Q4 2021 SAGE Therapeutics Inc Earnings Call

February 24, 2022

Good morning, welcome to Sage Therapeutics fourth quarter and full year 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 sages website at <unk>.

Good morning.

Welcome to Sage Therapeutics' fourth quarter and full year 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's website at SageRx.com.

Sage Rx Dot Com. This call is the property of Sage Therapeutics and recordings reproduction.

This call is the property of Sage Therapeutics and recordings, reproduction, or transmissions of this call without the written consent of Sage Therapeutics is strictly prohibited. Please note that this call is being recorded.

Or transmissions of this call without the written.

Consent of Sage Therapeutics is strictly prohibited.

Please note that this call is being recorded I would now like to introduce Helen Rubinstein director of Investor Relations at Sage.

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

Good morning, and thank you for joining Sage therapeutics fourth quarter and full year 2021 financial results conference call before we begin I encourage everyone to go to the investors and media section of our website at <unk> Dot Com, where you can find the press release related to today's call as well as the slides that contains supplemental detail I'd like to point out that we will.

Morning, and thank you for joining Sage Therapeutics' fourth quarter and full year 2021 Financial Results Conference call.

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

Be making forward looking statements, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties and our actual results may differ materially. Please consult the risk factors discussed in today's press release and in our SEC filings for additional detail. We will begin the call with prepared remarks by Barry Greene, Our Chief Executive Officer, who will.

We will begin the call with prepared remarks by Barry Green, our Chief Executive Officer, who will provide an overview of the progress from the previous quarter and full year 2021.

Provide an overview of the progress from the previous quarter and full year 2021, we will also be joined by Jim Doherty, Our Chief Development Officer, who will review recent development progress across our programs and Kimi Iguchi, Our Chief Financial Officer, who will review the financial results from the quarter, Chris <unk>, Our Chief commercial officer will join for Q&A with that I'll now.

We will also be joined by Jim Dougherty, our Chief Development Officer, who will review recent development progress across our programs, and Kimi Iguchi, our Chief Financial Officer, who will review the financial results from the quarter.

Chris Bennecke, our Chief Commercial Officer, will join for Q&A.

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

I'll turn the call over to Barry.

Thanks, Alan and thank you everyone for joining us this morning before I begin I want to take a moment to acknowledge the major events happening in the world stage. This morning, we're watching along with the rest of the world and our thoughts and prayers are with all those affected.

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

Before I begin, I want to take a moment to acknowledge the major events happening on the world stage this morning.

We're watching along with the rest of the world, and our thoughts and prayers are with all those affected.

Rest assured, we'll be focused on doing what we can, developing innovative medicines for brain health.

Rest assured we'll be focused on doing what we can developing innovative medicines for brain health.

And now let me turn back to our quarterly call.

Now, let me turn back to our quarterly call two.

2021 was an important year for SAGE, and going into 2022, we're well-positioned to advance our mission to pioneer solutions, to deliver life-changing brain health medicines so every person can thrive.

2021 was an important year for sage and going into 2022 were well positioned to advance our mission to pioneer solutions to deliver life changing brynhild medicines. So every person can thrive.

By leveraging our significant expertise in brain circuitry, we've demonstrated leadership in GABA-A and NMDA receptor pathways.

By leveraging our significant expertise in brain circuitry demonstrated leadership and Gaba and NMDA receptor pathways, we've developed a robust pipeline of programs, including six new chemical entity development candidates across 11 or more possible indications.

We've developed a robust pipeline of programs, including six new chemical entity development candidates across 11 or more possible indications.

We believe that with this novel pipeline, we have the potential to help the millions of people suffering from the unmet need in brain health disorders, and we look forward to helping as many as we can in the years to come.

We believe that with this novel pipeline, we have the potential to help millions of people suffering from the unmet need in brain health disorders, and we look forward to helping as many as we can in the years to come.

I'd like to begin by providing some context on mbd in PPD.

I'd like to begin by providing some context on MDD and PPD.

Families living with depression have not been well served.

Families living with depression have not been well served largely stigmatized depression as the dark shadow of human illness.

Largely stigmatized, depression is the dark shadow of human illness.

Current treatments are just not working well enough, with little innovation in the last 60 years.

Current treatments are just not working well enough with little innovation in the last 60 years the profile of treatments remain unchanged. Despite 35 approved treatments in the last 30 years.

The profile of treatments remain unchanged despite 35 approved treatments in the last 30 years.

Prevalence and impact continue to worsen, with a three to four-fold increase in people experiencing symptoms of depression since the start of the COVID-19 pandemic, and an estimated one in eight women with a recent live birth experiencing postpartum depression.

<unk> has an impact continued to worsen with a 3% to four fold increase in people experience symptoms of depression since the start of the COVID-19 pandemic and an estimated one in eight women with the recent library experiencing postpartum depression.

The economic implications are as dire as the health implications.

Yeah.

The economic implications are as dire as the health implications in 2020 economist estimated that depression and mood disorders caused the U S alone over 784 billion.

In 2020, economists estimated, that depression and mood disorders cost the U.S. alone over $784 billion.

Change is needed we need medicines that work faster last longer a well tolerated and look beyond depression is a lifelong chronic illness.

Change is needed.

We need medicines that work faster, last longer, are well-tolerated, and look beyond depression, as a lifelong chronic illness.

Current treatment approach results in a trial and error pattern delay.

The current treatment approach results in a trier-and-error pattern. Delays in resolving MDD symptoms, as seen with current antidepressants, are often associated with more severe depression, increased relapse rates, and worse long-term clinical outcomes.

Delays in resolving mbd symptoms seen with current antidepressants are often associated with more severe depression.

Greece relapse rates and worst long term clinical outcomes.

We believe patients deserve better.

We believe patients deserve better as a society, we can do better.

Innovative thinking at least the valuable advancements that benefits society. The riskiest thing we can do for people is to maintain the status quo and believe that what we have is good enough.

As a society, we can do better.

Innovative thinking leads to valuable advancements that benefit society.

The riskiest thing we can do for people is to maintain the status quo and believe that what we have is good enough.

The data are clear.

The nearly 7 million people diagnosed with MVD prescribed an antidepressant in each year.

For the nearly 7 million people diagnosed with MDD and prescribed an antidepressant each year, the average course of therapy is only seven weeks, and 80% of patients change treatments once or twice within the first year. And among those that have changed treatments, 50% changed within the first month.

Average course of therapy is only seven weeks and 80% of patients change treatments once or twice within the first year and among those that have changed treatments, 50% change within the first month.

Patients clearly need more from their therapy.

Patients clearly need more from their therapy. That's why we believe there's a significant opportunity for new therapy in the treatment of MPD like Saran alone if approved.

That's why we believe there's a significant opportunity for new therapy in the treatment of MDD, like xeranilone, if approved. One MDD population subset that stands apart in its need for new treatment options are those with MDD with elevated anxiety as a symptom of their depression. According to literature, which often refers to this population as anxious depression, up to two-thirds of people with MDD experience elevated anxiety symptoms as part of their depression. Based on its mechanism of action and data seen in studies to date, we believe xeranilone may be well-suited to help these people.

One <unk> population subset that stands apart its need for new treatment options are those with MTB with elevating xiety as a symptom of their depression.

According to literature, which often refer to this population as anxious depression up to two thirds of people with mbd experienced elevated anxiety symptoms as part of their depression.

Based on its mechanism of action and data seen in studies to date. We believe is around alone may be well suited to help. These people. We look forward to sharing more about MVD with elevating the IV in the future, but be sure. This is going to be a key focus going forward.

We look forward to sharing more about MDD with elevated anxiety in the future, but be sure this, is going to be a key focus going forward.

If we're successful in our efforts.

Commercials.

If we're successful in our efforts, we've commercialized this for partnership and engagement with all stakeholders, patients, healthcare professionals, payers, patient advocacy groups, and policymakers. These engagements are needed to enact the change necessary for MDD and PPD patients to get the care they deserve and for appropriate patients with MDD and PPD to receive xeranilone if approved.

The partnership engagement with all stakeholders patients health care professionals payers patient advocacy groups and policymakers. These.

These engagements are needed to enact the change necessary for <unk> and PPD patients get the care, they deserve and for appropriate patients with <unk> and PPD to receives around alone if approved.

We remain on track to start the rolling NDA submission in <unk> early this year and plan to complete the submission in the second half of 2022.

We remain on track to start the rolling NDA submission in MDD early this year and plan to complete the submission in the second half of 2022. As we shared previously, the planned NDA will include efficacy data from five studies, MDD-201B, Waterfall, Robbin, Coral, and the Japanese study. In addition to data from the Shoreline study on repeat treatment efficacy sustained beyond the treatment period, and lastly, safety data from the entirety of the program.

As we shared previously the planned NDA will include efficacy data from five studies mbd to OMB waterfall Robin coral and the Japanese study.

In addition to data from the shoreline study on repeat treatment efficacy sustained beyond the treatment period, and lastly safety data from the entirety of the program.

We also plan to submit an associated NDA with <unk> alone in PPD and the first half of 2023 any completion and results from the Skylark study.

We also plan to submit an associated NDA with xeranilone and PPD in the first half of 2023 pending completion and results of the Skylark, study. We announced this morning that the FDA granted fast-track designation for xeranilone and PPD. Fast-track designation is granted to drug candidates that treat serious or life-threatening conditions and demonstrate the potential to address unmet medical needs.

We announced this morning that the FDA granted fast track designation for us around alone in PPD faster.

Fast track designation is granted to drug candidates that treat serious or life threatening conditions and demonstrate the potential to address unmet medical needs.

Now turning to the recent advances in our neuropsych franchise led by SAGE 718, a wholly, owned first-in-class NMDA receptor PAM being developed as a potential oral therapy for cognitive disorders associated with NMDA receptor dysfunction. In our last quarterly call, we announced that SAGE 718 was awarded a Fast-Track designation, by the FDA for development as a potential treatment for Huntington's disease, specifically, Huntington's cognitive impairment. This designation was partially attributed to the promising early data we generated in, our Phase I study of SAGE 718, which demonstrated improvements in cognitive performance in patients with Huntington's cognitive impairment.

Now turning to the recent advances in our neuroscience franchise led by Sage 718, our wholly owned first in class NMDA receptor Pam being developed as a potential oral therapy.

<unk> disorders associated with NMDA receptor dysfunction.

In our last quarterly call we.

Sage 718 was awarded fast track designation by the FDA for development as a potential treatment for Huntington's disease, specifically Huntington's cognitive impairment.

This designation was partially attributed to the promising early data we generated in our phase one study of Sage 718, which demonstrated improvements in cognitive performance in patients with Huntington's cognitive impairment.

Patients are now enrolling in our phase II placebo controlled dimension study evaluating sage 718, and HD cognitive impairment and we plan to expand our work in this indication by initiating the phase II placebo controlled surveyor study in mid 2022 and began an open label extension study and AC cognition in la.

Patients are now enrolling in our Phase II placebo-controlled dimension study evaluating, SAGE 718 and HD cognitive impairment, and we plan to expand our work in this indication by initiating the Phase II placebo-controlled surveyor study in mid-2022 and begin an open-label extension study in HD cognition in late 2022.

<unk> 2022.

We're also advancing sage 718 in patients with mild cognitive impairment due to Parkinson's disease.

We're also advancing SAGE 718 in patients with mild cognitive impairment due to Parkinson's, disease.

We're also advancing SAGE 718 in patients with mild cognitive impairment due to Parkinson's, in mid-2022.

This placebo controlled phase II study evaluating <unk> in patients with mild cognitive impairment or Mci due Parkinson's in mid 2022.

Finally, SAGE 718 is also being evaluated as a potential treatment for patients with, Huntington's disease. We recently announced that SAGE 718 demonstrated improved performance and baseline on multiple, cognitive function tests in patients with mild cognitive impairment and mild dementia due to Alzheimer's.

Finally, <unk> is also being evaluated as a potential treatment for patients.

Okay.

Yes.

We recently announced that Sage 718 demonstrated improved performance from baseline on multiple cognitive function test in patients with mild cognitive impairment and mild dementia due to Alzheimer's.

These signals observed in the open-label luminary study were consistent with those seen in our, Parkinson's and Huntington's trials.

The signals observed in the open label Luminary study were consistent with those seen our Parkinson's and Huntington's trials, we plan to initiate a placebo controlled phase II study in Sage 718 in patients with Mci and mild dementia due to Alzheimer's, which is expected to begin enrolling later this year.

We plan to initiate a placebo-controlled Phase II study in SAGE 718 in patients with MCI, and mild dementia due to Alzheimer's, which is expected to begin enrolling later this year.

We've also made great progress on our neurology franchise, which features SAGE 324, another, internally-developed compound that is part of our collaboration with Biogen. Currently, SAGE 324 is being evaluated as a potential treatment for patients suffering, from essential tremor, ET, and other neurological disorders.

We've also made great progress on our neurology franchise, which features stage three to four another internally developed compound that is part of our collaboration with Biogen.

Currently say three to four is being valued as a potential treatment for patients suffering from a central tremor ETE and other neurological disorders.

Jim will provide more insight in this program and updates for the year.

I'd like to take a moment to thank the SAGE team for their hard work, commitment, and, dedication on behalf of patients.

I'd like to take a moment to.

Thank the sage team for their hard work commitment and dedication on behalf of patients 2021 was a data rich year, and we realized an important program advancements in multiple disease areas across all three of our brain health franchises.

2021 was a data-rich year, and we realized important program advancements in multiple, disease areas across all three of our brain health franchises.

This work last year built a solid foundation for continued progress in 2022, and I'm excited, by what the future holds for SAGE.

Worked last year built a solid foundation for continued progress in 2022.

Excited by what the future holds for Sage.

Additionally, I believe our balance sheet provides us the strategic and operational, flexibility to continue to grow our pipeline as we continue to evaluate each investment diligently to ensure our decision-making position does well in our efforts to create long-term value.

Additionally, I believe our balance sheet provides us the strategic and operational flexibility.

To continue to grow our pipeline as we continue to evaluate each investment diligently to ensure our decision making positions us well in our efforts to create long term value.

In closing, I'm confident we have the opportunity to build on the momentum from the fourth quarter, and throughout 2021 to generate continued success in 2022 as we advance our journey to become the leader in brain health and a top-tier biopharmaceutical company.

In closing I'm confident we have the opportunity to build on the momentum from the fourth quarter and throughout 2021 to generate continued success in 2022 as we advance our journey to become a leader in brand health and a top tier biopharmaceutical company.

Now, I'd like to turn the call over to Jim for a more detailed discussion of our recent, data and a preview of our expectations for 2022.

Now I'd like to turn the call over to Jim for more detailed discussion of our recent KOL data and a preview of our expectations for 2022 Jim.

Jim?

Thanks, Barry, and good morning, everyone.

Thanks, Barry and good morning, everyone throughout 2021 and in recent weeks, we've made important progress across our three brain health franchises and I'm pleased to highlight our next steps for each program.

Throughout 2021 and in recent weeks, we've made important progress across our three brain, health franchises, and I'm pleased to highlight our next steps for each program.

Starting with our depression franchise, we recently announced top-line results from our, CORAL study evaluating the efficacy and safety of zaranolone when co-initiated with standard antidepressant treatment, or ADT, compared to standard-of-care ADT co-initiated with placebo in patients with major depressive disorder, or MDD. The CORAL study was designed to address whether the rapid onset of efficacy seen with zaranolone, in our clinical trials would benefit people with MDD when co-initiated with an ADT. The zaranolone co-initiated with an ADT met the primary endpoint in CORAL, demonstrating, a statistically significant reduction in HAMD-17 scores at day three, the first measured time point, compared to standard-of-care ADT co-initiated with placebo.

Starting with our depression franchise, we recently announced topline results from our Coral study evaluating the efficacy and safety of is around loan when co initiated with standard anti depressant treatment or ADT.

The zaranolone co-initiated with an ADT also met the key secondary endpoint, a statistically, significant improvement in depressive symptoms over the full two-week treatment period at all scheduled visits. Taken together, these endpoints demonstrated a significant benefit of zaranolone in the, rapid reduction of depressive symptoms in the CORAL study. Additionally, zaranolone co-initiated with an ADT was well-tolerated, with no new safety, signals attributable to zaranolone identified.

Importantly, analysis of results from the Waterfall and Shoreline studies identified, MDD with elevated anxiety at baseline as a subgroup that is particularly responsive to zaranolone. When treated with standard-of-care ADTs, this subgroup of patients, which represents up, to 66% of all MDD patients, is less responsive to treatment. In the CORAL study, this pre-specified MDD subgroup was more responsive when co-initiated, with a standard-of-care ADT than standard-of-care ADT co-initiated with placebo, as measured by the primary and key secondary endpoints.

<unk> to standard of care ADT co initiated with placebo in patients with major depressive disorder or <unk>.

The core study was designed to address whether the rapid onset of efficacy seen was around land in our clinical trial would benefit people with MTBE when co initiated with an ADT.

Brand alone co initiated within ADT met the primary endpoint in coral demonstrating a statistically significant reduction in Ham D 17 scores at phase III. The first measured time points compared to standard of care ADT co initiated with placebo.

<unk> loan co initiated with an ADT also met the key secondary endpoint, a statistically significant improvement in depressive symptoms over the full two week treatment period at all scheduled visits.

Taken together these endpoints demonstrated a significant benefit was around alone and the rapid reduction of depressive symptoms in the coral study.

Additionally, <unk> initiated with an ADT was well tolerated with no new safety signals attributable to is around loan identified importantly.

Importantly analysis of results from the waterfall in shoreline studies identified mbd with elevated anxiety at baseline as a subgroup that is particularly responsive to is around loan.

When treated with standard of care Adt's. This subgroup of patients, which represents up to 66% of <unk> patients and less responsive to treatment in.

In the Coral study this pre specified MDT subgroup was more responsive when co initiated with the standard of care ADT than standard of care ADT co initiated with placebo as measured by the primary and key secondary endpoints.

This finding is important, and it's always important in drug development to know where, your drug works best, and, of course, critical in guiding potential commercial use.

This finding is important and it's always important in drug development nowhere drug works best and of course critical and guiding potential commercial use.

Finally, a few thoughts regarding zaranolone's mechanism of action. At the start of the Landscape and NEST programs, we hypothesized that zaranolone could lead, to rapid and sustained improvement of depressive symptoms through restoration of key neuronal networks dysregulated by depression.

Finally, a few thoughts regarding surround those mechanism of action at the start of the landscape and Thats programs. We hypothesize that is around loan could lead to rapid and sustained improvement of depressive symptoms through restoration of key neuronal networks. This regulated by depression clinical.

Clinical trials with zaranolone to date have generated efficacy and safety data supporting, this hypothesis, with zaranolone demonstrating the ability to address depressive episodes in a broad spectrum of patients with MDD with a varying profile of depressive symptoms. Zaranolone enhances the function of GABA-A receptors, key elements in the brain's primary, inhibitory system. GABAergic neurotransmission is vital for normal brain function, and significant evidence shows, that GABAergic function may be disrupted in depression. Importantly, zaranolone has three major effects on the GABAergic system, enhancing synaptic, GABA-A receptor function, enhancing extra-synaptic GABA-A receptor function, and enhancing GABA-A receptor expression.

Clinical trials with <unk> to date have generated efficacy and safety data supporting this hypothesis was around demonstrating the ability to address depressive episodes in a broad spectrum of patients with NPD with varying profile of depressive symptoms.

<unk> enhances the function of Gaba a receptors key elements in the brain's primary inhibitory system.

<unk> neurotransmission is vital for normal brain function and significant evidence shows that Gaba urgent function may be disrupted in depression.

Importantly, as our island has three major effects on the Gaba urgent system enhancing synaptic Gaba a receptor function.

Enhancing extra synaptic Gaba a receptor function and enhancing Gaba a receptor expression.

These effects of zaranolone, we believe, all contribute to its clinical profile in treating, depression.

These effects of us around loans, we believe all contribute to its clinical profile in treating depression.

We are often asked whether members of another class of GABA-A receptor enhancers, the benzodiazepines, have the same effects as zaranolone.

We're often asked whether members of another class of Gaba a receptor enhances the benzodiazepines have the same effects is around them.

The short answer is they don't.

The short answer is they don't although benzodiazepine share one of the effects is around loan, namely enhancement of synaptic Gaba a receptors that cannot match. The full profile was around loan as they neither enhanced extra synaptic Gaba a receptors nor enhance Gaba a receptor expression.

Although benzodiazepines share one of the effects of zaranolone, namely enhancement, of synaptic GABA-A receptors, they cannot match the full profile of zaranolone as they neither enhance extra-synaptic GABA-A receptors nor enhance GABA-A receptor expression.

Benzodiazepines are not antidepressant drugs. While they are useful medicines that treat a variety of conditions, including anxiety, and insomnia, they are not approved to treat depressive disorders, either alone or in combination with antidepressants. They are reported to have minimal effects on depressive symptoms as monotherapy, and, in some cases have been reported to worsen depressive symptoms. Anxiety and depressive symptoms can also return after cessation of treatment with benzodiazepines. Finally, benzodiazepines carry significant safety considerations, both alone and in, combination with ADTs, including the risk of dependence and withdrawal symptoms, cognitive impacts, and drug likability.

Benzodiazepines are not anti depressant drugs, while they're useful medicines that treat a variety of conditions, including anxiety and insomnia theyre not approved to treat depressive disorders, either alone or in combination with antidepressants.

Ported to have minimal effects on depressive symptoms as monotherapy and in some cases have been reported the worst in depressive symptoms.

Anxiety and depression symptoms can also return after cessation of treatment with <unk>.

Finally, benzodiazepines carry significant safety considerations, both alone and in combination with ADT.

The risk of dependence and withdrawal symptoms cognitive impacts and drug likeability.

With Zoranolone, we've seen improvement of both core depression symptoms as well as anxiety, symptoms in patients with MDD and PPD in the Landscape and NEST programs, with a differentiated tolerability profile.

With <unk>, we've seen improvement of both core depression symptoms as well as anxiety symptoms in patients with MTBE in PPD and the landscape of NES programs with a differentiated tolerability profile.

In the coral studies, Zoranolone was co-initiated with one of five major antidepressant drugs, in current use, including both SSRIs and SNRIs.

And the Coral studies, our island was co initiated with one of five major anti depressant drugs in current use including both Ssris and <unk>.

The demonstration in the Coral study a significant benefit for us around loan co administration with the standard of care Adt's over treatment with standard of care Adt's alone.

The demonstration in the coral study of significant benefit for Zoranolone co-administration with, these standard of care ADTs over treatment with standard of care ADTs alone at day three and over the treatment period was not a small feat.

<unk> three and over the treatment period was not a small feat.

We also look forward to results from those core subjects, who have enrolled in the shoreline re treatment study. These data will contribute significantly to a full understanding of the durability of responses around loan entering anda.

We also look forward to results from those coral subjects who have enrolled in the Shoreline, Retreatment Study.

These data will contribute significantly to a full understanding of the durability of, response to Zoranolone in treating MDD. Additionally, in the fourth quarter of 2021, we reported positive data from the Zoranolone, 50 milligram cohort in the ongoing Shoreline study in patients with MDD.

Additionally, in the fourth quarter of 2021, and we reported positive data from those around the 50 milligram cohort in the ongoing shoreline study in patients with NPD.

The Shoreline study is a naturalistic safety and tolerability study to investigate as needed, repeat treatment with Zoranolone over a one-year period in patients with MDD.

The shoreline study is a naturalistic safety and Tolerability study to investigate as needed repeat treatment was around loan over a one year period in patients with Mds and.

In the Zoranolone 50 milligram cohort, the majority of patients who responded to an initial, Zoranolone treatment course received only one treatment in total, and 80% received only one or two treatment courses during their time in this year-long study.

And as around 150 milligram cohort the majority of patients who responded to an initial ramp on treatment course received only one treatment in total and 80% received only one or two treatment courses during their time in this year long study.

This means that the potential for only two or four weeks of treatment each year.

Safety profile in this cohort was consistent with other studies. There was also no dependence drug likeability or additional side effects.

Safety profile in this cohort was consistent with other studies. There was also no dependence, drug likability, or additional side effects.

These data will be very useful in our NDA filing as you may be aware the FDA has communicated that real world evidence increasingly plays a role as a component in regulatory decision making.

These data will be very useful in our NDA filing.

As you may be aware, the FDA has communicated that real-world evidence increasingly plays, a role as a component in regulatory decision-making.

We are confident that the Shoreline study, the largest prospective naturalistic study, done in MDD, aligns with the FDA's efforts to emphasize real-world evidence that will transform patient healthcare and drug development. Enrollment in the Shoreline study is ongoing and has surpassed 1,000 patients.

We are confident that the shoreline study the largest prospective naturalistic study done in MPD aligns with the Fda's efforts to emphasize real world evidence that will transform patient healthcare and drug development enrolled.

Enrolment in the shoreline study is ongoing and has surpassed 1000 patients.

We now have six positive trials was around loan and mbd MPD in the landscape and <unk> programs and the profile we have seen in clinical trials to date includes.

We now have six positive trials with Zoranolone in MDD and PPD in the Landscape and NEST programs, and the profile we have seen in clinical trials to date includes rapid and sustained reductions in depressive symptoms, a well-tolerated safety profile, improvements in quality of life and overall health across domains of feeling, functioning, and well-being that were reported by patients and continued after completion of treatment.

Rapid and sustained reductions in depressive symptoms.

Well tolerated safety profile.

Improvements in quality of life and overall health across domains are feeling functioning and wellbeing that were reported by patients and continued after completion of treatment.

A short course of treatment that can be taken as needed with a novel mechanism of action, And a flexible treatment approach that may provide optionality to HCPs and patients To reiterate our filing strategy, we plan to begin the rolling submission for MDD in, early 2022 with the non-clinical modules submitted first.

A short course of treatment that can be taken as needed with a novel mechanism of action.

Flexible treatment approach that may provide optionality to hep's in patients.

To reiterate our filing strategy, we plan to begin the rolling submission for Mbd in early 2022 with the nonpolitical modules submitted first.

The clinical module will likely be the last module submitted for this filing, expected, to occur in the second half of 2022. Additionally, the ongoing Phase III Skylark study of Zoranolone in PPD is on track to, read out in mid-2022.

The clinical module will likely be the last module submitted for this filing expected to occur in the second half of 2022.

Additionally, the ongoing phase III Skylark study it was around alone in PPD is on track to read out in mid 2022.

We're looking forward to sharing more through several upcoming presentations at Scientific, Forums this year, as outlined on slide 29 of our corporate presentation.

We're looking forward to sharing more through several upcoming presentations at scientific forums. This year as outlined on slide 29% of our corporate presentation.

Turning to our neuropsychiatry franchise, we continue to advance the development of, SAGE 718, our lead NMDA receptor positive allotherapy modulator that is a potential oral therapy for disorders where impairment of cognition is one of the main drivers of disability. SAGE 718 was recently granted a Fast Track designation as a potential treatment for cognitive, impairment in Huntington's disease, or HD, which is an important benefit in our development efforts to bring this therapy to patients.

Turning to our neuropsychiatry franchise, we continue to advance the development of Sage 718, our lead NMDA receptor positive allosteric modulator that as a potential oral therapy for disorders, where impairment of cognition is one of the main drivers of disability.

<unk> was recently granted fast track designation as a potential treatment for cognitive impairment and huntington's disease, or HD, which is an important benefit in our development efforts to bring this therapy to patients with.

With the data from the SAGE 718 in HD patients in Phase I in hand, we have now begun dosing, patients in the DIMENSION study, a placebo-controlled Phase II study of SAGE 718 in HD cognitive impairment.

With the data from the Sage 708 in HD patients in phase one in hand, we have now begun dosing patients in the dimension study a placebo controlled phase two study of Sage 708, an HD cognitive impairment.

Additionally, we look forward to initiating enrollment in the SURVEYOR study, our second, Phase II study in HD cognitive impairment, expected to commence in mid-2022 with an open label extension study planned to initiate in late 2022.

Additionally, we look forward to initiating enrollment in the survey or study our second phase III study in HD cognitive impairment expected to commence in mid 2022 with an open label extension study planned to initiate in late 2022.

We are also advancing SAGE 718 in patients with mild cognitive impairment due to Parkinson's, disease, or PD. The PARADIGM study evaluated patients with mild cognitive impairment due to PD. Based on the positive impact that SAGE 718 had on multiple domains of cognition in that, study, we plan to initiate a Phase II placebo-controlled study of SAGE 718 in patients with mild cognitive impairment due to PD in mid-2022.

We are also advancing sage 708 in patients with mild cognitive impairment due to Parkinson's disease or PD.

The paradigm study evaluated patients with mild cognitive impairment due to PD.

Based on the positive impact that <unk> had on multiple domains of cognition in that study we plan to initiate a phase two placebo controlled study of Sage 708 in patients with mild cognitive impairment due to PD in mid 2022.

Finally, we are advancing SAGE 718 in patients with mild cognitive impairment and mild dementia, due to Alzheimer's disease, or AD. In the fourth quarter of 2021, we announced positive results from the LUMINARY study demonstrating, that patients with mild cognitive impairment and mild dementia due to AD who were on SAGE, 718 experienced improved performance from baseline on multiple tests of cognitive function. We expect to initiate a placebo-controlled Phase II study with SAGE 718 in patients with, mild cognitive impairment and mild dementia due to AD in late 2022.

Finally, we are advancing <unk> in patients with mild cognitive impairment and mild dementia due to Alzheimer's disease or <unk> in the fourth quarter of 2021, we announced positive results from the luminary study demonstrating that patients with mild cognitive impairment and mild dementia due to <unk>, who are on page 718.

<unk> experienced improved performance from baseline on multiple tests of cognitive function.

We expect to initiate a placebo controlled phase II study with <unk> in patients with mild cognitive impairment and mild dementia due to aid in late 2022.

Our confidence in the data seen to date with Sage 708 has led us to develop a very robust program across diseases of unmet need.

Our confidence in the data seen to date with SAGE 718 has led us to develop a very robust, program across diseases of unmet need.

Now, I'd like to highlight the advancements made in our neurology franchise, led by SAGE, 324, a next-generation positive allosteric modulator of GABA-A receptors, which we believe holds significant potential in the treatment of neurological conditions like essential tremor, or ET. Based in part on the positive data from the KINETIC study reported earlier in 2021, we, recently initiated a Phase IIb KINETIC-II dose-ranging study evaluating SAGE 324 in, ET in late 2021. KINETIC-II is designed to optimize the dose and frequency of SAGE 324 in ET. I'm pleased to share that the first patient has been dosed in the KINETIC-II study.

Now I'd like to highlight the investments made in our neurology franchise led by Sage <unk> for our next generation positive allosteric modulator of Gaba a receptors, which we believe hold significant potential in the treatment of neurological conditions like the central tremor or ETE.

Based in part on the positive data from the kinetics study reported earlier in 2021, we recently initiated a phase <unk> kinetic two dose ranging study evaluating phase III Q4 in EP and late 2021.

I think two is designed to optimize the dose and frequency of Sage in Q4.

I'm pleased to share that the first patient has been dosed in the kinetic two study.

In closing, our R&D strategy is both proactive and predictive. Everything we learn from a program can be applied to other programs, leveraging knowledge, to define the path forward while driving for seamless execution, with the goal of addressing unmet needs for patients who need new approaches. We believe our strategy may lead to improved chances of success across depression, neurology, and neuropsychiatric franchises.

In closing our R&D strategy is both proactive and predictive everything we learned from our program can be applied to other programs leveraging knowledge to define the path forward, while driving for seamless execution with the goal of addressing unmet needs for patients who need new approaches.

We believe our strategy may lead to improved chances of success across depression, neurology and neuropsychiatric franchises.

I am convinced our strategy is working and look forward to providing updates across our, three franchises this year.

I am convinced our strategy is working and look forward to providing updates across our three franchises. This year.

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

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

Kimi?

Thanks, Jim.

Thanks, Tim 2021 was a pivotal year for <unk>, we made important progress across all three of our brain health franchises and achieve key milestones towards our long term corporate goals.

2021 was a pivotal year for SAGE as we made important progress across all three of our, brain health franchises and achieved key milestones towards our long-term corporate goals.

I'm proud of the work we've achieved at SAGE, illustrated by the numerous data readouts, presentations at medical conferences and scientific forums, and the presentations well underway for the planned filing of our NDA for Xeranolam.

I am proud of the work we achieved at Sage illustrated by the numerous data read outs presentations at medical conferences and scientific forums in the presentation and the preparations well underway for the planned filing of our NDA for <unk> alone.

I'd like to reiterate what Barry noted in his opening remarks.

We're well-positioned to advance our mission to pioneer solutions to deliver life-changing, brain health medicine so every person can thrive.

We're well positioned to advance our mission to pioneer solutions to deliver life changing greenhouse medicine. So every person can thrive.

We're poised to achieve what we believe will be a significant progress in 2022 based on, the tremendous opportunity we have to invest in our robust portfolio. We have a unique opportunity to accelerate our clinical and corporate progress supported, by a strong balance sheet.

We're poised to achieve what we believe will be a significant progress in 2022 based on tremendous opportunity we have to invest in our robust portfolio.

We have a unique opportunity to accelerate our clinical and corporate progress supported by a strong balance sheet.

2022 will be a year of focused execution, a year where, if successful, we aspire to, create significant value for our society, especially patients, healthcare providers, and our shareholders.

122 will be a year of focused execution.

If successful we aspire to create significant value for our society, especially patients health care providers and our shareholders.

I'd like to start by highlighting our fourth quarter and end of year 2021 financials, and then provide some remarks on our financial guidance.

I'd like to start by highlighting our fourth quarter and end-of-year 2021 financials and, then provide some remarks on our financial guidance. We recorded $1.6 million in net revenue in the fourth quarter from the sales of Xeresso.

We recorded $1 6 million in net revenue in the fourth quarter sales as the rest of.

That compares to $1.7 million of net revenue from the sales of Xeresso for the same period, in 2020.

That compares to $1 7 million of net revenue from sales of the rest of it for the same period in 2020.

For the full year, net revenues for the sale of Xeresso in 2021 was $6.3 million, compared, to $6.7 million in 2020.

For the full year net revenues for the sale of the rest of 2021 with $6 3 million compared to $6 7 million in 2020.

We remain committed to moms, their families, and all those impacted by PPD.

We remain committed to modest their family and all of those impacted by PPD.

Research and development expenses were $75 4 million in the fourth quarter, including $9 1 million of noncash stock based compensation expense.

Research and development expenses were $75.4 million in the fourth quarter, including $9.1, million of non-cash stock-based compensation expense. That was compared to $81.7 million, including $10.1 million of non-cash stock-based compensation, expense for the same period of 2020.

That was compared to $81 7 million, including $10 1 million of noncash stock based compensation expense for the same period of 2020.

R&D expenses for the full year were $283.2 million, including $49.7 million of non-cash, stock-based compensation expense in 2021, compared to $292.7 million, including $42.4 million of non-cash stock-based compensation expense in 2020.

R&D expenses for the full year were $283 2 million, including $49 7 million of noncash stock based compensation expense in 2021 compared to $292 million 200.

Excuse me $292 7 million, including $42 4 million of noncash stock based compensation expense in 2020.

This reflects the impact of our collaboration with Biogen as we recognized a reduction in expenses of $79 8 million due to reinvest.

This reflects the impact of our collaboration with Biogen, as we recognized a reduction, in expenses of $79.8 million due to reimbursement under the collaboration, and the American Heart Association.

Members under the collaboration.

However, this reduction in R&D expenses was partially upset by an increase in spending on our wholly owned pipeline.

However, this reduction in R&D expenses was partially offset by an increase in spending on our wholly owned pipeline.

We expect to continue to invest in advancing our wholly owned pipeline in 2022.

We expect to continue to invest in advancing our wholly owned pipeline in 2022 in a smart and disciplined way.

Mark and disciplined way.

Selling general and administrative expenses were $51 6 million, including $11 5 million of noncash stock based compensation expense in the fourth quarter as.

Selling general and administrative expenses were $51.6 million, including $11.5 million, of non-cash stock-based compensation expense in the fourth quarter. That's compared to $53.5 million, including $10.6 million of non-cash stock-based compensation expense, for the same period of 2020.

That's compared to $53 5 million, including $10 6 million of noncash stock based compensation expense for the same period of 2020.

SG&A expenses for the full year, $183 5 million, including $54 9 million of noncash stock based compensation expense in 2021 compared to $197 million, including $51 8 million of noncash stock based compensation expense in 2020.

SG&A expenses for the full year were $183.5 million, including $54.9 million of non-cash stock-based compensation expense in 2021, compared to $197 million, including $51.8 million of non-cash stock-based compensation expense in 2020.

The decrease in SG&A.

The decrease in SG&A were primarily driven by the reimbursement from our collaboration, with Biogen.

We're primarily driven by the reimbursement from our collaboration with Biogen.

As we prepare for the potential launch of Zoranolone, we expect SG&A expense will increase in 2022. Recall, the collaboration includes 50-50 cost sharing in the United States for Zoranolone and SAGE 324.

As we prepare for the potential launches Sir Antelope, we expect SG&A expense will increase in 2022.

Recall the collaboration includes 50 50 cost sharing in the United States Teresa ran alone and Sage coming 'twenty four.

We reported a net loss of $124.7 million for the fourth, quarter, compared to net income of $974.9 million for the comparable period of 2020.

We reported a net loss of $124 7 million for the fourth quarter compared to net income of $974 9 million for the comparable period of 2020.

For the year ended December 31st, 2021, net loss was $457.9 million, compared to net income, of $606.1 million for the same period in 2020.

For the year ended December 31, 2021, net loss of $457 9 million compared to net income of $6 $6 1 million for the same period in 2020.

In both periods. The decrease is due to the collaboration revenue from Biogen in the fourth quarter of 2020.

In both periods, the decrease was due to the collaboration revenue from Biogen in the fourth quarter of 2020. As a reminder, in the fourth quarter of 2020, SAGE recorded a $1.1 billion of collaboration revenue from Biogen that consisted of an upfront payment of $875 million, plus $232.5 million in excess, proceeds from the equity investment under the Stock Purchase Agreement.

As a reminder, in the fourth quarter of 2020 stage recorded a $1 $1 billion of collaboration revenue from Biogen that consisted of an upfront payment of $875 million.

But $232 $5 million in excess proceeds from the equity investment under the stock purchase agreement.

Finally, we continue to maintain a solid financial foundation, ending the year with $1.7 billion, in cash, cash equivalents and marketable securities.

Finally, we continue to maintain a solid financial foundation, ending the year with $1 7 billion of cash cash equivalents and marketable securities.

Turning to financial guidance for 2022, we expect to end the year with approximately $1 3 billion of cash and cash equivalents we.

Turning to financial guidance for 2022, we expect to end the year with approximately $1.3 billion of cash and cash equivalents.

We do not anticipate any milestones from collaborations in 2022.

We do not anticipate any milestones from our collaborations in 2022.

Finally, we believe our cash and cash equivalents ongoing collaboration funding and potential revenue will support our operations into 2025.

Finally, we believe, our cash and cash equivalents, ongoing collaboration funding and potential revenue will support our operations into 2025.

At SAGE, we pride ourselves in being courageous, innovative and efficient across everything we do, always with a line of sight on how this work can benefit patients.

At stage, we pride ourselves in being courageous innovative and efficient across everything we do always look at the last set of how this work can benefit patients.

I look forward to providing updates on our progress.

I'll now turn it over to Helen to handle Q&A with Katherine Owen.

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

Helen?

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

Thanks, Kimmy.

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

The pound key.

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

Our first question comes from <unk> Richter with Goldman Sachs. Your line is open. Thanks for taking the question. This is Andrew on for solving I'm just curious on the feedback you've received from physicians post the coral results has their view on how they would use the drug or maybe even who they would treat changed in any way. Thanks. So much.

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

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

Yes, John Thanks for the question I'll start and I'll ask Jim to comment because we have received quite amount of feedback I can tell you that the feedback we've seen from potential prescribers post coral is quite encouraging.

Operator?

Thank you.

To ask a question, you'll need to press star one on your telephone.

To withdraw your question, you'd press the pound key.

Yes.

The rapidity of effect and the well tolerated profile and Duncan in some instances in the Gi effects improved profile ones around loans combined with an antidepressant really.

Our first question comes from Salveen Richter with Goldman Sachs.

Your line is open.

Opened eyes.

And it was very encouraging in the lines of Kols I will also tell you that the prospective analysis that we did with MVP with elevated anxiety was particularly interesting.

Thanks for taking the question.

This is Andrea on for Salveen.

As we talked on the call <unk> are also called anxious depression are patients that are not well served by current standard of care, that's well documented literature, including including Star D. So they were very interested in having a new drug to treat a patient population that they have said historically is very very hard to treat.

I'm just curious on the feedback, you've received from physicians post the coral results.

Has their view on how they would use the drug or maybe even who they would treat changed in any way?

Thanks so much.

Let me ask Jim to talk about additional feedback and then maybe Chris can talk about some of the patient types that we're hearing from potential prescribers Jim.

Yeah, Jim, thanks for the question.

I'll start and I'll ask Jim to comment because we have, received quite amount of feedback.

And as Barry mentioned, a lot of encouraging feedback really across a couple of different domains.

I can tell you that the feedback we've seen from potential prescribers post coral is quite encouraging.

Certainly when you think about the coral study were talking about co initiation with a standard of care antidepressant and we had chosen and are designed to include search rallying Escitalopram citalopram, Duloxetine and desolate does venlafaxine, so really a broad Sam.

Sampling of the standard of care antidepressants in an open label format and physicians were impressed both with the.

The rapidity of effect and the well-tolerated profile, in fact, in some instances in the GI effect improved profile when Zaranolone was combined with an antidepressant really opened eyes and was very encouraging in the minds of KOL.

The ability of around loan to demonstrate an improved performance over that broad range of antidepressants.

So quite a bit of interest in the tolerability profile of us around loans relative to two other standard of care anti depressants.

And finally, just to reiterate to Barry's point, we're very very encouraged by the results that we've seen in the cohort of subjects who.

I will also tell you that the prospective analysis that we did with MDD with elevated anxiety was, particularly interesting. As we talked on the call, MDD with elevated anxiety or also called anxious depression are patients that are not well-served by current standard of care.

That's well-documented in literature including STAR-D.

Show elevated anxiety at baseline who seem to be very sensitive to treatment was around loan.

They were very interested in having a new drug to treat a patient population that they have said historically is very, very hard to treat.

In contrast to as we keep hearing from Kols.

The challenge in treating those patients with standard of care and set a presence. So overall, we've been very pleased with the feedback <unk> been hearing so far from Kols, Chris do you want to talk a little bit about yes, I think with respect to patient types first let me let me take a step back when you consider what's happening in this marketplace, 70% of patients are either initiating or switching therapies.

Let me ask Jim to talk about additional feedback and then maybe Chris can talk about some of the, patient types that we're hearing from potential prescribers.

Jim?

Sure, Barry.

During the course of the year and as Barry pointed out many of those patients are switching multiple times in a given year. So what clinicians are really looking for is a therapy that works rapidly the sustained effect over time it doesn't carry the stigmatising side effects of some of the other therapies like sexual dysfunction in weight gain and quite frankly can be taken in a short course over.

A shortened time period that allows us to sustained effect over as we know from our studies our two year. So with that said when you have conversations with clinicians whether the kols are those that are out in practice everyday treating patients that are suffering with MTT and PPD theyre looking for those attributes of a therapy a therapy that works.

As Barry mentioned, a lot of encouraging feedback really across, a couple of different domains.

Certainly, when you think about the coral study, we're talking about co-initiation with a standard of care antidepressant.

We had chosen in our design to include Sertraline, F-Citalopram, Citalopram, Duloxetine, and Desdenlofaxine. Really, a broad sampling of the standard of care antidepressants in an open-label, format.

Physicians were impressed both with the ability of Zaranolone to demonstrate and improve performance over that broad range of antidepressants.

Also, quite a bit of interest in the tolerability profile of Zaranolone relative to other standard of care antidepressants.

Rapidly and sustains affected with coral what we've effectively done is we've we said with this therapy. There is an opportunity to demonstrate rapid efficacy as early as day, three and with studies like surely to pair that up that there is the sustained effect over time. So when you think about the practical patient that these physicians may see it may be.

Finally, just to reiterate to Barry's point, we're very, very encouraged by the results that, we've seen in the cohort of subjects who show elevated anxiety at baseline who seem to be very sensitive to treatment with Zaranolone, which in contrast to, as we keep hearing from KOLs, the challenge in treating those patients with standard of care antidepressants.

Overall, we've been very pleased with the feedback we've been hearing so far from KOLs.

Young adult like a college student or someone starting their first job, who really needs that rapid and lasting effective therapy without those stigmatising side effects and quite frankly that patient may also present with elevated anxiety is a feature of their MTBE theyre, telling us that patients like that young adult or an older adult that can't really stand to be.

On chronic therapy for the rest of their life and is really looking for a therapy that works rapidly and last that maybe another particularly good place to go. So there's a number of patient types that we've heard but again its paring quarrel with the other work that we have and really reinforcing the opportunity to make a difference in the lives of patients who need a therapy like saran alone.

Chris, do you want to talk a little bit about that?

Thanks, Chris Thanks, Jim.

Thank you. Our next question comes from Corey Cosmos.

Yeah.

With J P. Morgan your line is open.

Hey, good morning. Thanks for the question. This is typical on for Corey just 171.

I think with respect to patient types, first, let me take a step back.

The large randomized phase II trials in different indications that we are in a phase III in Huntington can you characterize what you would consider meaningful there's also each of those three populations.

When you consider what's happening in this marketplace, 70% of patients are either initiating or switching therapies over the course of a year. As, Barry pointed out, many of those patients are switching multiple times in a given year.

What clinicians are really looking for is a therapy that works rapidly, that sustains effect over time, doesn't carry the stigmatizing side effects of some of the other therapies like sexual dysfunction and weight gain, and quite frankly, can be taken in a short course over a shortened time period that allows them to sustain effect over, as we know from our studies, up to a year.

With that said, when you have conversations with clinicians, whether they're KOLs or those that are, out in practice every day treating patients that are suffering with MDD and PPD, they're looking for those attributes of a therapy, a therapy that works rapidly and sustains effect.

With CORAL, what we've effectively done is we've said, with this therapy, there's an opportunity to demonstrate rapid efficacy as early as day three, and with studies like SHROMlite to pair that up, that there's the sustained effect over time.

When you think about the practical patient that these physicians may see, it may be a young adult like a college student or someone starting their first job who really needs that rapid and lasting effect of therapy without those stigmatizing side effects.

We're also just interested in how long do these trials will take is it fair.

That data in 2023.

Yes, Tiffany I'll start and I'll ask Jim to comment further so 2022 'twenty three is certainly possible although.

When.

As we start trials, it's really important to get sites up and running you can understand what accrual rates look like before but proper guidance and we'll do that as soon as we can but let me take a step back. So sage 718 as you highlighted is a first in class positive modulator targeting NMDA.

We are studying sage 718 to demonstrate the improvement in cognitive impairment across a variety of neurological diseases and as we highlighted in the call and in past calls we have seen.

Data in Huntington's, Parkinson's and Alzheimer's consistent with ketamine placebo control study, where we saw significant significantly significant impact between placebo and drug and the data that we're seeing across all three <unk> General view is consistent with that.

You mentioned the word large trials so unlike.

Drugs that are trying to demonstrate.

Changes to disease progression and in fact are studying the slow decline of cognition over a long period of time, we create requiring long timeframes and begins we believe that the features of Sage 718 will allow us to conduct shorter term trials.

With a smaller end because we're actually measuring.

Sustained or even improvement in cognition. So we're really excited across all three of these neurodegenerative diseases, Jim you want to provide some more.

Just a little bit of detail around the dimension study for Sage 718.

I think the key of course is too.

Replicate the findings that we have seen from our earlier studies of Barry's, referring to we're actually seeing improvements in cognitive performance over.

Two week or so a period of time. So the dimension study as we will be the case for the PD and <unk> studies as well.

As intended as a three month study placebo controlled really looking to replicate that benefit that we've seen with sage seven one agent improving cognitive performance in both executive function working memory domains.

Thanks, Jim.

Thank you.

Our next question comes from <unk> Rahimi with Piper Sandler Your line is open.

Good morning team. Thank you for taking my questions.

I would love to hear your thoughts as we head into the Skylark data just to level set obviously the robin data.

And about 150 patients showed a four point difference in <unk> 17.

The effects were continued throughout day 42.

Remind us as we hadn't skylark like what what are changes that were introduced into the study compared to Robyn.

Should be our expectation given that this is a 50 milligram dose group and Robin ramp 30, Max So I think I would love to hear your thoughts as we headed into the data whether we should be expecting.

Yes, good Robyn data better than Robert data and maybe some rationale around that could be helpful. Thank you for the long winded question.

Thanks, guys.

I'll provide some context and then I'll ask Jim to really get into the details of Skylark changes as you highlighted we even the 50 milligram dose and the skylight trials. So it's a bigger it's a bigger study higher dose more more centers and I'll also highlight that PPD.

Quite frankly, that patient may also present with elevated anxiety as a feature of their MDD.

They're telling us that patients like that young adult or an older adult that can't really stand to be on chronic therapy for the rest of their life and is really looking for a therapy that works rapidly and lasts, that may be another particularly good place to go.

So there's a number of patient types that we've heard, but again, it's pairing CORAL with the, other work that we have and really reinforcing the opportunity to make a difference in the lives of patients who need a therapy like SHROMlite, and Rana La.

Often presents as depression with elevated anxiety. So we're really enthusiastic about helping moms in Skylake trial, Jim you want to talk about some of the other specific differences in what we expect.

Thanks, Chris.

Thanks, Jim.

Sure I think of course he has the key point is the design of Skylark, it's intended to be similar to the design to Robyn. So we havent made that many changes in the overall study design I think you've already highlighted the major one I would point out which is the dose is 50 milligrams, where the dose and Robyn was.

Thank you.

30 milligrams and what we've seen from other studies in the program, notably in the shoreline and waterfall for the 50 milligram dose as predicted seems to have an impact in overall response in the positive direction, where.

In the waterfall study we saw a significant.

Assuming a higher numbers of patients.

Showing beneficial.

Beneficial effect that the 50 milligram dose I think the other major element that's different in.

The.

Skylark study is the overall size of the study. So it is a larger study than the Robin study so with those.

Differences in mind, we're really expecting to see a similar kind of response in the Skylark study that we've seen in the Robin study and I would also note the profile similar to what we've seen in PPD studies with <unk>.

Our next question comes from Kori, Cosmos with J.P. Morgan.

<unk> alone.

Thanks, Tim So yes, we're really excited by.

Your line is open.

Hoping the envelope for skylark and moving forward PPD as well.

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

Hi.

Good morning.

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

Thanks for the question.

Follow up on Skylark I apologize if I missed this but I guess my question would be can you just remind us around the powering assumptions for Tyler kept both the 15 day 42 day endpoint I guess, what I'm trying to understand is how we should be thinking about the magnitude of effect that both of those time points.

This is Tiffany.

I'm for Kori.

Thank you very much.

Yeah, Laura Thanks, Jim do you want to take that.

Sure Laura as you know we don't.

Get into the specifics of powering assumptions for ongoing studies, but I think <unk>.

To the question we were just talking about we really have been guided by results from earlier studies, most notably the Robin study in our thinking for the design of the Skylark study. So we are confident that we've got to study sized appropriately to demonstrate a significant difference.

Words around alone.

The key time points.

Of course, the primary endpoint being in 2015.

Right and let me just thanks, Jim and let me just emphasize that we expect to see a statistically significant difference at 15, we don't necessarily expect to see that.

<unk> 42, the key here is that these moms get better fast and stay better it's quite possible.

And could you expected that at day 42, the placebo arm catches up.

Thanks, Laura.

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

Hi, good morning, Thanks for taking my question.

Just one on 718.

Just with regard to save money.

So with multiple large randomized phase, 2 trials and these different indications set for the year and a phase 3 in Huntington, can you characterize what you would consider meaningful results in each of these 3 populations?

Could you lay out for us.

The clinical development strategy beyond phase two trials that you are planning to initiate this year.

And we're also just interested in how long these trials will take.

What would be the next step then how do we think about kind of the timeline and what would be the endpoints that DSP with me.

Is it fair to expect, data in 2023?

For each indication and NCI across Huntington's Parkinson's and EDI.

Thanks.

Yes, Thank you and thanks for your note. This morning, all so I'll start and I'll ask Jim to elaborate further so as you highlighted we've started.

Yeah, Tiffany, I'll start and I'll ask Jim to comment further.

So, yeah, 2023 is certainly possible, although when, you know, as we start trials, it's really important to get sites up and running and understand what accrual rates look like before we can provide proper guidance.

And we'll do that as soon as we can.

The phase III.

Studies with Huntington's disease, and it's a program rather than just the single study and as we articulated we plan on starting the phase II Parkinson's study mid year.

But let me take a step back.

<unk> study towards more towards the end of the year.

So, SAGE 718, as you highlighted, is a first-in-class positive all-star modulator targeting NMDA.

We are starting with Huntington's because the biological hypothesis of states of an 18th starting with Huntington's, but it also is advantageous for us to start in a disease where.

We have fast track, but thats also an orphan disease, because we can.

Work with the agencies to make sure that we have the endpoints that matter and to be Frank if the phase III studies are wildly positive.

We'll certainly work with the.

The agencies to to understand next steps, including potential registration on top of those.

Phase two it's likely that with Parkinson's and Alzheimer's will require bigger.

Our phase III studies.

Can you all talk about endpoints and how we're thinking about cognex in specific disease end points.

We are studying SAGE 718 to demonstrate the improvement in cognitive impairment across a variety of neurological diseases.

Absolutely, yes, and I mean, as we think about the development program for Sage 718.

We talk a lot about following the science as Barry mentioned in each of the different indications. We do have good evidence for both NMDA receptor involvement in those in those patients but through our earlier work also showing some reasons to believe that say 708 is improving cognitive performance for all of these patients.

And as we highlighted in the call and in past calls, we have seen data in Huntington's, Parkinson's, and Alzheimer's consistent with the ketamine placebo control study, where we saw significantly significant impact between placebo and drug.

And then it really is also about efficient designs. So Barry mentioned in the case for Huntington's disease.

And the data that we're seeing across all three neurodegenerative diseases is consistent with that.

This is it makes sense from the science point of view, but also offers a dip.

<unk> pathway forward with an orphan population I think we'll have to see.

You mentioned the word large trials.

The PD and <unk> patient populations, what the past beyond the next set of studies looks like but we tend to think in terms of what we would call a serious de risking so we're adding to the evidence that we have with this very novel mechanism of action.

So, you know, unlike drugs that are trying to demonstrate, changes to disease progression and, in fact, are studying the slow decline of cognition over a long period of time, requiring long timeframes and big ends, we believe that the features of SAGE 718 will allow us to conduct shorter-term trials with a smaller end because we're actually measuring sustained or even improvement in cognition.

As we think about endpoints the primary endpoints in this set of studies are designed to directly follow up on the work that we've done in our Cognex program.

So, we're really excited across all three of these neurodegenerative diseases.

Jim, you want to provide some more?

But we're also very well aware that the FDA and other regulatory agencies are interested in understanding the real world benefits of improving cognitive performance.

Sure, Barry.

In our studies. We are also looking at ways of bridging two measures of function that would be meaningful for for patients with these various disorders. So it's there are several things going on as you enter this phase that really were the main effort is to show a significant benefit in <unk>.

Just a little bit of detail around the dimension study for SAGE 718.

I think, that the key, of course, is to replicate the findings that we've seen from our earlier studies that Barry's referring to.

Cognitive performance relative to placebo, but we also will be looking at understanding how that translates into benefits that are meaningful to patients and we think that'll be an important part of the program moving forward.

Got it and then just a quick follow up in Huntington would a three month endpoint to be adequate for approval do you have visibility at this stage about that.

Yeah, Amit not not not quite yet I mean, we are engaged with the agency to talk about durability.

Again, we're doing something that's never been done before demonstrating.

We're actually seeing improvements in cognitive performance over a two-week or so period of time.

Potential improvement in cognition, which we think we can demonstrate over.

Sure proved time, we've seen a couple of weeks now want a demonstrated across three months and as I mentioned, if the studies are very positive.

So, the dimension study, as will be the case for the PD and AD studies as well, is a three-month study, placebo-controlled, really looking to replicate that benefit that we've seen with SAGE 718 in improving cognitive performance in both executive function and working memory domains.

We will be aggressive in working with the agencies to figure out how we can get this drug the more huntington's patients to start.

Thanks, Jim.

Thank you.

Got it thank you.

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

Our next question comes from Yasmeen Rahimi with Piper Stanley.

Your line is open.

Hey, Thanks, so much for taking my question I wanted to use this opportunity to maybe ask about sort of a to bear cases that are floating around on stage with the stock where it is and maybe one on the regulatory side and one on the commercial side on the regulatory side I think the question I get a lot I'm sure other analysts do two centers around the as needed.

Dosing approach shoreline.

And whether or not what the totality of the data physicians and regulators are going to have enough information on how to dose the drug and how to kind of think about in shoreline. There was this six week interval between doses and how will that all sort of play out in the real world.

In depression practices and then on the commercial side I think the other area of skepticism right as an overarching view that changing the treatment paradigm is hard.

Generating use for a new branded drug that's more expensive and primary care practices is hard and that maybe the lower hanging fruit you could argue.

It would be in treatment refractory patients. So our pricing is higher and really prioritizing PPD and MDT subpopulations and so I'm sure you guys have heard this a lot I certainly hear it a lot.

And I would love your perspective on both of those issues. Thanks, so much.

Good morning, team.

Yes, Paul Thanks for the thanks for the question. So let me let me start.

With both regulatory and commercial and then I'll ask Jim to comment further on regulatory and Chris to comment further on on commercials. So I'll remind you that at the beginning of last year, we articulated that we designed to landscape in this programs in conjunction with the FDA to studies and NBD one in PPD.

Thank you for taking my questions.

I would love to hear your thoughts, as we head into the Skylark data, just to level set.

Obviously, the Robin data in about 150 patients showed a four-point difference in HMD 17.

The effects were continued throughout, day 42.

One of which is positive constituted a fireball package in the fall of last year. Following a positive waterfall, we reiterated the consistency of discussion we've had with the agency that waterfall.

So the filing package. However, there were two outstanding studies wondering mbd.

So, remind us, as we head into Skylark, what are changes that were introduced into the study compared to Robin?

What should be our expectation, given that this is a 50-milligram dose group and Robin ran 30 mgs?

Coral and one in PPD Skylark.

And they suggested and we agreed that we first file an MD, including the Coral study and then with PPD, including with Skylake study. So we're thrilled and we've discussed it the coral was positive now the other theme running through the year is that we observed.

So, I think I would love to hear your thoughts as we head into the data, whether we should be expecting equally as good Robin data, better than Robin data, and maybe some rationale around it could be helpful.

Thank you for the long-winded question.

Thanks, Yasmeen.

In the literature that.

I will provide some context, and then I will ask Jim to really get into, the details of Skylark and the changes.

Patients with MVP with elevated anxiety or anxious depression as well documented literature were not well served with current anti depressant.

As you highlighted, we are using the 50-milligram dose in the Skylark trial, so it is a bigger study, higher dose, more centers.

We did a retrospective analysis across our data and discovered that ran alone was particularly useful in mbd, but particularly with MPD with elevated anxiety and then we prospectively designed that that population that sub population into the study and Thats about two thirds of those annual diagnosed with MTBE not well.

So you can see that we have a very rich package for MTBE.

Predefined sub population mbd.

With anxious.

Elevated anxiety of the current state of accrued doesn't work well.

We're quite enthusiastic about the regulatory path forward, obviously following skylark smiling.

I will also highlight that PPD often presents as depression with elevated anxiety.

Smile, and indeed, an NDA for our PBT. So we're really excited about both <unk> and PPD and have a subpopulation in particular to guide potential treating physicians.

Where the drug just don't work well today. So it's not it's not like I've got a whole bunch of opportunities my Arsenal to help these patients with Mds with elevated.

And now turning to commercial and Christian highlighted there's five particular patient types that are not well served with current antidepressants where surround alone.

So, we are really enthusiastic about helping moms in the Skylark trial.

Particularly those with empty deal of anxiety can we're particularly well and also we are leaning in with proactive value based agreements. So what we're trying to do is work with payers.

To share risks, so the budget certainty and understand the right patients to treat.

It was around on so that we don't get step we don't get blocked there isn't a whole lot of paperwork to make sure that a patient in need is around on that so again, we've got work to do on the commercial side, but we particularly have ways that we are guiding potential prescribers on very specific patient types. So all in there Jim do you want to talk more about regulatory and then Chris maybe.

Jim, do you want to talk about some of the other specific differences and what we expect?

Sure, Barry.

Pick up on the commercial piece.

I think, of course, yes, the key point is the design of Skylark is intended, to be similar to the design to Robin.

So we haven't made that many changes in the overall study design. I think you've already highlighted the major one I would point out, which is the dose is 50 milligrams, where the dose in Robin was 30 milligrams.

Yeah, Paul I think what I would want to emphasize is when you step back and look at the program we're talking about.

And what we've seen from other studies in the program, notably in the shoreline and waterfall studies, 50 milligram dose, as predicted, seems to have an impact in overall response in the positive direction where in the waterfall study, we saw significant, significantly higher numbers of patients showing a beneficial effect at the 50 milligram dose.

Six positive trials at this 0.8.

I think the other major element that's different in the Skylark study is the overall size of the study. So it is a larger study than the Robin study.

Overall looking at.

Patients with depression, so 3500 patients.

Again, as you think about assembling the whole packages around alone.

We have data both.

As monotherapy as add on with co initiation with or without anti depressants standard Karen suppressants multiple antidepressants.

Multiple patient populations as Barry was saying.

Demographics across a very wide range and truly a differentiated tolerability profile as you think about all of those elements of course that was the original intent.

In the broad landscape of nest program is to provide a series of data points to help.

Both.

Providers patients Payors and understanding of this differentiated novel approach was around one so we're very excited and we're very comfortable moving forward as we assemble this package that we have the right information to help.

People understand how to best use around those moving forward.

Yes, thanks, Kevin to add context, Paul to what Barry already said isn't around the commercialization thinking that we're currently employing.

Speaking to practicing clinicians every day, we're talking to payers, whether they are national payers regional payers Pbms are idms and certainly we are engaging with patients and patient advocacy groups to really understand what it is that they're looking for in a new therapy and I think in various remarks. He hit it really well this is not a well satisfied market as I mentioned earlier.

A substantial amount of switching going on because patients are looking for better options clinicians are looking for better options for their patients and payers certainly recognized that with respect to what they see at a plan level. There is not a satisfied patient population there with respect to either the efficacy or the safety with the.

The access that they have to currently available adt's and it's an even more dire situation in the PPD World, where there are even fewer treatment options for those moms that are really looking for cure so with that being said, we recognized and as I mentioned earlier in the conversation that there are five patient types I spoken about the treatment naive young adult.

The older adult there there are many patients that are on <unk> that are still suffering there are patients that are experiencing breakthrough symptoms associated with their depression, because there is a death of a loved one or perhaps a job change or through adherence challenge patients, who quite frankly never get to really experience the benefit of their ADT because they don't have the time to.

Wait six or seven weeks in order to see that benefit of the side effects to tourism from ultimately, reaching the efficacy that they so desperately want and deserve so with that being said as you think about it MTGE with elevated anxiety is a is a thread that connects many of those patient types, whether theyre MDT patients or PPD patients and we have an opportunity to do better.

So with those differences in mind, we're really expecting to see a similar kind of response in the Skylark study that we've seen in the Robin study.

And I would also note the profile is similar to what we've seen in PPD studies with Brexanilin.

Thank you, Tim.

As the Rand alone for all of these patients and provide them with a rapid and lasting therapy that they deserve.

Thanks can I ask one quick follow up.

This is all really helpful onshore lines. Specifically this is I think where Jim I just wanted to get your feedback on regulatory.

Historically antidepressants rate had been approved with acute evidence of efficacy as you've alluded to in an open label extension data and this whole idea of maintenance of benefit is usually a post marketing issue, but given the way. This drug is dose right I think the maintenance question comes into play probably earlier.

Agree with that and I guess.

If you're talking to a doctor and they say hey, if I give this drug for a few weeks and the patient does better and then and then they feel worse three weeks later, how does kind of re dosing work because I think in the shoreline study you're restricted to not re dose for at least six weeks.

I'm just wondering if this is a regulatory question or not or if you think I'm harping on something that's ultimately a relevant thanks.

So, yes, we're really excited by, you know, opening the envelope for Skylark and moving forward PPD as well.

Thank you.

Jim you want to start and I can round it out.

And thanks, Paul for the question.

Our next question comes from Laura Chico with Web Bush Securities.

Yes, Paul So I would distinguish of course, the clinical trial, we have very specific parameters in the protocol, but really the study was designed to address exactly the question that you're asking which is.

Your line, is open.

What are the conditions on which subjects would need to re treatment and so we do have some very specific metrics in there that can be used but I think really the important point is that what youre seeing in this study is that for the vast majority of patients.

That actually is a relatively long interval right. So you've got at 50 milligrams. The majority of patients over 50%. It's that one two week course for a year and your updated about 80%. When you look at one or two courses. So I think yes. Yes. This is something that will need to be addressed in practice, but I don't think that its going to be that.

<unk> a process for physicians to move to <unk>.

The study in shoreline is designed to provide that real world evidence of exactly how to do that.

Yes, and just to just to round it out and thanks, Jim just to round it out from a commercial perspective Paul.

I imagine that most of the patient population will be that two to four weeks of drug there'll be very few that need the third fourth or fifth dose.

If someone takes two weeks and rebounds immediately that's not hauser at alone was designed for the 75% of patients that responded insurer on its for that group there will be some where different chronic medication may be more appropriate and surrounds not the right answer but for those patients, particularly MDT with elevated diet with these rental the right drug to reach.

Sure.

Alright, Thank you very much.

Thanks, Paul.

Thank you and as a reminder, please limit yourself to one question. Our next question comes from <unk> Ahmad with Bank of America. Your line is open.

Hey, good morning, guys.

Hi, guys. Good morning, I'm here is my one question so.

Thanks for taking the question.

Just to follow up on Skylark, I apologize if I missed this, but I guess my question would be, can you just remind us around the powering assumptions for Skylark at both the 15-day and 42-day endpoint?

I guess what I'm trying to understand is how we should be thinking about the magnitude of effect at both of those time points.

Thank you.

If you do end up.

And that discussion with the agency and the agency feels like maybe at least initially.

It might be best for induction therapy, and maybe you need to submit additional data over time.

Is that a scenario that you've planned for <unk> and <unk>.

How should we think about what the initial commercial opportunity would be.

Thank you very much.

That's the case.

Thanks, Zane Thanks for your one question.

Yeah, Laura, thanks.

Jim, you want to take that?

So look we and Jim's highlighted this win with now coral we have data in over 3500.

Sure.

So we have data.

With <unk> as a monotherapy about two thirds of the patients before coral where monotherapy, but a third.

We're on top of a stable antidepressant in the coral as you highlighted was the first time, we have data was around one was co initiated with the five different standard of care anti depressant to Jim's pilot. So we think we have a very rich package.

Laura, as you know, we don't get into the specifics of powering assumptions for ongoing studies, but I think similar to the question we were just talking about, we really have been guided by results from earlier studies, most notably the Robin study, and our thinking for the design of the Skylark study.

So we are confident that we've got the study sized appropriately to demonstrate a significant difference for the Zoran loan at the key time points, of course, the primary endpoint being at day 15.

Right.

Thanks, Jim.

New induction or not so.

<unk> is meant to treat for two weeks.

Get someone better fast as measured at day, three and keep them better as we've already highlighted shoreline indicates the majority of patients in the shoreline, which is more a real world situations only required two week treatment. So.

Induction or not I think a majority of patients out in the commercial world will trial will require two weeks and of course severe and maybe even longer.

<unk> studied followed them for year I'll also remind you that we're rolling patients from coral onto shoreline. So it will be quite interesting as those data rollout to understand what happens with <unk>.

Randall on Kona issue with antidepressant versus anti depressant alone and how many re treatments.

Needs.

Yeah.

Chris anything to add.

Let me just emphasize that we expect to see a statistical significant difference at 15.

Yes.

Something that I would add and I think Barry you covered it really thoroughly but taking a step back clinicians want to send patients home with a solution when they prescribe a product and they want that solution to work rapidly into last overtime and quite frankly with respect to the data that we've already demonstrated we have seen that this therapy works rapidly as early as day two.

We don't necessarily expect to see that at day 42.

<unk> it sustains effect out to a year and it has a safety profile that is.

Is unmatched with respect to some of the other therapies that are out there with respect to sexual dysfunction weight gain or that.

The fact that we haven't seen it with saran alone and the ability to take us over the short course is incredibly desirable for patients who don't want to be on chronic therapy in perpetuity for.

The rest of their lives. So we believe that with what we are delivering we are delivering a therapy, putting it in the hands of clinicians to ultimately enable patients to go home with the solution that is really at stake <unk> don't know that it works.

The key here is that these moms get better fast and stay better.

Okay. Thank you.

Thanks Zane.

It's quite possible and can be expected that at day 42, the placebo arm catches up.

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

Thanks, Laura.

Thank you.

Guys. Thank you for taking my question. So question is on the.

Our next question comes from Anif Adia with Needham and Company.

Your line is open.

Future application or additional application all of us at Amazon. So specifically in anxiety I think across the landscape studies you have seen benefit in patients that have elevated anxiety. What is your view on evaluating maybe think studying sort of analog and acute things.

Hi, good morning.

And can you also talk about other indication I understand MTBE PPD.

Big opportunities, but other indications or other applications all of this pathway.

Yes. Thanks for the question I'll start and I'll ask Jim to kind of round. It out so as we've talked about before and you. Just said we've got almost 7 million people per year in the United States alone that are diagnosed with MVD and prescribed an antidepressant and one in eight women experience in life.

Thanks for taking my question.

Just with regards to state 718, could you lay out for us the clinical development strategy beyond some of these two trials that you are planning to initiate this year?

What would be the next step and, you know, how do we think about kind of the timeline, and what would be the endpoints that the FDA would need for an indication and MCI across, Huntington's, Parkinson's, and AD?

Thanks.

Yeah, Ami, thank you, and thanks for your notes this morning also.

Worth experience PPD.

So those opportunities are very large our strategy along with our collaborators has really to do what we need to do to win in MTBE and PPE, including a robust phase III B four program. Following what we hope to be an approval zarin alone. So that's the strategy now there are other areas that we've talked about.

Developing general anxiety disorder seasonal anxiety disorder, which will be things, we'll be talking about in the future, but the real focus is to make sure that we have all the data we need to continue to provide the marketplace for appreciation of how to best use around alone in MTBE in PPD.

I'll start and I'll ask Jim to elaborate further.

Jim you want to add.

I would only add that.

So, you know, as you've highlighted, I mean, we've started the Phase 2 studies with Huntington's, disease and it's a program rather than just a single study, and as we articulated, we plan on starting the Phase 2 Parkinson's study mid-year and the Alzheimer's study more toward the end of the year.

We are certainly we have additional endpoints in our studies that we used to sort of fully understand the overall profiles around loan but to Barry's point. There is a significant focus on the indications that we're currently talking about.

We are starting with Huntington's because the biologic hypothesis of stage 7-18 started, with Huntington's, but it also is advantageous for us to start in a disease where we have a fast track, but that's also an orphan disease because we can work with the agencies to make sure that we have the endpoints that matter, and to be frank, if the Phase 2 studies are wildly positive, we will certainly work with the agencies to understand next steps, including potential registration on top of those Phase 2s.

It's likely that with Parkinson's and Alzheimer's, we'll require bigger or Phase 3 studies.

Can we also talk about endpoints and how we're thinking about cognacs and specific disease, endpoints?

We are continuing to collect data on anxiety benefits, we've talked earlier about the benefits of surround loan on sleep. So of course there are additional.

Texas or online that we think could be a benefit but those are for.

Later evaluation.

Absolutely.

Got it thank you Chris squeeze one more and it's on the P&L for kidney.

So with most of the studies a phase III study is now behind US can you just help us model.

Going forward should we expect it to go down I understand you gave.

The cash guidance also about G&A or SG&A as you start thinking about commercialization is it like a second half ramp up is helpful. Thank you.

Yes, let me let me start so as you very well know we're partnered on.

Saar and alone in phase III before with Biogen and get significant reimbursement for efforts and of course buy.

<unk> is doing the heavy lift ex U S for both.

Programs, which we get we get royalties so were very enthusiastic about the partnership as we've highlighted stage 70 team, particularly starting with an orphan diseases like Huntington's is a product that we can globalize on and that's our strategy we will.

Assuming positive data strong data approval package, we intend on bringing <unk> to as many <unk>.

Countries as it makes sense for us to do given the success of <unk> alone three to four on our balance sheet. So we do plan on an on.

Recognizing revenues from multiple countries around the world and the future for Sage 718.

Kim you want to take the rest.

Sure so.

Yeah, and, I mean, as we think about the development program for stage 7-18, we talk a lot about, following the science.

As Barry mentioned, in each of the different indications, we do have good evidence for, both NMDA receptor involvement in those patients, but through our earlier work, also showing some reasons believe that stage 7-18 is improving cognitive performance for all these patients.

Question on expenses and what to think about there during the year that we did talk about the fact that we believe the operating expenses, we are going to increase and that really related to the execution of our expanded and accelerated strategy.

And then it really is also about efficient design.

So Barry mentioned in the case for Huntington's disease, this is, it makes sense from the, science point of view, but also offers a different pathway forward with an orphan population.

I think we'll have to see in the PD and AD patient populations what the path beyond the, next set of studies looks like, but we tend to think in terms of what we would call serially de-risking.

So we're adding to the evidence that we have with this very novel mechanism of action.

To that point, as we think about endpoints, the primary endpoints in this set of studies, are designed to directly follow up on the work that we've done in our Cognex program.

But we're also very well aware that the FDA and other regulatory agencies are interested, in understanding the real world benefits of improving cognitive performance.

So in our studies, we're also looking at ways of bridging to measures of function that would, be meaningful for patients with these various disorders.

Which Barry just highlighted with Sage 718, when you look into 2022, we're going to have three.

Clinical trials across three indications and Sage 718, so that will be a big program.

We're also and we committed to making additional investments in our early clinical and research engine.

Again, there is where we want to really leverage what we have.

Expertise in brain circuitry, and making sure that we have our next clinical candidate.

So it's, there's several things going on as you enter this phase.

Really we're, the main effort is to show a significant benefit in cognitive performance, relative to placebo, but we also will be looking at understanding how that translates into benefits that are meaningful to patients.

The extent and accelerate strategy will continue to execute in 2022, so that again.

Lead to increases in R&D expenses over the year.

On the SG&A front, we will see additional increases in SG&A again.

As we continue to ramp the prelaunch activities together with Biogen.

Thank you so much.

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

And we think that'll be an important part of the program moving forward.

Got it.

Thanks, Good morning, and thanks for taking the questions I was just curious in terms of.

The coral data in terms of the phase III benefit that we saw was there sort of a disproportionate benefit in any of the domains of MPD and I'm just curious.

How big a contributor to the improvement with some of the sleep components and also I guess, perhaps bartlett.

The area is sort of where you really see improvement change from day three to teen cases.

And then just a quick follow-up, so in Huntington, would a three-month endpoint be adequate for, approval?

Yes. Thanks for the question. So I'll start and then Jim maybe you can carry it down we presented top line data will certainly present breakdowns of components of <unk> 17 in future Congresses, but as we've seen in.

Do you have visibility at this stage about that?

So improvement across most of the domain and him.

<unk> 17, it wasn't just one particular feature or not but.

Yeah, I mean, not, not, not quite yet.

I mean, we are engaged with the agency to talk, about durability.

Jim you want to talk about your thoughts there.

You know, again, we're doing something that's never been done before, demonstrating the potential improvement in cognition, which we think we could demonstrate over a short period of time.

We've seen in a couple of weeks, we now want to demonstrate it across three months.

I think thats the key point barrier, we have seen consistently is improvements across.

All of the domains of the <unk> 17 with surround alone and that will be the same thing for coral.

And as I mentioned, if the studies are very positive, you know, we'll be aggressive in working with the agency to figure out how we can get this drug to more Huntington's patients to start.

We'll of course be digging in more detail into individual pieces of data and communicating that as we go forward. So we will be looking at the distribution of Ham D scores over time, but I think the key point is that what we see is a pretty consistent picture of effects is around loan across the domains of the AMD.

Got it.

Thank you.

Okay, great. Thank you.

Our next question calls from Paul Matisse with Stiefel.

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

Your, line is open.

Hey, thanks so much for taking my question.

I wanted to use this opportunity to maybe, ask about sort of the two bear cases that are floating around in Sage with the stock where it is, and maybe one on the regulatory side and one on the commercial side.

Oh, Hey, guys. This is Matt on for Jay Thank you for taking our questions.

On the regulatory side, I think the question I get a lot, I'm sure other analysts do too, centers around the as-needed dosing approach, Shoreline, and whether or not with the totality of the data, physicians and regulators are going to have enough information on how to dose the drug and how to kind of think about in Shoreline, there was this six week interval between doses and how will that all sort of play out in the real world in depression practices.

Sorry, I was going to ask you specifically a question.

Just curious since you joined as CEO I believe since December 2020 already I was just curious how you viewed the evolution of Sage.

You took over and also your vision for the company has changed at all since that time and also just how you view personally in the next three to five years I really appreciate it.

And then on the commercial side, I think the other area of skepticism is an overarching, view that changing the treatment paradigm is hard, generating use for a new branded drug that's more expensive in primary care practices is hard, and that maybe the lower hanging fruit, you could argue, would be in treatment refractory patients or pricing higher and really prioritizing PPD and MDD subpopulations. And so I'm sure you guys have heard this a lot.

Hey, Matt Thanks.

I certainly hear it a lot.

Look it's been it's been phenomenal in terms of in terms of what everyone. At Sage has accomplished and how we work with our collaborators both in Japan and Biogen.

And the progress when I started as you mentioned in 2020.

And I would love your perspective on both of those issues.

Three late stage programs as ran on say three to four tenths of one eight.

And a number of studies in front of US we stand here today.

Thanks so much.

The robust pipeline those three late stage programs continue to move forward in fact.

Yeah, Paul, thanks for the question.

So, let me start with both regulatory and commercial, and then I'll ask Jim to comment further on regulatory and Chris to comment further on commercial.

So, I'll remind you that at the beginning of last year, we articulated that we designed a landscape and nest program in conjunction with the FDA, two studies in MDD, one in PPD, any one of which is positive, constituted a fileable package. In the fall of last year, following a positive waterfall, we reiterated the consistency of discussion we've had with the agency that waterfall constituted a filing package.

Turning to file the NDA for us around alone early this year. So everything we planned on doing is actually being.

However, there were two outstanding studies, one in MDD coral and one in PPD Skylark.

And they suggested and we agreed that we first file an MDD, including the coral study, and then with PPD, including the Skylark study.

So, we're thrilled and we've discussed that the coral was positive.

Now, the other theme running through the year is that we observed in the literature that, patients with MDD with elevated anxiety or anxious depression, as well documented in literature, were not well served with current antidepressants. We did a retrospective analysis across our data and discovered that ziranylum was particularly useful in MDD, but particularly with MDD with elevated anxiety.

And then we prospectively designed that, that population, that subpopulation into the coral study.

And that's about two-thirds of those annually diagnosed with MDD, not well served with antidepressants.

Certainly being executed obviously the weakness of biotech across the board starting in February last year, certainly is helpful for any of us, but as you heard from me and from Kimi.

So, you can see that we have a very rich package for MDD with a predefined subpopulation, MDD with anxious, with anxious, elevated anxiety that current standard of care doesn't work well.

So, we're quite enthusiastic about the regulatory path forward.

We have a very strong balance sheet to execute on our expand and accelerate so.

The view that I had coming in that we can.

Could be the leaders in brain health and a top tier biopharmaceutical company remain well on track to make that happen.

Awesome. Thank you really appreciate it.

Thanks, Matt.

Obviously, following Skylark, we'll file an NDA for PPD.

Okay.

Our next question comes from our cash to worry with Jefferies. Your line is open.

Hi, Thank you for taking our questions. This is the name for a cash could you just help us understand the real commercial opportunity in PPD and <unk> yesterday, the rest of our launch has been quite disappointing, but what have you learned from engaging that market, how many patients identify the low hanging fruit and how many.

So, we're really excited about both MDD and PPD and have a subpopulation in particular to guide potential treating physicians where the drugs just don't work well today.

Those issues.

Notwithstanding these patients at <unk>.

Typically a positive I don't know what allowed you to expand the market beyond the success of the vessel.

Thank you.

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

So, it's not like I've got a whole bunch of opportunities in my arsenal to help these patients with MDD, with elevated anxiety.

And now turning to commercial, and Chris can highlight it, there's five particular patient types that are not well served with current antidepressants where ziranylone, particularly those with MDD with elevated anxiety, can work particularly well.

Yes, thanks, Barry So so as you may be aware there are one in eight women, who with a recent live birth experience have experienced postpartum depression.

And also, we're leaning in with proactive value-based agreements.

And that's not acceptable with respect to really those moms having to suffer.

Suffered through the symptoms of depression as we've noted earlier the anxiety, that's often associated with that so with respect to the postpartum community. We know that there is an opportunity for us to do better with respect to our ability to provide them with a solution like sort of RSO or subsequently.

That's rent alone if approved so with that being said, we've learned a tremendous amount from our experience with the rest so around how to engage with clinicians how to engage with patients and patient advocacy organizations and also how to engage with payers to assure the availability of the access to medications like <unk>. So that as we move forward that we have.

So, what we're trying, to do is work with payers to share risks so they have budget certainty and understand the right patients to treat with ziranylone so that we don't get stuffed, we don't get blocked, there isn't a whole lot of paperwork to make sure that a patient in need of ziranylone gets it.

Really strong knowledge base to build on that we can introduce around alone into that into that market into that community. Now one of the questions. You asked is the points of differentiation and how that may impact commercialization, certainly zelle wrestle with respect to how it's administered in office is very different from Saran alone as an oral formulation that enables much.

To take the therapy in the comfort of their own home over a two week short course of therapy in order to see the benefits that we've seen in.

In our clinical studies to date, so with respect to how we see this evolving its going to profoundly change the way postpartum depression is treated now that moms will have the opportunity to take something that has the safety and efficacy profile of <unk> alone and as I said there is a substantial number of these women really need a therapy because right now in the marketplace. There is not something other.

And so Arezzo, that's meeting their needs vary.

Yes, Chris Thank you and let me just round that out so.

So, again, you know, we've got work to do on the commercial side, but we particularly have ways that we're guiding potential prescribers on very specific patients.

Because we're in the market right now.

We are understanding really important pieces of how to treat the people.

It's a very important moms are taken care by <unk> until the babies born and I'll focus turns to the baby and off the mall, so understanding pre screening questionnaires that need to be put in place that are available are.

Check on Mom's program, making sure that every mom has a plan for the fourth trimester.

A number of capabilities, we're putting in place now will help us really.

Many of the Kols vision is to understand moms at risk.

Send them home with a prescription.

For us around should they need it so they aren't in danger or endangering the baby's Booker families. So we're certainly learning a lot and it will be well prepared to help.

You said the 108.

Wide berth that potentially suffer from PPD.

Thank you.

Thank you. Our next question comes from this two month Kulkarni with Canaccord. Your line is open.

Brian Thanks for taking my question.

What are some of the specific factors that might prevent immediate xenon alone pre treatment is it patient response characteristics such as the average duration of maybe an mbd episodes are more related to the pharmacology of the drug itself. I guess this goes back to work with the main variables that maybe you're focused on 14 days of therapy, what's sustainable acute <unk> or 'twenty at things to potentially and share more durability.

Yes, Mark Thanks for the question, Jim you want to start and then I'll again.

Provide some color at the end.

Now of course, but I really.

It really I don't I Wouldnt say that there are pharmacological aspect I mean, what we're seeing is a rapid response to surround alone and what you see by by the end of that two week course.

As a.

A pretty robust response in a response that as as achieved its close to a maximum response. So it's much more about the benefit being seen with that two week course of treatment than anything to do with the pharmacology.

Yes, thanks, Thanks, Jim and Tomorrow again remind you that the.

The observation that it made by Sage and collaborator is is that that neural networks.

Dysfunctional very specific ways when people are living with depression, and <unk> was designed to reregulate those neural networks spectrum normative state and the two week course of treatment was the course hypothesized to make that happen as Jim said, we are seeing that having very well and the majority of patients as evidenced by shoreline now in terms of.

Of specific re treatment.

Keep in mind that pace.

Patient will come in with a dark mood.

Often elevated anxiety inability to sleep well known in two to three days that <unk> is working for them or not and again the majority of patients it does and the instructions.

Office will give us.

This should work in a couple of days, we'll check in with you in two to three days.

And after you're done you're therapy in the weeks following if your mood darkens your anxiety increases your sleep further disruption.

Either refill or called the office for a re treatment really will be pretty straightforward in the real world.

Thank you.

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

Great. Good morning, Thanks for taking my question. So I had two on phase III two four so for the phase II study expected to begin in mid 2022, what can you say at this point about study design.

Particularly about which additional parameters beyond safety that you might anticipate evaluating here.

And secondly, what level of regulatory interaction have you had.

On three to four and what do you think the path is to a pivotal program here.

Yes, let me let me start and then Jim So we designed for the kinetics to study is in our materials in our slides so quickly.

It's a multimodal study.

With the objective of having a dosing frequency to move say three to four into a phase III study.

We are studying <unk> amplification reductions come applications as well as activities of daily living.

15, 30, and 60 milligram dose and for those.

On the 60 milligram dose.

With high trading over very specific six week period to do that and when we're looking at the kind of parameters. We looked at for the kinetics study I'll remind you that in the kinetics study we saw a statistically significant reduction in tremor amplitude. We also saw a correlation between activities of daily living and reduction turnaround, but too which is very healthy.

<unk> for our path forward, because it's likely that the phase III study will be that feel function wellbeing activities of daily living type type study. So thats, how we think the path.

The path forward will look Jim anything to add.

I think what I would add Barry is conceptually and Barry said it the endpoint in this study is similar to the endpoint from the kinetics study and Thats important for continuity, but it's also important that we.

As we think the pivotal studies, we also feel that bridge to endpoints that are consistent with the benefits of patients are going to receive so activities of daily living will be element of the study. So we have both the bridge to the primary endpoint compares to back the kinetic but also looking forward, we'll be looking at showing what are the burner.

<unk> to patients in their daily lives that this reduction in tremor is providing.

Okay got it thank you.

Thank you and Thats all the time, we have for questions I would like to turn the call back to Barry Greene for closing remarks.

Thanks, everyone. Thank you operator really appreciate you joining us today for the.

& Types.

Progress we made for all of 2021, specifically, our fourth quarter I am grateful for the entire sales team our patients caregivers clinical investigators and all dedicated so much events, our mission to become a leader in brain health.

So I'll end there.

Jim, you want to talk more about regulatory and then Chris maybe, pick up on the commercial piece?

Yeah, and Paul, I think what I would want to emphasize is when you step back and look at the program, we're talking about six positive trials at this point and eight trials overall looking at patients with depression, so 3,500 patients.

And again, as you think about assembling the whole packages around them, we have data both, as monotherapy, as add-on with co-initiation, with or without antidepressants, standard care antidepressants, multiple antidepressants, multiple patient populations, as Barry was saying, demographics across a very wide range, and truly a differentiated tolerability profile.

As you think about all of those elements, of course, that was the original intent, in the broad Landscape and NEST program is to provide a series of data points to help both providers, patients, payers, an understanding of this differentiated novel approach with surround loan.

So we're very excited and we're very comfortable moving forward as we assemble this package that we have the right information to help people understand how to best use the round loan moving forward.

Chris?

Yeah, thanks, Jim.

And to add context, Paul, to what Barry already said in and around the commercialization thinking that we're currently, employing, we're out speaking to practicing clinicians every day.

We're talking to payers, whether they're national payers, regional payers, PBMs or IDNs, and certainly we're engaging with patients and patient advocacy groups to really understand what it is that they're looking for in a new therapy.

The progress we made last year really sets us up for a strong 2022 and beyond as I said on the call I'm very confident that we are emerging as the leaders in brain health and over the next couple of years will be a top tier biopharmaceutical company. Thank you.

And I think in Barry's remarks, he hit it really well.

This is not a well-satisfied market.

As I mentioned earlier, there's a substantial amount of switching going on because patients are looking for better options.

Clinicians are looking for better options for their patients.

And payers certainly recognize that with respect to what they see at a plan level that there is not a satisfied patient population there with respect to either the efficacy or the safety with the access that they have to currently available ADTs.

Can I ask one quick follow-up?

And it's an even more dire situation in the PPD world where there are even fewer treatment options for those moms that are really looking for care.

This is all really helpful.

So with that being said, we recognize, and as I mentioned earlier in the conversation, that there are five patient types. I've spoken about the treatment-naive young adult and the older adult.

On Shoreline specifically, this is, I think, where, Jim, I just wanted to get your feedback on regulatory.

There are many patients that are on ADTs that are still suffering.

Historically, antidepressants have been approved with acute evidence of efficacy, as you've alluded to, and then open-label extension data.

There are patients that are experiencing breakthrough symptoms associated with their, depression because there's a death of a loved one or perhaps a job change.

And this whole idea of maintenance of benefit is usually a post-marketing issue. But given the way this drug is dosed, right, I think the maintenance question comes into play, probably earlier.

Or there are adherence challenge patients who, quite frankly, never get to really experience the benefit of their ADT because they don't have the time to wait six or seven weeks in order to see that benefit or the side effects deter them from ultimately reaching the efficacy that they so desperately want and deserve.

Do you agree with that?

So with that being said, as you think about it, MDD with elevated anxiety is a thread that connects many of those patient types, whether they're MDD patients or PPD patients.

And I guess, you know, if you're talking to a doctor and they say, hey, if I give this drug for a few weeks and the patient does better and then they feel worse three weeks later, how does kind of redosing work?

And we have an opportunity to do better with Zoranilone for all these patients and provide, them with a rapid and lasting therapy that they deserve.

Because I think in the Shoreline study, you were restricted to not redose for at least six weeks.

Thanks.

And I'm just wondering if this is a regulatory question or not, or if you think I'm harping on something that's ultimately irrelevant.

Thanks.

Thank you very much.

Jim, you want to start and I can round it out?

Thanks, Paul.

Thank you, operator.

And thanks, Paul, for the question.

Thank you.

Thanks, everyone.

Absolutely.

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

Goodbye.

Yeah, Paul, so I would distinguish, of course, in a clinical trial we have very specific parameters in the protocol, but really the study was designed to address exactly the question that you're asking, which is, you know, what are the conditions on which subjects would need retreatment?

Our next question comes from Tazeen Ahmad with Bank of America.

And so we do have some very specific metrics in there that can be used.

Your line is open.

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

But I think really the important point is that, you know, what you're seeing in the study is that for the vast majority of patients, that actually is a relatively long interval, right?

Hi, guys.

So you've got at 50 milligrams, the majority of patients over 50%.

Good morning.

Thank you, operator.

It's that one two-week course for a year.

Here is my one question.

We really appreciate everyone joining us today for the progress we made for all of 2021, specifically our fourth quarter.

You may now disconnect.

And you're up to about 80% when you look at one or two courses.

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

I'm grateful for the entire Sage team, our patients, caregivers, clinical investigators, and all dedicated so much to advance our mission to become a leader in brain health.

So I think, yes, this is something that will need to be addressed in practice, but I don't think that it's going to be that complex a process for physicians to move to.

Thanks.

I think the progress we made last year really sets us up for a strong 2022 and beyond.

[music].

And the study in Shoreline is designed to provide that real world evidence of exactly how to do that.

Thanks, Tazeen.

As I said on the call, I'm very confident that we are emerging as leaders in brain health, and over the next couple of years, we'll be a top-tier biopharmaceutical company.

Yeah, and just to just to round it out, and thanks, Jim, just to round it out from a commercial perspective, Paul, we imagine that that most of the patient population will be that two to four weeks of drug.

Thanks for your one question.

Thank you.

There'll be very few that need the third, fourth or fifth dose.

So, look, we – and Jim's highlighted this.

Goodbye.

And, you know, if someone takes two weeks and rebounds immediately, that's not how Xeraniline was designed.

With Now Coral, we have data in over 3,500 patients.

This concludes today's conference call.

You know, for the 75% of patients that respond in Shoreline, it's for that group.

We have data with Xeraniline as a monotherapy.

Thank you for participating.

There will be some where a different chronic medication may be more appropriate and Xeraniline is not the right answer.

About two-thirds of the patients before Coral were monotherapy.

But, you know, for those patients, particularly MDD with elevated anxiety, we think Xeraniline will be the right drug to reach for.

About a third were on top of a stable antidepressant.

All right.

And then Coral, as you've highlighted, was the first time we have data where Xeraniline was co-initiated, with the five different standards of care antidepressants that Jim's highlighted. So we think we have a very rich package.

The induction or not, so, you know, Xeraniline is meant to treat for two weeks, get someone better fast, as measured at day three, and keep them better.

As we've already highlighted, Shoreline indicates the majority of patients in this Shoreline, which is more a real-world situation, only required two-week treatment.

So, you know, induction or not, I think the majority of patients out in the commercial world will require two weeks, in the course of a year, and maybe even longer.

I mean, the Shoreline study followed them for a year.

I'll also remind you that we're rolling patients from Coral onto Shoreline.

So it will be quite interesting as those data roll out to understand what happens with Xeraniline co-initiated, with antidepressants versus antidepressants alone and how many retreatments that group needs.

Chris, anything to add?

Yeah, there's something that I would add, and I think, Barry, you covered it really, thoroughly, but taking a step back, clinicians want to send patients home with a solution when they prescribe a product, and they want that solution to work rapidly and to last over time.

And quite frankly, with respect to the data that we've already demonstrated, we've seen, that this therapy works rapidly, as early as day three.

It sustains effect out to a year, and it has a safety profile that is unmatched with respect, to some of the other therapies that are out there, with respect to sexual dysfunction and weight gain, or the fact that we haven't seen it with serenolone.

And the ability to take this over the short course is incredibly desirable for patients, who don't want to be on chronic therapy in perpetuity for the rest of their lives.

So we believe that with what we're delivering, we are delivering a therapy, putting it in, the hands of clinicians to ultimately enable patients to go home with a solution that, as early as day three, they'll know that it works.

Okay.

Thank you.

Thanks, Suzeen.

Thank you.

Our next question comes from Yatin Sunja with Guggenheim.

Your line is open.

Hey, guys.

Thank you for taking my question.

So the question is on the future application or additional application of serenolone.

So specifically in anxiety, I think across the landscape studies, you have seen benefit, in patients that have elevated anxiety.

What is your view on evaluating, you know, maybe studying serenolone in acute anxiety?

And can you also talk about, like, other indication?

I understand MDD, PPD are very big opportunities, but, like, other indication, other applications, of this pathway?

Thank you.

Yeah.

Thanks for the question.

I'll start, and I'll ask Jim to kind of round it out.

So, you know, as we've talked about before, and you just said, you know, we've got almost, 7 million people per year in the United States alone that are diagnosed with MDD and prescribed an antidepressant, and one in eight women experiencing a live birth experience PPD.

So those opportunities are very large.

Our strategy, along with our collaborators, is really to do what we need to do to win, in MDD and PPD, including a robust Phase 3, B4 program following what we hope to be an approval of serenolone.

So that's the strategy.

Now, there are other areas that we've talked about developing general anxiety disorder, seasonal anxiety disorder, which will be – things will be talked about in the future.

But the real focus is to make sure that we have all the data we need to continue to provide, the marketplace for appreciation of how to best use serenolone in MDD and PPD.

Jim, you want to add?

I would only add that we are – certainly, we have additional endpoints in our studies, that we use to sort of fully understand the overall profile of serenolone.

So to Barry's point, there's a significant focus on the indications that we're currently, talking about.

We are continuing to collect data on anxiety benefits.

We've talked earlier about the benefits of serenolone on sleep.

So of course, there are additional effects of serenolone that we think could be of benefit, but those are for later evaluation.

Thank you.

Could I ask you one more?

It's on the P&L for Kimi.

So with most of the studies of Phase 3 studies now behind us, can you just help us model R&D going forward?

Should we expect it to go down?

I understand you give the cash guidance.

But also about G&A or S-G&A, as you start thinking about commercialization, is it like a second half ramp up?

Just help there.

Thank you.

Sure.

So the question on expenses and what to think about there. You know, during the year that we did talk about the fact that we believed our operating expenses were going to increase, and that really related to the execution of our expand and accelerate strategy, some of which Barry just highlighted with Sage 7-18.

So the expand and accelerate strategy will continue to execute in 2022. So that, again, will lead to increases in R&D expenses over the year.

On the SG&A front, we will see additional increases in SG&A, again, as we continue to ramp the prelaunch activities together with Biogen.

Thank you so much.

Thank you.

Our next question comes from Douglas Hau with HC Wainwright.

Your line is open.

Thanks.

Good morning, and thanks for taking the questions.

I was just curious, in terms of the CORAL data, in terms of the Day 3 benefit that we saw, was there sort of a disproportionate benefit in any of the domains of MDD?

And I'm just curious, you know, how big a contributor to the improvement was some of the sleep components?

And also, I guess perhaps, Barlow, do the areas sort of where you really see improvement change from Day 3 to Day 15?

Thank you.

Yeah, thanks for the question.

So I'll start, and then, Jim, maybe you can carry it down.

You know, we presented top-line data.

We'll certainly present breakdowns of components of MDD-17 in future Congresses.

But as we've seen in, you know, in the last couple of years, we've seen a lot of improvement.

Tim, you saw improvement across most of the domains in HAM-C17, it wasn't just one particular, feature or not.

But, Tim, do you want to talk about your thoughts there?

I think that's the key point, Barry, what we have seen consistently is improvements, across all of the domains of the HAM-C17 with Surround Lung, and that'll be the same thing for CORL.

We will, of course, be digging in more detail into individual pieces of data and communicating, that as we go forward.

So, we will be looking at the distribution of HAM-D scores over time, but I think the, key point is that what we see is a pretty consistent picture of effects of Surround, Lung across the domains of the HAM-D.

Okay, great.

Thank you.

Our next question comes from Jay Olsen with Oppenheimer.

Your line is open.

Oh, hey, guys.

This is Matt on for Jay.

Thank you for taking our questions.

Barry, I was going to ask you specifically a question.

Just curious, since you joined as CEO, I believe, since December 2020 already, just curious, how you viewed the evolution of SAGE since you took over, and also how you see it evolving over time.

And also, just how you view, personally, the next three to five years.

I really appreciate it.

Hey, Matt.

Thanks.

Look, it's been phenomenal in terms of what everyone at SAGE has accomplished and how, we work with our collaborators, both in Japan and at Biogen, and the progress.

When I started, as you mentioned, in 2020, we had three late-stage programs, Surround, Lung, SAGE 324, and SAGE 718, and a number of studies in front of us.

We're standing here today with a robust pipeline.

Those three late-stage programs are continuing to move forward.

In fact, we're preparing to file the NDA for Surround Lung early this year.

Everything we planned on doing is actually being, certainly being executed.

Obviously, the weakness of biotech across the board, starting in February last year, certainly isn't helpful for any of us.

But as you heard from me and from Kimmy, we have a very strong balance sheet to execute, on or expand and accelerate.

The view that I had coming in that we could be the leaders in brain health and a top-tier, biopharmaceutical company remain, we're on track to make that happen.

Awesome.

Thank you.

I really appreciate it.

Thanks, Matt.

Our next question comes from Aakash Tiwari with Jefferies.

Your line is open.

Hi.

Thank you for taking our questions.

This is Leo for Aakash.

Could you help us understand the real commercial opportunity in PPD?

And obviously, the Russell launch has been quite disappointing, but what have you learned, from engaging that market?

How many patients can you identify as a low-hanging fruit, and how many of those issues has acknowledging, of this patient has been?

What specifically about the Renal Lung would allow you to expand this market beyond the, success the Russell has?

Thank you.

Yeah.

Thanks for the question.

Chris, you want to start, and then I can round it out?

Yeah, thanks, Barry.

So, as you may be aware, there are one in eight women who, with a recent, live birth experience, have experienced postpartum depression.

And that's not acceptable with respect to really those moms having to suffer through the symptoms of depression and, as we've noted earlier, the anxiety that's often associated with that.

So, with respect to the postpartum community, we know that there's an opportunity for us to do better with respect to our ability to provide them with a solution like Zolreso or, subsequently, Zolrenilone, if approved.

So, with that being said, we've learned a tremendous amount from our experience with Zolreso around how to engage with clinicians, how to engage with patients and patient advocacy organizations, and also how to engage with payers to assure the availability and the access to medications like Zolreso so that, as we move forward, that we have a really strong knowledge base to build on that we can introduce Zolrenilone into that market and into that community.

Now, one of the questions you asked is the points of differentiation and how that may impact commercialization.

Certainly, Zolreso, with respect to how it's administered in office, is very different from Zolrenilone as an oral formulation that enables moms to take the therapy in the comfort of their own home over a two-week short course of therapy in order to see the benefits that we've seen in our clinical studies to date.

So, with respect to how we see this evolving, it's going to profoundly change the way postpartum depression is treated now that moms will have the opportunity to take something that has the safety and the efficacy profile of Zolrenilone.

And, as I said, there's a substantial number of these women who really need a therapy because, right now, in the marketplace, there is not something other than Zolreso that's meeting their needs.

Barry?

Yeah, Chris, thank you.

And let me just round that out.

So, you know, because we're in the market right now, we are understanding really important pieces of how to treat the people.

It's very important.

Moms are taken care of by OBGYNs until the baby's born, and all focus turns to the baby and off the mom.

So, understanding pre-screening questionnaires that need to be put in place, they're available.

Our Check on Moms program, making sure that every mom has a plan for the fourth trimester.

A number of capabilities we're putting in place now will help.

And, really, many of the KOL's vision is to understand moms at risk and send them home with a prescription for Zolrenilone should they need it so they aren't in danger or endangering the babies or families.

So, we're certainly learning a lot, and we'll be well prepared to help, as Chris said, the one in eight live births that have potential to suffer from PPD.

Thank you.

Our next question comes from, Sumanth Kulkarni with Canaccord.

Your line is open.

Good morning.

Thanks for taking my question.

So, what are some of the specific factors that might prevent immediate Zolrenilone treatment?

Is it patient response characteristics such as the average duration of maybe an MDV episode or more related to the pharmacology of the drug itself?

I guess this goes back to what were the main variables that made you focus on 14 days of therapy versus, say, a more acute 3 days or 28 days to potentially ensure more durability?

Sumant, thanks for the question.

Jim, you want to start and then I'll again provide some, color at the end?

Yeah, of course, Barry.

And Sumant, really, I don't, I wouldn't say that there are pharmacological, aspects.

I mean, what we're seeing is a rapid response to Zaranulone.

And what you see by the end of that two-week course is a pretty robust response and a response that has achieved its close to a maximum response.

So it's much more about the benefit being seen with that two-week course of treatment than anything to do with the pharmacology.

Yeah, thanks.

Thanks, Jim.

And Sumant, again, remind you that the, you know, the observation, that's been made by Sage and collaborators is that neuronal networks are dysfunctional in very specific ways when people are living with depression.

And Zaranulone was designed to re-regulate this neural network spectrum normative state. And the two-week course of treatment was the course hypothesized to make that happen.

As Jim said, we're seeing that happen very well in the majority of patients as evidenced by Shoreline.

Now in terms of specific re-treatment, you know, you keep in mind that a patient will, come in with a darkened mood, often elevated anxiety, inability to sleep.

They'll know in two, three days that if Zaranulone is working for them or not.

And again, the majority of patients it does.

And the instructions that the office will give is it should work in a couple of days.

We'll check in with you in two or three days.

And after you're done your therapy in the weeks following, if your mood darkens, your anxiety increases, your sleep is further disrupted, let's either refill or call the office for a re-treatment.

It really will be pretty straightforward in the real world.

Thank you.

Our last question comes from Vikram Parohit with Morgan Stanley.

Your line is open.

Great.

Good morning.

Thanks for taking my question.

So I had two on stage 3, 2, 4.

So, for the Phase 2 study expected to begin in mid-2022, what can you say at this point about study design, particularly about which additional parameters beyond safety that you might anticipate evaluating here?

And secondly, what level of regulatory interaction have you had on, 3, 2, 4 and what do you think the path is to a pivotal program here?

Yeah, let me start and then I'll ask Jim.

So the design for the Kinetic 2 study is in, our materials in our slides.

But quickly, it's a multi-month study with the objective of having a dose and frequency to move Stage 3, 2, 4 into a Phase 3 study.

We're studying tremor amplification or reduction in tremor amplification as well as activities of daily living at 15, 30 and then 60 milligram dose.

And for those that are on the 60 milligram dose, we're titrating over a very specific 6-week period to do that.

And we're looking at the kind of parameters we looked at for the Kinetic study. I'll remind you that in the Kinetic study, we saw a statistically significant reduction in tremor amplitude.

We also saw a correlation between activities of daily living and reduction in tremor amplitude, which is very helpful for a path forward because it's likely that the Phase 2 study will be that field function well-being activities daily living type study.

So that's how we think the path forward will look.

Jim, anything to add?

I think what I would add, Barry, is, conceptually, and Barry said it, the endpoint in the study, is similar to the endpoint from the kinetic study, and that's important for continuity, but it's also important that we, as we think to pivotal studies, we also build that bridge to endpoints that are consistent with the benefit the patients are going to receive.

So activities of daily living will be an element of the study, so we have both the bridge to, the primary endpoint that compares to back-to-kinetic, but also, looking forward, we'll be looking at showing what are the benefits to patients in their daily lives that this reduction in tremor is providing.

Okay.

Got it.

Thank you.

Thank you, and that's all the time we have for questions.

I'd like to turn the call back to Barry Greene for closing remarks.

Thanks, everyone.

[music].

Q4 2021 SAGE Therapeutics Inc Earnings Call

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