Q1 2021 SAGE Therapeutics Inc Earnings Call

May 4, 2021

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Good morning, welcome to Sage Therapeutics first quarter 2021 financial results Conference call. Currently all participants are in a listen only mode. This call is being webcast live on the Investor and media sections of Sage website at Sage Rx Dot Com. This call is property of Sage therapeutics and recording reproduction or transmission of this call without the expressed written.

Operator: Good morning. Welcome to SAGE Therapeutics' first quarter 2021 financial results conference call. Currently, all participants are in a listen-only mode. This call is being webcast live on the investor and media sections of SAGE's website at sagerx.com. This call is the property of SAGE Therapeutics, and recording and reproduction and transmission of this call without the express written consent of SAGE Therapeutics is strictly prohibited. Please note this call is being recorded. I would now like to introduce Jeff Boyle, Vice President of Investor Relations.

Consent of Sage Therapeutics is strictly prohibited. Please note. This call is being recorded I would now like to introduce Jeff Boyle, Vice President of Investor Relations at Sage.

Good morning, and thank you for joining Sage Therapeutics first quarter 2021 financial results conference call before we begin I encourage everyone to go to the Investor and media section of our website at Sage Rx Dot Com, where you can find the press release related to today's call as well as the slides that contains supplemental details.

Jeff Boyle: Good morning. Thank you for joining SAGE Therapeutics' first quarter 2021 financial results conference call. Before we begin, I encourage everyone to go to the investor and media section of our website, at sagerx.com, where you can find the press release related to today's call, as well as the slides that contain supplemental details. I'll 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.

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.

Jeff Boyle: Please consult the risk factors discussed in today's press release and in our SEC filings for additional details. We'll begin the call with prepared remarks by Barry Greene, our Chief Executive Officer, who will provide an overview of accomplishments during the quarter and some general content. Barry will then be joined by Steve Cain, our Chief Medical Officer, who will review recent clinical progress, and Kimi Iguchi, our Chief Financial Officer, who will review first quarter financials and discuss financial guidance. We will be joined for the Q&A session of the call by our Chief Research Officer, Jim Doherty. And with that, I'll turn the call over to Barry. Okay?

We will begin the call with prepared remarks by Barry Greene, Our Chief Executive Officer, who will provide an overview of accomplishments during the quarter and some general context. Barry will then be joined by Steve Cain, Our Chief Medical Officer, who will review recent clinical progress and Kimi Iguchi, Our Chief Financial Officer, who will review first quarter financials and discuss financial Guy.

We will be joined for the Q&A session of the call by our Chief Research Officer, Jim Doherty.

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

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

Barry E. Greene: Thanks, Jeff, and thank you, everyone, for joining us this morning. As we pass the one-year mark of the unprecedented public health crisis created by the COVID-19 pandemic, I'm extremely optimistic that we're turning the corner and containing this devastating impact the virus has had on society. However, and this is critically important, there is a hidden pandemic, the brain health pandemic. And while more and more is coming out about this pandemic, there's a long way to go. Indeed, as we know, during the COVID pandemic, we've seen rates of depression in the U.S. alone increase fourfold, while suicidality among adults has nearly doubled.

As we passed the one year Mark of the unprecedented public health crisis created by the COVID-19 pandemic.

I'm extremely optimistic that we're turning the corner in containing this devastating impact the virus has had on society. However.

However, and this is critically important there is a hidden pandemic the brain health pandemic and while more and more is coming out about this pandemic, there's a long way to go.

Indeed, as we know during the COVID-19 pandemic, we've seen rates of depression in the U S alone increased four fold by suite like Suicidality among adults has nearly doubled.

Barry E. Greene: These will likely affect the world for years to come, broadening the unmet need and further exposing the urgent need for novel brain health. And I'm very proud of the ongoing efforts at SAGE to make medicines that address the very real crisis in brain health. I'm pleased to report the significant advances we made over the last quarter across our depressions, Neuropsychiatry and Neurology Franchise We continue our mission to become the leading brain health company and a top tier bio-requirements, I believe the progress we've made in the first quarter of 2021 sets up for short, medium, and long-term value creation opportunities as we further advance our deep, SAGE-invented, organic pipe, At SAGE, we believe we have the potential to transform the lives of millions of people with brain health disorders who are in need of new, innovative therapies by modulating the GABA and NMDA pathways.

This will likely affect the world for years to come broadening the unmet need and further exposing the urgent need for novel brain Health medicines.

And I'm very proud of the ongoing effort to sage to make medicines that address the very real crisis from brain health.

I am pleased to report the significant advances we made over the last quarter across our depression.

Neuropsychiatry and neurology franchises.

We continue our mission to become the leading brain health company and a top tier biopharmaceutical company.

I believe the progress we've made in the first quarter of 2021 sets up for short medium and long term value creation opportunities as we further advance our deep sage invented organic pipeline.

At Sage, we believe we have the potential to transform the lives of millions of people with brain health disorders, who are in need of new innovative therapy by modulating, the Gaba and NMDA pathways.

And my understanding of dodges receptors, applying our unique chemical innovation to direct steroids, including Oxy sterile Chemistries. We've created novel therapeutic designed to modulate these pathways and highly specific and highly tailored ways.

Barry E. Greene: Now, by understanding Adagis receptors, applying our unique chemical innovation to neuroactive steroids, including oxysterol chemistries, we've created novel therapeutics designed to modulate these pathways in highly specific and highly tailored ways. We currently have three programs in late-stage development, with four ongoing Phase III trials, all of which are on track to lead up to Phase III. Additionally, we have four mid- and early-stage programs in clinical development, and we're committed to the goal of developing two or more high-quality INDs per year starting in 2023.

We currently have three programs in late stage development with four ongoing phase III trials, all of which are on track to read out this year.

Additionally, we are for mid and early stage programs in clinical development and we're committed to the goal of developing two or more high quality <unk> per year, starting in 2023.

In particular this quarter, we were thrilled to report positive topline data from our two lead programs that ran on the lead program in our depression franchise and Sage three two for the lead product in our neurology franchise.

Barry E. Greene: In particular, this quarter, we were thrilled to report positive top-line data from our two lead programs, Zetranolone, the lead program in our depression franchise, and SAGE 324, the lead product in our neurology. In March, we reported continued positive 12-month data from the 30-mg cohort and interim data from the 50-mg cohort of the ongoing Phase III Open Label Shoreline Study evaluating the safety, tolerability, and need for repeat dosing of xeranol in adults with major depressive disorders.

In March we reported continued positive 12 month data from the 30 milligram cohort and interim data from the 50 milligram cohort from the ongoing phase III open label shoreline study evaluating the safety tolerability and need for repeat dosing with <unk> in adults with major depressive disorder.

The 30 milligram showed that approximately 70% of participants had a positive response to an initial two weeks there.

Barry E. Greene: The 30 mg showed that approximately 70% of participants had a positive response to an initial two-week treatment and required at most one additional xeranolone treatment during the 12-month study period. Additionally, after the initial two weeks of analog treatment, more than 70% of patients who received 30 mg and 80% of patients who received 50 mg achieved a positive response at date 15. When we embarked on the Landscape Program, our goal was to develop a rapid-acting, short-duration, durable, treat-as-needed option, and we believe the data from Shoreline supports this potential product profile.

Treatment and required at most one additional as Randall on treatment during the 12 month study period.

And after the initial two weeks or animal treatment more than 70% of patients who receive 30 milligrams and 80% of patients who receive 50 milligrams achieved positive response at day 15.

When we embarked in the landscape program. Our goal is to develop a rapid acting short duration durable treat as needed option and we believe the data from shoreline support this potential product profile.

Moving to late stage program in our neurology franchise Sage three to four we recently announced positive phase two data from our kinetic studies of Sage three to four in essential tremor.

Barry E. Greene: Moving to the late stage program in the neurology franchise, SAGE 324, we recently announced positive phase 2 data from our kinetic study of SAGE 324 in central tremor. To remind you, what we were looking for from this study was a reduction in tremor amplitude of 30-50% that was sustained for the full study period. In other words, no loss of effect or tachyplasia. We're also looking for no adverse event surprises. The kinetic study achieved our objectives and more.

What we're looking for from this study.

Was a reduction in tremor amplitude of 30% to 50% that was sustained for the full study period in other words, no loss of effect or tacky flex.

We're also looking for no adverse events of price.

Next study achieved our objectives and more.

A statistically significant reduction from baseline in the Tetris item for upper limit tremor score at day 29 compared to placebo.

Barry E. Greene: We saw a statistically significant reduction from baseline in the Tetris Item 4 upper lunar tremor score at day 29 compared to placebo. The safety profile is generally consistent with previously reported data for SAGE 324, and just to be clear, we believe SAGE 324 has tremendous potential in essential tremors.

<unk> profile is generally consistent with previously ported data for Sage two four and just to be clear. We believe sage two four has tremendous potential and essential tremor.

The results from this study a statistically significant reduction in tremor and a statistically significant correlation in tremor reduction to our cash.

Activities of daily living are meaningful indicators that further development and optimization of dosing with Sage three to four are important next steps.

Think about fine tuning the therapeutic index and commercial profile, it's important potential therapy.

Barry E. Greene: and TREMOR, and a statistically significant correlation in tremor reduction to activities of daily living are meaningful indicators that further development and optimization of dosing with SAGE 324 are important next steps. We are thinking about fine-tuning the therapeutic index and commercial profile for this important potential therapy.

And to further set some context for the Kinect study we designed the study to evaluate what we knew was the high end of the dosing range.

We're looking for a big effect on tremor with no surprise adverse events, we administered a dose in the morning with your understanding patients would experience islands.

Our goal is to gain an understanding of the PK PD characteristics for Sage three to four and identify plasma levels correlate it to efficacy.

Barry E. Greene: And to further set some context for the Kinetic Study, we designed the study to evaluate what we knew was the high end of the dosing range.

We look forward to presenting these data at a later time and working with our collaborator at Biogen to optimize next steps for the continued development of Sage three to four to get to a dose and frequency for phase III.

Barry E. Greene: We are looking for a big effect on tremor with no surprise adverse events.

Barry E. Greene: We administer the dose in the morning with the understanding that patients would expect.

At this time, we don't think additional formulation work as necessary.

Barry E. Greene: Our goal was to gain an understanding of the PKPD characteristics of SAGE 324 and identify positive levels correlated to epilepsy. We look forward to presenting these data at a later time and in working with our collaborator at Biogen to optimize next steps for the continued development of SAGE 324 to get to a dose and frequency for Phase 3. At this time, we don't think additional formulation work is necessary.

Confident the work proposed to be done and our planned phase two b trial resulted in dose and frequency designed to optimize benefit risk and further development per central tremor.

This quarter also marked progress across our neuropsychiatry franchise, where we are evaluating said 70 <unk> a first in class NMDA receptor Pam as a potential oral therapy for cognitive disorders associated with NDA receptor dysfunction.

I'll provide an update on the positive data from the phase II paradigm study in a moment, but I want to confirm that we intend to initiate a phase two trial in Huntington's disease. Later this year as an important step towards pursuing initial indications for Sage 718.

Barry E. Greene: We're confident the work proposed to be done in a planned Phase 2b trial will result in a dose and frequency designed to optimize benefit-risk and further development for essential tumors. This quarter also marked progress across our neuropsychiatry franchise, where we are evaluating SAGE 718, a first-in-class NMDA receptor PAM, as a potential oral therapy for cognitive disorders associated with NMDA receptor dysfunction. I'll provide an update on the positive data from the Phase 2 paradigm study in a moment, but I want to confirm that we intend to initiate a Phase 2 trial in Huntington's disease later this year as an important step towards pursuing the initial indication for SAGE 718, assuming, of course, that the data continues to support that path.

Assuming of course, the data continue to support that path.

Recall, we previously reported encouraging phase one open label data measures of executive function in patients with HD and this combined with consistent positive data on test of executive function. We saw in paradigm study as well as our discussions with key opinion leaders patients and regulators.

Huntington's disease is a target for our initial indication.

Now on paradigm interim data cut showed patients demonstrated improved performance from baseline on multiple tests of executive function over 14 days of treatment.

<unk> are very similar to previous results in healthy volunteers and patients with Huntington's disease and further support development of Sage 718 for cognitive dysfunction.

Steve will provide additional details on these exciting data, but it is clear that sage 718 has the potential to become a very important treatment for multiple diseases, where cognitive dysfunction or the need for better executive function as a driver of disability.

Barry E. Greene: Recall, we previously reported encouraging Phase I open-label data in measures of executive function in patients with HD. This, combined with consistent positive data on tests of executive function we saw in the PARADIGM study, as well as our discussions with key opinion leaders, patients, and regulators, supports Huntington's disease as a target for our initial indication. Now on Paradigm, the interim data cut showed patients demonstrated improved performance from baseline on multiple tests.

In addition to H D and further work in Parkinson's, we intend to evaluate several other paths forward with Sage 718, Inc.

Excluding cognitive dysfunction associated with Alzheimer's disease with <unk>.

Ongoing luminary study in Alzheimer's disease on track to read out.

Later this year.

This means that by later this year in addition to initiating a placebo controlled phase II per Huntington's disease, we expect to have completed all three data readouts with Sage 718.

Accelerate our efforts to move this program forward.

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

Barry E. Greene: Multiple tests of executive function over 14 days.

Thanks, Terry and good morning, everyone.

We've made great progress across all three franchises to date, including positive data from Orissa ran alone in Sage 324 programs as Barry mentioned as well as positive results with Sage 708 from the paradigm study.

Barry E. Greene: But it's clear that SAGE 718 has the potential to become a very important treatment for multiple diseases, for cognitive dysfunction, or the need for better executive function as a driver of disability. In addition to HD and further work in Parkinson's, we intend to evaluate several other pathways

Our path towards HD as the initial indications and supported further by the results of the paradigm study as the news of the day.

Like to spend the majority of the next several minutes reviewing the progress in our neuropsychiatry franchise and our vision for further development of Sage seven money, our NMDA receptor Pam and development as a potential oral therapy for disorders, where cognition is what are the main drivers of disability, including the very encouraging results from paradigm.

Barry E. Greene: Please pass forward with SAGE 718, including cognitive dysfunction associated with Alzheimer's, with the ongoing luminary study in Alzheimer's disease on track to read out.

We're announcing today.

Before I get to the paradigm results and given the broad spectrum of potential indications for our NMDA program. We thought it would be really important to first level set and ensure that we clearly define what we're talking about when we use the word cognition.

Barry E. Greene: on track to read out later this year. This means that by later this year, in addition to initiating a placebo-controlled Phase 2 for Huntington's disease, we expect to have completed all three data readouts of SAGE 718 as we accelerate our efforts to move this program forward. With that, I'll turn the call over to Steve for more detail on the data we reported this quarter, as well as our additional clinical programs.

Technician can be defined as the sum of all of our mental abilities are fairly abstract definition with two key domains of cognition are executive function learning and memory.

Executive function is the conductor of the brand's orchestra.

Controls our ability to plan and make decisions and also adjust to the challenges our new situations as they arise.

Steve Cain: Thanks, Barry, and good morning, everyone. We've made great progress across all three franchises to date, including positive data from our Zaranulone and SAGE 324 programs, as Barry mentioned, as well as positive results with SAGE 718 and the Paradigm Study. Since our path towards EHD, as the initial indication, has been supported further by the results of the PARADIGM study as the news of the day, I'd like to spend the majority of the next several minutes reviewing the progress in our neuropsychiatry franchise and our vision for further development of SAGE 718, our NMDA receptor PAM, in development as a potential oral therapy for disorders where cognition is one of the main drivers of disability, including the very encouraging results from PARADIGM we're announcing today.

Also the core skill that allows us to react and adapt real time to navigate a constantly changing and evolving environment.

Executive functioning touches so many aspects of what we do on a daily basis and it becomes very difficult to operate independently as executive function declines for example.

Huntington's Parkinson's diseases.

You're probably also familiar with the concept of learning and memory, which is the ability to take in information file it away in our brands internal organization system, and then retrieve it at the appropriate time and place.

While we don't expect to see based on our mechanism of action or any impact positive for deleterious on performance metrics like attention and psychomotor Steve.

So what's so exciting about sage seven to one eight is that beginning with healthy volunteers and in patients with Huntington's disease, we were looking for and saw improvements in executive function.

And now in patients with Parkinson's disease Sage seven money has had a positive impact on multiple domains of cognition, including executive function and learning and memory.

Steve Cain: Before I get to the paradigm results, and given the broad spectrum of potential indications for our NMDA program, we thought it would be really important to first level set and ensure that we clearly define what we're talking about when we use the word cognition. Cognition can be defined as the sum of all of our mental abilities, a fairly abstract definition, but two key domains of cognition are executive function and learning and memory.

While not altering simple attention our reaction time, which are performance, but not true cognitive attributes typically enhanced by a <unk>.

To our knowledge there is nothing to date in clinical development that has generated data, suggesting this kind of profile with <unk>.

Potential ability to augment key cognitive domains without the challenges often associated with other approaches.

Steve Cain: Executive function is the conductor of the brain's orchestra. It controls our ability to plan, make decisions, and also adjust to challenges or new situations as they arise. It's also the core skill that allows us to react and adapt in real time to navigate our constantly changing and evolving environment.

Turning now to paradigm these data reinforce and extend previous positive findings from a new patient population Parkinson's disease.

So they didnt going to provide a brief summary of what we've seen with this initial data cut.

There have been eight patients aged 50 to 75 years old with mild cognitive impairment due to Parkinson's disease free.

Steve Cain: Executive functioning touches so many aspects of what we do on a daily basis, and it becomes very difficult to operate independently as executive function declines, for example, in Huntington's and Parkinson's disease. You're probably also familiar with the concept of learning and memory, which is the ability to take in information, file it away in our brain's internal organization system, and then retrieve it at the appropriate time and place. What we don't expect to see, based on our mechanism of action, are any impacts, positive or deleterious, on performance metrics like attention and psychomotor speed.

Sage 708, three milligrams daily for two weeks.

Similar to earlier findings in healthy volunteers as well as in patients with Huntington's disease patients from the paradigm study demonstrated improved performance from baseline on multiple tests of executive functioning over 14 days of treatment.

It's also important to note that in <unk>.

<unk> Sage 718 had no impact on attention and Psycho motor speed signals that are typically associated with other approaches like stimulus.

Emerging signals from the paradigm study also suggests that there are improvements in performance on tests of learning and memory of a similar timeframe and important finding sage 718 is currently being evaluated in another phase two open label study the luminary study in patients with mild cognitive impairment and mild dementia due to Alzheimer's disease.

Steve Cain: So what's so exciting about SAGE 718 is that beginning with healthy volunteers and then patients with Huntington's disease, we looked for and saw improvements in executive function. And now, in patients with Parkinson's disease, SAGE 718 has shown a positive impact on multiple domains of cognition, including executive function and learning and memory, while not altering simple attention or reaction time, which are performance but not true cognitive attributes typically enhanced by amphetamines

<unk>.

As in previous studies Sage 700, <unk> was generally well tolerated.

Specifically, there were no serious adverse events and no treatment emergent adverse events were determined to be related to Sage 718, it's worth repeating we have not seen any serious adverse events or treatment emergent adverse events related to sage 708 across all studies.

Sage 708 continues to demonstrate from these early trials are consistent and promising profile as a potential treatment to address multiple aspects of cognitive impairment.

So I'm excited by the performance of Sage to everyone in the paradigm study and we intend to activate a four week dosing arm from the paradigm study together additional data and the PD patient population and inform next steps.

Steve Cain: To our knowledge, there is nothing to date in clinical development that has generated data suggesting this kind of profile, the potential ability to augment key cognitive domains without the challenges often associated with other approaches. Throwing that out, these data reinforce and extend previous cognitive findings in the new patient population, Parkinson's disease. Today, I'm going to provide a brief summary of what we've seen with this initial data cut.

The data from paradigm also reinforced our decision to move forward in Huntington's disease, where sage seven money has performed similarly earlier phase one trial.

So we're planning to advance into a double blind placebo controlled phase II study in Huntington's later this year.

Positive will bring us one step closer in pursuing the initial indication for Sage 718.

We will provide greater detail on study design, because we are closer to trial initiation, but what I can share is that we'll be studying a similar battery of cognition tests as previously studied with the goal of sustained changes out to three months.

Steve Cain: To date, there have been 8 patients aged 50-75 years old with mild cognitive impairment due to Parkinson's disease who received SAGE 718 3mg daily for 2 weeks. Similar to earlier findings in healthy volunteers, as well as in patients with Huntington's disease, patients in the PARADIGM study demonstrated improved performance from baseline on multiple tests of executive functioning over 14 days of treatment. It's also important to note that in the study, SAGE 718 had no impact on attention in psychomotor speed, signals that are typically associated with other approaches like stimulus. Emerging signals from the PARADIGM study also suggest that there are improvements in performance on tests of learning and memory over a similar time frame.

Each day is an orphan disease estimated to affect more than 20000 people in the United States and kind of deterioration as one of the earliest and most disabling features of this devastating neurodegenerative disease.

Impairment may begin years before a formal diagnosis with no available treatment to slow the progression of decline leading to loss of independence. The unmet need for these patients is significant.

We have very high ambitions for NMDA platform with the ability to target conditions, where cognitive deficits really impair patients' ability to lead independent lives.

In addition to Sage 708, our neuroscience franchise also includes Sage 904.

And NMDA receptor Pam product candidate being evaluated as a potential oral therapy for other disorders associated with NMDA. Hypofunction. This is currently in an ongoing phase one study that we plan to complete this year and sage for 'twenty, one and oral NMDA Pam is being evaluated for potential use.

Steve Cain: An important finding is that SAGE 718 is currently being evaluated in another Phase II open-label study, the LUMINARY study, in patients with mild cognitive impairment and mild dementia due to Alzheimer's disease. As in previous studies, SAGE 718 was generally well tolerated. Specifically, there were no serious adverse events, and no treatment-emergent adverse events were determined to be related to SAGE 718.

In Neurodevelopmental disorders, and cognitive recovery and rehabilitation, which we expect to advance the preclinical studies later this year.

Turning now to our neurology franchise, we recently announced positive top line data from our phase II double blind kinetics study of Sage 324, assistant 60 milligrams in the central tremor.

Steve Cain: It's worth repeating, we have not seen any serious adverse events or treatment-emergent adverse events related to SAGE 718 across all studies. SAGE 718 continues to demonstrate from these early trials a consistent and promising profile as a potential treatment to address multiple aspects of cognitive impairment. And so, I'm excited by the performance of SAGE 718 in the Paradigm Study, and we intend to activate a four-week dosing arm in the Paradigm Study to gather additional data in the PD patient population and inform next steps.

Earlier open label studies Sage 324 demonstrated pharmacologic characteristics, we believe are well suited for development opportunities not only in essential tremor, but also in epilepsy and Parkinson's disease.

In the study 69 patients aged 18 to 80 years old were randomized one to one to receive either 60 milligrams sage 324 or matched placebo once daily in the morning for 28 days with a follow up period of an additional two weeks.

The trial evaluated treatment of Sage 324 at the high end of the dose range and the daily dose could be down titrated to 45 or 30 milligrams.

Steve Cain: The data from PARADIGM also reinforced our decision to move forward in fighting this disease, where SAGE 718 performed similarly in an earlier Phase I trial. So we're planning to advance into a double-blind, placebo-controlled Phase 2 study at Huntington's later this year, and if positive, will bring us one step closer to pursuing the initial indication for SAGE 718. We'll provide greater detail on the study design as we get closer to trial initiation.

<unk> was deemed to be not well tolerated.

The primary endpoint in this study was changed from baseline compared to placebo on day 29 in upper limb tremor score as measured by item four of the Tetris performance subscale, a physician administered scale designed to provide an accurate comprehensive assessment of essential tremor motor symptoms and have been shown to correlate with tetris.

Activity of daily living.

We are pleased that the study met its primary endpoint a statistically significant reduction in tetris item for upper limb tremor score from baseline at day 29 from the pre specified full analysis set.

Average placebo with a P value of 0.049, which corresponds to a 36% reduction from baseline in upper limb tremor amplitude and patients receiving sage 324 versus a 21% reduction in patients receiving placebo.

Steve Cain: But what I can share is that we'll be studying a similar battery of cognitive tests as previously studied with the goal of sustained changes out to three months. HD is an orphan disease estimated to affect more than 20,000 people in the United States.

Steve Cain: Cognitive deterioration is one of the earliest and most disabling features of this devastating neurodegenerative disease. Cognitive impairment may begin years before a formal diagnosis, and with no available treatment to slow the progression of decline, leading to loss of independence, the unmet need for these patients is significant. We have very high ambitions for our NMDA platform.

And patients with more severe tremor at baseline with a median tetris performance subscale upper limb tremor item four score of 12 or higher Sage 324 demonstrated a statistically significant reduction from baseline in tetris item for upper limb at day 29, compared to placebo with a P value of 0.007.

It corresponds to a 41% reduction from baseline in tremor amplitude day 29, compared to an 18% reduction for placebo.

Steve Cain: The ability to target conditions where cognitive deficits really impair patients' ability to lead independent lives. In addition to SAGE 718, our neuropsych franchise also includes SAGE 904. An NMDA receptor PAM product candidate being evaluated as a potential oral therapy for other disorders associated with NMDA hypofunction. This is currently an ongoing Phase 1 study that we plan to complete this year. In SAGE 421, an oral NMDA PAM is being evaluated for potential use in Neurodevelopmental Disorders and Cognitive Recovery and Rehabilitation, which we expect to advance to preclinical studies later this year.

62 per cent of patients who receive sage 324 were down titrated in dose as allowed by the study protocol discontinuation as were noted in 38% of the patients receiving sage three between core and.

Adverse events were generally consistent with the safety profile of Sage three each week, we're seeing to date and what other Gaba Pam shipment.

Treatment emergent adverse events that occurred in 10% or more of patients and the Sage 324 treatment group and a rate at least twice as high as that of patients in the placebo group were somnolence dizziness that was disorder diplopia dysarthria disturbance.

These data exceeded our expectations for the 60 milligram dose and we're focusing on optimizing dose and frequency for the ongoing development of Sage 324 in essential tremor, along with our collaborators at Biogen.

Steve Cain: Turning now to our neurology franchise, we recently announced positive top-line data from our phase two double-blind kinetic study of SAGE 324 at 60 milligrams in a central tremor. In earlier open-label studies, SAGE 324 demonstrated pharmacologic characteristics we believe are well-suited for development opportunities not only in essential tremor but also in epilepsy and Parkinson's disease. In the study, 69 patients aged 18 to 80 years old were randomized one-to-one to receive either 60 mg SAGE 324 or matched placebo once daily in the morning for 28 days, with a follow-up period of an additional two weeks.

We're encouraged by the potential of Sage 324 for a central tremor disorder with a high unmet need and as Barry mentioned, we're confident in our ability to develop a dose and frequency regimen for further development of the chronic treatment of essential tremor.

Sage 324, our neurology franchise includes Sage 689, a potent investigational product with rapid absorption good viability and solid formulation flexibility with potential in areas of high unmet need.

Including acute agitation mania or even migraine.

So planning to advance stage 319, an oral extra synaptic Gaba a receptor, preferring Pam to preclinical studies for potential use in disorders of social interaction.

Steve Cain: The trial evaluated treatment as age 324 at the high end of the dose range, and the daily dose could be down titrated to 45 or 30 milligrams if 60 was deemed to be not well tolerated. The primary endpoint in the study was change from baseline compared to placebo on day 29 in upper limb tremor score as measured by item 4 of the Tetris Performance Subscale, a physician-administered scale designed to provide an accurate, comprehensive assessment of essential tremor motor symptoms that has been shown to correlate with Tetris activity of daily living.

Turning to our depression franchise March reported continued positive data from our phase III shoreline study, which was designed to naturalistic, we followed patients with major depressive disorder, and evaluate the safety and Tolerability of Saran alone 30 milligrams in adults for up to one year. As a reminder of the study was amended in May 2020 to include.

A 50 milligram dose of <unk> alone.

Data reported showed that after the initial two weeks of rental and treatment more than 70% of patients who received 30 milligrams and 80% of patients who received 50 milligrams achieved positive response by day 15.

And the 30 milligram cohort at day 15, the mean change from baseline was $15 two points and 73, 5% of patients achieved response, and 40% achieved remission as measured by a ham D score of less than or equal to seven.

Steve Cain: We are pleased the study met its primary endpoint, a statistically significant reduction in TETRIS item 4 upper limb tremor score from baseline at day 29 in the pre-specified full analysis set compared to placebo with a p-value of 0.049, which corresponds to a 36% reduction from baseline in upper limb tremor amplitude in patients receiving SAGE 324 versus a 21% reduction in patients receiving placebo. In patients with more severe tremor at baseline, with a median TETRIS performance subscale upper limb tremor item 4 score of 12 or higher, SAGE 324 demonstrated a statistically significant reduction from baseline in TETRIS item 4 upper limb at day 29 compared to placebo with a p-value of 0.007 that corresponds to a 41% reduction from baseline in tremor amplitude at day 29 compared to an 18% reduction for placebo.

Approximately 70% of participants with positive response to the initial two week 30 milligram treatment required. It most when additional is around alone treatment. During a 12 month study.

And the 50 milligram cohort at day 15 of the initial treatment course, the mean Ham D change from baseline was 16.

85% of patients achieved response and 43, 2% achieve remission.

Of the 489 patients from the 30 milligram cohort continuing in the study 42, 9% used only the single initials around alone of course 25, 6% used a total of two courses 11, 9% use a total of three courses 10, 8% used a total of four courses and eight 8% used Ito.

It'll have five courses in both cohorts of rental and was generally well tolerated with an adverse event profile consistent with data reported earlier.

We're also announcing plans to reopen enrollment and the 50 milligram cohort of the shoreline study increasing the target enrollment of 500 patients remain on track to report top line one year data from shoreline 50 milligrams in late 2021 with data from the expanded 50 milligram cohort is expected in 2022.

Steve Cain: 62% of patients who received SAGE 324 down-tritrated in dose, as allowed by the study protocol, and discontinuations were noted in 38% of patients receiving SAGE 324. Adverse events were generally consistent with the safety profile of SAGE 324 seen to date and one other GABA PAM. Treatment-Emerging Adverse Events that Occurred in 10% or More of Patients in the SAGE 324 Treatment Group and a Rate at Least Twice as High as that of Patients in the Placebo Group with Thomulence, Dizziness, Balance Disorder, Diplopia, Dysarthria, and Deep Disturbance

Additionally, we plan to offer patients from the coral study the ability to rollover into the shoreline study following completion of the <unk> study.

These extensions allow sage to collect additional long term data on patients treated with the rental and 50 milligrams.

And finally, we remain on track to report topline data from the Phase III waterfall study from the first half of this year and from phase III Coral and Skylark cities by the end of the year.

Steve Cain: These data exceeded our expectations for the 60 mg dose, and we're focusing on optimizing dose and frequency for the ongoing development of SAGE 324 in essential tremor, along with our collaborators at Biogen. We're encouraged by the potential of SAGE 324 for essential tremor, a disorder with a high unmet need. As Barry mentioned, we're confident in our ability to develop a dose and frequency regimen for further development in the chronic treatment of essential tremor.

We believe this progress positions us well to continue to expand and accelerate our pipeline in order to advance our mission of making medicines that matter.

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

Thanks for let.

Let me start by congratulating our sales team on another great quarter as a result of that commitment termination.

So we're off to a great start in 2021 reporting positive data from free trial with another seven including three pivotal trials are on track to read out later this year.

Steve Cain: Beyond SAGE 324, our neurology franchise includes SAGE 689, a potent investigational product with rapid absorption, good viability, and solid formulation flexibility with potential in areas of high unmet need, including acute agitation, mania, or even migraine. We're also planning to advance SAGE 319, an oral extrasynaptic GABA-A receptor preferring PAM, to preclinical studies for potential use in disorders of social interaction.

As a reminder, this is the first full quarter of our transformative collaboration with Qiagen person right.

24.

This collaboration includes 50 50 cost and profit sharing president.

<unk> 24 in the analyst day.

By design, the collaboration provides financial and operational flexibility enable us to potentially expand it will accelerate not only our near term development of Joanne alone. It takes from 24, but also increased investment in our wholly owned products and accelerate our pipeline.

Steve Cain: Turning to our depression franchise, in March, we reported continued positive data from our Phase 3 Shoreline Study, which was designed to naturalistically follow patients with major depressive disorder and evaluate the safety and tolerability of xeranilone, 30 mg, in adults for up to one year. As a reminder, the study was amended in May 2020 to include a 50 mg dose of xeranilone. Data reported showed that after the initial two weeks of Ritalin treatment, more than 70% of patients who received 30mg and 80% of patients who received 50mg achieved a positive response by day 15.

So now let me walk through the highlights of our first quarter financials, and then close with some thoughts on our financial filings.

Revenues were $1 6 million in the first quarter from the sales of the rest from.

That was compared to $2 3 million for the same period of 2020.

We remain committed to launch their families all of those impacted by people.

Our targeted commercial efforts aimed to help moms with Ptv, who may benefit from shrink Elisa <unk> asthma.

Selling general and administrative expenses were $40 million in the first quarter compared to 70 million from the same period of 2020.

The decrease in SG&A expenses was primarily due to a especially in a company underwent during the second quarter of 2020.

Steve Cain: In the 30 mg cohort at day 15, the mean change from baseline was 15.2 points, and 73.5% of patients achieved a response, and 40% achieved remission as measured by a HAM-D score of less than or equal to 7. Additionally, approximately 70% of participants with a positive response to an initial 2-week 30mg treatment required at most one additional xeraniline treatment during a 12-month study. In the 50 mg cohort, at day 15 of the initial treatment course, the mean HAM-D change from baseline was 16.

Research and development expenses were 58 million in the first quarter compared to $64 million per the same period of 2020.

The decrease was primarily a result of the $20 million reimbursement by Biogen related to the ongoing Saran alone.

24 clinical programs.

And all set by an increase in spending on our waterfall and cross study.

Going forward prior to launch, we expect R&D and SG&A expenses related to their analog and Sage 324, well represent approximately 50% of total collaboration program costs.

Steve Cain: 80.5% of patients achieved response, and 43.2% achieved remission. Of the 489 patients in the 30-mg cohort continuing in the study, 42.9% used only the single initial xeraniline course, 25.6% used a total of two courses, 11.9% used a total of three courses, 10.8% used a total of four courses, and 8.8% used a total of five courses. In both cohorts, xeraniline was generally well-tolerated with an adverse event profile consistent with data reported earlier.

Our list of whether stage or Biogen performance of work.

Essentially this sharing of expenses and establish a new baseline for sage.

Representing a lower net investment per center in Sorrento intense from 24.

Collaboration spend will increase as the programs advance, but we'll continue to be share with five and 50 50 in the U S.

Additionally, this allows us to further invest in our wholly owned pipeline.

Cleaning from 718, and our discovery engine.

We reported a net loss of $96 million per the first quarter of 2021.

That was compared to $127 million for the comparable period of 2020.

Finally, we can pull other maintain a solid financial foundation and in the first quarter here with $2 billion in cash cash equivalents and marketable securities.

Steve Cain: We're also announcing plans to reopen enrollment in the 50-milligram cohort of the Shoreline study, increasing the target enrollment to 500 patients. We remain on track to report top-line one-year data from Shoreline 50 milligrams in late 2021, with data from the expanded 50-milligram cohort expected in 2022. Additionally, we plan to offer patients from the CORAL study the ability to roll over into the SHORELINE study following completion of the CORAL study. These extensions allow SAGE to collect additional long-term data on patients treated with Xeranil and 50mg.

Not expect any milestone payments from collaboration during 2021 and anticipate over the year with net cash balance of more than $1 7 billion.

The cash on hand in addition to the ongoing cost sharing with Biogen will allow us to expand and accelerate the pipeline and continue to invest thoughtfully sequencing assets. We believe will create near mid and long term value creation opportunity for our stakeholders with the potential if we're successful.

To positively impact more than 450 million people worldwide.

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

Steve Cain: And finally, we remain on track to report top-line data from the Phase 3 Waterfall study in the first half of this year and from the Phase 3 Coral and Skylark studies by the end of the year. This was an important quarter for SAGE, marked by progress across our entire pipeline. We're excited about the year ahead, with several milestones in front of us, including multiple Phase 3 readouts expected. We believe this progress positions us well to continue to expand and accelerate our pipeline in order to advance our mission of making medicines that matter. I'll now turn the call over to Kimi for a review of the financials. Kimi?

Jeff.

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

Now I'll turn it over to the operator operator.

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

And to withdraw your question press the pound key.

<unk> borrowings.

<unk> roster.

Our first question will come from the line of style of English share from Goldman Sachs. You May you may begin.

Your line is Andrea on for <unk>. Thanks for taking the question maybe.

Kimi E. Iguchi: Let me start by congratulating the SAGE team on another great quarter as a result of their commitment, determination, and execution. We're off to a great start in 2021, reporting positive data from three trials, with another seven, including three pivotal trials, on track to read out later this year. As a reminder, this is the first full quarter of our transformative collaboration with Biogen for Xeranolone and SAGE 324.

Maybe just one on this additional farmer dosing cohort for the paradigm study.

If you could provide a little bit more color on what you are looking to understand there. Thanks so much.

Yeah, Andrea I'll start out and then turn it over to Jim for additional details so you're asking about Sage 718, we're really excited by the neuroscience franchise and Sage 718.

Our first sort of NMDA receptor modulator in clinical studies and as we've talked about in the call. We're very excited by that.

Kimi E. Iguchi: This collaboration includes 50-50 costs and profit sharing for Zoranilum and SAGE 324 in the United States. By design, the collaboration provides financial and operational flexibility, enabling us to potentially expand and accelerate not only our near-term development of Zoranolone and SAGE 324 but also increase investment in our wholly-owned products and accelerate our. Now, let me walk through the highlights of our first quarter financials and then close with some thoughts on our financial guide.

The forward progress into Huntington's disease, other initial indication and the continued.

Efficacy and safety profile, we're seeing with Sage 718.

Two the luminary data that we reported out today. So all in all we have a very robust package.

In doing drug development, we're looking to learn more and more as we advance Sage 718, and maybe Jim can talk about some specifics with a four week program before we can start absolutely. Thanks.

Thanks, Bert Yes, so of course as Barry said, we're very excited about the potential for Sage 708, and for the NMDA platform in general and I think one other things you are hearing today from Steve is that we're seeing consistent types of responses across multiple patient populations now so some of the design in the study.

Kimi E. Iguchi: Revenues were $1.6 million in the first quarter from the sales of Xerath, but that was compared to $2.3 million for the same period of 2020. We remain committed to moms, their families, and all those impacted by PPD. Our targeted commercial efforts aim to help moms with PPD who may benefit from treatment with the REST-O gain access to care.

Paradigm was to keep things as close as possible to what we had done previously so we're only very patient population and so because of that the design for paradigm was quite similar to what we had done before a two week dosing period, given the results that we're seeing today and given the investment that we've.

Made to get the trial to this point as we've done in the past, we're trying to be efficient here and continue to.

Leverage our learnings and collect as much information as possible and so moving to a part b where patients that are already teed up to enter into the trial to give us some information on slightly longer dosing interval.

Kimi E. Iguchi: That was compared to $64 million for the same period of 2020. The decrease was primarily a result of the $22 million reimbursement by Biogen related to the ongoing Xeronalone and SAGE 324 clinical programs and offset by an increase in spending on our waterfall and coral studies. Going forward and prior to launch, we expect R&D and SG&A expenses related to Zoranilone and SAGE 324 will represent approximately 50% of total collaboration program costs, regardless of whether SAGE or Biogen performs the work.

Going to advance our understanding of the whole program.

Yes.

Yeah.

Thank you. Our next question comes from the line Ritu burrow from Cowen you may begin.

Good morning, guys. Thanks for taking the question.

To get some get your color on helping us inform the ethylene waterfall safety data, specifically I've had a lot of conversations with clients about what is acceptable to patients and what is acceptable some noise.

Just just.

And back to mountain data, where you saw 6% to 7% I believe rates at each and given the higher dose.

Kimi E. Iguchi: Essentially, this sharing of expenses establishes a new baseline for SAGE, representing a lower net investment percent on seranolone in SAGE 324. Collaboration spend will increase as the program is advanced but will continue to be shared with buyers 50-50 in the U.S. Additionally, this allows us to further invest in our wholly-owned pipeline, including SAGE 718 and our Discovery Inc. We reported a net loss of $96 million for the first quarter of 2021.

How should we think about what's acceptable.

And is there a threshold.

A written threshold into public domain by FDA on.

What might complicate actual approval either on station or something else. Thanks.

Yes to all of them.

Let me start out with some context and I'll ask Steve.

To talk about.

What we're looking for out of out of water flow more specifically and why we think it's a rental and has the potential to be a transformative medicine. So I'll remind you that we have studied saran alone and over 3000 subjects and patients.

Kimi E. Iguchi: That was compared to $127 million for the comparable period of 2020. Finally, we continue to maintain a solid financial foundation, ending the first quarter of the year with $2 billion in cash, cash equivalents, and marketable securities. We do not expect any milestone payments from collaborations during 2021 and anticipate ending the year with a cash balance of more than $1.7 billion. The cash on hand, in addition to the ongoing cost sharing with Biogen, will allow us to work to expand and accelerate the pipeline and continue to invest thoughtfully in sequencing assets we believe will create near, mid, and long-term value creation opportunities for our stakeholders, with the potential, if we're successful, to positively impact more I'll now turn it over to Jeff to handle the Q&A with the operator. Okay, Jeff? Thanks Kimi

To date the profile, we've seen is extraordinarily consistent we've seen rapid onset of action three to four days patients report, they're feeling better as we reported on the shoreline data and I won't repeat everything Steve said, we've seen remarkable efficacy two weeks ago, 30, and 50 with most patients requiring only one or two.

Two week doses and entire year.

And and the safety profile.

Has been consistent also at those dose levels.

Important is not necessarily specific numbers of adverse events, it's whether patients stay on the drug or not and because of the unique profile here literally two weeks, maybe two to four weeks of dosing, we've seen remarkable compliance and what we're looking for here is.

A drug that patients will take for two weeks.

So they get better faster and stay better and what we said and just to be clear we hit the primary endpoint given the different benefit risk lives around alone over 35 Years' worth of anti depressants. We are a very important medicine in the landscape. Let me, let me ask Steve to provide a little bit more color.

Jeff Boyle: Thanks, Kimi. Before I turn it over to the operator, I'll ask that you limit yourself to one question. If you have an additional question, feel free to return to the Q&A. Now, I'll turn it over to the operator. Thank you. As a reminder, to ask a question, you will need to press star 1 on your telephone. And to withdraw your question, just press the pound key. Please stand by while we compile the Q&A roster.

Yes, so Richard Thanks for the question. So first things first and foremost we're really confident in the profile every bit of information that we get from the trials really points to a unique profile both in terms of benefit as well as in terms of what what the adverse event profile might look like I remind you and your clients are a few things number one.

<unk> is something that is often desirable for patients with depression and many people have sleep disruptions and we believe that's what's leading to the to the much smaller dropout rate is very low dropout rate from our clinical trials, we do exit interviews and patient's perceptions are that that's not something that would potentially limit their use.

Operator: Hi everyone, this is Andrea on behalf of Salveen. Thanks for taking the question. Maybe just one on this additional four-week dosing cohort for the paradigm study, just if you could provide a little bit more color on what you're doing.

Barry E. Greene: Yeah, Andrea, I'll start out and then turn it over to Jim for additional details. So you're asking about SAGE 718. We're really excited by the Neuropsych franchise and SAGE 718, our first sort of NMDA receptor modulator in clinical studies. And as we talked about on the call, we're very excited by the forward progress into haunting disease as our initial indication and the continued efficacy and safety profile we're seeing with SAGE 718 through the luminary data that we reported out today.

Remember patients are taking the medication for two weeks in any case.

And often this can be beneficial many of these people are taking additional measures to help them sleep.

The second is the numbers that we're reporting are actually comparable if not better than many drugs that are used right now to treat depression, and so I'd advise people to take a look at the labels for anti depressants that or income and use in the reports that we have who are either somnolence sedation and so forth or are are well within the parameters.

The drugs that are approved for the treatment of depression, even standard anti depressant. So.

Barry E. Greene: So all in all, we have a very robust package. In doing drug development, we're looking to learn more and more as we advance SAGE 718. And maybe Jim can talk about some specifics with a four-week program or four-week study. Yeah, absolutely. Thanks, Barry.

Right now the profile is one that we know is going to be beneficial for patients. We're looking forward to the waterfall data, but we're very confident in terms of the overall profile.

Okay.

Thank you. Our next question will come from the line of Susanna Rod from Bank of America, you may begin.

Hi, Good morning, Thanks for taking my question and I guess as it relates to the waterfall study in terms of durability.

Just based on the work that we've done I think back on day 15, you should have good data.

Jim Doherty: Yes, so, as Barry said, we're very excited about the potential for SAGE 718 and for the NMDA platform in general. And I think one of the things you're hearing today from Steve is that we're seeing consistent types of responses across multiple patient populations now. So some of the design of the study for Paradigm was to keep things as close as possible to what we had done previously, so we're only varying the patient population.

I think what's beyond that so maybe longer term day 42 things of that nature I guess first of all when you have that information available at the top line and how important is that based on your doctor feedback to have a longer durability of response.

Treatment regimen. Thank you.

Yeah. It does thanks, thanks for the question.

I'll I'll start out and turn it to Steve to provide a little bit more so we're very excited and confident in our soon.

Jim Doherty: And so because of that, the design for Paradigm was quite similar to what we had done before, a two-week dosing period. Given the results that we're seeing today and given the investment that we've made to get the trial to this point, as we have done in the past, we're doing a lot better.

Envelope opening per waterfall, we're looking forward to the data and let me just be very clear that the primary endpoint in 15 days and having a statistical significant is really what we're looking for for this drug theres nothing out there that gets patients better faster and keeps them better.

But of course, we're looking at all of the secondary endpoints and hopeful that they show promise per day 42, what we're looking for is consistency of effect in the drug arm not necessarily versus versus placebo, but again a P value in the primary endpoint is the most important aspect of waterfall.

Operator: Thank you for joining us today.

Operator: And so moving to Part B where patients that are already teed up to enter the trial to give us some information on a study of a longer dosing interval is going to advance our understanding of the whole program. Thank you. Our next question comes from Ritu Baral from Canada. You may begin.

Steve you want to provide a little bit more.

Sure.

For many years I was practicing psychiatrist in treating patients with depression and the most important thing you look for is consistency of response and understanding exactly what's going to happen. So what we look for is an understanding of what to expect after somebody takes the medication. The data we've seen to date has been very consistent a majority of it.

Operator: Good morning guys, thanks for taking the question. I wanted to get your color on helping us inform the upcoming waterfall safety data. Specifically, I've had a lot of conversations with clients about what is acceptable sedation and what is acceptable somnolence. Just going back to mountain data where you saw 6-7%, I believe, rates of each, and given the higher dose, how should we think about what's acceptable and whether there is a threshold? A written threshold in the public domain by FDA on what might complicate actual approval, either on sedation or somnolence. Thanks. Yeah, Ritu. Let me start out with some context, and I'll ask Steve.

Patients really remain well they don't have an immediate bounce back after the two weeks of dosing is at an initial concern and.

Fact, even in the mountain study patients remained well and very few have recurrence of symptoms over the course of six months. So.

Is absolutely.

Absolutely critical our primary endpoint is day 15, but we want to understand is what proportion of patients stay well during the follow up period as well as reputations, maybe but proportionate patients may require re treatment. Those are day that we're getting from waterfall.

Barry E. Greene: Yeah, Ritu, let me start out with some context, and I'll ask Steve to talk about what we're looking for in waterfowl more specifically and why we think zaranolone has the potential to be a transformative medicine. I'll remind you that we have studied zaranolone in over 3,000 subjects and patients. And to date, the profile we've seen is extraordinarily consistent. We've seen a rapid onset of action, three to four days; patients report they're feeling better.

And what we've seen is something we've talked about before more than 70% of patients need no more than two treatments in a year. That's transformative for patients is absolutely essential to understand that we're talking about four weeks of treatment over the course of a year.

48 weeks without additional need for therapy.

That's what's so unique about two and seven and that's what we're looking for it in both the waterfall data.

As well as the entire landscape program.

Barry E. Greene: As we reported on the Shoreline data, and I won't repeat everything Steve said, we've seen remarkable efficacy at two weeks, both 30 and 50, with most patients requiring only one or two two-week doses in an entire year. And the safety profile has been consistent at dose-to-dose levels.

And so it's a profile that we think is going to be really really important for patients.

If we're successful.

Okay, and we will see that level of thing about the top line.

So when you kind of look to our prior releases should give you a sense of the kinds of information, but is that we'll have in the release, but it is.

So those are things that we're focusing on are the primary endpoint as well as the key secondary is very similar to what we've done for other acute.

Barry E. Greene: What's important is not necessarily specific numbers of adverse events; it's whether patients stay on the drug or not. And because of the unique profile here, literally two weeks, maybe two to four weeks of dosing, we've seen remarkable compliance. And what we're looking for here is a drug that patients will take for two weeks so they get better faster and stay better. And as we've said, and just to be clear, if we hit the primary endpoint, given the different benefit-risk profile of Zaranolone over 35 years of antidepressants, we have a very important medicine in the landscape. Let me ask Steve to provide a little bit more color. Yeah.

Okay.

Sure.

Yes.

Yeah.

Our next question will come from the line of Yasmin Rami from Piper Sandler you may begin.

Hi team congrats on the great progress and sharing data from paradigm.

One question for you I guess.

I wanted to understand maybe the thought behind really increasing the shoreline.

To enroll an additional 500 patients in coral is this expansion into the open label based on communication with regulators.

Just put a little bit color.

Steve Cain: So, Ritu, thanks for the question. First and foremost, we're really confident in the profile. Every bit of information that we get from the trials really points to a unique profile, both in terms of benefit as well as in terms of, you know, what the adverse event profile might look like. I'll remind you and your clients of a few things.

Color around what prompted the interest to increase the numbers on the open label on it would be very helpful and thank you for taking my question.

Thanks for the question actually.

I actually very much appreciate the congratulatory note on the positive data, we're very excited by the emerging data from Sage 718 in <unk> and <unk>.

Thrilled we're moving that forward so rapidly into huntington's disease supported by other data presented day in Parkinson's disease.

Steve Cain: Number one, somnolence is something that is often desirable for patients with depression. Many people have sleep disruptions, and we believe that's what's leading to the much smaller dropout rate, a very low dropout rate, from our clinical trials. You know, we do exit interviews, and patients' perceptions are that that's not something that would potentially limit their use. Remember, patients are taking the medication for two weeks in any case, and often this can be beneficial.

So back to your question about about true lines look we wanted an opportunity first and foremost as patients roll off of clinical studies coral that should those patients continued need another two week course of dosing and you'll note from Steve's prepared comments that very few patients require additional doses, but the good news is those that did.

Responded yet again, so we've got a very promising benefit risk profile.

<unk> was around alone and wanted the opportunity for other patients to benefit <unk>.

Rental, particularly those rolling off of coral and other patients out there.

Jim you want to offer other thoughts.

Steve Cain: Many of these people are taking additional meds to help them sleep. The second point is that the numbers that we're reporting are actually comparable, if not better, than many drugs that are used right now to treat depression. And so, I advise people to take a look at the labels for antidepressants that are in common use. And, you know, the reports that we have for either somnolence, sedation, and so forth are well within the parameters of drugs that are approved for the treatment of depression, even standard antidepressants.

I think that covers most of it Barry but the other thing I would add is day.

Yes.

There are with an integrated set of trials in the landscape program to Barry's point locations are rolling off of coral Theres the opportunity for them to participate in shoreline and we are seeing quite a lot of value in our ongoing naturalistic study for shoreline and our view of it is that it's going to continue to provide us.

More information from what we believe is going to be a transformative therapeutic approach and so we're looking at all opportunities to gather more information funds around alone in shoreline.

Steve Cain: So, you know, right now, the profile is one that we know is going to be beneficial for patients. We're looking forward to the waterfall data, but we're very confident in terms of the overall profile. Thank you. Our next question comes from Tazeen Ahmad from Bank of America. You may begin.

Very likely continued to deliver very important data until your flow program.

Yeah, great great Great comment, Jim and just to put a fine point out yes. There was no specific regulatory requests were no regulatory requests at all to increase and this was the sage decision as Jim highlighted to provide opportunity to get more data and benefit patients.

Operator: Hi, good morning. Thanks for taking my question. I guess as it relates to the waterfall study, in terms of durability, just based on the work that we've done, it seems like on day 15 you should have good data. As we look beyond that to maybe longer terms, day 42, things of that nature, I guess first of all, would you have that information available at the top line? And how important is it, based on your doctor's feedback, to have a longer durability of response for these acute treatment regimens? Thank you. Yes,

Thank you Barry.

Our next question will come from the line of Cory <unk> from J P. Morgan you may begin.

Hey, Good morning. This is Turner on for Cory. Thanks for taking my question. So just 1718 can you provide any additional granularity on what sort of improvement you saw in cognition, maybe just how it stacks up relative to your expectations, but also kind of relative to what we've seen in Huntington disease Huntington's disease since that seems like the lead indication.

One forward.

Yeah.

Thanks, Tim for the question and let me, let me ask Steve to address that.

Sure.

We're looking for as we.

Moving to other areas is to is to both look at not just executive function, but learning and memory. So what we what we saw as we expanded the the domains of cognition. We looked at in these patients is not only improvements in executive function, but also learning and memory and we think that's really important for two reasons.

Barry E. Greene: Yeah, Tazeen, thanks for the question. I'll start out and turn it over to Steve to provide a little bit more. So, you know, we're very excited and confident in our soon envelope opening for Waterfall. We're looking forward to the data.

Barry E. Greene: The primary endpoint at 15 days and having statistical significance is really what we're looking for for this drug. There's nothing out there that gets patients better, faster, and keeps them better. But, you know, we're looking at all the secondary endpoints and hopeful that they show promise. For day 42, what we're looking for is consistency of effect in the drug arm, not necessarily versus, but versus placebo. But again, a p-value in the primary endpoint is the most important aspect of the waterfall. Steve, do you want to provide a little bit more?

One different patient populations have different challenges so huntington's.

Executive function, primarily and that was our hypothesis going in and Parkinson's, There's both executive function challenges as well as.

Dementia, so learning and memory and we think that will also.

Lead into our broader understanding isn't moving to luminary in Alzheimer's, where the primary challenges are learning and memory. So as we learn more and more about the 71 eight the mechanism and its utility that will really inform how we move forward in both the huntington's as well as the other indications.

Great. Thanks.

Thanks Turner.

Our next question will come from the line.

Chico from Wedbush you may begin.

Thanks, very much for taking my question.

Steve Cain: Sure, you know, I was a practicing psychiatrist and treating patients with depression, and the most important thing you look for is consistency of response and understanding exactly what's going to happen. So what we look for is an understanding of what to expect after somebody takes a medication. The data we've seen to date has been very consistent. So, you know, while it's absolutely critical our primary endpoint is day 15, what we want to understand is what proportion of patients stay well during the follow-up period as well as, you know, what proportion of patients may require a retreatment.

I just wanted to circle back on the shoreline question. So you said FDA did not asking for any additional data, but I guess I'm trying to understand is there still a plan to submit a filing for the 30 milligram dose as Randall and I guess just back of the envelope. It would seem like with the expansion of the shoreline cohort and then enrolling the coral pace.

There's probably over a thousand subjects that would have been on the 50 Meg sales set a longer term. Once the study is complete so just trying to understand how the 30 milligram dose fits into everything in terms of the regulatory strategy. Thank you.

Yeah Elvira. Thanks, Thanks for the question and then let.

Let me, let me provide some broad context and ask Jim to provide a little bit more switching or you know your math your math is close.

Steve Cain: These are data that we're getting from Waterfall, and, you know, what we've seen is something we've talked about before. More than 70% of patients need no more than two treatments in a year. That's transformative for patients, so it's absolutely essential to understand that. We're talking about four weeks of treatment over the course of a year, 48 weeks without additional need for therapy. That's what's so unique about 217, and that's what we're looking for in both the Waterfall data as well as the entire Landscape Program. And so it's a profile that we think is going to be really, really important for patients if we're successful.

We will have a significant and when submitting.

The package to the FDA should waterfall would be successful in the ongoing discussions with the FDA successful.

What I said earlier was there was no specific request by the agency to increase and the shoreline expansion or to provide greater opportunity for patients and more data and we also as you can imagine we're getting tremendous requests from investigators kols and of course patients in desperate need of.

Before studies read out we could we can turn a expanded access program with most drugs.

Multiple doses are good to have so we do plan on talking to ANP growth of about 50, and a 30 milligram.

It does but Jim can you provide a little bit more.

Sure Good morning, Laura.

I think Barry said it well the way we think about this is that the entire landscape program is designed to produce a package of information about surround alone. So absolutely all of the data on around loading, including our extensive dataset on the 30 milligram dose will be included in our filing.

Operator: You can look to our prior releases to give you a sense of the kinds of information that we'll have in the release. But as Barry said, the things that we're focusing on are the primary endpoint as well as the key secondaries, very similar to what we've done for other acute studies. Okay, thank you. Our next question will come from Yasmeen Rahimi of Piper Sandler.

That isn't really anything out of the ordinary that discussion will be around the drug itself and all of the data will be included in any potential filing.

Thanks, guys.

Operator: Hi team, congrats on the great progress.

Our next question will come from the line of.

Our cash <unk> from Wolfe Research you may begin.

Operator: Thank you for sharing data from Paradigm with us. One question for you: I just wanted to understand maybe the thoughts behind really increasing the shoreline.

Hi.

Cash pay practices mention day couldn't play MDT mandates the only change patients for 15 days. So they also look at day 28 data for their N D day drug candidate that in.

Operator: to enroll an additional 500 patients in CORL. Is this expansion into open label based on communication you had with regulators?

Operator: You could just put a little bit of color around what prompted the interest to increase.

Ingo occasionally have wonderful the secondary end point at day 48 by 2002, and how important is that day 42 data from the Red hat on filing and holidays at D. A.

Operator: Thank you for taking my question.

Barry E. Greene: Thanks for the question, Yasmeen, and actually, very...

Barry E. Greene: I actually very much appreciate the congratulatory note on the positive data. We're very excited by the emerging data for SAGE 718, and we're thrilled we're moving that forward so rapidly into Huntington's disease, supported by the data presented today in Parkinson's disease. So, we've got a very promising benefit-risk profile with Xeranil and wanted the opportunity for other patients to benefit from Xeranil, particularly those rolling off of coral and other patients out there. You know, Jim, do you want to offer other thoughts?

The open label shoreline study.

Putting evidence for that your ability at all from the ran alone. In addition, we also noticed what else other trial has completed enrollment.

543 subjects with only two arms and about 15% to 20% dropout rate interest they actually think what if a child has.

About 80.

About 90% power to detect two four to $2 five <unk> day difference to placebo and lastly, whatsapp scales <unk> tend to increase equally look at patients with <unk> cut off of <unk>.

Jim Doherty: I think that covers most of it, Barry, but the other thing I would add is to say, you know, there are, with an integrated set of trials in the Landscape Program, to Barry's point, as patients are enrolled.

Dave I just got a full 28, thank you.

Yeah. Thanks.

There were a number of questions in there. So let me, let me provide a little bit of context and ask Steve to.

Jim Doherty: We are seeing quite a lot of value in our ongoing naturalistic study for Shoreline, and our view of it is that it's going to continue to provide useful information for what we believe is going to be a transformative therapeutic approach. And so we're looking at all opportunities to gather more information on Doratalone, and Shoreline will very likely continue to deliver very important data to the overall program.

Comment, maybe Jim might want to come and so look again, we're very excited by the waterfall readout as we've talked about previously we had the opportunity to.

To increase the end twice.

Unfortunately, we are in the brain health pandemic and as I commented on the call. The rates of depression are three to four fold the United States alone. So Unfortunately, there's a lot of people suffering from M. D day out there at rates greater than we had prior to the pandemic lockdown. So that is that increased and provides significant powering on on the primary endpoint.

Barry E. Greene: Great comment, Jim, and just to put a fine point on you guys, there was no specific regulatory request, or no regulatory request at all, to increase N. This was a SAGE decision, as Jim highlighted, to provide an opportunity to get more data and benefit patients.

What we're looking for statistical significance at day 15.

Operator: Our next question will come from the line of Corey Seymour from JPMorgan. You may begin. Hey, good morning.

That is this is such a unique profile the benefit risk here differentiates from again 35 years of drugs being developed.

Operator: This is a turnaround for Corey. Thanks for taking my question. So, just one on 718.

In the area and we're very excited by that.

Steve you want to provide a little bit more.

Barry E. Greene: Can you provide any additional granularity on what sort of improvement you saw in cognition? Maybe just how it's stacked up relative to your expectations, but also kind of relative to what we've seen in Huntington's disease, since that seems like the lead indication going forward. Yeah, thanks, Turner, for the question. And let me let me ask Steve to address that. Sure.

Sure.

Yourself is designed to show differences a day 15, that's the reason why we have breakthrough therapy designation the ability to get patients better within two weeks is what got US let's look at the FDA interested in this program, it's what's unique about the profile.

And we've seen statistical significance and clinically meaningful differences as early as day three day eight day 15, and those within those benefits are maintained the only real way to assess what that looks like in terms of pattern per patients that have gotten better is to use shoreline data and again. These are this is an overall program that was agree.

Steve Cain: You know, what we're looking for as we move to other areas is not just executive function but learning and memory. So what we saw as we expanded the domains of cognition we looked at in these patients was not only improvements in executive function but also learning and memory. And we think that's really important for two reasons. One, different patient populations have different challenges. So Huntington's is about executive function primarily, and that was our hypothesis going in.

With the FDA, when we had breakthrough where we actually naturalistic, let's see what happens to patients when they're when they're treated upfront and then followed over the course of the year for need for re treatment and what we've seen is the patients require 70 per cent of the patients plus required no more than two treatments in a year and half of them only required one treatment.

So this gives a lot of information about how a drug that works very rapidly would be used in real life and it's a very unique overall profile. So.

Steve Cain: In Parkinson's, there are both executive function challenges as well as dementia, so learning and memory. And we think that will also lead into our broader understanding as we move into luminary and Alzheimer's, where the primary challenges are learning and memory. So as we learn more and more about the 718, its mechanism, and its utility, that will really inform how we move forward in both Huntington's as well as the other indications.

Our primary absolutely central to the day 15, we're looking to see.

Sensually patients being you know instead of improved remain well the real data for that aspect really comes from from shoreline and we have a very substantial and now growing database around that and it continues to support the idea of episodic treatment.

Operator: Great. Thanks. Thanks, Turner. Our next question will come from the line of Laura Chico from Wedbush. You may begin.

Okay.

Yes.

Thank you.

And as a quick reminder, please limit yourself to one question.

Our next question will come from the line of Jay Olson from Oppenheimer you may begin.

Oh, Hey, guys. Thanks for taking the question I'm curious about the Sage 324, I think you're leading that development program with Biogen can you just talk about communications you are planning to pursue and whether or not you plan to study $3 24 in Parkinson's disease epilepsy patients. Thank you.

Operator: Thanks very much for taking the question. I just wanted to circle back on the Shoreline question. So you said FDA did not ask you for any additional data, but I guess I'm trying to understand, is there still a plan to submit a filing for the 30 milligram dose of Durandalone? And, you know, just back of the envelope, it would seem like with the expansion of the Shoreline cohort and then enrolling the coral patients, there are probably over a thousand subjects that would have been on the 50 mg dose at a longer term So just trying to understand how the 30 milligram dose fits into everything in terms of the regulatory strategy. Thank you.

Yeah Jay.

And so look that.

We're really excited about.

For the virology franchise.

We believe it's a novel potential treatment for chronic neurological conditions.

And we thought very differently about movement disorders. So if this is successful in the initial indication of central tremor will be the first new treatment in over 50 years.

Really excited by that as I mentioned, we're very confident that in the phase <unk> will reach the dosing frequency that is a profile would take into phase III and then commercialize book profile with that profile and talking to our collaborative advisors will map out additional indications, but we do believe that there are a number of additional indications we can pursue.

Barry E. Greene: Thanks for the question. Let me provide some broad context and ask Jim to provide a little bit more. Your math is close.

Three to four you know whatsoever that next step of dose and frequency and essential tremor.

Anything else to offer.

Yeah, I think I think what I'd say is you know as we dialed in what profile, we're looking for where we're working closely with investigators were working with patients and patient advocacy groups. We're even doing exit interviews with the patients that participated in our trials to understand exactly what they're looking for in a medicine. This is something that we've been you've been looking to central tremor.

Barry E. Greene: We will have a significant end when submitting the What I said earlier was there was no specific request by the agency to increase N. The Shoreline expansion was to provide greater opportunities for patients and more data. We also, as you can imagine, are getting tremendous requests from investigators, KOLs, and, of course, patients in desperate need. Before our studies read out, we can turn to the expanded access program. With most drugs, multiple doses are good to have, so we do plan on talking to the agency both about a 50 and a 30 milligram dose. But Jim, can you provide a little bit more? Sure.

For for quite some time and you know right.

Right now the data on hand, really speaks to upper limb tremor being ones. That's a driver of disability, we could see that when we when we look at the correlation with improvements in activities of daily living so overall, our growing understanding of 324 something that not only is it unique but it is something that we think is a really a great.

Jim Doherty: Sure, and good morning, Laura. I think Barry said it well.

Example would be of the approach that we take to R&D. So we've had preliminary data in some of these other indications Parkinson's non clinical data in epilepsy right now our focus is on essential tremor, but we certainly have broader interest in the other areas moving forward Jim.

Jim Doherty: The landscape program is designed to produce a package of information about xeronalin. So, absolutely all of the data on xeronalin, including our extensive data set on the 30 mg dose, will be included in the filing.

Yes, maybe to build on that a little bit. Your other question was about other potential indications.

And free to four we see is as the lead molecule for neurology franchise and as Steve was just saying, it's a little bit to do with the way, we think about R&D in general.

Jim Doherty: And yeah, that isn't really anything out of the ordinary. The discussion will be around the drug itself, and all of the data will be.

Operator: All of the data will be included in any potential filing. Our next question will come from the line of Akash Tewari from Wolf Research. You may begin.

Talk a lot about two things following the science and leading with human data and they are following the science in this case means we understand that there are multiple patient populations, who could potentially benefit from a Gaba potentiate molecule like sage 324, and especially with that profile of that is optimized for chronic delivery and so that leads us to the second point.

Operator: Hi, this is Leo for Akash. Recently, practices mentioned they couldn't claim MDT treatment if they only treated patients for 15 days.

Operator: [inaudible] In addition, we also noticed that the Waterfall trial has completed enrollment of 543 subjects.

Leading with human data and although our key focus at the moment on the program is in the central tremor as you've been hearing we do have data from an earlier program.

Operator: It is fair to think the Waterfall trial has about 90% power to detect 2.4 to 2.5 HMD differences between placebo. And lastly, what subscales of HMD17 tend to increase if we look at patients with an HMD cutoff of 20 versus 24 versus 28? Thank you. Yeah, thanks.

Preliminary look at potential efficacy in Parkinson's disease, and we've got an absolute raft of preclinical data.

Indicating that this mechanism and this molecule would be valuable treatment for epilepsy.

Barry E. Greene: I think there are a number of questions in there, so let me provide a little bit of context and ask Steve to comment. Maybe Jim might want to comment, too.

A lot of potential value for the neurology franchise, and that's something that our partners Biogen are well aware of and that'll be the subject of ongoing conversations but the key focus for now is essential tremor, but we think that there is a lot of potential from the molecule in other.

Barry E. Greene: So, look, again, we're very excited by the Waterfall readout. As we talked about previously, we had the opportunity to increase the N twice. Unfortunately, we are in a brain health pandemic.

Groups in neurology as well.

Thanks.

Great. Thanks for taking the question.

All right.

And our next question will come from the line from <unk> from Stifel. You may begin.

Great. Thank you.

Have you guys talked with Biogen about scenario planning.

If waterfall and Carl were to fail, but the phase III postpartum study were to succeed would you launch this drug in PPD, and then kind of figure everything else out later or would you wait and then separately, what's the status of our future trials and anxiety and bipolar depression and is the kind of is the initiation of those studies at all.

Barry E. Greene: The benefit risk here differs from, again, 35 years of drugs being developed in the area. We're very excited by that. Steve, do you want to provide a little bit more?

Steve Cain: The study itself is designed to show differences at day 15. That's the reason why we have the Breakthrough Therapy designation. The ability to get patients better within two weeks is what got the FDA interested in this program. It's what's unique about the profile, and we've seen statistical significance and clinically meaningful differences as early as day 3, day 8, and day 15, and those benefits are maintained. So, this gives a lot of information about how a drug that works very rapidly would be used in real life, and it's a very unique overall profile.

Upon what we see in M. D day. Thank you.

Okay. Thanks, Paul Thanks for the question so.

Again, I'll remind you that the data we've seen was around alone now in over 3000 subjects and patients has been highly consistent rapid onset of effect three or four day been very durable as IMC.

Steve and Jim have highlighted with the with an adverse event profile. It's been consistent. So we are highly encouraged by the upcoming data Readouts, we sat down with the agency are mapped out three unique.

Steve Cain: So, you know, for our primary, absolutely essential to date 15, we're looking to see, essentially, patients that have improved and remain well. The real data for that aspect really comes from Shoreline, and we have a very substantial and now growing database around that, and it continues to support the idea of episodic treatment.

Per unique approaches three unique different.

Ways to potentially get approval to an M. D D as you've highlighted and why in PPD and we believe that one of those phase threes needs to be positive for us to have a drug on the market. So we're very enthusiastic about all three approaches and believe that.

As you've seen with many drugs.

Need one positive phase III here, that's an agreement with the agency, yes, some scenario planning with Biogen, a very high level, but not in any.

Operator: Thank you. And as a quick reminder, please limit yourself to one question. Our next question will come from the line of Jay Olson from Oppenheimer. You may begin. Oh, hey guys, thanks for taking the question. I'm curious...

E Mail and we believe we are a very important drug here not only for MB DNP can be but potentially other indications and will share more about those those paths forward as we've mapped that out with biogen.

Operator: Our next question will come from the line of Jay Olson from Oppenheimer. You may begin.

Yeah.

Our next question will come from the line of Andrew Tsai from Jefferies. You may begin.

Operator: Hey guys, thanks for taking the question. I'm curious about SAGE 324. I think you're leading that development program with Biogen. Can you just talk about the indications you're planning to pursue and whether or not you plan to study 324 in Parkinson's disease or epilepsy patients? Thank you.

Thanks, and good morning.

My question is around the waterfall and I know you guys aren't very good at controlling that and I don't think I've ever been an issue for you, but I'm just curious to see what steps you've taken to ensure there won't be a higher than expected placebo response out to day 42.

Basically I'm just curious to see how confident you are that scenario wouldn't happen. Thanks.

Barry E. Greene: So, look, we're really excited about SAGE 2B for its neurology franchise. We believe it's a novel potential treatment for chronic neurological conditions, and we thought very differently about movement disorders. So, you know, if this is successful in the initial indication of central tremor, it will be the first new treatment in over 50 years. So we're really excited about that.

Yeah, Andrew Thanks for highlighting that.

I'll make a comment and I'll turn it over to Jim talk about the conduct.

Of the studies. So we have you know Wednesday, the shoreline data with decreasing and in waterfall.

We are increasing our safety database is a very large indication as we're all aware so the bigger the safety database that better importantly, Andrew it was not seen guidance, we've committed to delivering.

Barry E. Greene: As I mentioned, we're very confident that in SAGE 2B, we'll reach a dose and frequency that is a profile to take into phase three and then a commercializable profile. With that profile and talking to our collaborators at Biogen, we'll map out additional indications, but we do believe that there are a number of additional indications we could pursue with SAGE 324 once we're over that next step of dose and frequency in central tremor. Steve, anything else to offer?

Topline results from phase III in the first half of this year and we tend to conclusion I can do that so we're enthusiastic about the progress of the program is fully enrolled and we're looking forward to it.

Jim you want to talk about specifics of.

The control placebo in our thoughts there.

Absolutely and Andrea Thanks, Andrew Thanks for the question.

As I think you know we are we put a lot of thought and focus into into design and I think the answer is that we've talked a lot about the waterfall design in.

Steve Cain: Yeah, I think I think what I'd say is, you know, as we dial in what profile we're looking for, we're working closely with investigators, we're working with patients and patient advocacy groups, we're even doing exit interviews with the patients that participated in our trials to understand exactly what they're looking for in a medicine. This is something that we've been looking into essential tremor for quite some time.

Modifications that we made in design based on learnings, but.

The other important thing to remember is many of the things that we have learned through multiple trials in the landscape program.

Much remain in the design of waterfall and I think that's our view on things like controlling for placebo effect I think.

What we tried to do is do.

Steve Cain: And, Right now, the data on hand really speaks to upper limb tremor being one that's a driver of disability. We can see that when we look at the correlation with improvements in activities of daily living. So overall, our growing understanding of 324 is something that, you know, not only is it unique, but it's something that we think is really a great example of the approach that we take to R&D. So, you know, we've had preliminary data in some of these other indications, Parkinson's, and non-clinical data in epilepsy.

Do very rigorous about our execution and that is something that we are doing again with the waterfall study.

Yeah.

Thanks very much.

Thanks, Andrew.

Our next question will come from the line Nemo the tradeoff Garg from Citi you may begin.

Hey, guys. Thanks for taking my question.

So I'm just kind of curious about the next steps kind of after a waterfall I know you've talked about you know not necessarily meeting the Redwood study at this point given the data you're seeing from shoreline.

Other studies, but I guess is there are there kind of differences in next steps depending on the magnitude of effect that you see in waterfall and assuming it is statistically significant just depending on kind of the differential between drug versus placebo is there do you envision there being kind of any differences in next steps or you know as long as it's really just.

Steve Cain: Right now, our focus is on essential tremor, but we certainly have broader interests in other areas moving forward. Jim? Yeah, maybe to build on that a little bit, you know, the question was about other potential indications and, as 3-2-4 we see it as the lead molecule for neurology.

One path forward.

Yeah.

Jim Doherty: And as Steve was just saying, it has a little bit to do with the way we think about R&D in general, and we talk a lot about two things.

Thanks for the question I'll I'll I'll take it and if Steve has other other collaros Kim So yeah as we said what we're counting on for waterfall is a statistically significant result result at day 15.

Jim Doherty: and we talk a lot about two things, following the science and leading with human data. And so, following the science in this case means we understand that there are multiple patient populations who could potentially benefit from a GABA-potentiating molecule like SAGE-324, and especially with that profile that's optimized for chronic delivery. And so that leads us to that second point of leading with human data. And although our key focus at the moment on the program is the central tremor, as you've been hearing, we do have data from early.

If that's true and we have an adverse event profile, that's consistent with what we've seen already over 3000 subjects and patients. We have a very important medicine with a very differentiated benefit risk than anything that exists in the market today. So statistically significant need for clean we have a drug and I think the unmet need is so.

Extreme that kols patient groups and the regulators appreciate that that's what we're looking for so obviously.

The data matter an effect size matters to some extent, but we're really looking for statistical significance our plan through the waterfall would be positive.

Jim Doherty: and an earlier program, a preliminary look.

Jim Doherty: There's a lot of potential value for the neurology franchise, and that's something that our partners at Biogen are well aware of, and that'll be

Sit down with the agency and being very clear and mapping out next steps, we could start a rolling submission we could file a waterfall.

Key that we're looking for just to be clear. It is also timing of coral and we would not want to get into a situation, where we filed an NDA had another major data readout submitted that readout.

Jim Doherty: The key focus for now is essential tremor, but we think that there is a lot of potential for the molecule in other groups in neurology as well. Great, thanks for taking the question. And our next question will come from Paul Matteis from Stateful. You may begin.

Went into kind of a three months.

And so should the agency wants to coral.

We'd likely wait the whole clinical sector for both waterfall and coral.

You asked about Redwood I'll remind you that before data existed as it exists today a question.

Operator: Have you guys talked with Biogen about scenario planning? If waterfall and coral were to fail but the phase three postpartum studies were to succeed, would you launch this drug in PPD and then kind of figure everything else out later? Or would you wait?

Jeff how many times in the year can you effectively and safely treat a patient that that's not really a question with all the data we have right now waterfall shoreline that needs to be so we're very confident.

Assuming a positive waterfall that redwood will not be a a regulatory requirement for filing the NDA we might have other.

Post approval commitments that would map out as soon as we talked from the agency.

Operator: And then separately, what's the status of future trials for anxiety and bipolar depression? And is the initiation of those studies at all contingent upon what we see in MDD? Thank you. Hey, thanks, Paul.

Thank you Matt.

Yeah. The only thing I'd say is when we started this program we set out to identify a drug with a very unique profile and medicine that lines.

Closely with patient interest it's quick.

Barry E. Greene: Thanks for the question. So again, I'll remind you that the data we've seen with zaranolone now in over 3000 subjects and patients has been highly consistent, rapid onset. The effect, three or four days, has been very durable, as I and Steve and Jim have highlighted, with an adverse event profile that's been consistent.

The effects are durable and they're long treatment free intervals.

The data that we get from shoreline really supports that approach what we're looking for is that next study.

We're showing the acute effects.

The day 15 endpoints so that is.

Absolutely essential.

And it's it's important the other the other thing I'd add is that sometimes people wonder about effects versus effect size, what we've seen across the board. It's been very consistent are large.

Barry E. Greene: So, you know, we are highly encouraged by the upcoming data readouts. We sat down with the agency and mapped out three unique approaches, three unique ways to potentially get approval, two in MDD, as you highlighted, and one in PPD. And we believe that one of those phase three trials needs to be positive for us to have a drug on the market. So, we're very enthusiastic about all three approaches and believe that, you know, as you see with many drugs, we need one positive phase three trial here.

Rapid and sustained improvements in the drug group placebo varies quite a bit Inc.

So it was.

We're very confident around physical significance being the the the primary end point here and the goal prior to filing.

Our next question comes from the line of.

[noise], Gary Mckinnon from BMO capital markets you may begin.

Hi, This is Evan <unk> filling in for Gary Thanks for taking my question.

So regarding the phase III or what are the next steps in terms of developing the protocol from phase II B are there like any additional data you would be looking at.

Barry E. Greene: And that's an agreement with the agency. Yes, the scenario plan with Biogen is very high-level, but not. We believe we have a very important drug here, not only for MDD and PPD but potentially other indications. And we'll share more about those paths forward as we map that out with Pfizer. Our next question will come from the line of Andrew Stile from Jefferies. You may begin.

In the next several months that could help inform how you move forward in terms of dose timing of dose in patient population and if so when would you release some of that debt.

Yeah. Thanks for the question. So let me let me.

Operator: Thanks, and good morning. My question is about the waterfall, and I know you

Operator: You guys are very good at controlling this, and I don't think this has ever been an issue for you, but I'm just curious to see what steps you've taken to ensure there won't be a higher-than-expected placebo response out to day 42. Basically, I'm just curious to see how confident you are that this scenario wouldn't happen.

As to be dose and frequency and we'll likely test a couple of different ones to make sure that we have the right the right profile going into phase.

Barry E. Greene: Yeah, Andrew, thanks for highlighting that. And let me make a comment, and I'll turn it over to Jim to talk about the conduct of the study. So with the Shoreline data, with the increasing N in waterfall, we're increasing our safety database. It's a very important indication, as we're all aware. So the bigger the safety database, the better.

Phase III, so we're very encouraged by.

By the kinetic readout, particularly the patients that were the worst operations over 12 hour, we saw 41% reduction.

Our central timber very important reduction for these patients the Jim you want to talk about any specifics on next steps.

Yeah, absolutely Barry and I wouldn't when we think about the results from Qinetiq as as you heard earlier.

Barry E. Greene: Importantly, Andrew, we've not changed guidance. We've committed to delivering the top-line results for Phase 3 in the first half of this year, and we intend to continue to do that. So we're enthusiastic about the progress of the program. It's fully enrolled, and we're looking forward to the readout. Jim, do you want to talk about

Statistically significant.

<unk> affects on the primary endpoint and sustained over a 28 day period with an adverse event profile that consistent with what we understand about the drug and about the mechanism of action. So the question to be answered from Qinetiq was can we see efficacy can we see efficacy without tachyphylaxis, which we're excited about because thats the result of that.

Jim Doherty: And you want to talk about the specifics of... Control Placebo and Higher Thoughts there?

Jim Doherty: Control, Placebo, and Higher Thoughts there. Yeah, absolutely. And Andrew, thanks. Andrew, thanks for the question. As I think you know, we put a lot of thought and focus into design. And I think the answer is that we've talked a lot about the waterfall design and the modifications that we made in design based on learnings. But the other important thing to remember is many of the things that

We see the focus on the.

The to be in the rest of the phase III program is on dosing strategy and remember three two for the long half life drug that's been optimized for chronic dosing that gives us a lot of flexibility in exactly the dosing strategy that we'll use for pivotal studies and so that's going to be focused and I think Barry mentioned there are a number of different thing.

Jim Doherty: We have learned through multiple trials in the Landscape Program.

Things that we can look at modifying so certainly dose level dose frequency. There are a number of aspects that we're looking at and so the stage and Biogen teams will we'll figure out what's the most efficient way to answer those questions and in phase two day.

Jim Doherty: I think what we try to do is be very rigorous about our execution, and that is something that we are doing again with the water.

Jim Doherty: and That is something that we are doing again with the waterfall study.

Operator: Our next question comes from the line of Neena Bitritto Garg from Citi. You may begin.

Thank you that is all.

Time, we have for questions today, I'll turn the call back over to Barry Greene for any closing remarks.

<unk>.

Operator: Hey guys, thanks for taking my question. So I'm just kind of curious about the next steps, kind of after waterfall. I know you've talked about not necessarily meeting the Redwood study at this point, given the data you're seeing from Shoreline and, you know, a number of other studies, but I guess, are there, are there kind of differences in next steps depending on the magnitude of the effect that you see in waterfalls?

Thanks, operator, and thanks, everyone for joining us. This morning, we are very pleased with the significant progress from the first quarter and we're excited about the potential for additional milestones throughout the day.

Earlier this year.

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Operator: And assuming it is statistically significant, you know, just depending on the kind of the differential between drug versus placebo, is there, do you anticipate there being any kind of differences in the next steps or, you know, as long as it's steps?

Barry E. Greene: So, as we said, what we're counting on for waterfall is a statistically significant result at day 15. If that's true, and we have an adverse event profile that's consistent with what we've seen already in over 3,000 subjects and patients, we have a very important medicine with a very differentiated benefit-risk profile than anything that exists in the market today. So statistically significant at day 15, we have a drug. And I think the unmet need is so extreme that KOLs, patient groups, and the regulators appreciate that that's what we're looking for. So, obviously, obviously, data matter, and effect size matters. We're looking for statistics of significance.

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And talking about in treating brain health issues, we're excited to see this progress and for others joining us in what we have been acknowledged as a big lift.

Now more than ever a patient suffering with brain health issues need better more effective treatment and the sage team is working tirelessly to deliver on our vision of bringing such treatment patients. So they can get better sooner.

Barry E. Greene: Our plan, should Waterfall be positive, is to sit down with the agency and be very clear in mapping out next steps. We could start a rolling submission; we could file Waterfall. A key that we're looking for, just to be clear, is also timing for coral. We would not want to get into a situation where we filed an NDA, had another major data readout, submitted that readout, and went into kind of a three-month extension. So, should the agency want to see coral, we'd likely wait for the whole clinical section for both Waterfall and coral. Now, you asked about Redwood.

Thanks, everyone look forward to further discussions.

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

[music].

Barry E. Greene: I'll remind you that before data existed as it exists today, a question was asked, how many times in a year can you effectively and safely treat a patient? That's not really a question with all the data we have right now. Waterfall, shoreline, that needs to be asked.

Barry E. Greene: So, we're very confident, as we are assuming a positive waterfall, that Redwood will not be a regulatory requirement for filing NDAs. We might have other post-approval commitments that we'll map out as soon as we talk to the agency. Steve Aikman, Yeah, the only thing I'd say is, you know, when we started this program, we set out to identify a drug with a very unique profile, a medicine that, you know, aligns closely with patient interest, it's quick, the effects are durable, and, you know, they have long treatment The data that we get from Shoreline really supports that approach. What we're looking for is that next study where we show the acute effects. That's the D815 endpoint.

Steve Aikman: So that's absolutely essential, and it's important. The other thing I'd add is that sometimes people wonder about effect versus effect size, rapid and sustained improvements in the drug group versus placebo varies quite a bit, and so that's why we're very confident around statistical significance being the primary endpoint here in the goal prior to filing. Our next question comes from Gary Mackman from BMO Capital Markets. You may begin.

Operator: Hi, this is Evan Hua filling in for Gary. Thanks for taking my question.

Operator: What are the next steps in terms of developing the protocol for Phase 2B? Are there any additional cuts of data you'll be looking at in the next several months that could help in this process?

Operator: Thank you all for joining us today.

Barry E. Greene: Yeah, thanks for the question. So, let me hit it at a high level and ask Jim to talk about it. So, the team at SAGE and Biogen is actually going through the detailed kinetic data, looking at dose, duration, PK, and PD, and the value of those data will help us design the Phase 2B dose and frequency, and we'll likely test a couple different ones to make sure that we have the right profile going into Phase 3. So, we're very encouraged by the kinetic readout, particularly the patients that were the Warsaw patients over 12, where we saw a 41% reduction in essential tremor, a very important reduction for these patients.

[music].

Jim Doherty: Jim, do you want to talk about any specifics and next steps?

Jim Doherty: Yeah, absolutely, Barry. And when we think about the

Jim Doherty: So the focus on 2B and the rest of the Phase II program is on dosing strategy. And remember, 3-2-4 is a long, half-life drug that's been optimized for chronic dosing. That gives us a lot of flexibility in exactly the dosing strategy that we'll use for pivotal studies, and so that's going to be the focus. And as I think Barry mentioned, there are a number of different things that we can look at modifying.

Jim Doherty: So certainly, dose level, dose frequency, there are a number of aspects that we're looking at. And so the Stage and Biogen teams will figure out what's the most efficient way to answer those questions in Phase 2B.

Operator: Page PAGE of NUMPAGES www.verbalink.com Page PAGE of NUMPAGES

Barry E. Greene: This concludes all the time we have for questions today. I'll turn the call back over to Barry Greene for any closing remarks.

Barry E. Greene: Thanks, Operator. Thanks, everyone, for joining us this morning. We are very pleased with the significant progress in the first quarter, and we're excited by the potential for additional milestones throughout the balance of this year. And I want to acknowledge that May is Mental Health Awareness Month, and I'm excited to see the real movement across the world, a movement that encourages people to speak up and change the narrative on brain health and mental wellness.

Barry E. Greene: There's also a growing awareness of the global impact the current mental health pandemic is having on the young and the old. In fact, just this week, MTV convened a groundbreaking coalition of media companies and mental health experts to harness the power of media and storytelling, kicking off at Bear Together, a mental health storytelling summit, drawing talent including Oprah Winfrey, Trevor Noah, and Regina King, among many others. The coalition unveiled a first-of-a-kind comprehensive mental health media guide, which provides best practices and evidence-based recommendations to empower content creators and entertainment to expand portrayals of mental health to further encourage viewers to speak up and get help.

Barry E. Greene: True progress, as we further lean in, is a very real challenge presented by a lack of progress in talking about and treating brain health issues. We're excited to see this progress and for others to join us in what we acknowledge is a big lift. Now more than ever, patients suffering with brain health issues need better, more effective treatment, and the SAGE team is working tirelessly to deliver on our vision of bringing such treatment to patients so they can get better sooner.

Barry E. Greene: Thanks, everyone. Looking forward to further discussions. Be well.

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

Operator: Welcome to SAGE Therapeutics' First Quarter 2021 Financial Results Conference Call. Currently, all participants are in a listen-only mode. This call is being webcast live on the investor and media sections of SAGE's website at sagerx.com. This call is the property of SAGE Therapeutics, and recording, reproduction, and transmission of this call without the express written consent of SAGE Therapeutics is strictly prohibited. Please note this call is being recorded. I would now like to introduce Jeff Boyle, Vice President of Investor Relations at

Jeff Boyle: Please consult the risk factors discussed in today's press release and in our SEC filings for additional details. We'll begin the call with prepared remarks by Barry Greene, our Chief Executive Officer, who will provide an overview of accomplishments during the quarter and some general context. Barry will then be joined by Steve Cain, our Chief Medical Officer, who will review recent clinical progress, and Kimi Iguchi, our Chief Financial Officer, who will review first quarter financials and discuss financial guidance. We will be joined for the Q&A session of the call by our Chief Research Officer, Jim Doherty. And with that, I'll turn the call over to Barry. Okay?

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Barry E. Greene: These will likely affect the world for years to come, broadening the unmet need and further exposing the urgent need for novel brain health. And I'm very proud of the ongoing efforts at SAGE to make medicines that address the very real crisis of brain death. I'm pleased to report the significant advances we made over the last quarter across our depression, Neuropsychiatry, and Neurology Franchise. We continue our mission to become the leading brain health company and a top-tier biopharmaceutical company. I believe the progress we've made in the first quarter of 2021 sets us up for short, medium, and long-term value-creation opportunities as we further advance our deep, SAGE-invented, organic pipeline.

Barry E. Greene: At SAGE, we believe we have the potential to transform the lives of millions of people with brain health disorders who are in need of new, innovative therapies by modulating the GABA and NMDA pathways. Now, by understanding Adagis receptors, applying our unique chemical innovation to neuroactive steroids, including oxysterol chemistries, we've created novel therapeutics designed to modulate these pathways in highly specific and highly tailored ways.

Good morning, welcome to Sage Therapeutics first quarter 2021 financial results Conference call. Currently all participants are in a listen only mode. This call is being webcast live on the Investor and media section of Sage website at Sage Our X Dot Com. This call is property of Sage therapeutics and recordings reproduction or transmission of this call without the express written consent.

Barry E. Greene: We currently have three programs in late stage development with four ongoing phase three trials, all of which are on track to lead up. Additionally, we have four mid- and early-stage programs in clinical development, and we're committed to the goal of developing two or more high-quality INDs per year starting in 2023. In particular, this quarter, we were thrilled to report positive top-line data from our two lead programs, Ranalone, the lead program in our depression franchise, and SAGE 324, the lead product in our neurology.

Sage Therapeutics is strictly prohibited. Please note. This call is being recorded I would now like to introduce Jeff Boyle, Vice President of Investor Relations at Sage.

Good morning, Thank you for joining Sage Therapeutics first quarter 2021 financial results conference call before we begin I encourage everyone to go to the Investor and media section of our website at Sage Rx Dot Com, where you can find the press release related to today's call as well as the slides that contains supplemental details.

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

Barry E. Greene: In March, we reported continued positive 12-month data from the 30-mg cohort and interim data from the 50-mg cohort of the ongoing Phase III Open Label Shoreline Study evaluating the safety, tolerability, and need for repeat dosing with Zoranil in adults with major depressive disorders. 30 mg showed that approximately 70% of participants had a positive response to an initial two-week treatment and required at most one additional geranolone treatment during the 12-month study period. And after the initial two weeks of random treatment, more than 70% of patients who received 30 milligrams and 80% of patients who received 50 milligrams achieved a positive response.

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

He will then be joined by Steve Kaye, Our Chief Medical Officer, who will review recent clinical progress and Kimi Iguchi, Our Chief Financial Officer, who will review first quarter financials and discuss financial guidance will.

We will be joined for the Q&A session of the call by our Chief Research Officer, Jim Doherty.

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

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

As we passed the one year Mark of the unprecedented public health crisis created by the COVID-19 pandemic.

I'm extremely optimistic that we're turning the corner in containing this devastating impact the virus has had on society. However.

Barry E. Greene: Funded response at day 15.

Barry E. Greene: When we embarked on the Landscape Program, our goal was to develop a rapid-acting, short-duration, durable, treat-as-needed option, and we believe the data from Shoreline supports this potential product profile.

However, and this is critically important there is a pandemic the brain health pandemic.

And while more and more is coming out about this pandemic, there's a long way to go and indeed as we know during the COVID-19 pandemic, we've seen rates of depression in the U S alone increased four fold by suite like suicide Ality. Among adult has nearly doubled these will likely affect the world for years to come broadening.

Barry E. Greene: Moving to the late-stage program in the neurology franchise, SAGE 3-2-4, we recently announced positive Phase 2 data from our kinetic study of SAGE 3-2-4 in central tremor. To remind you, what we were looking for from this study was a reduction in tremor amplitude of 30-50% that was sustained for the full study period. In other words, no loss of effect or tachyplasia. We're also looking for no adverse event surprises. The kinetic study achieved our objectives and more.

Unmet need and further exposing the urgent need for novel brain Health medicines.

I'm very proud of the ongoing effort to sage to make medicines that address the very real crisis from Brighthouse.

I'm pleased to report the significant advances we made over the last quarter across our depression.

Neuropsychiatry and neurology franchises.

Barry E. Greene: We saw a statistically significant reduction from baseline in the Tetris Item 4 upper limber tremor score at Day 29 compared to placebo. The safety profile is generally consistent with previously reported data for SAGE-324. And just to be clear, we believe SAGE-324 has tremendous potential for essential tremors. The results from this study, a statistically significant reduction in traffic...

We continue our mission to become the leading brain health company.

Tier biopharmaceutical company.

I believe the progress we've made in the first quarter of 2021 sets up a short medium and long term value creation opportunities as we further advance our deep sage invented organic pipeline.

Barry E. Greene: We think about fine-tuning the therapeutic index and commercial profile for this important potential therapy.

And my understanding of dodges receptors, applying our unique chemical innovation generic steroids, including Oxy sterile Chemistries. We've created novel therapeutic designed to modulate these pathways and highly specific and highly tailored ways.

Barry E. Greene: And to further set some context for the kinetic study, we designed the study to evaluate what we knew was

Barry E. Greene: With the high end of the dose. We are looking for a big effect on tremor with no surprise adverse events.

We currently have three programs in late stage development with four ongoing phase III trials, all of which are on track to read out this year.

Barry E. Greene: We administer the dose in the morning with the understanding that patients would expect.

Barry E. Greene: Our goal is to gain an understanding of the PKPD characteristics of SAGE 324 and identify positive levels correlated to efficacy. We look forward to presenting these data at a later time and to working with our collaborator at Biogen to optimize next steps for the continued development of SAGE 324 to get to a dose and frequency for Phase 3. At this time, we don't think additional formulation work is necessary. We're confident the work proposed to be done in a planned Phase 2b trial will result in a dose and frequency designed to optimize benefits for all patients.

Additionally, we are for mid and early stage programs in clinical development and we're committed to the goal of developing two or more high quality IND per year, starting in 2023.

In particular this quarter, we were thrilled to report positive top line data from our two lead programs.

The lead program in our depression franchise and Sage three two for the lead product in our neurology franchise.

In March we reported continued positive 12 month data from the 30 milligram cohort and interest data from the 50 milligram cohort from the ongoing phase III open label shoreline study evaluating the safety tolerability and need for repeat dosing with <unk> in adults with major depressive disorder.

Barry E. Greene: Optimized Benefit Risk and Further Development for Essential Tumors

Barry E. Greene: This quarter also marked progress across our neuropsychiatry franchise, where we are evaluating SAGE 718, a first-in-class NMDA receptor PAM, as a potential oral therapy for cognitive disorders associated with NMDA receptor dysfunction. I'll provide an update on the positive data from the Phase 2 paradigm study in a moment, but I want to confirm that we intend to initiate a Phase 2 trial in Huntington's disease later this year as an important step towards pursuing the initial indication for SAGE 718, assuming, of course, that the data continues to support that path.

The 30 milligram showed that approximately 70% of participants had a positive response to initial two week.

Treatment and required at most one additional day ran alone treatment during the 12 month study period.

And after the initial two weeks around on treatment with a 70% of patients who receive 30 milligrams and 80% of patients who receive 50 milligrams achieved positive response at day 15.

When we embarked in the landscape program. Our goal is to develop a rapid acting short duration durable treat as needed option and we believe the data from shoreline support potential product profile.

Barry E. Greene: Recall, we previously reported encouraging Phase I open-label data in measures of executive function in patients with HD, and this, combined with consistent positive data on tests of executive function we saw in the PARADIGM study, as well as our discussions with key opinion leaders, patients, and regulators, support Huntington's disease as a target for our initial indication. Now, on Paradigm, the interim data cut showed patients demonstrated improved performance from baseline on multiple tests of executive function over 14 days of treatment.

Moving to late stage program in our neurology franchise Sage three to four we recently announced positive phase two data from our kinetic study from say three to four in essential tremor true.

What we were looking for from this study.

It was a reduction in tremor amplitude of 30% to 50% that will sustain for the full study period in other words, no lost the fact or tacky flow.

We're also looking for no adverse events of price the Kinect study achieved our objectives and more.

We saw a statistically significant reduction from baseline in the Tetris item for upper limb tremor score at day 29 compared to placebo.

Barry E. Greene: Results that are very similar to previous results in healthy volunteers and patients with Huntington's disease and further support the development of SAGE 718 for cognitive dysfunction. Steve will provide additional details on these exciting data, but it's clear that SAGE 718 has the potential to become a very important treatment for multiple diseases, for cognitive dysfunction, or the need for better executive function as a driver of disability. In addition to HD and further work in Parkinson's, we intend to evaluate several other

Safety profile is generally consistent with previously ported data for Sage three to four and just to be clear. We believe sage two four has tremendous potential in essential tremor.

Results from this study a statistically significant reduction in tremor, and a statistically significant correlation in trimble reduction activities.

Activities of daily living are meaningful indicators that further development and optimization of dosing, let's say three to four are important next steps.

About fine tuning the therapeutic index and commercial profile, it's important potential therapy.

And to further set some context for the Kinect study we designed the study to evaluate what we knew was the high end of the dosing range.

We're looking for a big effect on tremor with no surprised adverse events, we administered a dose in the morning with the understanding patients would experience islands.

Barry E. Greene: Pass Forward with SAGE 718, including cognitive dysfunction associated with Alzheimer's, with the ongoing luminary study in Alzheimer's disease on track to read out.

Our goal was to gain an understanding of the PK PD characteristics for Sage three to four and identify plasma levels correlate it to efficacy.

Steve Cain: on track to read out later this year. This means that by later this year, in addition to initiating a placebo-controlled Phase 2 for Huntington's disease, we expect to have completed all three data readouts of SAGE 718 as we accelerate our efforts to move this program forward. With that, I'll turn the call over to Steve for more detail on the data we reported this quarter, as well as our additional clinical programs.

We look forward to presenting these data at a later time and working with our collaborators at <unk>.

And to optimize next steps for the continued development of stage three to four to get to a dosing frequency for phase III.

At this time, we don't think additional formulation work as necessary.

We're confident the work proposed to be done and our planned phase two b trial resulted in dose and frequency designs optimized benefit risk and further development per central tremor.

Steve Cain: Thanks, Barry, and good morning, everyone. We've made great progress across all three franchises to date, including positive data from our Zaranulone and SAGE 324 programs, as Barry mentioned, as well as positive results with SAGE 718 and the Paradigm Study. Since our path towards ADHD as the initial indication has been supported further by the results of the PARADIGM study is the news of the day, I'd like to spend the majority of the next several minutes reviewing the progress in our neuropsychiatry franchise and our vision for further development of SAGE 718, our NMDA receptor PAM, in development as a potential oral therapy for disorders where cognition is one of the main drivers of disability, including the very encouraging results from PARADIGM we're announcing today.

Provide an update on positive data from the phase II paradigm study in a moment, but I want to confirm that we intend to initiate a phase two trial in Huntington's disease. Later this year as an important step towards pursuing initial indications for Sage 718, assuming of course, the data continue to support that path.

Recall, we previously reported encouraging phase one open label data measures of executive function in patients with HD and this combined with consistent positive data on test of executive function. We saw him paradigm study as well as our discussions with key opinion leaders patients and regulators support Huntington's disease is a target.

For our initial indication.

Now on paradigm interim data cut showed patients demonstrated improved performance from baseline on multiple tests of executive function over 14 days of treatment.

They're very similar to previous results in healthy volunteers and patients with Huntington's disease and further support development of Sage 718 per cognitive dysfunction.

Steve will provide additional details on these exciting data, but it's clear that sage 718 has the potential to become a very important treatment for multiple diseases, where cognitive dysfunction or the need for better executive function as a driver of disability.

Steve Cain: Executive function is the conductor of the brain's orchestra. It controls our ability to plan, make decisions, and also adjust to challenges or new situations as they arrive. It's also the core skill that allows us to react and adapt in real time to navigate our constantly changing and evolving environment.

In addition to HD and further work in Parkinson's, we intend to evaluate several other paths forward with Sage 718, Inc.

In cognitive dysfunction associated Alzheimers disease, but the other.

The luminary study in Alzheimer's disease on track to read out.

Steve Cain: Executive functioning touches so many aspects of what we do on a daily basis that it becomes very difficult to operate independently as executive function declines, for example, in Huntington's and Parkinson's diseases. You're probably also familiar with the concept of learning and memory, which is the ability to take in information, file it away in our brain's internal organization system, and then retrieve it at the appropriate time and place. What we don't expect to see, based on our mechanism of action, are any impacts, positive or deleterious, on performance metrics like attention and psychomotor speed.

Later this year.

This means that by later this year in addition to initiating a placebo controlled phase II per Huntington's disease, we expect to have completed all three data readouts from Sage 718.

Accelerate our efforts to move this program forward.

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

Thanks, Terry and good morning, everyone.

Path towards HD as the initial indications and supported further by the results of the paradigm study as the news of the day I'd like to spend the majority of the next several minutes reviewing the progress in our neuropsychiatry franchise and our vision for further development of Sage seven money, our NMDA receptor Pam and development as a potential oral therapy.

Steve Cain: So, what's so exciting about SAGE 718 is that beginning with healthy volunteers and then patients with Huntington's disease, we looked for and saw improvements in executive function. Now, in patients with Parkinson's disease, SAGE 718 has shown a positive impact on multiple domains of cognition, including executive function and learning and memory, while not altering simple attention or reaction time, which are performance but not true cognitive attributes typically enhanced by amphetamines To our knowledge, there is nothing to date in clinical development that has generated data suggesting this kind of profile, the potential ability to augment key cognitive domains without the challenges often associated with other approaches. Turning now to Paradigm, these data reinforce and extend previous cognitive findings in a new patient population, Parkinson's disease. Today I'm going to provide a brief summary of what we've seen with this initial data cut.

For disorders, where cognition is what are the main drivers of disability, including the very encouraging results from paradigm, we're announcing today.

Technician can be defined as the sum of all of our mental abilities are fairly abstract definition with two key domains of cognition are executive function and learning and memory.

Executive function as the conductor of the brand's orchestra, the controls our ability to plan make decisions and also adjust to the challenges our new situations as they arise.

It's also the core skill that allows us to react and adapt in real time to navigate a constantly changing and evolving environment.

Executive functioning touches so many aspects of what we do on a daily basis and it becomes very difficult to operate independently as executive function declines for example in Huntington's Parkinson's diseases.

Steve Cain: To date, there have been 8 patients aged 50-75 years old with mild cognitive impairment due to Parkinson's disease who received SAGE 718 3 mg daily for 2 weeks. Similar to earlier findings in healthy volunteers, as well as in patients with Huntington's disease, patients in the PARADIGM study demonstrated improved performance from baseline on multiple tests of executive functioning over 14 days of treatment. It's also important to note that in the study, SAGE 718 had no impact on the tension in psychomotor speed, signals that are typically associated with other approaches like stimulus.

Well, we don't expect to see based on our mechanism of action or any impacts positive word deleterious on performance metrics like attention and Psycho motor speed. So.

So what's so exciting about sage 718 does that beginning with healthy volunteers and in patients with Huntington's disease, we were looking for and saw improvements in executive function.

And now in patients with Parkinson's disease Sage seven money has had a positive impact on multiple domains of cognition, including executive function and learning and memory.

Steve Cain: Emerging signals from the PARADIGM study also suggest that there are improvements in performance on tests of learning and memory over a similar time frame, an important finding as SAGE 718 is currently being evaluated in another Phase II open-label study, the LUMINARY study, in patients with mild cognitive impairment and mild dementia due to Alzheimer's. As in previous studies, SAGE 718 was generally well tolerated. Specifically, there were no serious adverse events, and no treatment-emergent adverse events were determined to be related to SAGE 718.

Not altering simple attention our reaction time, which are performance, but not true cognitive attributes typically enhanced by amphetamines.

To our knowledge there is nothing to date in clinical development that has generated data, suggesting this kind of profile.

Potential ability to augment key cognitive domains without the challenges often associated with other approaches.

Turning now to paradigm these data reinforce and extend previous positive findings from a new patient population Parkinson's disease.

So they didnt going to provide a brief summary of what we've seen with this initial data cut.

There have been eight patients aged 50 to 75 years old with mild cognitive impairment due to Parkinson's disease.

Steve Cain: It's worth repeating, we have not seen any serious adverse events or treatment-emergent adverse events related to SAGE 718 across all studies. SAGE 718 continues to demonstrate from these early trials a consistent and promising profile as potential treatments to address multiple aspects of cognitive impairment. And so, I'm excited by the performance of SAGE 718 in the Paradigm Study, and we intend to activate a four-week dosing arm in the Paradigm Study to gather additional data in the PD patient population and inform next steps.

Sage 7183 milligrams daily for two weeks.

Similar to earlier findings in healthy volunteers as well as in patients with Huntington's disease patients from the paradigm study demonstrates improved performance from baseline on multiple tests of executive functioning over 14 days of treatment.

It's also important to note.

Betty Sage seven one they had no impact on attention and Psycho motor speed signals that are typically associated with other approaches like stimulus.

Steve Cain: The data from PARADIGM also reinforced our decision to move forward in fighting this disease, where SAGE 718 performed similarly in an earlier Phase I trial. So, we're planning to advance into a double-blind, placebo-controlled Phase 2 study at Huntington's later this year that, if positive, will bring us one step closer to pursuing the initial indication for SAGE 718. We will provide greater detail on study design as we get closer to trial initiation, but what I can share is that we will be studying a similar battery of cognitive tests as previously studied with the goal of sustained changes out to three months. HD is an orphan disease estimated to affect more than 20,000 people in the United States.

Disease.

As in previous studies Sage 718 was generally well tolerated.

Specifically, there were no serious adverse events and no treatment emergent adverse events were determined to be related to Sage 708, it's worth repeating we have not seen any serious adverse events or treatment emergent adverse events related to sage 718 across all studies.

So 708 continues to demonstrate from these early trials are consistent and promising profile as a potential treatment to address multiple aspects of cognitive impairment.

So I'm excited by the performance of Sage to everyone. In the paradigm study, we intend to activate a four week dosing arm from the paradigm study together additional data and the PD patient population and inform next steps.

The data from paradigm also reinforced our decision to move forward in Huntington's disease, where Sage 718 has performed similarly in an earlier phase one trial.

So we're planning to advance into a double blind placebo controlled phase II study in Huntington's later this year.

Positive will bring us one step closer in pursuing the initial indication for Sage 718.

Each day is an orphan disease estimated to affect more than 20000 people in the United States and cognitive deterioration because one of the earliest and most disabling features of this devastating neurodegenerative disease.

Cognitive impairment, we begin years before a formal diagnosis with no available treatment to slow the progression of decline leading to loss of independence. The unmet need for these patients is significant.

We have very high ambitions for NMDA platform with the ability to target conditions, where cognitive deficits really impair patients' ability to lead independent lives.

In addition to Sage 718, our neuroscience franchise also includes Sage 904.

And NMDA receptor Pam product candidate being evaluated as a potential oral therapy for other disorders associated with NMDA hypofunction.

<unk> is currently in an ongoing phase one study that we plan to complete this year and sage for 'twenty, one and oral NMDA Pam is being evaluated for potential use.

In Neurodevelopmental disorders, and cognitive recovery and rehabilitation, which we expect to advance the preclinical studies later this year.

Turning now to our neurology franchise, we recently announced positive top line data from our phase II double blind kinetics study of Sage 324, assistant 60 milligrams in essential tremor.

Steve Cain: The trial evaluated treatment as age 324 at the high end of the dose range, and the daily dose could be down titrated to 45 or 30 milligrams if 60 was deemed to be not well tolerated. The primary endpoint in the study was change from baseline compared to placebo on day 29 in upper limb tremor score as measured by item four of the Tetris Performance Subscale, a physician-administered scale designed to provide an accurate, comprehensive assessment of essential tremor motor symptoms that has been shown to correlate with Tetris activity of daily living.

In the study 69 patients aged 18 to 80 years old were randomized one to one to receive either 60 milligram Sage 320 pool or matched placebo once daily in the morning for 28 days with a follow up period of an additional two weeks.

The trial evaluated treatment. This age 324 at the high end of the dose range and the daily dose could be down titrated to 45 or 30 milligrams.

60 was deemed to be not well tolerated.

Steve Cain: We are pleased the study met its primary endpoint, a statistically significant reduction in TETRIS item 4 upper limb tremor score from baseline at day 29 in the pre-specified full analysis set compared to placebo with a p-value of 0.049, which corresponds to a 36% reduction from baseline in upper limb tremor amplitude in patients receiving SAGE 324 versus a 21% reduction in patients receiving placebo. In patients with more severe tremor at baseline, with a median TETRIS performance subscale upper limb tremor item 4 score of 12 or higher, SAGE 324 demonstrated a statistically significant reduction from baseline in TETRIS item 4 upper limb at day 29 compared to placebo with a p-value of 0.007 that corresponded to a 41% reduction from baseline in tremor amplitude at day 29 compared to an 18% reduction for placebo.

Activity of daily living.

It corresponds to a 41% reduction from baseline in tremor amplitude day 29, compared to an 18% reduction for placebo.

Steve Cain: 62% of patients who received SAGE 324 down-tritrated in dose, as allowed by the study protocol, and discontinuations were noted in 38% of patients receiving SAGE 324. Adverse events were generally consistent with the safety profile of SAGE 324 seen to date and one other GABA PAM. Treatment-Emerging Adverse Events that Occurred in 10% or More of Patients in the SAGE 324 Treatment Group and a Rate at Least Twice as High as that of Patients in the Placebo Group for Thomulence, Dizziness, Balance Disorder, Diplopia, Dysarthria, and Deep Disturbance

62% of patients who receive sage 324 were down titrated in dose as allowed by the study protocol discontinuation as were noted in 38 per cent of patients receiving sage 324.

Adverse events were generally consistent with the safety profile of Sage to each week, we're seeing to date and what other Gaba Pam shipment.

Treatment emergent adverse events that occurred in 10% or more of patients in the phase III reported treatment group and a rate at least twice as high as that of patients in the placebo group, where some lunch dizziness that was disorder, diplopia dysarthria and deep disturbance.

Encouraged by the potential of Sage 324 for a central tremor disorder with a high unmet need and as Barry mentioned, we are confident in our ability to develop a dose and frequency regimen for further development in the chronic treatment of essential tremor.

Steve Cain: Beyond SAGE 324, our neurology franchise includes SAGE 689, a potent investigational product with rapid absorption, good viability, and solid formulation flexibility with potential in areas of high unmet need, including acute agitation, mania, or even migraine. We're also planning to advance SAGE 319, an oral extrasynaptic GABA-A receptor, preferring PAM to preclinical studies for potential use in disorders of social interaction.

Jan Sage 324, our neurology franchise includes Sage 689, a potent investigational product with rapid absorption good viability and solid formulation flexibility with potential in areas of high unmet need.

Including acute agitation media or even migraine.

We're also planning to advance stage 319, an oral extra synaptic Gaba a receptor, preferring Pam to preclinical studies for potential use in disorders of social interaction.

Steve Cain: Turning to our depression franchise, in March, we reported continued positive data from our Phase 3 Shoreline Study, which was designed to naturalistically follow patients with major depressive disorder and evaluate the safety and tolerability of seranilone, 30 mg in adults, for up to one year. As a reminder, the study was amended in May 2020 to include a 50 mg dose of seranilone. Data reported showed that after the initial two weeks of Ritalin treatment, more than 70% of patients who received 30mg and 80% of patients who received 50mg achieved a positive response by day 15.

<unk> milligram dose on day rate alone.

Data reported showed that after the initial two weeks Randall and treatment more than 70% of patients who received 30 milligrams and 80% of patients who received 50 milligrams achieved positive response by day 15.

Steve Cain: In the 30 mg cohort at day 15, the mean change from baseline was 15.2 points, and 73.5% of patients achieved a response, and 40% achieved remission, as measured by a HAM-D score of less than or equal to 7. Additionally, approximately 70% of participants with a positive response to an initial 2-week 30mg treatment required at most one additional xeraniline treatment during a 12-month study. In the 50 mg cohort at day 15 of the initial treatment course, the mean HAM-D change from baseline was 16.

And the 30 milligram cohort at day 15, the mean change from baseline was $15 two points from 73, 5% of patients achieved response, and 40% achieved remission as measured by a ham D score of less than or equal to seven.

Approximately 70% of participants with positive response to and the initial two week 30 milligram treatment required at most one additional day ran alone treatment during a 12 month study.

And the 50 milligram cohort at day 15 of the initial treatment course, the mean Ham D change from baseline was 16.

85 per cent of patients achieved response and 43, 2% achieve remission.

The 489 patients from the 30 milligram cohort continuing in the study 42, 9% used only the single initials around alone of course 25, 6% used a total of two courses 11, 9% used a total of three courses 10, 8% used a total of four courses and eight 8% used to each other.

Five questions in both cohorts of rental and was generally well tolerated with an adverse event profile consistent with data reported earlier.

Steve Cain: We're also announcing plans to reopen enrollment in the 50mg cohort of the Shoreline study, increasing the target enrollment to 500 patients. We remain on track to report top-line one-year data from Shoreline 50mg in late 2021, with data from the expanded 50mg cohort expected in 2022. Additionally, we plan to offer patients from the CORAL study the ability to roll over into the SHORELINE study following completion of the CORAL study. These extensions allow SAGE to collect additional long-term data on patients treated with Xeranil and 50mg.

Additionally, we plan to other patients from the Coral study the ability to rollover into the shoreline study following completion of the coral study.

These extensions allow sage to collect additional long term data on patients treated with Serrano from 50 milligrams.

And finally, we remain on track to report topline data from the Phase III waterfall study from the first half of this year and from Phase III Coral and Skylark studies by the end of the year.

This was an important quarter for sage marked by progress across our entire pipeline. We're excited about the year ahead with several milestones in front of us, including multiple phase III Readouts expected. We believe this progress positions us well to continue to expand and accelerate our pipeline in order to advance our mission of making medicines that matter.

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

Cool.

Let me start by congratulating, our full steam on another great quarter as a result of that net.

Termination.

So we're off to a great start in 2021 reporting positive data from free trial with another seven including three pivotal trials on track to read out later this year.

Kimi E. Iguchi: As a reminder, this is the first full quarter of our transformative collaboration with QIAGEN for Zaranolone and SAGE 324. This collaboration includes 50-50 costs and profit sharing for Zoranilum and SAGE 324 in the United States. By design, the collaboration provides financial and operational flexibility, enabling us to potentially expand and accelerate not only our near-term development of Zoranolone and SAGE 324 but also increase investment in our wholly-owned products and accelerate our. Now, let me walk through the highlights of our first quarter financials and then close with some thoughts on our financial guide.

As a reminder, this is the first full quarter of our transformative collaboration with Biogen personally hand alone.

Sure.

This collaboration called 50, 50 cost and profit sharing price in Ireland.

Page 24 in the army.

By design, the collaboration provides financial and operational flexibility enable us to potentially expand and accelerate not only our near term development of Joanne alone. It takes till 'twenty four but also.

Increased investment in our wholly owned products and accelerate our pipeline.

So now let me walk through the highlights of our first quarter financials, and then close with some thoughts on our financial guidance.

Kimi E. Iguchi: Revenues were $1.6 million in the first quarter from the sales of Xerath, and that was compared to $2.3 million for the same period of 2020. We remain committed to moms, their families, and all those impacted by PPD. Our targeted commercial efforts aim to help moms with PPD who may benefit from treatment with doresto gain access to treatment with doresto.

Revenues were $1 69 in the first quarter from the sales of the reform.

That was compared to $2 3 million for the same period of 2020.

We remain committed to launch their families all of those impacted by people.

Our targeted commercial efforts aim to help moms with T T D.

Benefit from shrink unless the last downturn.

Yeah.

Kimi E. Iguchi: Selling general and administrative expenses were $40 million in the first quarter, compared to $70 million for the same period of 2020. The decrease in SG&A expenses was primarily due to the restructuring of the company which it underwent during the second quarter of 2020. Research and development expenses were $58 million in the first quarter. That was compared to $64 million for the same period in 2020. The decrease was primarily a result of a $22 million reimbursement by Biogen related to the ongoing Xeronalone and SAGE 324 clinical programs and offset by an increase in spending on our waterfall and coral studies.

Selling general and administrative expenses were $40 million in the first quarter compared to 70 million from the same team carried at 2020.

The decrease in SG&A expenses was primarily due to a especially in a company underwent during the second quarter of 2020.

Research and development expenses were 58 million in the first quarter compared to 64 million for the same period of 2020.

The decrease was primarily a result of the $20 million reimbursement by Biogen related to the ongoing surround alone Sage 324 clinical programs.

And all set by an increase in spending on our waterfall and claw study.

Kimi E. Iguchi: Going forward and prior to launch, we expect R&D and SDNA expenses related to Zoranilone and SAGE 324 to represent approximately 50% of total collaboration program costs, regardless of whether SAGE or Biogen performs the work. Essentially, this sharing of expenses establishes a new baseline for SAGE, representing a lower net investment percent for seranolone in SAGE 324. Collaboration spend will increase as the programs advance but will continue to be shared with buyers 50-50 in the U.S. Additionally, this allows us to further invest in our wholly owned pipeline, including SAGE 718 and our Discovery Inn.

Going forward I think prior to launch we expect R&D and SG&A expenses related to zero handle on it takes 24, well represent approximately 50% of total collaboration program costs.

Regardless of whether stage or buys and performance of work.

Essentially this share or any other expenses establishes a new baseline for sage.

Representing a lower net investment per center in Sorrento. It takes from 24.

Collaboration spend will increase as the programs advance, but we'll continue to be share with buyers and 50 50 in the U S.

Additionally, this allows us to further invest in our wholly owned pipeline and cleaning from 718 and our discovery engine.

Kimi E. Iguchi: We reported a net loss of $96 million for the first quarter of 2021. That was compared to $127 million for the comparable period of 2020. Finally, we continue to maintain a solid financial foundation, ending the first quarter of the year with $2 billion in cash, cash equivalents, and marketable securities. We do not expect any milestone payments from collaborations during 2021 and anticipate ending the year with a cash balance of more than $1.7 billion.

We reported a net loss of 96 million for the first quarter of 2021.

That was compared to 127 million so the cash.

Comparable period of 2020.

Finally, we continue to maintain a solid financial foundation and in the first quarter of the year with $2 billion in cash cash equivalents and marketable securities.

Not expect any milestone payments from collaboration during 2021 and anticipate over the year with a cash balance of more than $1 7 billion.

Kimi E. Iguchi: The cash on hand, in addition to the ongoing cost sharing with Biogen, will allow us to work to expand and accelerate the pipeline and continue to invest thoughtfully in sequencing assets we believe will create near, mid, and long-term value creation opportunities for our stakeholders, with the potential, if we're successful, to positively impact more than 450 million people worldwide. I'll now turn it over to Jeff to handle Q&A with the operators.

To positively impact more than 450 million people worldwide.

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

Jeff.

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

Now I'll turn it over to the operator operator.

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

And to withdraw your question press the pound key.

<unk> bylaws.

The Q&A roster.

Our first question offline.

Fisher from Goldman Sachs, You May you may.

Hi, everyone. This is andrea on for <unk>. Thanks for taking my question.

Maybe just one on this additional four week dosing cohort for the paradigm study.

If you could provide a little bit more color on what you are looking to understand there. Thanks so much.

Barry E. Greene: Yeah, Andrea, I'll start out and then turn it over to Jim for additional details. So you're asking about SAGE 718. We're really excited about the Neuropsych franchise and SAGE 718, our first sort of NMDA receptor modulator in clinical studies. And as we talked about in the call, we're very excited by the forward progress in Huntington's disease as our initial indication and the continued efficacy and safety profile we're seeing with SAGE 718 through the luminary data that we reported out today.

Yeah, Andrea I'll start out and then turn it over to Jim <unk> for additional details. So youre asking about Sage 718, we're really excited by the neuroscience franchise and Sage 718.

Our first sort of NMDA receptor modulator in clinical studies and as we've talked about in the call. We're very excited by that.

The forward progress into Huntington's disease, other initial indication and the continued.

Efficacy and safety profile, we're seeing with Sage 718.

Two the luminary data that we reported out today. So all in all we have a very robust package.

Barry E. Greene: So all in all, we have a very robust package. In doing drug development, we're looking to learn more and more as we advance SAGE 718, and maybe Jim can talk about some specifics with a four-week program or four-week study. Thanks, Barry.

In doing drug development, we're looking to learn more and more as we advance Sage 718, and maybe Jim can talk about some specifics with a four week program before we can start absolutely.

Thanks, Matt Yeah. So of course as Barry said, we're very excited about the potential for Sage 718, and for the NMDA platform in general and I think one other things Youre hearing today from Steve is that we're seeing consistent types of responses across multiple patient populations now so some of the design in the study.

Jim Doherty: Yes, so of course, as Barry said, we're very excited about the potential for SAGE 718 and for the NMDA platform in general. And I think one of the things you're hearing today from Steve is that we're seeing consistent types of responses across multiple patient populations now. So some of the design of the study for Paradigm was to keep things as close as possible to what we've done previously, so we're only varying the patient population. And so because of that, the design for Paradigm was quite similar to what we had done before, a two-week dosing period. Given the results that we're seeing today, and given the...

Paradigm was to keep things as close as possible to what we have done previously so we're only very patient population and so because of that the design for paradigm was quite similar to what we had done before a two week dosing period, given the results that we're seeing today and given the investment that we.

Made to get the trial up to this point as we've done in the past we were trying to be efficient here and continue to.

Operator: Thank you for joining us today.

Operator: Thank you. Our next question comes from Ritu Baral from Canada. You may begin.

Operator: Good morning, guys. Thanks for taking the time to answer the question. I wanted to get your input on helping us inform the upcoming waterfall safety data. Specifically, I've had a lot of conversations with clients about what is acceptable sedation and what is acceptable somnolence. Just going back to mountain data where you saw 6 to 7%, I believe, rates of each, and given the higher dose, how should we think about what's acceptable? And is there a threshold?

Going to advance our understanding of the whole program.

Yes.

Yeah.

Thank you. Our next question comes from the line Richard Burrows from Cowen you may begin.

Oh, good morning, guys. Thanks for taking the question.

To get some get your color on helping us inform the ethylene waterfall safety data specifically you have had a lot of conversations with clients about what is acceptable to patients and what is acceptable some noise.

Just just.

Operator: A written threshold in the public domain by FDA on what might complicate actual approval, either on sedation or somnolence. Thanks. Yeah, Ritu, I'll start out with some context. And I'll ask Steve to talk about, you know, what we're looking for out of the water.

And back to mountain data, where you saw 6% to 7% I believe rates, each and given the higher dose.

How should we think about what's acceptable.

And is there a threshold.

A written threshold into public domain by FDA on what.

What might complicate actual approval either obligation or something else. Thanks.

Barry E. Greene: Yeah, Ritu, let me start out with some context and I'll ask Steve to talk about what we're looking for in waterfowl more specifically and why we think zaranolin has the potential to be a transformative medicine. I'll remind you that we have studied zaranolin in over 3,000 subjects and patients. And to date, the profile we've seen is extraordinarily consistent. We've seen a rapid onset of action, three to four days; patients report they're feeling better.

Yes to all of them.

Let me start out with some context and I'll ask Steve.

To talk about.

The day the profile, we've seen is extraordinarily consistent we've seen rapid onset of action three to four days patients report, they're feeling better as we reported on the shoreline data and I won't repeat everything Steve said, we've seen remarkable efficacy two weeks the $30 50, with most patients requiring only one or two.

Two week doses and entire year.

And and the safety profile.

Has been consistent also.

Barry E. Greene: What's important is not necessarily specific numbers of adverse events; it's whether patients stay on the drug or not. And because of the unique profile here, literally two weeks, maybe two to four weeks of dosing, we've seen remarkable compliance. And what we're looking for here is a drug that patients will take for two weeks so they get better, faster, and stay better. And as we've said, and just to be clear, if we hit the primary endpoint, given the different benefit-risk profile of Zaranolone over 35 years of antidepressants, we have a very important medicine in the landscape. Let me ask Steve to provide a little bit more color. Yeah.

At those dose levels.

A drug that patients will take for two weeks.

So they get better faster and stay better and what we said and just to be clear we hit the primary endpoint given the different benefit risk from surround alone over 35 Years' worth of anti depressants. We are a very important medicine in the landscape. Let me, let me ask Steve to provide a little bit more color.

Yeah. So Richard Thanks for the question, So first and foremost we're really confident in the profile every bit of information that we get from the trials really points to a unique profile both in terms of benefit as well as in terms of you know what what the adverse event profile might look like I remind you and your clients are a few things number one.

Some lines is something that is often desirable for patients with depression and many people have sleep disruptions and we believe that's what's leading to the to the much smaller drop out rate is very low dropout rate from our clinical trials, we do exit interviews and patient's perceptions are that that's not something that would potentially limit their use.

Remember patients are taking the medication for two weeks in any case.

And often this can be beneficial many of these people are taking additional measures to help them sleep.

The second is the numbers that we're reporting you actually comparable if not better than many drugs that are used right now to treat depression and so.

Advised people take a look at the labels for anti depressants that or income in Houston.

The reported that we have who are either somnolence sedation, and so forth or R. R.

Well within the parameters of drugs that are approved for the treatment of depression, even standard anti depressants. So.

Right now the profile is one that we know is going to be beneficial for patients. We're looking forward to the waterfall data, but we're very confident in terms of the overall profile.

Okay.

Thank you. Our next question will come from line of COVID-19.

Xena Rod from Bank of America, you may begin.

Hi, Good morning, Thanks for taking my question I guess as it relates to the waterfall study in terms of their ability to pay.

So the work that we've done it seems like on day 15, you should have good data.

I think beyond that so maybe a longer term day 42 things of that nature I guess first of all when you have that information available at the top line and how important is that based on your doctor feedback to have a longer durability of response.

Non residential thank you.

Yeah. It does thanks for the question, let me I'll start out.

Operator: Yeah, Tazeen, thanks for the question. I'll start out and turn it over to Steve to provide a little bit more. So, you know, we're very excited and confident in our soon envelope opening for Waterfall. We're looking forward to the data. And let me just be very clear. The primary endpoint at 15 days and having statistical significance is really what we're looking for for this drug. There's nothing out there that gets patients better, faster, and keeps them better.

Turning to Steve to provide.

A little bit more so we're.

Excited and confident in our soon.

Envelope opening for waterfall, we're looking forward to the data and let me just be very clear the primary endpoint in 15 days and having a statistical significant is really what we're looking for for this drug theres nothing out there that gets patients better faster and keeps them better.

Steve you want to provide a little bit more.

Sure.

Operator: But, you know, we're looking at all the secondary endpoints and hopeful that they show promise. For day 42, what we're looking for is consistency of effect in the drug arm, not necessarily versus, versus placebo. But again, a p-value in the primary endpoint is the most important aspect of water quality. Steve, do you want to provide a little bit more? Sure, you know, you know, um,

Patients really remain well they don't have an immediate bounce back after two weeks of dosing.

Concern.

In fact, even in the mountain study patients remained well and very few have recurrence of symptoms over the course of six months. So.

Well.

It's absolutely critical to our primary endpoint is day 15, but we want to understand is what proportion of patients stay well during the follow up period as well as reputations, maybe what proportion of patients may require a re treatment. Those are day that we're getting from waterfall.

Operator: Okay, and we will see that level of data on the top line. You can look to...

Operator: You can look to our prior releases to give you a sense of the kinds of information that we'll have in a release. But as Barry said, the things that we're focusing on are the primary endpoint as well as the key secondaries, very similar to what we've done for other acute studies.

48 weeks without additional need for therapy.

What's so unique about 207 and that's what we're looking for it in both the waterfall data.

As well as the entire landscape program.

And so.

It's a profile that we think is going to be really really important for patients.

If we're successful.

Operator: Okay, thank you. Our next question will come from Yasmeen Rahimi of Piper Sandler. You may begin.

Okay, and we will stay at that level the thing about the top line.

So when you kind of look to our prior releases should give you a sense of the kinds of information, but is that we'll have in our release.

Is.

Various other things that we're focusing on are the primary endpoint as well as the key secondary is very similar to what we've done for other acute.

Operator: Hi team, congrats on the great progress and sharing.

Okay.

Sure.

Operator: Thank you for sharing the data from Paradigm with us. One question for you: I just wanted to understand, maybe, the thoughts behind it.

Yes.

Our next question will come from the line of Yasmin Rami from Piper Sandler you may begin.

Hi team congrats on the great progress and sharing data from paradigm for US one question for you I just wanted to understand maybe let's talk behind really increasing the shoreline.

Operator: If you could just put a little bit of color around what prompted the interest to increase the numbers on the open label arm, it would be very helpful for us. And thank you for taking my question.

To enroll an additional 500 patients in coil is the expansion into the open label based on communication, we had with the regulators. If you could just put a little bit color.

Color around what prompted the interest to increase the numbers on the open label on it would be very helpful and thank you for taking my question.

Barry E. Greene: Thanks for the question, Yasmeen. I actually very much appreciate the congratulatory note on the positive data. We're very excited by the emerging data for SAGE 718, and we're thrilled we're moving that forward so rapidly into Huntington's disease, supported by the data presented today in Parkinson's disease. So, you know, back to your question about TrueLine. Look, we wanted an opportunity, first and foremost, as patients rolled off the clinical studies coral, to need another two-week course of dosing. You'll note in Steve's prepared comments that very few patients require additional doses, but the good news is that those that did responded yet again.

Hi, Thanks for the question actually.

I actually very much I appreciate the congratulatory note on the positive data, we're very excited by the emerging data from Sage 718 in and we're thrilled we're moving that forward so rapidly into Huntington's disease supported by other data present, a day in Parkinson disease.

So back to your question about about children's book, we wanted an opportunity first and foremost as patients roll off of clinical studies coral.

Should those patients continued need another two week course of dosing and you'll note from Steve's prepared comments that very few patients require additional doses, but the good news is those that did responded yet again, so we've got a very promising benefit risk profile.

Barry E. Greene: So, we've got a very promising benefit-risk profile with Zaranulone and wanted the opportunity for other patients to benefit from Zaranulone, particularly those rolling off of coral and other patients out there. You know, Jim, you want to offer other...

It was around alone and wanted the opportunity for other patients to benefit <unk>, particularly those rolling off of coral and other patients out there Jim.

Jim you want to offer other thoughts.

Jim Doherty: I think that covers most of it, Barry, but the other thing I would add is to say, you know, with an integrated set of trials in the Landscape Program, to Barry's point, as patients are rolling off of Coral, there's the opportunity for them to participate in Shoreline, and we are seeing quite a lot of value in our ongoing naturalistic study for Shoreline. And our view of it is that it's going to continue to provide useful information for what we believe is going to be a transformative therapeutic approach. And so, we're looking at all opportunities to gather more information on Doratalone. And Shoreline will very likely continue to deliver very important data to the overall program.

I think that covers most of it Barry but the other thing I would add day.

Yes.

There are with integrated set of trials in the landscape program to Barry's point mutations are rolling off of coral is the <unk>.

Opportunity for them to participate in shoreline and we are seeing quite a lot of value in our ongoing naturalistic study for shoreline and our view of it is that it's going to continue to provide useful information from what we believe is going to be a transformative therapeutic approach and so we're looking at all opportunities to gather more information.

Bonds are out alone in shoreline.

Very likely continued to deliver very important data until youre from program.

Jim Doherty: Great comment, Jim, and just to put a fine point on you guys, there was no specific regulatory request, or no regulatory request at all, to increase that, and this was a SAGE decision, as Jim highlighted, to provide an opportunity to get more data and benefit patients.

Yeah, great Great comment, Jim and just to put a fine point, yes. There was no specific regulatory requests were no regulatory requests at all to increase and this was the sage decision as Jim highlighted to provide the opportunity to get more data and benefit patients.

Operator: Our next question will come from the line of Corey Seymour from JPMorgan. You may begin. Hey, good morning.

Thank you Barry.

Our next question will come from the line of Cory <unk> from J P. Morgan you may begin.

Operator: This is a turnaround for Corey. Thanks for taking my question. So, just one on 718.

Hey, good morning. This is a turnaround for Cory Thanks for taking my question. So just one on 708 can you provide any additional granularity on what sort of improvement you saw in cognition, maybe it's how it stacks up relative to your expectations, but also kind of relative to what we've seen in Huntington disease Huntington's disease since that seems like the lead indication.

Barry E. Greene: Can you provide any additional granularity on what sort of improvement you saw in cognition, maybe just how it's stacked up relative to your expectations, but also kind of relative to what we've seen in Huntington's disease, since that seems like the lead indication going forward? Yeah, thanks, Turner, for the question. And let me let me ask Steve to address that.

Forward.

Yeah.

Thanks, Tim for the question and let me, let me ask Steve to address that.

Steve Cain: Sure, you know, what we're looking for as we move to other areas is not just executive function but learning and memory. So what we saw as we expanded the domains of cognition we looked at in these patients was not only improvements in executive function but also learning and memory. And we think that's really important for two reasons. One, different patient populations have different challenges. So Huntington's is about executive function primarily, and that was our hypothesis going in.

Sure.

We're looking for as we.

One different patient populations have different challenges so huntington's.

Executive function, primarily and that was our hypothesis going in Parkinson's, there's both executive function challenges as well as.

Steve Cain: In Parkinson's, there are both executive function challenges as well as dementia, so learning and memory. And we think that'll also lead to our broader understanding as we move into Alzheimer's and other forms of dementia, where the primary challenges are learning and memory. So as we learn more and more about the 718, the mechanism, and its utility, that will really inform how we move forward with both Huntington's as well as the other indicators. Great, thanks. Thanks, Turner. Our next question will come from the line of Laura Chico from Whitebush. You may begin.

Dementia, so learning and memory and we think that will also.

Lead into our broader understanding has been moving to luminary in Alzheimer's where the primary challenges are learning and memory. So as we learn more and more about the 71 eight the mechanism and its utility that will really inform how we move forward in both the huntington's as well as the other indications.

Great. Thanks.

Thanks Turner.

Our next question will come from the line Laura Chico from Wedbush you may begin.

Operator: Thanks very much for taking the question. I just wanted to circle back on the Shoreline question. So you said FDA did not ask you for any additional data, but I guess I'm trying to understand, is there still a plan to submit a filing for the 30 milligram dose of seraniline? And I guess, just back of the envelope, it would seem like with the expansion of the Shoreline cohort and then enrolling the coral patients, there's probably over a thousand subjects that would have been on the 50 mg dose at a longer term So just trying to understand how the 30 milligram dose fits into everything in terms of the regulatory strategy. Thank you.

Thanks, very much for taking my question.

I just wanted to circle back on the shoreline question. So you said FDA did not ask you for any additional data, but I guess I'm trying to understand is there still a plan to submit a filing for the 30 milligram dose as they ran alone and I guess just back of the envelope. It would seem like with the expansion of the shoreline cohort and then enrolling the coral pace.

<unk>, there's probably over a thousand subjects that would have been on the 50 Meg sales set a longer term. Once the study is complete so just trying to understand how the 30 milligram dose fits into everything in terms of the regulatory strategy. Thank you.

Barry E. Greene: Yeah, Laura, thanks. Thanks for the question. And, you know, let me provide some broad context and ask Jim to provide a little bit more. So your math, your math is, is close.

Yeah Elvira. Thanks, Thanks for the question and you know what.

Let me provide some broad context and ask Jim to provide a little bit more so to your math your math is close.

We will have a significant and when submitting.

Uh huh.

Barry E. Greene: We will have a significant end when submitting the What I said earlier was there was no specific request by the agency to increase N. The Shoreline expansion was to provide greater opportunities for patients and more data. We also, as you can imagine, are getting tremendous requests from investigators, KOLs, and, of course, patients in desperate need. Before our studies read out, we can turn to the Expanded Access Program. With most drugs, multiple doses are good to have, so we do plan on talking to the agency both about a 50 and a 30 milligram dose. Jim, can you provide a little bit more?

The package to the FDA should waterfall would be successful in the ongoing discussions with the FDA successful.

As I said earlier was there was no specific request by the agency to increase and the shoreline expansion was to provide greater opportunity for patients and more data and we also as you can imagine we're getting tremendous requests from investigators Kols and then of course patients in desperate need of.

Before studies read out we could we can turn.

<unk> expanded access program with most drugs.

Multiple doses are good to have so we do plan on talking to both about 50, and a 30 milligram.

It does but Jim can you provide a little bit more.

Jim Doherty: Sure. And good morning, Laura. I think Barry said it well. The way we think about this is that

Sure Good morning, Laura.

I think Barry said it well the way we think about this is that the entire landscape program is designed to produce a package of information about surround alone. So absolutely all of the data on surround loading, including our extensive dataset on the 30 milligram dose will be included in the filing.

Jim Doherty: The entire Landscape Program is designed to produce a package of information about Zoranolone. Absolutely, all of the data on Zoranolone, including our extensive data set on the 30 mg dose, will be included in the filing. That isn't really anything out of the ordinary.

That isn't really anything out of the ordinary that discussion will be around the drug itself and all of the data will be included in any potential filings.

Jim Doherty: The discussion will be around the drug itself. All of the data will be included in any potential filing. Our next question will come from the line of Akash Tewari from Wolf Research. You may begin. Hi, this is Leo on behalf of Akash. And recently, Praxis mentioned they couldn't claim MDD.

Thanks, guys.

Our next question will come from the line of.

Our cash <unk> from Wolfe Research you may begin.

Hi, This is a cash pay practices mention day couldn't play MDT checkmate eight the only change patients for 15 days. So they also look at day 28 data for their NDA drop any day.

Operator: So they also look at day 28 data for their MDD trial candidates. So in your case, we have the Waterfall secondary endpoint at day 48, sorry, 42. And how important is that day 42 data for the RENALONG filing? And how did FDA view the Open Label Shoreline Study as supporting evidence for the durability of RENALONG?

Okay. We have a wonderful the secondary end point at day 48, I'll talk about what day, two and how important is that day 42 data from the Red hat on filing and holidays at D. A.

The open label shoreline study.

Putting evidence for that your ability at all from the ran alone. In addition, we also noticed what else other trial has completed enrollment.

Operator: Page PAGE of NUMPAGES www.verbalink.com

543 subjects with only two arms and about 15% to 20% dropout rate interest they actually think what if a child has.

Operator: to 20% dropout rate, is it fair to think the Waterfall trial has about 90% power to detect 2.4 to 2.5 HMD differences between placebo? And lastly, what subscales of HMD17 tend to increase if we look at patients with an HMD cutoff of 20 versus 24 versus 28? Thank you. Yeah, thanks.

About 80 is having about 90% power to detect two four to $2 five hand day difference to placebo.

And lastly, what's that scales offhand day 17 tend to increase equally look at patients with <unk> cut off of 10 day, but there's plentiful of its 28. Thank you.

Yeah. Thanks.

Barry E. Greene: I think there are a number of questions in there, so let me provide a little bit of context and ask Steve to comment. Maybe Jim might want to comment, too.

There were a number of questions in there. So let me, let me provide a little bit of context and ask Steve.

To comment maybe Jim might want to comment. So look again, we're very excited by the waterfall readout as we've talked about previously we had the opportunity to.

Barry E. Greene: So look, again, we're very excited by the Waterfall readout. As we talked about previously, we had the opportunity to increase the N twice. Unfortunately, we are in a brain health pandemic.

To increase the end twice.

Barry E. Greene: And as I commented on the call, the rates of depression are three to four times higher in the United States alone. So unfortunately, there are a lot of people suffering from MGD out there at rates greater than we had prior to the pandemic lockdown. So that increased N provides significant powering on the primary endpoint. This is such a unique profile. The benefit risk here differs from, again, 35 years of drugs being developed in the area. We're very excited by that. Steve, do you want to provide a little bit more? Sure.

What we're looking for statistical significance at day 15.

That is this is such a unique profile the benefit risk here differentiates from again 35 years of drugs being developed.

In the area and we're very excited.

Out of that.

Steve you want to provide a little bit more.

Sure.

Steve Cain: The study itself is designed to show differences at day 15. That's the reason why we have Breakthrough Therapy designation. The ability to get patients better within two weeks is what got the FDA interested in this program. It's what's unique about the profile.

Study itself is designed to show differences at day 15, and that's the reason why we have breakthrough therapy designation the ability to get patients better within two weeks is what got US let's look at the FDA interested in this program, it's what's unique about the profile.

Steve Cain: And we've seen statistical significance and clinically meaningful differences as early as day 3, day 8, and day 15. And those benefits are maintained. The only real way to assess what that looks like in terms of pattern for patients that have gotten better is to use shoreline data. And, again, this is an overall program that was agreed with the FDA when we had Breakthrough, where we actually naturally see what happens to patients when they're treated up front and then followed over the course of a year for need for retreatment.

And we've seen statistical significance and clinically meaningful differences as early as day three day eight day 15 in those and those benefits are maintained the only real way to assess what that looks like in terms of pattern per patients that have gotten better.

To use shoreline data and again. These are this is an overall program that was agreed with the FDA. When we had breakthrough we actually naturalistic we see what happens to patients when they're when they're treated upfront and then followed over the course of the year for need for re treatment and what we've seen is the patients require 70 per cent of the patients plus.

Steve Cain: And what we've seen is that patients require – 70% of the patients plus require no more than two treatments in a year, and about half of them only require one treatment. So, this gives a lot of information about how a drug that works very rapidly would be used in real life, and it's a very unique overall profile. So, you know, for our primary, absolutely essential to date 15, we're looking to see, essentially, patients who have improved and remain well. The real data for that aspect really comes from Shoreline, and we have a very substantial and now growing database around that, and it continues to support the idea of episodic treatment.

No more than two treatments in a year and half of them only required one treatment.

This gives us a lot of information about how a drug that works very rapidly will be used in real life and it's a very unique overall profile. So.

We're our primary absolutely central to day 15, we're looking to see.

Essentially patients being instead.

Instead of improved remain well the real data from that aspect really comes from from shoreline and we have a very substantial and now growing database around that and it continues to support the idea of episodic treatment.

Thank you.

And as a quick reminder, please limit yourself to one question.

Our next question will come from the line of Jay Olson from Oppenheimer you may begin.

Oh, Hey, guys. Thanks for taking the question I'm curious about Sage 324, I think you're leading that development program with Biogen can you just talk about the indications you are planning to pursue and whether or not you plan to study $3 24 in Parkinson's disease epilepsy patients. Thank you.

Operator: Our next question will come from the line of Jay Olson from Oppenheimer. You may begin.

Yeah, Jay the question so look.

But we're really excited about forward.

<unk> Prologis franchise.

We believe it's a novel potential treatment for chronic neurological conditions.

We thought very differently about movement disorders. So if this is successful in the initial indication of central tremor would be the first new treatment in over 50 years.

Really excited by that as I mentioned, we're very confident that in the phase two b will reach a dose and frequency that is.

So probably taken into phase III, and then of course logical profile with that profile and talking to our collaborative buys and we'll map out additional indications, but we do believe that there are a number of additional indications.

Pursue with Sage three to four.

Over that next step of dose and frequency in the sense of tremor.

Barry E. Greene: So, look, with that in mind, we're really excited about SAGE 2B for its neurology franchise. We believe it's a novel potential treatment for chronic neurological conditions, and we think very differently about movement disorders. So, you know, if this is successful in the initial indication of central tremor, it will be the first new treatment in over 50 years. So we're really excited about that. As I mentioned, we're very confident that in SAGE 2B, we'll reach a dose and frequency that is a profile to take into phase three and then a commercializable profile. With that profile and talking to our collaborators at Biogen, we'll map out, Steve, anything else to offer? Yeah, I think so...

Anything else to offer.

Yeah, I think I think what I'd say is you know as we dial in what profile, we're looking for where we're working closely with investigators were working with patients and patient advocacy groups. We're even doing exit interviews with the patients that participated in our trials to understand exactly what they're looking for in a medicine. This is something that we've been.

<unk> been looking to essential tremor.

For quite some time and.

Right now the data on hand, really speaks to upper limb tremor being ones. That's a driver of disability, we could see that when we when we look at the correlation with improvements in activity of daily living so overall, our growing understanding of 324 something that not only is it unique but it is something that we think is really a great.

Example of the of the approach that we take to R&D. So we've had preliminary data in some of these other indications Parkinson's non clinical data in epilepsy right now our focus is on essential tremor, but we certainly have broader interest in other areas moving forward Jim.

Yes, maybe to build on that a little bit. The question was about other potential index.

That's very true for we see as the lead molecule for neurology franchise and as Steve was just saying, it's a little bit to do with the way, we think about R&D in general.

Steve Cain: Yeah, maybe to build on that a little bit, you know, the question was about other potential indications.

Talk a lot about two things following the science and leading with human data and sort of following the science. In this case means we understand that there are multiple patient populations, who could potentially benefit from a GAAP a potential molecule like sage 324, and especially with that profile of that.

Jim Doherty: And what that in this case means is that there are multiple patient populations who could potentially benefit from a GABA-potentiating molecule like SAGE-324, and especially with that profile that's optimized for chronic delivery. And so that leads us to that second point of leading with human data, and although our key focus at the moment on the program is essential tremor, as you've been hearing, we do have data from an earlier program.

Optimized for chronic delivery and so that leads us to the second point of leading with human data and although our key focus at the moment on the program is in essential tremor as you've been hearing we do have data from an earlier program.

Preliminary look at potential efficacy in Parkinson's disease, and we've got an absolute raft of preclinical data.

Jim Doherty: There is lots of pre-clinical data indicating that this mechanism and this molecule would be valuable.

Jim Doherty: Treatment for epilepsy. So there's a lot of potential.

Indicating that this mechanism and this molecule would be valuable treatment for epilepsy.

Jim Doherty: There's a lot of potential value for the neurology franchise, and that's something that our partners at Biogen are well aware of, and that'll be the subject of ongoing conversation.

A lot of potential value for the neurology franchise, and that's something that our partners Biogen are well aware of that will be the subject of ongoing conversations but the key focus for now is the central tremor, but we think that theres a lot of potential for the molecule in other.

Jim Doherty: That'll be the subject of ongoing conversations. But the key focus for now is essential tremor, but we think that there's a lot of potential for the molecule in other groups in neurology as well. Great, thanks for taking the question. And our next question will come from Paul Matteis from STFL.

Groups in neurology as well.

Thanks.

Great. Thanks for taking the question.

All right.

And our next question offline.

<unk> from Stifel you may begin.

Operator: You may begin. Great, thank you. Have you guys talked with Biogen about scenario planning? If waterfall and coral were to fail but the phase three postpartum studies were to succeed, would you launch this drug in PPD and then kind of figure everything else out later? Or would you wait?

Great. Thank you.

Have you guys talked with Biogen about scenario planning, if waterfall and Carl were to fail, but the phase III postpartum study were to succeed would you launch this drug in PPD, and then kind of figure everything else out later or would you wait and then separately, what's the status of our future trials and anxiety.

And bipolar depression and is the kind of is the initiation of those studies at all contingent upon what we see in M. D day. Thank you.

Okay. Thanks, Paul Thanks for the question so.

Barry E. Greene: Thanks for the question. So again, I'll remind you that the data we've seen with zaranolone now in over 3000 subjects and patients has been highly consistent, rapid onset, and the effect, three or four days, has been very durable, as I and Steve and Jim have highlighted.

I'll remind you that the data we've seen was around alone now in over 3000 subjects and patients has been highly consistent rapid onset of effect three or four day been very durable.

And Steve and Jim have highlighted with the adverse event profile. It's been consistent so we are highly encouraged by the upcoming data readouts.

Barry E. Greene: With an adverse event profile, it's been consistent, so we are highly encouraged by the upcoming data readouts. We sat down with the agency and mapped out three unique approaches, three unique ways to potentially get approval, two in MDD, as you highlighted, and one in PPD. We believe that one of those phase threes needs to be positive for us to have a drug on the market. So we're very enthusiastic about all three approaches and believe that, as you see with many drugs, we need one positive phase 3 here.

We sat down with the agency are mapped out three unique.

Per unique.

Purchased through unique different.

Ways to potentially get approval to an M D as you've highlighted and one in PPD and we believe that one of those phase threes needs to be positive for us to have a drug on the market. So we're very enthusiastic about all three approaches and believe that.

As you've seen with many drugs, we need one positive phase III here, that's an agreement with <unk>.

Barry E. Greene: And that's an agreement with the agency. Yes, the scenario plan with Biogen is at a very high level, but not quite. We believe we have a very important drug here, not only for MDD and PPD but for potentially other indications. And we'll share more about those paths forward as we map that out with biotech.

Agency, Yes from scenario plan with Biogen at a very high level, but not in any.

Retail and we believe we have a very important drug here not only for MB DNP can be but potentially other indications and will share more about the path forward as we mapped that out with Biogen.

Yeah.

Our next question will come from the line of Andrew Tsai from Jefferies. You may begin.

Operator: Andrew Stier from Jefferies

Operator: And I know you guys are very good at controlling this, and I don't think this has ever been an issue for you, but I'm just curious to see what steps you've taken to ensure there won't be a higher-than-expected placebo response out to day 42. Basically, I'm just curious to see how confident you are that this scenario wouldn't happen.

Thanks, and good morning.

My question is around waterfall and I know you guys aren't very good at controlling that and I don't think I've ever been an issue for you, but I'm just curious to see what steps you've taken 10 share there won't be a higher than expected placebo response out to day 42.

Basically I'm just curious to see how confident you are that scenario wouldn't happen. Thanks.

Barry E. Greene: Yeah, Andrew, thanks for highlighting that. And let me make a comment, and I'll turn it over to Jim to talk about the conduct of the study. So with, you know, the shoreline data, with the increasing N and waterfall, you know, we're increasing our safety database. It's a very important indicator, as we're all aware. So the bigger the safety database, the better.

Yeah, Andrew Thanks for highlighting that.

It's a comment and I'll turn it over to Jim talk about the conduct.

The study so we are with the shoreline data with decreasing and waterfall.

We are increasing our safety database is a very large indication as we're all aware so the bigger the database the better importantly, Andrew It was not seems guidance we've committed to delivering.

Barry E. Greene: Importantly, Andrew, we've not changed guidance. We've committed to delivering the top line results for phase three in the first half of this year, and we intend to continue to do that. So we're enthusiastic about the progress of the program. It's fully enrolled, and we're looking forward to the readout. Jim, you want to talk about specific...

The topline results from phase III in the first half of this year and we tend to continue to do that so we're enthusiastic about the progress of the program is fully enrolled and we're looking forward to that.

Jim you want to talk about specifics of.

Jim Doherty: I want to talk about the specifics of...

The control placebo and power thoughts there yes.

Jim Doherty: Control, Placebo, and Higher Thoughts are there. Yeah, absolutely. And Andrew, thanks, Andrew. Thanks for the question. As I think, you know, we put a lot of thought and focus into it.

Absolutely and Andrea Thanks, Andrew Thanks for the question.

As I think you know we.

We've put a lot of thought and focus into into design and I think the answer is that we've talked a lot about the waterfall design in.

Jim Doherty: We've talked a lot about the waterfall design and modifications that we made to the design based on learnings, but the other important thing to remember is many of the things that we have learned through multiple trials in the landscape program very much remain in the design of the waterfall. And I think that's our view on things like controlling for placebo effects.

Modifications that we made in design based on learnings, but.

The other important thing to remember is many of the things that we have learned through multiple trials in the landscape program.

Much remain in the design of waterfall and I think that's our view on things like controlling for placebo effect I think.

What we try to do is do.

Jim Doherty: Our next question will come from the line of Neena Bitritto Garg from Citi. You may begin.

Do very rigorous about our execution and that is something that we are doing again with the waterfall study.

Okay.

Thanks very much.

Thanks, Andrew.

Operator: Hey guys, thanks for taking my question. So I'm just kind of curious about the next steps, kind of after waterfall. I know you've talked about not necessarily meeting the Redwoods study at this point, given the data you're seeing from Shoreline and, you know, a number of other studies, but I guess, are there, are there kind of differences in next steps depending on the magnitude of the effect that you see in waterfalls?

Our next question comes from the line of Nino The tradeoff Garg from Citi you may begin.

Hey, guys. Thanks for taking my question.

So I'm just kind of curious about the next steps kind of after a waterfall I know you've talked about not necessarily meeting the Redwood study at this point given the data you're seeing from shoreline.

Operator: Yeah, Neena, thanks for the question. I'll take it. And if, you know, Steve has other callers.

Barry E. Greene: What we're counting on for waterfall is a statistically significant result at day 15. If that's true, and we have an adverse event profile that's consistent with what we've seen already in over 3,000 subjects and patients, we have a very important medicine with a very differentiated benefit-risk profile than anything that exists on the market today. So statistically significant at day 15, we have a drug. And I think the unmet need is so extreme that KOLs, patient groups, and the regulators appreciate that that's what we're looking for.

One path forward.

Yeah.

Thanks for the question I'll I'll I'll take it in.

Steve has other other collaros Kim so yeah, as we said what we're counting on for waterfall is a statistically significant result result at day 15.

If that's true and we have a an adverse event profile that's consistent with what we've seen already over 3000 subjects and patients. We have a very important medicine with a very differentiated benefit risk than anything that exists in the market today. So statistically significant need for clean we have a drug and I think the unmet need is still.

Extreme that kols patient groups and the regulators appreciate that that's what we're looking for so obviously.

Barry E. Greene: So obviously..., you know, data matters, and effect size matters. We're looking for statistics of significance. Our plan, should Waterfall be positive, is to sit down with the agency and be very clear in mapping out next steps. We could start a rolling submission; we could file Waterfall.

Do the matter an effect size matters to some extent, but we're really looking for statistical significance our plan.

<unk> will be positive.

Sit down with the agency and being very clear of mapping out next steps, we could start a rolling submission we could file waterfall.

Barry E. Greene: A key that we're looking for, just to be clear, is also timing for coral. We would not want to get into a situation where we filed an NDA, had another major data readout, submitted that readout, and went into kind of a three-month extension. So should the agency want to see coral, we'd likely wait the whole clinical session for both Waterfall and coral. Now you asked about Redwood.

Key that we're looking for just to be clear. It was also the timing of coral and we would not want to get into a situation, where we filed an NDA had another major data readout submitted that readout.

Went into kind of a three month extension so should the agency wanted to coral.

You'd likely wait the whole clinical section for both waterfall and coral.

You asked about Redwood I'll remind you that before Dana existed as it exists today. A question was asked how many times in a year from you.

Effectively and safely treat a patient that's not really a question with all the data we have right now waterfall shoreline that needs to be so we're very confident assuming a positive waterfall that redwood will not be a a regulatory requirement for filing an NDA we might have other.

Post approval commitments that would map out as soon as we talk to the agency.

Thank you Matt.

Steve Cain: Yeah, the only thing I'd say is, you know, when we started this program, we set out to identify a drug with a very unique profile, a medicine that, you know, aligns closely with patient interest, it's quick, the effects are durable, and, you know, they have long treatment-free intervals. The data that we get from Shoreline really supports that approach. What we're looking for is the next study where we show the acute effects.

Yeah. The only thing I'd say is when we started this program we set out to identify a drug with a very unique profile of a medicine that you know.

It aligns closely with patient interest it's quick.

Facts are durable and they're long treatment free intervals, we locked the data that we get from shoreline really supports that approach. What we're looking for is that next study, where we're showing the acute effects.

Steve Cain: That's the day 15 endpoint. So that's, that is absolutely essential. And it's important. The other thing I'd add is that sometimes people wonder about effect versus effect size. Well, we've seen across the board, it's been very consistent, our large, rapid, and sustained improvements in the drug group compared to placebo varies quite a bit, and so that's why we're very confident around statistical significance being the primary endpoint here prior to filing. Our next question comes from Gary Mackman from BMO Capital Markets. You may begin.

Day 15 end point, so that's <unk>.

Essential.

And it's important the other the other thing I'd add is that sometimes people wonder about effects versus affects us what we've seen across the board. It's been very consistent are large.

Rapid and sustained improvements in the drug group placebo varies quite a bit.

So.

That's why we're very confident around physical significance being the.

Primary end point here in the Gulf prior to filing.

Our next question comes from the line of.

Gary Nachman from BMO capital markets you may begin.

Operator: Hi, this is Eddie.

Hi, This is Evan Clark filling in for Gary Thanks for taking my question.

Operator: I'm filling in for Gary. Thanks for taking my question. So regarding stage 3-4, what are the next steps in terms of developing the protocol for phase 2b? Are there any additional cuts of data you'll be looking at in the next several months that could help inform how you move forward in terms of timing of dose and patient population? And if so, when would you release some of that data?

So regarding the phase III, two or what are the next steps in terms of developing the protocol from phase two b are there like any additional cuts of data you'll be looking at.

In the next several months that could help inform how you move forward in terms of dose timing of dose and pay per patient population and if so when would you release some of that debt.

Yes. Thanks for the question. So let me let me.

Operator: Yeah, thanks for the question. So, let me let me.

Barry E. Greene: We hit it at a high level when I asked Jim to talk about it. The team at SAGE and Biogen is pouring through the detailed kinetic data, looking at dose, duration, and PK.

Hinted at a high level and ask Jim to talk about it. So the team of Sage and Biogen is actually pouring through the detailed kinetic data looking at looking at those duration PK PD and the value of those data will help us design, the phase <unk> dose and frequency and we'll likely test a couple of different ones to make sure that we have the right.

Jim Doherty: and the value of those data will help us design the phase 2b dose and frequency, and we'll likely test a couple different ones to make sure that we have the right profile going into phase 3. So we're very encouraged by the kinetic readout, particularly the patients that were the worst off patients over 12, where we saw a 41% reduction in essential tremor, a very important reduction for these patients. Jim, do you want to talk about any specifics and next steps?

The right profile going into phase.

Phase III, so we're very encouraged by.

By the kinetic read out.

Particularly the patients that were the worst off business over 12, we saw 41% reduction in <unk>.

Central timber very important reduction for these patients.

Jim you want to talk about any specifics on next steps.

Jim Doherty: Yeah, absolutely, Barry, and when we think about...

Yeah, absolutely Varian.

When we think about the results from Qinetiq as you heard earlier.

Jim Doherty: So let's talk about the results from KINETIC. As you heard earlier, statistically significant effects on the primary endpoint were sustained over a 28-day period with an adverse event profile that's consistent with what we understand about the drug and about the mechanism of action. So the question to be answered from KINETIC was, can we see efficacy? Can we see efficacy without tachypelaxis, which we're excited about because that's the result that we saw.

Statistically significant.

Next on the primary endpoint and sustained over a 28 day period with an adverse event profile consistent with what we understand about the drug and about the mechanism of action.

The question to be answered from Qinetiq was can we see efficacy can we see efficacy without tachyphylaxis, which we're excited about because thats. The result that we see so the focus on the.

Jim Doherty: The focus on 2B and the rest of the Phase II program is on dosing strategy. And remember, 324 is a long, half-life drug that's been optimized for chronic dosing. That gives us a lot of flexibility in exactly the dosing strategy that we'll use for pivotal studies. And so that's going to be the focus.

The to be in the rest of the phase III program is on dosing strategy and remember three two for the long half life drug that's been optimized for chronic dosing that gives us a lot of flexibility in exactly the dosing strategy that we'll use for pivotal studies and so thats going to be focused and I think Barry mentioned, there are a number of different <unk>.

Jim Doherty: There are a number of different things that we can look at modifying, so certainly dose level, dose frequency, there are a number of aspects that we're looking at. So the SAGE and Biogen teams will figure out

Things that we can look at modifying so certainly dose level dose frequency. There are a number of aspects that we're looking at and so at this stage and Biogen teams will we'll figure out what's the most efficient way to answer those questions and in phase two day.

Jim Doherty: And I hope that SAGE and the teams will figure out what's the most efficient way to answer those questions in Phase 2B. Thank you. That is all the time we have for questions today.

Thank you.

Time, we have for questions today, I'll turn the call back over to Barry Greene for any closing remarks.

Barry E. Greene: I'll turn the call back over to Barry Greene for any closing remarks. Thanks, Operator. Thanks, everyone, for joining us this morning. We are very pleased with the significant progress in the first quarter, and we're excited by the potential for additional milestones throughout the balance of this year. And I want to acknowledge that May is Mental Health Awareness Month, and I'm excited to see the real movement across the world, a movement that encourages people to speak up and change the narrative on brain health and mental wellness.

<unk>.

Thanks, operator, and thanks, everyone for joining us. This morning, we are very pleased with the significant progress in the first quarter and we're excited about the potential for additional milestones throughout the balance of this year.

And I want to acknowledge that May is mental health awareness month, and I'm excited to see the real movement across the world.

<unk> encouraged people to speak up and change the narrative on brain health and mental wellness.

Barry E. Greene: There's also a growing awareness of the global impact the current mental health pandemic is having on the young and the old. In fact, just this week, MTV convened a groundbreaking coalition of media companies and mental health experts to harness the power of media and storytelling, kicking off with Better Together, a mental health storytelling summit, drawing talent including Oprah Winfrey, Trevor Noah, and Regina King, among many others. The coalition unveiled a first-of-a-kind comprehensive mental health media guide, which provides best practices and evidence-based recommendations to empower content creators and entertainment to expand portrayals of mental health to further encourage viewers to speak up and get help.

There is also growing awareness of the global impact of the current mental health pandemic is having on the young and the old in fact, just this week MTV convene to groundbreaking coalition of media companies and mental health experts to harness the power of media and storytelling kicking off at better together, a mental health storytelling summit, drawing talent, including local win.

Free Trevor Noah Regina King among many others.

<unk> built the first of a kind comprehensive mental health media guide would provide best practices and evidence based recommendations to empower content creators and entertainment to expand portrayals of mental health to further encourage yours to speak up and get help true progress as we further lean in very real challenge presented by a lack of progress.

True progress, as we further lean in, is a very real challenge presented by a lack of progress in talking about and treating brain health issues. We're excited to see this progress and for others to join us in what we have acknowledged is a big lift. Now more than ever, patients suffering with brain health issues need better, more effective treatment, and the SAGE team is working tirelessly to deliver on our vision of bringing such treatment to patients so they can get better sooner.

And talking about in treating brain health issues, we're excited to see this progress and for others, joining us and what we have acknowledged as a big lift.

Now more than ever a patient suffering with brain health issues be better more effective treatment and the sage team has worked tirelessly to deliver on our vision of bringing such treatment patients. So they can get better sooner.

Thanks, everyone. Looking forward to further discussions. Be well. This concludes today's conference call. Thank you for participating. You may now disconnect.

Thanks, everyone looking forward to further discussions you all.

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

Q1 2021 SAGE Therapeutics Inc Earnings Call

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