-week course of therapy.

They would plan to check in with the patient at the end of that two-week period where they would hear about the efficacy and the tolerability profile of the product.

Patients would then go on to experience symptom-free life.

I may have missed.

And as needed, you know, at the six-month period, the patient would then check back in with the physician with an update.

Chris you covered it well and Gary I Hope Thats the answer I guess, just a point on use.

We believe that since Zelle Russell is the only approved drug in PPD and <unk> if approved the only oral medicine that that if we do our job right rental will quickly become standard of care in PPD won an eight live births about half a million women a year experienced PPD and with <unk>.

<unk> drug we do believe that that.

That diagnosis rates risk factor assessments will go way up because now there is something to do about it.

Chris covered it well there is a significant opportunity there are some places where.

<unk> will be used to interrupt the cycling of many anti depressants, the patient's experience and other groups like young adults, where we believe that that is rental and should be used as quickly in the treatment paradigm as possible, but more on that to come.

Okay, great very helpful. Thank you thanks, Eric.

Thank you.

Our next question comes from Neena <unk> Garg with Citi. Your line is now open.

Hey, guys. Thanks for taking my question I just wanted to go back to some of the questions on shoreline that were asked earlier and I was just wondering if you could give us an update on how.

So, let's Shoreline is the largest naturalistic study ever run in depression. It's a it's a study where patients were enrolled, and then asked every other every two weeks how they were doing.

Isn't that you interact with and the FCA are thinking about the re treatment criterias.

And as as you're aware, 80% of those enrolled in Shoreline that responded required only one or two, two weeks, of course, a two week course in the course of a year.

We're used to in shoreline and how well that aligns with physician practice and how they would actually think about re treating a patient.

I'm really just trying to understand if the.

One to two treatments per year and will translate into the real world setting. Thanks.

Yes, Thanks Nina.

We believe that shoreline represents a real world evidence study. The agency is looking for more and more real word evidence in shoreline checks.

Most of the boxes for what Youre looking for with real World evidence studies.

Keep in mind that that patient.

So two to four weeks of drug in the course of the year, and a majority of those that, respond Shoreline only needed one course of treatment in the year.

Patients were diagnosed with mbd they were given drug for two weeks.

And then on day 15, and on they know Theyre not on drug. So if there was a liability or any need to be on drug we'd see a lot more re treatment. The fact that a majority of patients stayed well. After one course of treatment for a full year is a testament to the durability of the rental and in fact that 80% of patients who respond to the initial two.

The treatment was around alone 50 milligram only received one or two treatments of course of the year with a median time of 249 days. So as you heard from Chris.

And of course, retreatment for patients that responded was consistent and no additive safety issues.

Today's practices to diagnose a patient give them a prescription instead of instructing them to.

To hang in there.

Hanging in there this could take four to eight weeks to work I believe physicians will tell their patients that they should feel better.

As little as two or three days after two evening courses of of Durant alone and as is done with practice today physicians are offices, often check back in two weeks today, they're checking back to understand the side effect profile and if any other drugs that are required to minimize side effects Gi effects.

Now, obviously, in between that two-week period and six-month period, if there were one of the hallmark symptoms of depression, if that were to return for the patient, the patient then certainly would reach out back to the clinician, and the clinician could prescribe the second two-week course.

Potential sexual dysfunction thats seen at that time at that time and then in this case, it's how how patients are doing after those two weeks and then classically there's a six months follow up so as Chris highlighted this is a paradigm shift in how <unk>.

So, again, as I said, you know, this really reflects a change in the treatment paradigm, not a change in the way that clinicians are actually managing their patients.

<unk> treated but not necessary a paradigm shift in how a physician practices with their depressed patient.

Got it thank you thanks Nina.

Thank you.

Our next question comes from Stephen <unk> with RBC capital markets. Your line is now open.

Great. Thanks. This is Steve on for Brian Congrats on the progress and thanks for taking our question curious if you can provide a bit more color on what youre expecting to see in the phase two work with NMDA, Pam and how you think about making a go no go decision efficacy, especially given the significant variability in potential responses, but I'm curious from the phase one with different stat Sig there on efficacy or just <unk>.

And what would give you confidence to move forward. Thanks.

Steve Thanks for the question and thanks for the congratulatory note I'll start and then ask al to comment so what's remarkable about Sage 718 first in class NMDA Pam is that in the early work to date, the ketamine placebo controlled studies, the Huntington's Parkinson's and Alzheimer's study we ask.

You saw a rapid improvement in cognition in a short period of time either to or in some studies four weeks, we saw it in two weeks, but continued out to four weeks.

As you're well aware.

Studies drug cognition to date or dementia to date.

With a very large and with a very long time tried to demonstrate most not successfully.

Slowing of cognitive decline over a period of time, so we're looking for improvement in cognition.

If you think about the Huntington's study, where we are running parallel studies demonstrating the numerical change, but also kind of what it means in real life.

We believe that that is.

Dramatically positive that translates into a package that we'd be enthusiastic to meet with the agency and talk about.

The fastest path to clinic for the Parkinson's and Alzheimer's study.

We're looking for.

A broad benefit risk profile trends in that improvement, but but likely phase III studies to follow so anything to add there.

Yes, I think it's interesting that most of the studies that are involved with these diseases in the past with other drug approaches or other approaches are specific to that those disease types. You have a specific study is trying to reduce.

All right.

Hey, tangled up.

These Apis nuclear will be other diseases as well.

Our approach is looking to improve brain circuitry and synaptic function and what we're seeing as you pointed out some very similar results in all three of those studies, which is very encouraging we're seeing very rapid improvement in executive function and memory with most of the approaches that are looking for the disease by changing the positioning of the plaque.

With these respective disease.

What we're seeing is those take longer because you are looking to modify the course of disease and stop the degradation of the brain where were doing is were improving static function. That's why I think we've seen there's also very early amount of time as you pointed out.

Yes, Steve hopefully that answers your question, but what we believe we are.

Developing with Sage 718 is a disease course modifier and the idea here is.

To improve executive function learning and memory, allowing patients living with these conditions to live more independently for much longer period of time.

Great. Thanks. Thanks.

Thank you. Our next question comes from Joon Lee with <unk>. Your line is now open.

Good morning. This is Austin on for Jim Thanks for taking the questions.

Just another question on 718, we were just wondering if you could provide a little color on why you are starting a phase III safety study.

On 718 before the phase III.

Thank you.

Yes, and thanks for the question so with Sage 718, we've been pretty clear that.

We are running.

Series of Phase II studies Huntington study in Parkinson's studies have been kicked off.

The Alzheimer's study that will be kicked off but it ended the year. We've designed the Huntington study in a way that will have numerical changes in kind of real world evidence on what that means as al talked about in the comments.

And if those data are robustly positive we will meet with the agency on the most rapid approach to get <unk> to market for Huntington's.

For Parkinsons and Alzheimers following the phase III studies will likely run phase III studies based upon the learnings from the phase II.

Okay. Thank you and congrats on the progress.

Thank you.

Our next question comes from Danielle Brill with Raymond James Your line is now open.

Hi, guys. This is Alex on for Danielle.

Just a quick one going back to the rainforest I know you qualitatively addressed this question.

Part I Wonder if you could expand a little bit more on the depression symptom amelioration, specifically, what the Delta was for AMD at the end of the 14 day treatment period.

Yes, Alex.

If you will will at upcoming medical meetings present rainforest just as a reminder, it was it was.

We stopped.

Both that and Redwood with a 30 milligram dose after consulting with the agency they are not required for.

Regulatory filing and it enrolled.

And did not fully enroll so the stats plan can't really be looked at what we can say today is that the profile is around alone in rainforest with consistent with data seen to date that is improvement in depressive symptoms anxiety and as the purpose of the study.

Trends to improve sleep sleep architecture, and again, we will report more out in upcoming medical conferences.

Great I appreciate the color.

Thanks, Alex.

That concludes today's question and answer session I would like to turn the call back to Barry Greene for closing remarks.

Thanks, operator, and thank you all for joining US this morning to review our second quarter progress as.

As we work to advance clinical and preclinical programs across our franchises moves around on closer to launch and commercialization of approved and reinvest our learnings and efforts to develop and launch transformative brand health medicines across the organization. We are deeply committed to continuing our focused execution in the <unk>.

Balance of 2022 and beyond.

Look forward to future updates on our progress in our mission to pioneer solutions to deliver life changing brain health medicines. So every person can thrive right. Thanks again, everyone have a great.

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

The conference will begin shortly to raise your hand during Q&A you can dial star one one.

So the totality of the Shoreline data will be included in the NDA filing.

And we're very excited about the opportunity to introduce this as we hear from clinicians, they're waiting for Zoranilone.

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It's a large safety database, and we believe it will be instructive to clinicians on when retreatment can be used.

And I really do just want to clarify on the regulatory side, given the whole back, history with Redwood and the utility of that study versus Shoreline, do you look at Shoreline as a maintenance study with the ability to have maintenance claims from that?

Good morning.

Welcome to Sage Therapeutics second quarter 2022 financial results Conference call.

Currently all participants are in listen only mode.

This call is being webcast live on the investors and media section of sages website at Sage Rx 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 Helen Rubinstein director of Investor Relations at Sage.

And I'll ask Chris to comment on how this is a paradigm shift in the treatment of depression, but not necessarily a paradigm shift in a clinician's practice.

Or, yeah, just trying to get a little more specific there.

Good morning, and thank you for joining Sage Therapeutics second quarter 2020 financial results conference call before we begin I encourage everyone to investors and media section of our website at <unk> Dot Com, where you can find the press release.

Related to today's call is Bob <unk>.

Jane supplemental detail.

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

Agents are subject to certain risks and uncertainties and our actual results may differ materially. Please consult the risk factors discussed in today's press release and in our SEC filings for additional detail.

The conference call with prepared remarks by Barry Greene, Our Chief Executive Officer, who will provide an overview of our progress during the second quarter.

We will also be joined by Al Robichaud, Our Chief Scientific Officer, who will review recent progress and development activities across our program.

Chris <unk>, our Chief business Officer, who will provide an update on our progress preparing for the launches of <unk> and MTBE in PPD, if appraisals and Kimi Iguchi, our Chief Financial Officer will review the financial results from the quarter.

I'll now turn the call over to Barry.

So we're going to submit the Shoreline as a safety data, we believe it will be instructive to retreatment.

Yeah, Paul, thanks.

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

It's a little early to talk about exactly what will be in the label of the guidelines for retreatment.

The first half of 2022 was important for Sage as we continued our focused execution across our pipeline.

We started the year by meeting our goals and achieving expected milestones on or ahead of plan timelines.

We have a tremendous sense of urgency to create innovation and meaningful medicines for people, who currently lack adequate treatment options.

Our goal is to decrease disability and suffering while improving the health and productivity of people their families and health care system.

We're making progress across the entire company as we work to further establish stage as a leader in brain health and a top tier biopharmaceutical company.

But I'll remind you that that, you know, physicians can use Duranilone or any other approved drug as they see fit, and as they learn more about the opportunities of how to use these medicines.

So again, we're going to submit Shoreline as part of the filing.

I'd like to now take a moment to review our progress in the second quarter and offer some context as to how we're thinking about the future of sage.

Chris, you want to talk about impact to practice?

It's a large safety database.

Starting with the depression franchise, we and Biogen recently announced positive results from the Phase III Skylark study evaluating <unk> alone and women with postpartum depression or PPD.

Yeah, sure.

We believe it will be instructive to a retreatment.

We believe the totality of the data generated with <unk> alone support the potential of <unk> alone as a rapidly acting generally well tolerated oral therapeutic to treat major depressive disorder or <unk> as well as PPD with sustained effect.

Thanks, Barry.

People with depression deserve new treatment options.

We believes around alone has the potential to deliver that important new options.

With the placebo controlled studies of <unk> alone and <unk> reported.

We are focused on completing the NDA filing for <unk>, which you announced the start of in May as a rolling submission.

As we've shared our NDA will include both <unk> and PPD and one filing and we believe this is an exciting opportunity to accelerate our planned submission in PPD, providing the opportunity to brings around alone to people with mbd in PPD as efficiently as possible.

Our planned filing timeline, if we received priority review.

<unk> a possible <unk> date for <unk> in the third quarter of 2023.

Work is well underway and on track for the potential launches around alone and MTBE in PPD.

Strategically, we're thinking big about the opportunity in both <unk> and PPD as we develop a focused launch plan, which we expect to scale with success.

To launch successfully will need to continue to deepen our engagement with key stakeholders around the profound unmet need that exists for those living with <unk> and PPD.

We plan to educate payers on the <unk>.

Randall and value proposition, which is supported by the weight of the clinical evidence from the landscape in this program.

Lastly, we expect to further build internal capabilities intended to enable strong launch execution.

We believe that if we continue to successfully act on these items and execute on our launch plans.

Clinicians will prescribes ran alone an MD in PPD with the sense of urgency.

<unk> with MD in PPD will astra's around alone and payers will enable access to this critically needed treatment. All of this is important to both indications are approved.

To further support these preparations we announced this morning that Chris <unk> has been promoted to Chief business Officer Christopher.

Chris will provide more details on our ongoing commercialization preparation efforts later in the call.

Additionally, we made progress during the quarter in our neuroscience franchise led by Sage 718.

Wholly owned first in class NMDA Pam.

Impaired cognition is a significant morbidity of these diseases and can have a dramatic impact on people's ability to live life independently and to thrive.

We're committed to advancing the <unk> program with the goal of further demonstrating its therapeutic potential and novel approach.

Our neurology franchise led by Sage three to four is being evaluated as a potential treatment for people suffering from a central tremor and other neurological disorders.

Movement disorders can make the simplest activities of daily life difficult if not impossible.

We've made encouraging progress across all our therapeutic areas in the second quarter and to date.

Closer to delivering our science to patients and creating value for society.

Ultimately advancing our mission to fearless and lead the way to create a world with better brain health. So every person can thrive.

I want to thank the entire sales team the patients in our clinical studies and their families. All those involved in running clinical studies and our collaborators for the hard work and dedication.

The next 18 months will be pivotal for us as we continue to execute on our <unk> program and across our broader pipeline.

And we're excited for the journey ahead.

Even in these extraordinary times I'm confident we can deliver the next chapter in our success.

With that I'll turn the call over to al for more detailed discussion of our portfolio progress and current clinical expectations.

<unk>.

Thanks, Barry and good morning, everyone as Barry mentioned, we made important pipeline progress during the second quarter I am pleased to detail our advances as well as comments on our early development programs.

Now, what we've heard from key opinion leaders that we've engaged with in market research, you know, this in and of itself is an advancement in treatment.

You know, functionally, with regard to how they've been treating depression, this is a change in the treatment paradigm.

They would plan to check in with the patient at the end of that two-week period where they would hear about the efficacy and the tolerability profile of the product.

Patients would then go on to experience symptom-free life.

And as needed, you know, at the six-month period, the patient would then check back in with the physician with an update.

Thank you.

So again, as I said, you know, this really reflects a change in the treatment paradigm, not a change in the way that clinicians are actually managing their patients.

And we're very excited about the opportunity to introduce this as we hear from clinicians, they're waiting for Duranilone.

Or, yeah, just trying to get a little more specific there.

28% to <unk> 45, compared to placebo as well as change from baseline in the CGI S score at day 15.

Yeah, Paul, thanks.

Notably surround 50 milligrams demonstrated a statistically significant and clinically meaningful reduction in depressive symptoms compared to placebo as measured by change from baseline <unk> 17 at day 15 of four points and a corresponding P value of zero.

So again, we're going to submit Shoreline as part of the filing.

It's a large safety database.

We believe it will be instructive to a retreatment.

007.

These results are remarkable and reinforced the data observed across is around alone clinical development program in which treatment with surround alone resulted in a rapid reduction in depressive symptoms that was sustained throughout the follow up period with a generally well tolerated safety profile.

Skylark study underscores the potential was around alone to be an important differentiator therapy, if approved and completed the placebo controlled trials in both our landscape and this programs and NPD in PPD.

We also presented data from our human abuse potential study with <unk> alone in the second quarter and this study is around 130 milligram and 60 milligram both doses in the therapeutic range demonstrated lower abuse potential compared with alprazolam, one five milligrams and three milligrams and 90 milligrams is around alone was.

Comparable to our <unk>. These.

These data along with our clinical data support viable medical use and lower like ability and abuse potential was around alone.

I'd also like to highlight that we announced in early June that enrollment is complete and the shoreline study. It was around one and MDT Shaw is the largest naturalistic study done to date in depression and is examining as needed intermittent dosing over the course of one year.

When, we met with the agency, and I think it was the fall of last year, we confirmed that Shoreline would be sufficient as part of the filing, and the Redwood study no longer needed to be run because we had sufficient data of retreatment.

So we'll provide more as we interact with the agency and get into label negotiations.

Okay.

Thanks, Barry.

We recently presented data from the previous reported cohort of the shoreline study at the American Society of clinical Psychopharmacology annual meeting as.

Thanks, Paul.

Thank you.

As a reminder, in the 50 milligram cohort of the shoreline study, 80% of patients who responded to the initial two week treatment with Sorel alone 50 milligrams only received one or two treatment courses during their time in this year long study with a median time the second treatment course of 249 days.

Our next question comes from Ami Fadia with Needham.

Your line is now open.

These data support our belief is around alone can have remarkable durability. We look forward to sharing more data from <unk> clinical development program and key scientific forums over the next several quarters I will highlight specifically our upcoming data presentations at the 2022 Psych Congress in September .

Good morning.

Thanks for taking my question.

Maybe just a follow-up to the previous question.

Do you anticipate the indication for the product to be just treatment of depression, or would, it be classified as something more specific, such as acute treatment?

And do you expect the FDA to limit the number of treatments in a year?

In addition, we are sharing an update on both the rainforest and Redwood studies today as a reminder, the rainforest study was designed to investigate the efficacy and safety of 30 milligrams was railroad a sleep architecture and NPD. The same objective primary endpoint measured in trials of insomnia disorders.

And then I have a question on the pipeline.

Ami, thanks for the question.

Study was designed to examine fixed schedule intermittent dosing of 30 milligrams as our zircon alone throughout the course of a year.

This study was also designed to complement the shoreline study, which examined the as needed intermittent dosing of the railroad.

Based on our discussions with the FDA at the time, we suspended both the rainforest and Redwood studies in early 2020 before they were completed.

These decisions were based on our plans to advance the program with the 50 milligram dose of <unk>.

Furthermore, we believe and confirmed with the agency. Neither study is needed to support our NDA filings that said I'd like to share some high level findings from these studies.

Starting with the rainforest study, although terminated early study provided important insights on the potential effect of is around alone and the improvement of sleep parameters in patients with MTT.

The study was not fully enroll with only 87 patients randomized.

Directionality of the improvement in sleep architecture was clear with the railroad 30 milligram showing numerical advantage over placebo and objective measures of quality of sleep, including wake after sleep onset total sleep time latency. The persistency median number of wakening medium duration of weakening and endpoints.

Following rems sleep.

<unk> is one of the most common symptoms associated with depression and disturbances asleep associated with decline in quality of life is.

It's very clear that improving sleep in depression is associated with better outcomes, making the findings from our rainforest study are encouraging as they suggest that <unk> may provide a steep benefit to patients suffering with mbd.

As many of the prisoners can negatively impact sleep architecture. This would be an exceptional potential benefit of Dorado and treatment.

We believe that data across is around our own clinical development program, along with the directional learnings from the rainforest study reinforce that <unk> mechanism of action may address multiple aspects of depression, including the core depressive symptoms as well as symptoms of anxiety insomnia.

Turning now to the Redwood study the fixed schedule intermittent dosing of 30 milligrams was around alone.

Three patients with MTB were enrolled in the open label Phase of the study and two patients proceed into the randomized phase before it was terminated.

Given the low number of patients random randomized there is enough data from the Redwood study to identify any trends will.

But we can say is that no additional safety findings were reported.

So in terms of specifics of the label, again, it's too, early to talk about label specifics until we really get into it with the agency.

In terms of re treatment, we do have data from another study in the clinical development program. The open label shoreline study and NPD that I mentioned earlier.

When, we met with the agency, and I think it was the fall of last year, we confirmed that Shoreline would be sufficient as part of the filing and the Redwood study no longer needed, to be run because we had sufficient data of retreatment.

We've said previously, and we anticipate an indication statement, something like for the treatment of MDD and PPD, so pretty straightforward indication statement.

We believe these data afford the closest real world evidence, we have to date on the potential of <unk> therapy in the treatment of NBD may help guide patients and health care providers in treatment choices, if <unk> is approved.

As we talked about with Paul's question, we believe Shoreline will be instructive for retreatment.

Additionally, in the shoreline study for those patients who use one or more re treatments efficacy and safety outcomes were similar to those observed in initial treatment course.

We've got data up to five retreatments in the course of the year, and we believe that the total data set will be instructive for retreatment.

So we'll provide more as we interact with the agency and get into label negotiations.

We look forward to sharing the data collected from the rainforest study as well as additional data across the entire clinical development program at upcoming conferences.

Okay.

Thanks, Eric.

Thanks, Paul.

<unk> is one of our wholly owned programs and was granted fast track designation by the FDA as a potential treatment for cognitive impairment and huntington's disease or HD.

Thank you.

Our next question comes from Ami Fadia with Needham.

We also investigated sage 718 people with mild cognitive impairment due to Parkinson's disease, or <unk> and people with mild cognitive impairment and mild dementia due to Alzheimer's disease or <unk>.

Your line is now open.

Sage 708 data had been consistent and demonstrated improvement an important test of executive function across multiple open label studies to date, including the paradigm and luminary studies in people with mild cognitive impairment due to PD and people with mild cognitive impairment and mild dementia due to avid's respectively.

Additionally, placebo controlled ketamine exposure study subjects. We received 71 eight demonstrated a statistically significant improvement on several cognitive tests, including the two back test compared to those treated with placebo multiple time points.

And our <unk> clinical studies, we are making progress in enrolling the phase II dementia study and the phase III surveyor study in people with HD cognitive impairment.

We believe the complementarity of these two studies will help us understand the potential benefits of Sage 708, an HD.

Basically the survey is that he will help us to answer the <unk> question.

So what do these cognitive effects move for patients in activities of daily living and what impact with Sage 708 have other everyday lives.

Turning to our other clinical programs and Neurodegenerative diseases enrollment and the precedent study a phase II placebo controlled study of Sage 708, and people with mild cognitive impairment due to PD is going very well. We also remain on track to initiate a placebo controlled phase II study with <unk> 708, and people with mild cognitive impairment and mild.

Dementia due to a.

Planned to begin in late 2022.

Lastly, I'd also like to highlight recent advancements in our neurology franchise led by Phase III, two four and next generation positive allosteric modulator of Gaba a receptors, which we believe hold significant potential in the treatment of neurological conditions like essential tremor, where ETE is a disease that has limited treatment options for patients.

This had no innovation for over 50 years.

We are pleased to announce that we have initiated our phase two long term open label safety study with phase III for <unk>.

The aim of this study is to assess the long term safety and Tolerability of <unk> hundred two for over a multi year period with the incidence of treatment emergent adverse events as a primary endpoint.

In addition, we are continuing to enroll in our phase <unk> kinetic two dose ranging study evaluating phase III for AEP to optimize the dose and frequency and continue to expect enrollment completion to occur in late 2022.

Good morning.

To close for me, it's been a rewarding journey over the last decade and are proud of the team was moved this dynamic pipeline forward. We're excited about what's to come in the next 18 months and believe our organization is poised to continue building our momentum generated in the first half of the year is one of the leaders in brain health.

Thanks for taking my question.

Maybe just a follow-up to the previous question.

Do you anticipate the indication for the product to be just treatment of depression, or would it be classified as something more specific, such as acute treatment?

And do you expect the FDA to limit the number of treatments in a year?

As Chris highlighted, the normal course of practice would be to prescribe a medicine, in this case, if it's Zoranolone, rather than instructing the patient that, you know, hang in there, this could take four to eight weeks to work. We believe that patients will be instructed that please take this at night with your dinner.

Now I'll turn the call over to Chris to provide additional context on our planned approach as you prepare for the potential commercialization of surround alone and Mgd and PPD Chris.

And then I have a question on the pipeline.

You may feel better in two or three days.

Thanks Al I am pleased to be with you. All this morning to share updates on our commercialization preparations for <unk> alone.

Ami, thanks for the question.

Take the full two-course treatment.

Patients with depression urgently need new treatment options that are safe, we're quickly and offer lasting effects and increase in the global prevalence of depression has been consistently reported since 1990 and approximately one in five adults in the United States will experience mbd at some point in their lives.

So in terms of specifics of the label, again, it's too early, to talk about label specifics until we really get into it with the agency.

And as normal, I'll check back in with you in two weeks.

If you're dark in mood, anxiety, increases, or sleep disruption occurs again, please check back in.

Otherwise, we'll see you in six months.

So as Chris highlighted, in the normal course of practice, and if there's a retreatment required, we believe that we've got data that instructs on retreatment.

We've said previously, and we anticipate an indication statement, something like for the treatment of MDD and PPD. So pretty straightforward indication statement.

So, Bayard, do you still anticipate an adcom, or that's left there at this point?

As we talked about with Paul's, question, we believe Shoreline will be instructive for retreatment. We've got data up to five retreatments in the course of the year.

No change in anticipation or not.

Whether an adcom is used or not, it's at the sole, discretion of the agency.

There's no regulatory statute for exactly how or when they share with us.

And we believe that the total data set will be instructive for retreatment.

Current treatments for mbd in PPD are often not adequate to address the profound challenges of treating depression.

As Chris highlighted, the normal course of practice would be to prescribe a medicine, in this case, if it's Zoranolone, rather than instructing the patient that, you know, hang in there. This could take four to eight weeks to work. We believe that patients will be instructed that please take this at night with your dinner.

You may feel better in two or three days.

Take the full two-course treatment.

This on top of more people seeking treatment for depression.

Care system that fails to appropriately screen and assess and a significant portion of the population failing to receive care to.

To put it simply the current treatment paradigm relies on a try and fail approach that does not meet the needs of many people with MD in PPD.

Something must change because those who suffer from depression, many of whom are family and friends deserve better.

Stages prepared to be at the forefront of that solution with our plans for a single NDA filing pre saran alone that will include both MDT and PPD indication, we have a clear commercialization strategy, which prioritizes stakeholder engagement leverages disease state awareness and build capabilities that we believe will enable us to execute at a high level.

We think that we'll learn more clearly after our NDA filing, and again, if we get prior review, a PDUFA date in the third quarter of next year.

Of course, we're preparing for an adcom, and we are going to be very well prepared if they choose an adcom.

If they don't want an adcom, and it signals speed of approval, that would be great.

Scale with success.

If they do hold an adcom, we look forward to that as well, because it'll allow us to feature the totality of the Zoranilone data and really put it on display.

I'd also like to provide some high level thoughts on our approach to market access.

Got it.

Payers are telling us that the unmet need for patients with <unk> and PPD is clear.

I guess I've asked roughly one or two questions, but maybe just one quick one on 718.

Prevalence of depression continues to rise despite available treatments and new treatment options that were quickly are desperately needed.

When do we anticipate data from any of these ongoing studies?

And if you start to see positive data come through, would you anticipate developing all, of these three indications on your own, or would you consider partnering?

To that end, we are thinking strategically about pricing and access and working to design an approach that considers the needs of payers and healthcare professionals and most importantly patients and their families. Our overall goal with Saran alone. It if approved is to ensure that appropriate patients with MDM PPD, who are prescribed saran alone can quickly receive it.

Thank you.

Yeah.

Thanks, Ami.

So we're excited by the SAGE 718 program, a first-in-class NMDA PAM. We recently announced the initiation of studies for SAGE 718 in Huntington's mild cognitive, impairment and MCI due to Parkinson's disease, and we anticipate starting a placebo-controlled, Alzheimer's study by the end of the year. And as you're well aware, we presented data from the various studies showing consistent, improvement in executive function, learning, and memory.

As such we believe that it's essential that we work with payers to try to minimize barriers that can impact the health care professionals ability to prescribe saran alone to treat MDM PPD. So their patients have the potential to obtain rapid and sustained relief of their depressive symptoms.

So as we get these studies up and running and enrolling, we'll provide further guidance, on exactly the timing of data readout.

In terms of phase threes, that's something that we'll make a determination on once some, of the phase twos read out.

Clearly, the Huntington studies have been designed in a way that if positive, we'll, meet with the agency to discuss the fastest way of getting SAGE 718 to the market.

And as normal, I'll check back in with you in two weeks.

Okay.

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

If your darkened mood, anxiety increases, or sleep disruption occurs again, please check back in.

Otherwise, we'll see you in six months.

Thank you.

Thanks, Chris our financial results for the second quarter of 2022 are detailed in our press release issued this morning I.

Thanks, Ami.

So as Chris highlighted, in the normal course of practice, and if there's a retreatment required, we believe that we've got data that instructs on retreatment.

As a reminder, in the interest of time, we ask that you limit yourself to one question, and rejoin the queue for any follow-ups.

I'd like to take a moment to provide some context and highlight a few key points.

Our next question comes from Jay Olson with Oppenheimer.

At the end of the second quarter, we continued to be in a strong cash position that we believe will provide our organization with the flexibility to make strategic investments across our franchises and support the launches around alone.

Your line is now open.

Good morning.

By the way.

So, Barry, do you still anticipate adcoms, or that's left there at this point?

Thank you for the update and for taking the question.

Our net loss for the second quarter of 2022, with a $126 3 million and we ended the quarter with cash cash equivalents and marketable securities of $1 5 billion.

No change in anticipation or not.

Whether an adcom is used or not, it's at the sole discretion of, the agency.

There's no regulatory statute for exactly how or when they share with us.

We think that we'll learn more clearly after our NDA filing.

Turning to operating expenses R&D expenses increased to $77 3 million in the second quarter of 2022 compared to $66 2 million to the same period in 2021.

The increase in spend was primarily related to spending on page $3 24 on our wholly owned pipeline with.

Sage 718.

Looking forward, we expect R&D spend to continue to increase in the coming quarters as we advanced the six planned and ongoing phase II study with Sage 718 <unk> hundred.

24.

And earlier.

Importantly, the flexibility provided by our strong cash position allows us to invest in our wholly owned pipeline, where our confidence is demonstrated by our dance. They are three potential indications for <unk> 17, and continued work on class eight 689, <unk> thousand 19 on page 21.

SG&A expenses increased to $52 4 million in the second quarter of 2022.

Care to $43 3 million for the same period of 2021.

The increase is primarily related to hiring employees to support ongoing activities in anticipation of potential future product launches of our product candidates.

As you heard from Barry we are preparing for the potential launches they ran alone.

We expect that SG&A expenses will increase as we continue commercial preparation.

As part of our collaboration with Biogen quite shortly developing Duran alone Sage 324, with a 50 50 cost sharing in the United States.

During the second quarter, we recorded $23 8 million in reimbursement from Biogen related to our collaboration and license agreement.

Looking ahead into the rest of 2022, we're reaffirming the financial guidance that we provided earlier this year we.

We anticipate having cash cash equivalence and marketable securities of approximately $1 3 billion at the end of 2022.

We do not anticipate receipt of any milestone payments from collaborations in 2022.

We believe that our current cash cash equivalents and anticipated funding from our ongoing collaboration.

<unk> revenue will support operations into 2025.

Despite the uncertain market environment, we all face Sage continues to act from a position of strength.

I'm confident that we'll continue to execute throughout the remainder of 2022 and ARPA state to deliver life changing brain health medicine, So abbvie pricing can drive.

Moreover, our posted stage in April quick decision, making facilitating disciplined investments that we believe will provide value over the long term as we execute our efforts to lead in brain health.

While were thinking big about this around one opportunity we have.

Very mindful of the capital allocation prior to launch we plan to invest appropriately and be prepared to scale with it.

I'll now turn it over to Hal Alejandro Q&A with the operator.

Alan.

Thanks, Kenny before I turn it over to the operator I'll ask that you limit yourself to one question and you have an additional question. Please feel free to returns. Thank you.

Now I'll turn it over to the operator to handle Q&A operator.

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

Please standby, while we compile the Q&A roster.

Our first question comes from Sal <unk> with Goldman Sachs. Your line is now open.

Hi, Thanks for taking our question. This is Tommy on for Celgene and our questions about rain Forest will reinforce was terminated are there plans to share the data with the agency is there the possibility that findings from this study could be included on the label in some way and are there plans to restart. These studies with a 50 milligram dose. Thank you.

Can you please remind us the original objectives of the Redwood and Rainforest studies and, whether or not you plan to continue pursuing those objectives and whether any of the study results are going to be included in the NDA filing?

Thank you.

Yeah.

Yes, Tommy Thanks. Thanks for the question. So we will be presenting data from the rainforest study, which as you mentioned the 30 milligram dose.

Thanks for the question, Jay.

Let me first comment that the discussion you led with Greg Mattingly was just outstanding.

It was terminated early we made that decision in conjunction with the agency and as a reminder.

Thanks for doing that.

I think it really highlighted how someone who uses seraniline thinks about that drug.

Neither rain forest or Redwood data are required for the NDA filing of course, those data will be shared.

The data we saw in <unk> for us was consistent.

The totality of data seen to date was around alone.

Reduction in depressive symptoms reduction in anxiety and importantly, this is what specifically being studied.

<unk> in sleep and sleep architecture, it's too early to talk about exactly what's in the label or what will be able to use them promotion, but these findings will be important as we commercialize <unk>, Chris anything to add.

That was very instructive, not only for us, but I think for many in the community trying, to understand the use of seraniline, so thanks for that.

In terms of Rainforest and Redwood, we don't anticipate running a Redwood study now or, any time in the future.

As we've highlighted, we believe that the retreatment data in Shoreline, which will, be part of the submission, will be instructive not only from a safety database perspective, but in terms of how retreatment can be used.

In terms of Rainforest, which is the study MDD, those with insomnia, we actually saw, very positive results consistent with the totality of the seraniline data, and that's a study we might run in the future.

We have more to do with our collaborators, Biogen, to outline the unmet needs in the, Phase 3b4, so stay tuned for more on that later.

No very well.

Excited about the opportunity and we'll continue to see the impact of reinforced as future opportunities moving forward.

Great.

Thanks Tommy.

Yeah.

Thank you.

Thanks, Jay.

Our next question comes from Ritu <unk> with Cowen Your line is now open.

Good morning, guys. Thanks for taking the question.

I wanted to ask about how confident you feel about the regulatory pathway that youre going to be embarking on shortly specifically.

No.

Is there any learnings from the axiom quest.

Ongoing.

Film review.

That you've taken away or that is green dot will better prepare you for what the FDA wants on the outside.

Arsenal in the process.

Thank you.

Yes. Thank.

Thank you for that question I would I would say, we're highly confident in the interactions we've had with.

Our next question comes from Yasmeen Rahimi with Fiber Sandler.

With FDA stem.

Can tell you that all modules are are in hand, and going very well.

The non clinical CMC modules as well as the clinical modules are all well on schedule.

Obviously, there are there are things that can happen that are unforeseen, but we feel very good about all of the modules that are in preparation and the interactions we have with the agency and I believe that a fast acting antidepressant, that's oral and short courses desperately needed in the word world today, and we believe the agencies understand that.

Have the conversation still been interactive relatively real time.

Yes.

I'd say I'd say this regular interaction and updates with the FDA. There is both formal and informal kind of E mail interactions, but yes, theres been theres been regular interactions and things are going things are going well we anticipate.

And again, if we get back to, again, if we get prior review, a PDUFA date in the third quarter of next year.

The filing by the end of the year and as we said on the call. If we get priority review <unk> date in the third quarter of next year and we're excited for the interactions.

Great. Thanks, Thanks for you too.

Of course, we're preparing for an adcom, and we are going to be very well prepared if they choose an adcom.

Thank you.

Our next question comes from Paul Matisse with Stifel. Your line is now open.

If they don't want an adcom, and it signals speed of approval, that would be great.

Your line is now open.

Hey, Thanks, so much following up on <unk> question on the regulatory.

But sorry side can you clarify how are you framing shoreline in the NDA are you framing this study adds.

Maintenance study or are you framing this as sort of a broader open label safety study with more quality qualitative conclusions and then to that point what are you proposing for for.

For re dosing in the real World are you proposing something that is as restricted of shoreline, where you have to wait at least six weeks and we have very specific criteria for monitoring or are you kind of proposing a paradigm, where physicians have a lot more discretion in that thanks. So much.

Hi, this is Safna on for Yas.

Yes, Thanks, Paul for the question. So let's shoreline is the largest naturalistic study ever run in depression.

Thank you for taking our questions.

So regarding the Shoreline, study, you mentioned that the median time to the second treatment course was 249 days.

It's a study where patients were enrolled and.

And then asked every other every two weeks how they were doing.

And as.

As Youre aware, 80% of those enrolled in shoreline that responded required only one or two weeks or.

Two of course in the course of the year. So two to four weeks of drug in the course of the year and a majority of those that respond shoreline only needed one course of treatment in the year and of course re treatment for patients.

That responded.

Rental or any other approved drug as they see fit and as they learn more about the opportunities of how to use. These medicines, Chris you want to talk about impact of practice.

Yes sure. Thanks, Barry so so the profile seen with prominent clinical trials to date in particular the landscape studies.

We have demonstrated that with respect to saran alone, we've seen rapid and sustained reduction in depressive symptoms and is generally well tolerated safety profile with a short 14 day course of treatment.

Can you tell like what's the shortest and the longest duration before which the patient needed, the second dose?

Physicians have prescribed the product so with respect to see the product being used this will enable physicians opportunity to offer patients treatment free periods in between depressive episodes. So the patients don't have to locations on a chronic basis now what we've heard from key opinion leaders that we've engaged with.

And what's the longest time duration for safety analysis in the Shoreline to date?

Market research.

The efficacy and the Tolerability profile of the product patients would then go on to experience some free symptom free life and as needed at the six month period.

<unk> backend with the physician with an update now obviously in between that two week period in period, if there were.

One of the hallmark symptoms of depression, if that were to return for the patient to patient and certainly would reach out back to the clinician and the clinician could prescribe. The second two week course, so again as I said this really reflects changing the treatment paradigm not a change in the way that clinicians are actually managing their patients and we're very excited about the opportunity to introduce this.

We hear from clinicians they're waiting for <unk>.

Thank you.

Just trying to get a little more specific there yes, Paul thanks.

So again, we're going to submit shoreline as part of the filing it's a large safety database. We believe it will be instructive to a re treatment when we met with the agency.

I think it was the fall of last year, we confirm that shoreline.

Would be sufficient as part of the filing and the Redwood study no longer needed to be run because we had sufficient data of re treatments. So we'll provide more as we as we interact with the agency and get into label negotiations.

Yeah, Swapnil, thanks for the discussion.

Okay. Thanks, Bert Thanks, Paul.

So Shoreline is a very instructive study.

Thank you.

Our next question comes from Amit <unk> with Needham Your line is now open.

Again, it was the largest naturalistic study run to date in depression. We've enrolled over 1500 patients, and it was a one year duration study.

Good morning, Thanks for taking my question, maybe just a follow up to the previous question.

Do you anticipate.

The indication for the product to be.

Treatment of depression or would it be cloud.

Classify that something was supposed to say Chris is acute treatment.

Do you expect the FDA to limit the number of treatments in the year.

And then I have a question on the pipeline.

Amit Thanks for the question so in terms of.

The specifics of the label again, it's too early to talk about label specifics until we really get into it with the agency. We have said previously and we anticipate an indication statements something like for the treatment of <unk> and PPD, so pretty straightforward.

Pretty straightforward.

Straightforward indication statement.

As we talked about with Paul's question, we believe shoreline will be instructive for re treatment. We've got data up to five recruitment in the course of the year and.

So the majority of patients that responded in Shoreline required only one two week course in the course of a year.

Patients will be instructed that.

Please take this at night with dinner, you may feel better in two or three days.

The full two course.

Treatment and as normal I'll check back in view in two weeks, if you're dark and mood anxiety increases or sleep disruption occurs again please.

Please check back in otherwise, we'll see in six months, so as Chris highlighted.

In the normal course of practice and if theres a recruitment required we believe that we've got data that instructs on re treatment.

Mhm.

Do you still anticipate AD com or less.

Less clear at this point.

No change in anticipation or not.

Whether an AD com is used or not at the sole discretion of.

The agency Theres, no regulatory statute for exactly how or when they share with us.

We think that we'll learn more clearly after our <unk>.

NDA filing and again, if we get priority review <unk> date in the third quarter of next year of course, we are preparing for an AD com and we are going to be very well prepared if they choose an AD com if they don't.

Wanted to Ed come in it.

Got it.

Signal speed of approval that would be great if the.

If they do hold, an adcom, we look forward to that as well, because it'll allow us to feature the totality of the, Zoranil on data and really put it on display.

I do hold the AD comm, we look forward to that as well because it will allow us to feature the totality of the <unk> data and really put it on display.

Got it.

I guess I've asked roughly one or two questions, but maybe just one quick one on 718.

I guess my boss.

Good afternoon, two questions, but maybe just one quick one on.

Kevin money.

When do we anticipate data from any of these ongoing studies?

When do we anticipate data from <unk>.

From any of these ongoing studies and.

And if you start to see positive data come through, would you anticipate developing all, of these three indications on your own, or would you consider partnering?

If you start to see positive data come through would you anticipate developing all of these three indications on your own or would you consider partnering.

Thank you.

Yes.

Yeah.

Yeah. Thanks, Amit.

Thanks, Ami.

Really excited by the Sage 718 program a first in class.

NMDA Pam, we recently announced the initiation of studies for Sage 718 in Huntington mild cognitive impairment.

And Mci due to Parkinson's disease, and we anticipate starting a placebo controlled Alzheimer's study.

By the end of the year and as Youre, well aware, we presented data from from.

The various studies showing consistent.

Improvement in executive function learning and memory, so as we.

So as we get these studies up and running and enrolling, we'll provide further guidance, on exactly the timing of data readout.

Get these studies up and running and enrolling will provide further guidance on.

Exactly the timing of data Readouts in terms of.

In terms of phase threes, that's something that we'll make a determination on once some, of the phase twos read out.

<unk> threes.

It's something that we will make a determination on what some of the phase II readout clearly the Huntington studies have been designed in a way that.

Clearly, the Huntington studies have been designed in a way that if positive, we'll, meet with the agency to discuss the fastest way of getting SAGE 718 to the market.

If positive.

We will meet with the agency to discuss the fastest way of getting Sage 718 to the market.

Okay.

Thank you.

Okay. Thank you thanks Tommy.

Thanks, Ami.

As a reminder, in the interest of time, we ask that you limit yourself to one question, and rejoin the queue for any follow-ups.

As a reminder, in the interest of time, we ask that you limit yourself to one question and rejoin the queue for any follow ups.

Our next question comes from Jay Olson with Oppenheimer.

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

Your line is now open.

Good morning.

Thank you for the update and for taking the question.

Good morning, Thank you for the update and for taking the question.

Thank you.

Thanks for the question Jay.

Thanks for the question, Jay.

Let me first comment that the discussion you led with Greg Mattingly was just outstanding.

Let me first comment that the.

Discussing you led with Greg not only with just outstanding things Youre doing that I think it really highlighted how someone who uses around oil and thinks about.

Thanks for doing that.

I think it really highlighted how someone who uses seraniline thinks about that drug.

It was very instructive, not only for us, but I think for many in the community trying, to understand the use of seraniline, so thanks for that.

In terms of Rainforest and Redwood, we don't anticipate running a Redwood study now or, any time in the future.

We don't anticipate running a redwood study now or anytime in the future as we've highlighted we believe that the retreat in data in shoreline, which were part of the submission will be instructive not only from a safety database perspective, but in terms of how re treatment can be used in terms of rainforest study MVD.

In terms of Rainforest, which is the study MDD of those with insomnia, we actually saw, very positive results consistent with the totality of the seraniline data, and that's a study we might run in the future.

Those with insomnia Directionally saw very positive results consistent with the totality of these rental and data and that's the study we might run in the future we have more to do with our collaborators biogen through that outline the unmet needs in the phase III before so stay tuned for more on that later.

We have more to do with our collaborators, Biogen, to outline the unmet needs in the, Phase 3b-4, so stay tuned for more on that later.

Great.

Thank you.

Great. Thank you thanks Jay.

Thanks, Jay.

Thank you.

Yes.

Thank you.

Our next question comes from Yasmeen Rahimi with Fiber Sandler.

Okay.

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

Yeah.

Your line is now open.

Hi, this is shopping around for.

Yes. Thank you for taking our questions. So regarding the shoreline study you mentioned that the median time to the second treatment course was 200 and party 90 days.

Can you tell us whats the sharpest and the longest duration before which the patient needed the second dose.

And what's the longest kind.

Duration for safety analysis in the short line to date. Thank you.

Hi, this is Shatner on for Yas.

Yes, no. Thanks for the discussion so shoreline.

Your line is very instructive study again it was the largest naturalistic study run to date in depression, we've enrolled over 500 patients and it was a one year duration study so.

Thank you for taking our questions.

The majority of patients that responded in shoreline required only one two week course in the course of the year and the <unk>.

And the 80% of patients had one or two two week courses in the course of a year.

So it really speaks to the effectiveness and durability of Shoreline.

So regarding the, Shoreline Study, you mentioned that the median time to the second treatment course was 249 days.

The fact that the median time to retreat was 249 days, I think is demonstrable that the majority of patients first depressive episode was treated, and treated well, and then potentially another trigger event caused another depressive episode requiring a retreatment.

Can you tell like what's the shortest and the longest duration before which the patient needed, the second dose?

Potentially another trigger event caused another depressive episode, requiring a re treatment, but again the majority of those responded did not require re treatment in terms of short and long duration will be providing more data as we prevent shoreline.

But again, a majority of those responded did not require retreatment.

And what's the longest time duration for safety analysis in the Shoreline to date?

In terms of short and long duration, we'll be providing more data as we prevent, Shoreline as we presented ASCP, more details for Shoreline in meetings to come.

We presented a SCP.

More details for sure lying in meetings to come.

Thank you.

Yeah, Swapnil, thanks for the discussion.

Our next question comes from Yatin Suneja with Guggenheim Partners.

Our next question comes from Tim <unk> with Guggenheim Partners. Your line is now open.

So Shoreline is a very instructive study.

Your line is now open.

Alright, Thanks for taking my question just a question.

In line.

I mean, we've increased.

<unk> seen the <unk>, so just trying to get a sense of some of the DDI work that you might have done can you just comment on that and also showing positive impact on sleep.

Thanks for taking my question.

Across multiple studies.

Ken.

<unk> combined with some of the sleep AIDS are.

Sedative and <unk> that are out there. So just trying to get a sense of the combo and also if you can characterize some of the driving study that you might have conducted more than what the key findings. Thanks.

Again, it was the largest naturalistic study run to date in depression. We've enrolled over 1500 patients, and it was a one year duration study.

Just a question in line.

So the majority of patients that responded in Shoreline required only one two week course in the course of a year.

And the 80% of patients had one or two two week courses in the course of a year.

Yes.

So it really speaks to the effectiveness and durability of Shoreline.

I guess a few questions. There, let me start with half in driving and I'll ask al to comment on the drug to drug interaction studies. So.

But again, a majority of those responded did not require retreatment.

In terms of short and long duration, we'll be providing more data as we prevent, Shoreline as we presented ASCP, more details for Shoreline in meetings to come.

Thank you.

Any CNS drug entering the market must be analyzed for abuse potential. The Hap studies are one of the standard elements used by the agency when considering abuse potential for CNS active medication.

I mean, we've recently seen the HAP, study.

And as a reminder, there is a 90 day review period following.

We believe that given what we know in the brain penetrant.

<unk> is around alone that will be scheduled for a drug which is not an issue.

Prescribing and again we're entirely.

Cited about the totality of zorana alone in both <unk> and PPD.

<unk> meaningful reductions in depressive symptoms with consistent improvements in mood and anxiety the rapid onset of action, which we've talked about as little as two or three days. The two week treatment course, and the well tolerated potential certainly as an oral therapy that.

We clearly believe the world needs in terms of driving studies those are complete and will be part of the submission there.

I will call them Checkbox studies that require to be run we anticipate as in many drugs, including over the counter drugs there'll be.

So just trying to get a sense of some of the DDI work that you might have done.

Can you just comment on that?

And also, you know, you're showing positive impact on sleep across multiple studies.

Sure Larry.

Yes.

Recall that most of the studies that we've done in the past.

Well it doesn't pass where many of the patients were on the depression. So what we've seen consistently throughout all of the studies that we have seen no differences in risk.

Our safety profile of those patients on whether they are on it with one another drug or Theyre. Not in addition, you'll recall call study was Ron can comment with a dose of a depression.

Again saw pretty much the same response as well as the safety profile of those molecules not counting.

Side effects associated with depression.

Okay.

Data suggest that we don't see any any issues with dosing compound with other anti depression as I've said and most of all clinical trials had patients in them.

On Stateline depressant so.

It doesn't prohibit the use and we don't see any differences in response rate between those two patient sets.

Thank you.

Our next question comes from Yatin Suneja with Guggenheim Partners.

So can Ronalon be combined with some of the sleep aids or sedative and your lytics that are out there?

Our next.

<unk> comes from Marc Goodman with SBB Leerink.

Your line is now open.

So just trying to get a sense of the combo use.

Yes, hi.

Mentioned above.

About the launch and how youre going to scale appropriately with respect to spend can you give us a little more color. What you mean or are you trying to say that we should not expect.

And also, if you can characterize some of the driving study that you might have conducted, what would the key findings?

Thanks.

500 person sales force between the two companies and aggressive DTC on the television.

Six months. After launch are you trying to say that it could be something different than that or maybe you could just give us a sense.

What you meant there and then just on dimension and survey or whats. The timeline first timelines you can tell us when do you think those phase twos will readout. Thanks.

Yeah, it's in, I guess, a few questions there.

Thanks, Mark and I'll ask Chris and actually <unk> to comment as well so what we're what we're saying is we and Biogen are actually thinking very big about the MDT in PPD.

Opportunities and we will use an omnichannel approach.

To put the right capital allocation to launch and as you see uptake with.

With psych with primary care to continue scale with an update rather than scale ahead of that uptake.

Success, Chris Kimi anything to add.

Let me start with HAP and driving and I'll ask Al to comment on the drug to drug interaction study.

So any CNS drug entering the market must be analyzed for abuse potential. The HAP studies are one of the standard elements used by the agency when considering abuse potential for CNS active medication.

And as a reminder, there's a 90-day DEA review period following HAP approval.

So the HAP study with Zoranolone was consistent with the FDA guidance on this type of study.

And we expect the FDA to consider data from the HAP study and the entire development program of Zoranolone for recommendation to the DEA.

We believe that given what we know and the brain penetrance of Zoranolone, that will be a scheduled, for drug, which is not an issue for prescribing.

And again, we're entirely excited about the totality of Zoranolone in both MDD and PPD, clinically meaningful reductions in depressive symptoms with consistent improvements in mood and anxiety, the rapid onset of action, which we've talked about as little as two or three days, the two-week treatment course, and the well-tolerated potential certainly is an oral therapy that we clearly believe the world needs.

In terms of driving studies, those are complete and will be part of the submission.

There are, I'll call them, checkbox studies that require to be run.

We anticipate, as in many drugs, including over-the-counter drugs, there'll be a warning in the label, something like, please don't operate or drive or operate heavy machinery until the full use of the drug is known.

Pain that relief over a period of time without stigmatising side effects associated with other antidepressants that they've become all too familiar with over the last 30 to 35 years with that said that.

That's consistent with many drugs, even drugs like Benadryl, which are used over-the-counter.

That in and of itself, it's something that we've seen from the ran alone over the course of the landscape of NES studies, So with respect to our go to market approach, it's going to be absolutely important that we get out there quickly with that message with the data that we have to reach those clinicians that you talked about getting to with an omnichannel approach also making sure.

Al, you want to talk about the, DDI studies?

Sure, Larry.

Great question.

You know, recall that most of these studies that we've done, in the past, most of the studies that we've done in the past were, many of the patients were on antidepressants at the time.

So what we've seen consistently throughout all the studies is that we've seen no differences in response or safety profile of those patients on whether they're on another drug or they're not.

In addition, you recall the CORAL study was run concomitant with a dose of an antidepressant. And we, again, saw pretty much the same response as well as the safety profile of those molecules, not counting the side effects associated with the antidepressant.

Our preclinical data and all the clinical data suggest that we don't see any issues with dosing the compound with other antidepressants, as I said, and most of our clinical trials had patients in them on stabilizing antidepressants. So it doesn't prohibit the use, and we don't see any differences in the response rate between those two patient sets.

Thank you.

We're able to reach patients with that message around what is around alone has the potential to deliver it.

So without saying, but I will mention that it's important for us to think about educating them proactively partnering with payers to make sure that they are aware of this around alone at its approval and what it ultimately can deliver as you might imagine we've already had those conversations with payers and we'll continue to stay engaged with payers educating and proactively preparing for the launches of rent alone.

With that that important stakeholder group, Kevin Yes, So mark I think again your question around.

Our next question comes from Mark Goodman with SVB Lyrinc.

Your line is now open.

Yeah, hi.

You mentioned about the launch and how you're going to scale appropriately with, respect to spend.

Can you give us a little more color what you mean?

Are you trying to say that we should not expect a 500-person sales force between the two companies and, you know, aggressive TTC on the TV, you know, six months after launch?

Are you trying to say that it's going to be, something different than that?

G&A, we're thinking about it is how to be very smart and disciplined.

Investing.

Or maybe you could just give us a sense of what you meant there.

And a good example of that was really the decision we made with Sage 904 to help that program because it didnt meet the criteria that we had set for us and so we're going to continue that.

<unk> balance sheet, but we're still being very disciplined in how we think about investing our capital.

And then just on dimension and surveyor, what's the timeline, best timeline you can tell us for when you think those phase twos will read out?

And Mark your question about <unk>.

Sage 718, we highlighted earlier in the call the initiation of <unk>.

Thanks.

<unk> Parkinson's and by the end of the year, the Alzheimers study and as those studies ramp up and sites.

Come online in accrual is clear we will provide updates on when the data will read out.

Yeah, thanks, Mark.

Thanks.

Mark.

Thank you.

Thanks for taking my question.

And I'll ask Chris and actually Kimmy to comment as well.

Our next question comes from Vikram <unk> with Morgan Stanley . Your line is now open.

Just a question in line.

So what we're saying is we in Biogen are actually thinking very big about, the MDD and PPD opportunities, and we'll use an omni-channel approach, you know, leaning in on digital to start.

I mean, we've recently seen the HAP, studies.

Good morning. This is Scott will answer.

We're just trying to get a sense of some of the DDI work that you might have done.

But we're also saying that we're going to be smart about capital allocation and think about starting at an appropriate size with Salesforce, with DTC, and other omni-channel tools, and then scale with success.

Thank you for taking my question.

You mentioned in the release that non labor changes pose the Russell I expect that based on the sunburst study.

Could you provide a bit more.

Detail on what you observed in the studies.

Yeah, well thanks for the question. So the Sunbird study was evaluating the safe use administration russow.

Can you just comment on that?

I think it's a best practice to put the right capital allocation to launch, and as you see uptake with psych, with primary care, to continue to scale with that uptake rather than scale ahead of that uptake.

You know, lessons learned from many, many drug launches that sometimes companies over-capitalize the launch. So we're being very clear that we're going to spend appropriately to launch well, and we anticipate success of launch, and then we'll scale with that success rather than scaling before the success.

In our home <unk> setting.

As you highlighted we don't plan to make any label changes there were no new safety signals related to Zurich Tso identified in this study was kind of.

A human use potential study.

Rather than a placebo controlled efficacy study the study enrolled as expected and recruit on time and importantly, the sunbird cellulite seeds to develop the operational capability to run a virtual or decentralized study model that will leverage in future studies.

We remain committed to providing optionality.

Moms with PPD, and we're really optimistic that.

And also, you know, you're showing positive impact on sleep across multiple studies.

With the output of Skylark that zorana alone if approved will significantly improve access for women in need of treatment for PPD.

Chris, Kimmy, anything to add?

Okay.

Thank you for the update thanks Kessel.

Thank you.

So can Zoranolone be combined with some of the sleep aids or sedative anxiolytics that are out there?

Our next question comes from Gary Nachman with BMO. Your line is now open.

So just trying to get a sense of the combo use.

Thanks, guys good morning.

So in your early payer discussions on surround alone when you consider pricing.

Or will you assume for average number of treatment courses per patient per year based on the shoreline data and how you think that's going to factor into pricing.

And how payers are going to view the drug given its profile.

And also, if you can characterize some of the driving study that you might have conducted, what would the key findings be?

And then just I guess more generally.

What is the market research, telling you about each of the MDT in PPD opportunities.

Yeah, it's in.

And where are you seeing saran alone they have a bigger impact early on when it's launched.

Both from a payer standpoint also in terms of physician and patient.

Desire for the job.

Thanks, Gary Let me turn it over to Chris and I'll loop back at the end.

So I guess a few questions there.

Let me start with HAP and driving.

Yeah, Barry.

Yes, thanks, Barry so with respect to the first question around pricing obviously, it's early to get into discussion specifically on where we're going to be with pricing <unk> Biogen, we'll provide that clarity on pricing in and around the time of approval. If were successful what I can say is that as we think about pricing we're thinking about it in.

I'll take it first, and then I'll pass it over to Kimmy.

So with respect to what, we've learned from key opinion leaders and clinicians from both market research and scientific exchanges that, you know, functionally they want faster relief, and they want a therapy that can not only deliver that fast relief but sustain that relief over a period of time.

Relation to.

In a place with access at the same time, so with respect to both pricing and access it's critical that we design an approach that considers the needs of payers themselves physicians as well as importantly.

Patients who opened the product now our overall goal. It's around what is approved to ensure that appropriate patients are able to get in saran alone for both <unk> and PPD, maybe you can get it when they need it and the clinicians.

The product with out without any sort of mix and in the process now what that means is that we as an organization need to partner with payers to make sure that things like prior authorizations and step edits or mitigated by virtue of the way that we collaborate and think about the contracting process I know historically, we've talked about opportunity.

For us to introduce proactive value based agreements with this important stakeholder audience and that's going to be an important piece of the strategy as we think about how we're going to make sure that the product is ultimately available. So we're leaning in on those VBA conversations that we're having right now in and around conversations around unmet need and the data that we've been able to demonstrate.

Straight with respect to the landscape and nest around how is the rent alone has the potential to offer.

Distinct opportunity for payers to make the product available for those with both <unk> and PPD. So more to come on price, but were thinking the approach holistically and it around pricing and access and again, making sure that we're educating and proactive partnering with payers with the goal of enabling avalanche access.

The question around some of the opportunities and where we see bigger impact with respect to hcp's payers and patients.

Taking a step back and thinking about the opportunity in the marketplace with respect to depression, there are $21 million or so people that experience one or more depressive episodes in a given year.

And given that number there's still are 7 million patient and mgd, who are either new to therapy, adding therapy or switching therapy, what we know from the market research.

Without the stigmatizing side effects associated with other antidepressants that they've become, all too familiar with over the last 30 to 35 years.

All with just a 14 day course of therapy.

I think in <unk> for those patients that are new to therapy, adding therapy or switching it offers a profound opportunity our opportunity there is to really make sure that out of the gate at the launches around alone that we are engaged with those clinicians and we demonstrate the opportunity to introduce our rent alone early in the treatment process where patients can have.

The best expected effects with both <unk> and with <unk> now with respect to payers I covered payers.

What I think the opportunity there is in and around.

To educate and proactively partner with those payers, so im not going to say.

And last but not least I think patients I think as Barry noted in our in his comments about our go to market approach, it's going to be really important from an omnichannel perspective, the patients early our awareness around alone and the distinction that surround alone offers relative to perhaps the way that they've experienced other antidepressants in the past with respect to the rapid onset of <unk>.

Actions and the sustained relief all over just requiring a two week course of therapy. So with that said Barry hand, it back to you to cover off on anything I may have missed it.

And I'll ask Al to comment on the drug to drug interaction study.

With that said, that, you know, that in and of itself, you know, it's something that we've seen from the rent alone over the course of the landscape and NEST studies.

So with respect to our go-to-market approach, it's going to be absolutely important that we get out there quickly with that message, with the data that we have to reach those clinicians that you talked about getting to with an omni-channel approach, also making sure that we're able to reach patients with that message around what the rent alone has the potential to deliver.

And it goes without saying, but I will mention that it's important for us to think about educating and proactively partnering with payers to make sure that they're aware of the rent alone at its approval and what it ultimately can deliver.

As you might imagine, we've already had those conversations with payers and will continue to stay engaged with payers, educating and proactively preparing for the launch of the rent alone with that important stakeholder group.

Kimmy?

And as a reminder, there's a 90-day DEA review period following HAP approval.

Yeah, so Mark, I think, you know, again, your question around and scaling is a great one right now, especially in this environment.

So the HAP study with Zoranolone was consistent with the FDA guidance on this type of study.

We're going to be very smart about how we ramp up our costs in the SG&A side.

Chris you covered it well and Gary I Hope Thats the answer I guess, just a point on US we believe that since zelle Russell is the only approved drug in PPD and <unk> if approved the only oral medicine that that.

And we expect the FDA to, consider data from the HAP study and the entire development program of Zoranolone for recommendation to the DEA.

And that's part of that scaling that, Chris just talked about.

But, you know, we're thinking about that across the entire organization.

So, you know, even in the R&D space, we're thinking about it, you know, across G&A, we're thinking about it is how to be very smart and disciplined in our investing.

You know, and a good example of that was really the decision we made with SAGE 904 to halt that program because it didn't meet the criteria that we had set forth.

We believe that given what we know and the brain penetrance of Zoranolone, that will be a Schedule IV drug, which is not an issue for prescribing.

And so we're going to continue that, you know, we have a balance sheet, but we're still being very disciplined in how we think about investing our capital.

In terms of driving studies, those are complete and will be part of the submission.

We do our job right rental will quickly become standard of care.

There are, I'll call them, checkbox studies that require to be run.

That's consistent with many drugs, even drugs like Benadryl, which are used over-the-counter.

In PPD won an eight live births about half a million women a year experienced PPD and with available drug we do believe that the.

The diagnosis rates risk factor assessments will go way up because now there is something to do about it mbd, Chris covered it well there is a significant opportunity there are some places where.

<unk> will be used to interrupt the cycling of many anti depressants a patient's experience.

And other groups like young adults, where we believe that that is rental and should be used as quickly in the treatment paradigm as possible, but more on that to come.

Al, you want to talk about the DDI studies?

Okay, great very helpful. Thank you thanks, Eric.

Sure, Larry.

Thank you.

Our next question comes from Neena <unk> Garg with Citi. Your line is now open.

Great question.

Hey, guys. Thanks for taking my question I just wanted to go back to some of the questions on shoreline that were asked earlier and I was just wondering if you could give us an update on how.

It isn't that you interact with and the FCA are thinking about the return criterias.

<unk> used in shoreline and how well that aligns with the physician practice and how they would actually think about re treating a patient.

I'm really just trying to understand.

One to two treatments per year.

Translate into the real world setting.

Yes, Thanks Nina.

We believe that shoreline represents a real world evidence study. The agency is looking for more and more real word evidence in shoreline checks.

Most of the boxes for what Youre looking for with real World evidence studies.

Keep in mind that that patient.

Patients were diagnosed with mbd they were given drug for two weeks.

And then on day 15, and on they know Theyre not on drug. So there was a liability or any need to be on drug we'd see a lot more re treatment. The fact that a majority of patients stayed well. After one course of treatment for a full year is a testament to the durability of <unk> and the fact that 80% of patients who respond to the initial too.

The treatment was around alone 50 milligram only received one or two treatments of course of the year with a median time of 249 days. So as you heard from Chris.

Today's practices to diagnose a patient give them a prescription.

Stead of instructing them to.

To hang in there.

Hanging in there this could take four to eight weeks to work I believe physicians will tell their patients that they should feel better.

As little as two or three days after two evening courses of of.

<unk> alone and as it's done with practice today physicians are officers often check back in two weeks today. They are checking back to understand the side effect profile and if any other drugs are required to minimize side effects Gi effects.

Potentially sexual dysfunction thats seen at that time at that time and then in this case, it's how how patients are doing after those two weeks and then classically there's a six months follow up so as Chris highlighted this is a paradigm shift in how.

Precious treated but not necessary a paradigm shift in how a physician practices with their depressed patient.

Got it thank you thanks Nina.

Thank you.

Our next question comes from Stephen <unk> with RBC capital markets. Your line is now open.

Alright. Thanks. This is Steve on for Brian Congrats on the progress and thanks for taking our question curious if you can provide a bit more color on what youre expecting to see in the phase two work with NMDA Pam how you think about making a go no go decisions inherent efficacy, especially given the significant variability in potential responses and what I'm curious from the phase one looking for stat Sig there on efficacy or just.

Trends in what would give you confidence to move forward. Thanks.

And Mark, your question about SAIT 718, we highlighted earlier in the call the initiation, of Hundin's, Parkinson's, and by the end of the year, the Alzheimer's study.

And as those studies ramp up and sites come online and accrual is clear, we'll provide, updates on when the data will read out.

Thanks, Mark.

You saw a rapid improvement in cognition in a short period of time either to or in some studies four weeks, we saw it in two weeks, but continued out to four weeks.

As Youre well aware study.

Studies, Jonathan cognition to date or dimension to date have with a very large and with a very long time tried to demonstrate most not successfully the slowing of cognitive decline over a period of time. So we're looking for improvement in in cognition. If you think about the Huntington's study where.

Thank you.

We're running parallel studies, demonstrating the numerical change, but also kind of what it means in in.

Real life.

We believe that Thats.

Dramatically positive that translates into a package that we'd be enthusiastic to meet with the agency and talk about the <unk>.

Fastest path to clinic.

The Parkinson's and Alzheimer's study.

Looking for.

A broad benefit risk profile trends in that improvement.

But likely phase III studies to follow so Alan anything to add there.

You know, recall that most of these studies that we've done, in the past, most of the studies that we've done in the past were, many of the patients were on antidepressants at the time.

Yes, I think it's interesting that you have.

Most of the studies that are involved with these diseases in the past with other drug approaches or other approaches or are specific to that those disease types. You have a specific study is trying to reduce a beta or or.

Okay tangles.

This office nuclear will be other diseases as well.

So what we've seen consistently throughout all the studies is that we've seen no differences in response or safety profile of those patients on whether they're on another drug or they're not.

Our approach is looking to improve brain circuitry and synaptic function and what we're seeing as you pointed with very similar results in all three of those studies, which is very encouraging we're seeing very rapid improvement and executive function and memory with most of the approaches that are looking for the disease by changing the <unk>.

In addition, you recall the CORAL study was run concomitant with a dose of an antidepressant. And we, again, saw pretty much the same response as well as the safety profile of those molecules not counting the side effect associated with the antidepressant.

Our preclinical data and all clinical data suggest that we don't see any issues with dosing the compound with other antidepressants, as I said, and most of our trials had patients in them on stable antidepressants. So it doesn't prohibit the use, and we don't see any differences in the response rate between those two patient sets.

<unk> of the plaque which use perspective, what we're seeing is those take longer because you are looking to modify the course of disease and stop the degradation of the rate. We're doing we're improving staff that function Thats why I think we will.

<unk> results in a very early about Tom as you pointed out.

Yes, Steve hopefully that answers your question, but what we believe we are.

Our developing with Sage 718 is the disease course modifier and the idea here is.

To improve executive function learning and memory, allowing patients living with these conditions to live more independently for much longer period of time.

Great. Thanks. Thanks.

Thank you. Our next question comes from Joon Lee with <unk>. Your line is now open.

Good morning. This is Austin on for Joon, Thanks for taking the questions.

Just another question on 718, we were just wondering if you could provide a little color on why you are starting a phase III safety study.

On 2018 before the phase III.

Okay.

Yes, and thanks for the question so with Sage 718, we've been pretty clear that.

We are running.

Series of Phase II studies Huntington study in Parkinson's studies have been kicked off.

The Alzheimers study that will be kicked off but it ended the year with design. The Huntington study in a way that we will have numerical changes in kind of real world evidence on what that means as al talked about in the comments and if those data are robustly positive we'll meet with the agency on the most rapid approach to get <unk> to market for Huntington's.

For Parkinsons and Alzheimers following the phase II studies will likely run phase III studies based upon the learnings from the phase II.

Okay. Thank you and congrats on the progress.

Thank you.

Our next question comes from Danielle Brill with Raymond James Your line is now open.

Hi, guys. This is Alex on for Danielle just a quick one going back to <unk> for US I know you qualitatively addressed this question in the most part I Wonder if you could expand a little bit more on the depression symptom amelioration, specifically, what the point Delta was for Ham D. At the end of the 14 day treatment period.

Yes.

Yes, Alex what what you will will at upcoming medical meetings present rainforest just as a reminder, it was it was.

We stopped.

Both that and Redwood with a 30 milligram dose after consulting with the agency they are not required for.

For regulatory filing and it enrolled very did not fully enroll so the stats plan can't really be looked at what we can say today is that the profile ebbs around alone in rainforest with consistent with data seen to date that is improvement in depressive symptoms anxiety and as the purpose of the study.

Trends to improve sleep sleep architecture, and again, we'll report more out and up.

Coming out of the conferences.

Great appreciate the color.

Thanks, Alex.

That concludes today's question and answer session I'd like to turn the call back to Barry Greene for closing remarks.

Thank you.

Our next question comes from Vikram Purohit with Mark and Stanley.

Thanks, operator, and thank you all for joining US this morning to review our second quarter progress.

Our next question comes from Mark Goodman with, SVB Lyrinc.

Your line is now open.

As we work to advance clinical and preclinical programs across our franchises moves around on closer to launch commercialization of approved and reinvest our learnings and efforts to develop and launch transformative brand health medicines across the organization. We are deeply committed to continuing our focused execution in.

Your line is now open.

Good morning.

Yeah, hi.

This is Gaspo Han from Vikram.

You mentioned about the launch and how you're going to scale appropriately with respect to spend.

Thank you for taking our question.

You mentioned in the release that no label changes for Xeresso are expected based on, the SunBird study.

Could you provide a bit more detail on what you observed in the study?

Yeah, Gaspo.

Can you give us a little more color what you mean?

Yeah, I think we're good.

Thanks for the question.

Are you trying to say that we should not expect a 500-person sales force between the two companies and aggressive TTC on the TV six months after launch?

We're good.

So, the SunBird study was evaluating the safe use administration of Xeresso in a home use, setting.

Or are you trying to say that it's going to be something different than that?

Yeah, Gaspo.

As you highlighted, we don't plan to make any label changes.

Maybe you could just give us a sense of what you meant there.

There were no new safety signals related to Xeresso identified in the study.

And then just on dimension, and surveyor, what's the best timeline you can tell us for when you think those Phase IIs will read out?

It was kind of a human use potential study rather than a placebo-controlled efficacy, study.

In the balance of 2022 and beyond.

Thanks.

The study enrolled as expected and recruited on time. And importantly, the SunBird study allowed SAGE to develop the operational capability, to run a virtual or decentralized study model that we'll leverage in future studies.

Thanks, Mark.

So, we remain committed to providing optionality to moms with PPD.

Good morning.

And I'll ask Chris and actually, Kimmy to comment as well.

And we're really optimistic that, you know, particularly with the output of Skylark that, Xeranolone, if approved, will significantly improve access for women in need of treatment for PPD.

Look forward to future updates on our progress in our mission to pioneer solutions to deliver life changing brain health medicines. So every person can thrive right.

This is Gaspo on for Vikram.

So, in your early payer discussions on Xeranolone, when you consider pricing, what will you assume, for average number of treatment courses per patient per year based on the Shoreline data and how you think that's going to factor into pricing and how payers are going to view the drug given its profile?

So what we're saying is we in Biogen are actually thinking very big about the MDD and PPD opportunities, and we'll use an omni-channel approach, leaning in on digital to start.

Thank you for the update.

Thank you for taking our question.

And then just, I guess, more generally, you know, what is the market research telling, you about each of the MDD and PPD opportunities and where you think Xeranolone may have a bigger impact early on when it's launched, you know, both from a payer standpoint, also in terms of physician and patient desire for the drug?

But we're also saying that we're going to be smart about capital allocation and think about starting at an appropriate size with sales force, with DTC and other omni-channel tools, and then scale with success. I think it's a best practice to put the right capital allocation to launch.

Thanks, Gaspo.

You mentioned in the release that no label changes for Xeresol.

Thanks.

And as you see uptake with psych, with primary care, to continue to scale with that uptake rather than scale ahead of that uptake.

Thank you.

I expect that based on the SunBird study.

Thanks, Gary.

Lessons learned from many, many drug launches that sometimes companies overcapitalize, the launch. So we're being very clear that we're going to spend appropriately to launch well, and we anticipate success of launch, and then we'll scale with that success rather than scaling before the success.

Our next question comes from Gary Nachman with BMO.

Look forward to future updates on our progress and our mission to pioneer solutions to deliver life-changing brain health medicines so every person can thrive.

Look forward to future updates on our progress and our mission to pioneer solutions to deliver, life-changing brain health medicines so every person can thrive.

Could you provide a bit more detail on what you observed in the study?

I'm going to turn it over to Chris, and I'll loop back at the end.

Chris, Kimmy, anything to add?

Your line is now open.

Thanks again, everyone.

Yeah, Gaspo, thanks for the question.

Yeah.

Yeah, Barry.

Thanks, guys.

So the SunBird study was evaluating the safe use administration of Xeresol in a home use, setting.

Thanks, Barry.

I'll take it first, and then I'll pass it over to Kimmy.

As you highlighted, we don't plan to make any label changes.

So, with respect to the first question around pricing, you know, obviously, it's early to, get into discussions specifically on where we're going to be with pricing. Sage and Biogen will provide that clarity on pricing in and around the time of approval, if we're successful.

So with respect to what we've learned from key opinion leaders and clinicians from both market research and scientific exchanges, that functionally they want faster relief, and they want a therapy that can not only deliver that fast relief but sustain that relief over a period of time without the stigmatizing side effects associated with other antidepressants that they've become all too familiar with over the last 30 to 35 years.

There were no new safety signals related to Xeresol identified in the study was kind, of a human use potential study rather than a placebo controlled efficacy study.

What I can say is that as we think about pricing, we're thinking about it in relation to how, it interplays with access at the same time.

With that said, that in and of itself is something that we've seen from Zoranolone over the course of the landscape and NEST studies.

So, with respect to both pricing and access, it's critical that we design an approach that, considers the needs of payers themselves, physicians, as well as, importantly, the patients who ultimately get the product.

Thanks again, everyone have a great.

Have a great day.

So we remain committed to providing optionality to moms with PPD.

Now, our overall goal at Xeranolone is approved to ensure that appropriate patients are able, to get Xeranolone for both MDD and PPD, that they can get it when they need it, and that clinicians can provide the product without any sort of mitigation in the process.

This concludes today's conference call.

And it goes without saying, but I will mention that it's important for us to think about educating and proactively partnering with payers to make sure that they're aware of Zoranolone at its approval and what it ultimately can deliver.

And we're really optimistic that, you know, particularly with the output of Skylark that, Xeranilone, if approved, will significantly improve access for women in need of treatment for PPD.

Now, what that means is that we, as an organization, need to partner with payers to make sure that, things like prior authorizations and step edits are mitigated by virtue of the way that we collaborate and think about the contracting process.

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

As you might imagine, we've already had those conversations with payers and will continue to stay engaged with payers, educating and proactively preparing for the launch of Zoranolone with that important stakeholder group.

Thank you for the update.

I know, historically, we've talked about the opportunity for us to introduce proactive, value-based agreements with this important stakeholder audience, and that's going to be an important piece of the strategy as we think about how we're going to make sure that the product is ultimately available.

Goodbye.

Kimmy?

Thanks, Gaspo.

So we're leaning in on those VBA conversations that we're having right now, in and around, conversations around unmet need, and the data that we've been able to demonstrate with respect to Landscape and Nest around how Xeranolone has the potential to offer a distinct opportunity for payers to make the product available for those with both MDD and PPD.

Thank you for participating.

Yeah, so Mark, I think, you know, again, your question around scaling is a great one right now, especially in this environment.

Thank you.

So more to come on price, but we're thinking about the approach holistically in and around, pricing and access, and again, making sure that we're educating and proactively partnering with payers with the goal of enabling at-launch access.

You may now disconnect.

We're going to be very smart about how we ramp up our costs in the SG&A side, and that's part of that scaling that Chris just talked about.

Our next question comes from Gary Nachman with BMO.

I think the question around some of the opportunities and where we see a bigger impact with respect, to ACPs, payers, and patients, taking a step back and thinking about the opportunity in the marketplace, with respect to depression, there are 21 million or so people that experience one or more depressive episodes in a given year.

But, you know, we're thinking about that across the entire organization.

Your line is now open.

And given that number, there still are 7 million patients in MDD who are either new to therapy, adding therapy, or switching therapy.

So, you know, even in the R&D space, we're thinking about it, you know, across G&A, we're thinking about it, is how to be very smart and disciplined in our investing, you know, and a good example of that was really the decision we made with Stage 904 to halt that program because it didn't meet the criteria that we had set forth.

Thanks, guys.

What we know from the market research is that, you know, given that there are a number of, generic medications that have been available now for 30 to 35 years, there still is profound unmet need, and patients need new therapies with new MOAs like Xeranolone that offer rapid and lasting relief without the tolerability issues and the stigmatizing side effects that you see with other therapies that they become exposed with, all with just a 14-day course of therapy.

And so we're going to continue that, you know, we have a balance sheet, but we're still being very disciplined in how we think about investing our capital.

Good morning.

You know, again, I think in MDD, for those patients that are new to therapy, adding therapy, or switching, it offers a profound opportunity.

Mark, your question about SAIT 718, we highlighted earlier in the call the initiation of Hundin's, Parkinson's, and by the end of the year, the Alzheimer's study, and as those studies ramp up and sites come online and accrual is clear, we'll provide updates on when the data will read out.

So, in your early payer discussions on Xeranilone, when you consider pricing, what will you assume, for average number of treatment courses per patient per year based on the Shoreline data?

Our opportunity there is to really make sure that, out of the gate at the launch of Xeranolone, that we are engaged with those clinicians and we demonstrate the opportunity to introduce Xeranolone early in the treatment process, where patients can have the best expected, effects with both MDD and with PTD.

Thanks, Mark.

And how do you think that's going to factor into pricing and how payers are going to view, the drug given its profile?

Now, with respect to payers, I covered all payers and what I think the opportunity there, is in and around to educate and proactively partner with those payers, so I'm not going to say much more.

Thank you.

And then just, I guess, more generally, you know, what is the market research telling, you about each of the MDD and PPD opportunities, and where you think Xeranilone may have a bigger impact early on when it's launched, you know, both from a payer standpoint, also in terms of physician and patient desire for the drug?

And last but not least, I think patients, I think, as Barry noted in his comments about, our go-to-market approach, it's going to be really important from an omni-channel perspective that patients early are aware of Xeranolone and the distinction that Xeranolone offers relative to perhaps the way that they've experienced other antidepressants in the past with respect to the rapid onset of action and the sustained relief all over just requiring a two-week course of therapy.

Our next question comes from Vikram Parohit with Mark and Stanley.

Thanks.

So with that said, Barry, I'm going to hand it back to you to cover off on anything I, may have missed.

Your line is now open.

Thanks, Gary.

Yeah, Chris, you covered it well.

Let me turn it over to Chris, and I'll loop back at the end.

And Gary, I hope that that's the answer.

Yeah.

I guess just, a point on use. We believe that since Xelresto is the only approved drug in PPD and Xeranil, if approved, will be the only oral medicine that if we do our job right, Xeranil will quickly become standard of care in PPD.

Thanks, Barry.

One in eight live births, about half a million women a year experience PPD.

And with a available drug, we do believe that diagnosis rates, risk factor assessments will go way up because now there's something to do about it.

What I can say is that as we think about pricing, we're thinking about it in relation to how, it interplays with access at the same time.

In MDD, Chris covered it well.

So, with respect to both pricing and access, it's critical that we design an approach to, it that considers the needs of payers themselves, physicians, as well as, importantly, the patients who ultimately need the product.

There's a significant opportunity.

Now, our overall goal, if Xeranilone is approved, to ensure that appropriate patients are able, to get Xeranilone for both MDD and PPD, that they can get it when they need it, and that clinicians can prescribe the product without any sort of mitigation in the process.

There are some places where Xeranil, will be used to interrupt the cycling of many antidepressants that patients experience and other groups like young adults where we believe that Xeranil should be used as quickly in the treatment paradigm as possible, but more on that to come.

Okay, great.

I know historically we've talked about opportunity for us to introduce proactive value-based, agreements with this important stakeholder audience, and that's going to be an important piece of the strategy as we think about how we're going to make sure that the product is ultimately available.

Very helpful.

So, we're leaning in on those VBA conversations that we're having right now, in and around, conversations around unmet need, and the data that we've been able to demonstrate with respect to landscape and nest around how Xeranilone has the potential to offer a distinct opportunity for payers to make the product available for those with both, MDD and PPD.

Thank you.

So, more to come on price, but we're thinking about the approach holistically in and around, pricing and access, and, again, making sure that we're educating and proactively partnering with payers with the goal of enabling at-launch access.

Thanks, Gary.

I think the question around some of the opportunities and where we have a bigger impact with respect, to ACPs, payers, and patients, taking a step back and thinking about the opportunity in the marketplace, with respect to depression, there are 21 million or so people that experience one or more depressive episodes in a given year, and given that number, there still are, 7 million patients in MDD who are either new to therapy, adding therapy, or switching therapy.

Thank you.

What we know from the market research is that, you know, given that there are a number, of generic medications that have been available now for 30 to 35 years, there still is profound unmet need, and patients need new therapies with new MOAs like Xeranilone that offer rapid and lasting relief without the tolerability issues and the stigmatizing side effects that you see with other therapies that they become exposed with, all with just a 14-day course of therapy.

Our next question comes from Nina Petrino-Garg with Citi.

So, you know, again, I think in MDD, for those patients that are new to therapy, adding therapy, or switching, it offers a profound opportunity.

Your line is now open.

Our opportunity there is to really make sure that, out of the gate at the launch of Xeranilone, that we are engaged with those clinicians and we demonstrate the opportunity to introduce Xeranilone early in the treatment process where patients can have the best expected, effects with both MDD and with PAD.

Hey, guys.

Now, with respect to payers, I covered all the payers and what I think the opportunity, there is in and around to educate and proactively partner with those payers, so I'm not going to say more.

Thanks for taking my question.

And last but not least, I think patients, I think, as Barry noted in his comments about, our go-to-market approach, it's going to be really important from an omni-channel perspective that patients early are aware of Xeranilone and the distinction that Xeranilone offers relative to perhaps the way that they've experienced other antidepressants in the past with respect to the rapid onset of action and the sustained relief all over just requiring a two-week course of therapy.

I just want to go back to some of the questions, on Shoreline that were asked earlier.

So with that said, Barry, I'll hand it back to you to cover off on anything I may have, missed.

I was just wondering if you could give us an update on how, you know, physicians that you interact with and the FDA are thinking about the retreatment criteria specifically that were used in Shoreline and how well that aligns with physician practice and how they would actually think about retreating a patient.

Chris, you covered it well, and Gary, I hope that that's the answer.

I'm really just trying to understand if the one to two treatment courses per year, will translate into the real world setting.

I guess just a point, on use.

Thanks.

We believe that since Xelresto is the only approved drug in PPD, and Xeranil, if approved, will be the only oral medicine that, if we do our job right, Xeranil will quickly become standard of care in PPD.

Yeah, thanks, Nina.

One in eight live births, about half a million women a year experience PPD, and with an available drug, we do believe that diagnosis, rates, risk factor assessments will go way up, because now there's something to do about it.

We believe that Shoreline represents a real world evidence study. The, agency is looking for more and more real world evidence and Shoreline checks most of the boxes for what you're looking for with real world evidence studies.

In MDD, Chris covered it well, there's a significant opportunity.

Keep in mind that patients were diagnosed with MBD.

There are some places where Xeranil will be used to interrupt the cycling of many antidepressants that patients experience, and other groups, like young adults, where we believe that Xeranil should be used as quickly in the treatment paradigm as possible, but more on that to come.

They were given drug for two weeks.

Okay, great.

Then on day 15 and on, they know they're not on drugs.

Very helpful.

So if there was a likability or any need to be on drug, we'd see a lot more retreatment.

Thank you.

The fact that a majority of patients stayed well after one course of treatment for a full year is a testament to the durability of xeranilone.

Thanks, Gary.

And the fact that 80% of patients who respond to the initial two week treatment with xeranilone 50 milligram only received one or two treatments the course of the year with a median time of 249 days.

Thank you.

So as you heard from Chris, you know, today's practice to diagnose a patient, give them a prescription, instead of instructing them to hang in there, this could take four to eight weeks to work.

Our next question comes from Nina Petrino-Garg with Citi.

I believe physicians will tell their patients that they should feel better in as little as two or three days after two evening courses of xeranilone.

Your line is now open.

And as is done with practice today, physicians, our offices often check back in two weeks.

Hey, guys.

Today, they're checking back to understand the side effect profile and if any other drugs are required to minimize side effects, GI effects, potentially sexual dysfunction that's seen at that time.

Thanks for taking my question.

And then in this case, it's how patients are doing after the two weeks.

I just want to go back to some of the questions, on Shoreline that were asked earlier.

And then classically, there's a six month follow up.

I was just wondering if you could give us an update on how physicians that you interact with, and the FDA, are thinking about the retreatment criteria that were used in Shoreline, and how well that aligns with physician practice, and how they would actually think about retreating a patient.

So as Chris highlighted, this is a paradigm shift in how Thank you, our next question comes from Stephen Mallon with RBC Capital Markets, your line, is now open.

I'm really just trying to understand if the one to two treatment courses per year will translate into the real world setting.

Great, thanks, this is Steve, I'm for Brian, congrats on the progress and thanks for taking, our question.

Yeah, thanks, Nina.

I'm curious if you can provide a bit more color on what you're expecting to see in the, phase two work with the NMDA PAMs and how you'll think about making a go, no-go decision there on efficacy, especially given the significant variability and potential responses in run-in periods from the phase one.

We believe that Shoreline represents a real world evidence study. The agency is looking for more and more real world evidence, and Shoreline, checks most of the boxes for what you're looking for with real world evidence studies.

Looking for stats there on efficacy or just trends and what will give you confidence to, move forward.

Keep in mind that patients were diagnosed with MBD.

Thanks.

They were given drug for two weeks.

Steve, thanks for the question and thanks for the congratulatory note.

Then on day 15 and on, they know they're not on drugs.

I'll start and then ask Al to comment.

If there was a likability or any need to be on drug, we'd see a lot more retreatment.

So what's remarkable about SAGE 718, First in Class, and NMDA PAM is that in the early, work to date, the ketamine placebo-controlled studies, the Huntington's, Parkinson's, and Alzheimer's study, we actually saw a rapid improvement in cognition in a short period, of time, either in two or in some studies four weeks. We saw it in two weeks but continued out to four weeks.

The fact that a majority of patients stayed well after one course of treatment for a full year is a testament to the durability of xeranilone.

As you're well aware, studies drawn in cognition to date or dementia to date have, with a very, large end, with a very long time, tried to demonstrate, most not successfully, the slowing of cognitive decline over a period of time.

In fact, that 80% of patients who responded to the initial two-week treatment with xeranilone 50 milligram only received one or two treatments the course of the year, with a median time of 249 days.

So we're looking for improvement in cognition.

As you heard from Chris, today's practice is to diagnose a patient, give them a prescription.

If you think about the Huntington's study where we're running parallel studies demonstrating, the numerical change but also kind of what it means in real life, we believe that that's, if dramatically positive, that translates into a package that we'd be enthusiastic to meet with the agency and talk about the fastest path to clinic.

Instead of instructing them to hang in there, this could take four to eight weeks to work.

For the Parkinson's and Alzheimer's study, we're looking for a broad benefit-risk profile, not just in that improvement but likely, you know, Phase III studies to follow.

I believe physicians will tell their patients that they should feel better in as little as two or three days after two evening courses of xeranilone.

So, Al, anything to add there?

As is done with practice today, physicians or offices often check back in two weeks.

Yeah, Barry, I think it's interesting that, you know, most of the studies that are involved, with these diseases in the past with other drug approaches or other approaches are specific to those disease types.

Today, they're checking back to understand the side effect profile and if any other drugs are required to minimize side effects, GI effects, potentially sexual dysfunction that's seen at that time.

You have specific studies trying to reduce A-beta or retangles of the disease, alpha-synuclein, and the other diseases as well.

In this case, it's how patients are doing after the two weeks.

Our approach is looking to improve brain circuitry and synaptic function, and what we're seeing, as you pointed out, is very similar results in all three of those studies, which is very encouraging.

Then classically, there's a six-month follow-up.

We're seeing very rapid improvement in executive function and memory.

As Chris highlighted, this is a paradigm shift in how, Thank you.

With most of the approaches that are looking to modify the disease by changing the position, of the plaque with each respective disease, what we're seeing is those take longer because you're looking to modify the course of the disease and stop the degradation of the brain.

Our next question comes from Stephen Mallon with RBC Capital Markets.

What we're doing is we're improving synaptic function, and that's why I think we've seen, results in a very early amount of time, as you pointed out.

Your line is now open.

Yeah, Steve, hopefully that answers your question.

Great.

But, you know, what we believe we are developing with SAGE 718 is a disease course modifier, and the idea here is to improve executive function, learning, and memory, allowing patients living with these conditions to live more independently for a much longer period of time.

Thanks.

Operator Thank you.

This is Steve.

Our next question comes from June, Lee with Truist.

I'm for Brian.

Your line is now open.

Congrats on the progress and thanks for taking our question.

June Lee Good morning.

I'm curious if you can provide a bit more color on what you're expecting to see in the, phase two work with the NMDA PAMs and how you think about making a go, no-go decision there on efficacy, especially given the significant variability and potential responses in running periods from the phase one.

This is Austin on for June.

Looking for stats there on efficacy or just trends and what will give you confidence to, move forward.

Thanks for taking the questions.

Thanks.

Just another question on 718.

Steve, thanks for the question and thanks for the congratulatory note.

We were just wondering if, you could provide a little color on why you're starting a phase three safety study on 718 before the phase two.

I'll start and then ask Al to comment.

Thank you.

Dr. John Borlaug Yes, and thanks for the question.

As you're well aware, studies driving cognition to date or dementia to date have, with a very, large end, with a very long time, tried to demonstrate, most not successfully, the slowing of cognitive decline over a period of time.

So with, SAGE 718, we've been pretty clear that we are running a series of phase two studies, a Huntington study and Parkinson's studies have been kicked off.

So we're looking for improvement in cognition.

The Alzheimer's study will be kicked off by the end of the year.

We've designed the Huntington study in a way that will have numerical changes and kind of real world evidence on what that means as Al talked about in the comments.

For the Parkinson's and Alzheimer's study, we're looking for a broad benefit-risk profile, not just in that improvement but likely, you know, Phase III studies to follow.

And if those data are robustly positive, we'll meet with the agency on the most rapid approach to get SAGE 718 to market for Huntington's.

So, Al, anything to add there?

For Parkinson's and Alzheimer's following the phase two studies, we'll likely run phase, three studies based on the learnings from the phase two.

Yeah, Barry, I think it's interesting that most of the studies that are involved with, these diseases in the past with other drug approaches or other approaches are specific to those disease types.

Okay, thank you and congrats on the progress.

You have specific studies trying to reduce A-beta or retangles of the disease, alpha-synuclein, and the other diseases as well.

Thank you.

Our approach is looking to improve brain circuitry and synaptic function, and what, we're seeing, as you pointed out, is very similar results in all three of those studies, which is very encouraging.

Our next question comes from Danielle Brill with Raymond James.

We're seeing very rapid improvement in executive function and memory.

Your line is now open.

Hi, guys.

What we're doing is we're improving synaptic function, and that's why I think we've seen, results in a very early amount of time, as you pointed out.

This is Alex on for Danielle.

Yeah, Steve, hopefully that answers your question.

Just a quick one going back to rainforest.

I know, you qualitatively addressed this question the most part.

Coordinator Thank you.

I wonder if you could expand a little bit more on the depression symptom amelioration, specifically what the point delta was for HamD at the end of the 14-day treatment period.

Our next question comes from June, Lee with Truist.

Yeah, Alex.

Your line is now open.

Will upcoming medical meetings present rainforest?

June Lee Good morning.

Just as a reminder, we stopped both that and Redwood with a 30 milligram dose after consulting with the agency.

This is Austin on for June.

They're not required for regulatory filing and it enrolled very, you know, did not fully enroll.

Thanks for taking the questions.

So, the stats plan can't really be looked at.

Just another question on 7-18.

What we can say today is that the profile of, xeronalone in rainforest was consistent with data seen to date.

We were just wondering if, you could provide a little color on why you're starting a Phase 3 safety study on 7-18 before the Phase 2.

That is improvement in depressive symptoms, anxiety, and as the purpose of the study, trends to improve sleep architecture.

Thank you.

And again, we'll report more out in upcoming medical conferences.

Austin Thanks for the question.

Appreciate the color.

So with Stage 7-18, we've been pretty clear that we are running a series of Phase 2 studies.

Thanks, Alex.

Huntington, study and Parkinson's studies have been kicked off.

That concludes today's question and answer session.

The Alzheimer's study will be kicked off by the end of the year.

I'd like to turn the, call back to Barry Green for closing remarks.

We've designed the Huntington study in a way that will have numerical changes and kind of real-world evidence on what that means, as Al talked about in the comments.

Thanks, operator.

And if those data are robustly positive, we'll meet with the agency on the most rapid approach to get Stage 7-18 to market for Huntington's.

And thank you all for joining us this morning to review our second quarter, progress.

For Parkinson's and Alzheimer's following the Phase 2 studies, we'll likely run Phase 3 studies based upon the learnings from the, Phase 2.

As we work to advance clinical and preclinical programs across our franchises, move xeronalone closer to launch commercialization if approved, and reinvest our learnings and efforts to develop and launch transformative brain health medicines across organizations, we're deeply committed to continuing our focused execution in the balance of 2022 and beyond.

Okay.

Thank you and congrats on the progress.

Thank you.

Our next question comes from Danielle Brill with Raymond James.

Your line is now open.

Hi, guys.

This is Alex on for Danielle.

Just a quick one going back to Rainforest.

I know, you qualitatively addressed this question the most part.

I wonder if you could expand a little bit more on the depression symptom amelioration, specifically what the point delta was for HAM-D at the end of the 14-day treatment period.

Yeah, Alex.

Will upcoming medical meetings present Rainforest?

Just as a reminder, we, stopped both that and Redwood with a 30-milligram dose after consulting with the agency.

They're not required for regulatory filing.

And it enrolled very, you know, it did not fully enroll.

So, the stats plan can't really be looked at.

What we can say today is that the profile of Zoranolone in Rainforest was consistent with data seen to date.

That is improvement in depressive symptoms, anxiety, and as the purpose of the study, trends to improve sleep architecture.

And again, we'll report more out in upcoming medical conferences.

Great.

Appreciate the color.

Thanks, Alex.

This concludes today's question and answer session.

I'd like to turn the call back to, Barry Green for closing remarks.

Thanks, operator.

And thank you all for joining us this morning to review our second quarter, progress.

As we work to advance clinical and preclinical programs across our franchises, move Zoranolone closer to launch commercialization if approved, and reinvest our learnings and efforts to develop and launch transformative brain health medicines across organizations, we're deeply committed to continuing our focused execution in the balance of 2022 and beyond.

Q2 2022 SAGE Therapeutics Inc Earnings Call

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