Sage Therapeutics, Inc. (SAGE) Earnings Call Transcript & Summary

Good morning. Welcome to Sage Therapeutics conference call to discuss top line results from the SKYLARK Study. [Operator Instructions] This call is being webcast live on the Investors & Media section of Sage's website at sagerx.com. This call is the property of Sage Therapeutics, and recording, reproduction or transmission of this call without the express written consent of Sage Therapeutics is strictly prohibited. Please note that this call is being recorded. I would now like to introduce Helen Rubinstein, Director of Investor Relations at Sage.

Good morning, and thank you for joining Sage Therapeutics conference call to discuss top line results from the Phase III SKYLARK Study of zuranolone in postpartum depression. Before we begin, I encourage everyone to go to the Investors & Media section of our website at sagerx.com, where you can find the press release and slides related to today's call. I'd like to point out that we will be making forward-looking statements, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. Please consult the risk factors discussed in today's press release and in our SEC filings for additional details. We'll begin the call with prepared remarks by Barry Greene, our Chief Executive Officer, who will provide an overview of this morning's announcement. Barry will then be joined by Jim Doherty, our Chief Development Officer, who will review the data in more detail; and Chris Benecchi, our Chief Commercial Officer, who will share some context on our planned approach to commercialization in PPD if zuranolone is approved for that use. Kimi Iguchi, our Chief Financial Officer, will join for the Q&A portion of the call. I'd now like to turn the call over to Barry.

Thanks, Helen, and thank you, everyone, for joining us this morning. I'm thrilled to be with you all to review the robustly positive results from the Phase III SKYLARK Study [ in postpartum ] depression or PPD. I'll begin by discussing the key highlights from this study. Then, as Helen said, I'll turn the call over to Jim to walk through the results from the SKYLARK Study in greater detail and Chris to share some context on our planned commercialization approach if zuranolone is approved. As you may have already seen from our press release with our collaborator, Biogen, the SKYLARK Study met its primary and all secondary endpoints. Results of the day 15 primary endpoint were very robust, with zuranolone 50-milligram demonstrating a statistically significant and clinically meaningful reduction in HAMD-17 score compared to placebo. Zuranolone 50-milligram also demonstrated statistically significant reductions in HAMD-17 total score compared to placebo at all measured time points throughout the study. In fact, a statistically significant and clinically meaningful reduction in HAMD scores were seen as early as day 3, the first measured time point, and continued through days 28 and 45. We also saw a stat sig improvement in the CGI-S score with zuranolone 50-milligram compared to placebo at day 15. These results reinforce our belief in the potential for the rapid onset and sustained effects of zuranolone in treating PPD and reinforced the overall data we have seen in over 3,000 patients in PPD and MDD. Additionally, zuranolone 50-milligram was well tolerated in the SKYLARK Study, demonstrating the safety profile in the trial consistent with that seen in other trials with the NEST and LANDSCAPE programs to date. With the positive results from the SKYLARK Study, we believe that data generated to date supports the potential of zuranolone to become the future standard of care for PPD. Our aim is to gain FDA approval to be able to offer this innovative treatment option, with the goal of reducing negative impact PPD has on women and their families that can last for generations. PPD is one of the most common medical complications during and after pregnancy. An estimated 1 in 8 mothers, or approximately 0.5 million women in the United States, report experiencing the symptoms of PPD each year. This is an area of significant unmet need. If left untreated, symptoms of PPD may persist for months or years and may have devastating consequences for the mother, child and family with potential generational impact. Notably, PPD symptoms can be associated with significant impairment in mother-infant bonding and maternal functions, including breastfeeding and caring for the child. Children of mothers with PPD symptoms are at long-term heightened risk for negative behavioral, cognitive and psychological outcomes throughout child and into adulthood. To avoid this generational impact, it's clear that women need timely access to innovative treatment options for PPD. We believe that with zuranolone, we have an opportunity to offer treatment options that may help to address this unmet need. If approved, zuranolone will be the first oral medication specifically indicated to treat PPD. Looking forward, we've begun the NDA submission for zuranolone in MDD, which we expect to complete in the second half of 2022. And we remain on track to submit an associated NDA to FDA for zuranolone in the treatment of PPD planned for early 2023. We believe that the results shared today provide meaningful evidence that reinforces the profile of zuranolone demonstrated across clinical trials to date. The SKYLARK Study marks the seventh positive clinical trial evaluating zuranolone in PPD and MDD. The data to date continued to show a consistent clinical profile that includes rapid and sustained antidepressive effects with a well-tolerated short-course treatment. We believe that a rapid-acting, long-duration, short-course oral treatment that's well tolerated provides the attributes that people with MDD and PPD tell us they want most of the treatment. And we look forward to continuing our work aimed at bringing this important innovative treatment option to patients. Before I turn the call over to Jim, I want to thank the participants of the SKYLARK Study, their families and caregivers, the trial investigators, everyone in the clinical site and, importantly, all the people at Sage whose dedication to this program has been vital to our success. With that, I'll turn the call over to Jim to discuss the results in more detail. Jim?

Thanks, Barry, and good morning, everyone. I'd like to reiterate our thanks to the study participants, their families and caregivers, the trial investigators, everyone at the clinical sites and Sage employees and collaborators for their contributions to the SKYLARK Study. A tremendous amount of effort goes into the successful conclusion of a clinical trial. We're grateful for those who have invested so much time and energy in making this moment possible. I'll now walk through the data we shared this morning. Starting on Slide 4, I'll begin by reviewing the SKYLARK Study design. The SKYLARK Study was a Phase III randomized, double-blind, placebo-controlled trial assessing the efficacy and safety of zuranolone 50 milligrams compared to placebo in adult women with PPD. The study enrolled women with HAMD scores at or above 26 at baseline. The 200 patients enrolled in the study were randomized to receive zuranolone 50 milligrams or a placebo once nightly for 14 days. After the treatment period, people in this study were then followed for an additional 4 weeks. The primary endpoint in the SKYLARK study was the change from baseline in HAMD-17 total score at day 15. The key secondary endpoints were changed from baseline in HAMD-17 total score at days 3, 28 and 45 as well as change from baseline in the CGI-S score at day 15. As a reminder, zuranolone is a next-generation positive allosteric modulator, or PAM, of GABA A receptors that is in development as a potential first-in-class oral treatment for MDD and PPD. Turning to the efficacy results from the SKYLARK Study. As you can see on Slide 5, zuranolone 50 milligrams demonstrated a statistically significant and clinically meaningful reduction in depressive symptoms compared to placebo as measured by change from baseline in HAMD-17 at day 15, the primary endpoint. The least squares mean difference at day 15 was 4 points with a p-value of 0.0007. We're excited about these results, which we believe demonstrate the robust reduction in depressive symptoms seen with zuranolone treatment in this trial. As Barry mentioned, zuranolone also met all key secondary endpoints in the study. Turning to Slide 6. I'll review those findings of additional time points. As you can see from this slide, zuranolone 50 milligram demonstrated statistically significant and clinically meaningful reductions in depression symptoms compared to placebo as measured by change from baseline in HAMD-17 at days 3, 28 and 45, with highly significant p-values at each time point. We believe these results reinforce the data seen in other studies in the LANDSCAPE and NEST program, demonstrating a rapid onset of reduction of depressive symptoms that was sustained throughout the follow-up period. Importantly, these results further validate findings from other studies with zuranolone across PPD and MDD, showing that patients who responded to zuranolone maintained that response through the follow-up period, while after zuranolone treatment course had concluded. The other key secondary endpoint was change from baseline in the CGI-S at day 15, which is shown on Slide 7. The CGI-S is a clinician-administered 7-point scale, which rates the severity of a person's disease at the time of assessment. At day 15, zuranolone 50 milligram demonstrated a statistically significant and clinically meaningful improvement in CGI-S score compared to placebo with a p-value of 0.0052. Turning to safety results on Slide 8. The study showed that zuranolone 50 milligrams was generally well tolerated and demonstrated a safety profile consistent with other trials in the LANDSCAPE and NEST programs to date. The most common adverse events occurring in 5% or greater in patients in the zuranolone 50-milligram arm were somnolence, dizziness, sedation, headache, diarrhea, nausea, urinary tract infection and COVID-19. These findings support the safety profile of zuranolone that we've seen in the clinical program to date. The majority of treatment-emergent adverse events reported in the study were mild or moderate in severity, consistent with prior zuranolone trials. Importantly, there were no signals for increased suicidality or withdrawal symptoms in the study as measured by the Columbia Suicide Severity Rating Scale and the 20-item Physician Withdrawal Checklist, respectively. Turning finally to Slide 10. In summary, we're incredibly excited about the results from the SKYLARK Study. These data support the differentiated profile zuranolone has demonstrated to date in 7 positive clinical trials in PPD and MDD. Based on that totality of data, we believe that, if approved, zuranolone may provide a unique treatment option for people suffering with PPD and MDD, a treat-as-needed approach for depressive episodes with the potential for rapid onset and sustained antidepressant benefit. These results from the SKYLARK Study complete the set of placebo-controlled trials set out in the LANDSCAPE and NEST programs. We look forward to updating you with more details from the SKYLARK Study in the coming months. I'll now turn the call over to Chris to provide context on our planned go-to-market approach in PPD if zuranolone is approved. Chris?

Thanks, Jim, and good morning, everyone. I'm pleased to be here today to share more detail on our planned approach if zuranolone is approved to help women with PPD. Starting with Slide 10. As you've heard from Barry, it's clear that there's tremendous unmet need in PPD and that women suffering from PPD deserve urgent medical treatment. In fact, if left untreated, PPD can be devastating for mothers, babies and their families with impact that can last for generations. There are a few critical points I'd like to highlight on the potential consequences of untreated PPD. First, mothers with PPD often face challenges bonding with their infants. Additionally, they may feel overwhelmed and anxious, feel isolated and feel that they've lost their identity. Second, mothers with PPD are at a higher risk for suicide and substance abuse. Unfortunately, in the U.S., suicide is the leading cause of pregnancy-related mortality. Third, if left untreated, PPD can result into persistent depressive symptoms and prolonged maternal morbidity and mortality, including harm to the child. What's often overlooked when discussing PPD is that the burden of illness extends to the child, the family and the health care system as shown on Slide 11. Undiagnosed PPD in a mother can result in long-term emotional problems for the child such as delayed or impaired developmental, psychological, cognitive and physical outcomes throughout childhood and into adulthood. PPD also puts a strain on family relationships. And this burden extends to society. From the perspective of the health care system, households of women with PPD experience an estimated 22% higher health care costs than those of women without PPD. New accessible treatment options are desperately needed for postpartum depression. Slide 12 highlights the urgency in treating PPD, which I'll remind you is one of the most common medical complications during and after pregnancy. In the United States, an estimated 1 in 8 women experience PPD symptoms, equating to about 0.5 million women. Of those who experience PPD symptoms, only about 28% are actually diagnosed with PPD. These women deserve a treatment option that allows them the potential to return to feeling like themselves and to bond with their babies. That's why the results we shared this morning from the SKYLARK Study are so compelling and meaningful. The SKYLARK study further reinforces the profile of zuranolone that we've seen in clinical trials to date, which is shown on Slide 13. We're excited by the opportunity this compelling profile may offer to help women with PPD. To that end, if approved, we expect the successful commercialization of zuranolone in PPD will require an approach that is designed to educate and engage stakeholders, including patients, HCPs, payers, patient advocates and policymakers. Our goal will be to create a positive experience for these women with PPD who are prescribed zuranolone. We plan to help mobilize HCPs in partnership with patient advocates and policymakers to utilize available risk screening tools, so all mothers can be screened and those who are experiencing PPD can be diagnosed and treated with urgency. And finally, we plan to drive awareness of unmet need among payers and employ an access strategy that minimizes barriers for women who are prescribed zuranolone. The positive results from the SKYLARK Study shared today bring us one step closer to our goal of being able to help mothers suffering from PPD by offering zuranolone as a novel first-in-class oral treatment option. I look forward to sharing more detail on our plans for potential commercialization in both PPD and MDD in the coming months. And with that, I'll now turn the call over to Helen to handle Q&A with the operator. Helen?

Thanks, Chris. 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 the Q&A. Operator?

[Operator Instructions] Our first question comes from Yasmeen Rahimi with Piper Sandler.

Maybe 2 quick, one clarification question. Could you comment on what were the rates of discontinuation in the study in the SKYLARK? And then two, when we compare the data to ROBIN, it's really perfectly aligned. However, the somnolence and sedation rates, as expected, are slightly higher in the SKYLARK, given it's a higher dose group. So I guess the question for you here is, as you're thinking about filing in PPD, would you be moving forward with the 50 mg dose group or actually decide to go with 30? Because it seems like you're not getting an additional benefit with 50. Sorry for the long-winded question. I appreciate any comments you have for me, and thank you for taking it.

This is Jim. Appreciate the questions. I think a couple of points around discontinuations. We're seeing discontinuations across all causes, really pretty much balanced between placebo and the drug arm. So about 12% in the placebo arm, about 14% in the drug arm. I would say, importantly, discontinuations due to adverse events are about 1% in each arm. You correctly point out that compared to the earlier ROBIN study, the frequency, the percentages for adverse events like somnolence and sedation are a little bit higher. I would say very consistent with what we've seen from other studies with the 50-milligram dose. So very consistent across the program. And I think thinking about dose for the PPD indication, I think what we've got now is 2 very robust studies, one at 30 and one at 50. It really will be a question of totality of the data. So all the data will be included in submission to the FDA for PPD. And we'll have to look at ultimately what the label looks like in conjunction with the agency.

Yes. Just to jump in, Jim. Sorry, I was -- so we actually do -- we think the dose -- the starting dose should be 50 milligrams. What -- our goal is to offer optionality. Obviously, we have to work with the agency and the label. But we want to offer multiple doses. If, in the rare case, dose reduction is required, we want to have that optionality for moms and their treating physicians. And of note, taking medicine in the evening with the meal and getting a good night's sleep is actually a benefit to people living with PPD and depression overall because many of them require sleep aids. So we're thrilled with the overall results of the SKYLARK data and the benefit/risk that it offers to treat, if approved, for moms with PPD.

Our next question comes from Paul Matteis with Stifel.

Appreciate it, and congrats. Barry, we talked about this briefly, but just to kind of broader -- clarify more broadly. So from a regulatory perspective, I guess, you're going to be finalizing the MDD submission. And is it clear that these data won't be part of the submission for MDD? And I guess we've seen in the past, right, that at the end of the day, the agency wants all the data that's available on a drug and oftentimes just ask for everything and that can constitute a major amendment. So just sort of curious if you can give any sort of clarification on your confidence in really splitting the MDD and PPD regulatory processes, given that it's likely going to be the same division, same reviewer and have some overlap.

Yes. Thanks, Paul, and appreciate the congratulatory note. We do believe the SKYLARK result supports the overall data package for zuranolone. And we have started the rolling submission of the NDA for MDD. And our plan remains to file the MDD NDA at the second half of the year and getting that rolling submission started, followed by a subsequent PPD NDA submission. That's the agreement that we and the agency reached in the fall of last year really for the most efficient way of filing the package. And I'll note that if we're approved in MDD, given the Fast Track Designation in PPD, it's quite possible that during the DEA review period, the 3-month period, that we get an approval for PPD, enabling us to commercialize both MDD and PPD at the same time. So it really is about efficiency in filing and how we present the data to the agency, but that's the plan right now.

Our next question comes from Cory Kasimov with JPMorgan.

This is Tiffany on for Cory. Congrats on the data and the progress to date. Just a quick question on how -- what we've learned from ZULRESSO in terms of how it informs the market opportunity for zuranolone in postpartum and just how you're kind of thinking about the market there as you go forward.

Thanks, Tiffany, appreciate the congratulations and the question. Let me turn it over to Chris to talk about the market opportunity.

Yes. Thanks for the question. As I'm sure you're aware, we've been active in the postpartum market now for approximately 3 years with ZULRESSO or brexanolone. And over the course of that time, we've learned a great deal about how to interact with physicians, how to interact with payers and how to interact with moms that are suffering from postpartum depression. So there's been significant learning that's come from that opportunity. As you've heard us talk about, we are in a brain health pandemic, including maternal and mental health crisis that's been exacerbated by COVID-19. So postpartum depression has only continued to grow worse over that time period. We know that there are a significant number of moms that are living with postpartum depression. During the course of our conversation this morning, we talked about 1 in 8 moms or approximately 0.5 million women that are suffering with postpartum depression. Only about 28% are actually diagnosed, and fewer than 60% or so are actually treated with therapy. So as we've had conversations with clinicians and with payers, what we know is that more is actually needed for these moms. They need rapid and sustained resolution of their disease. And that we know that by virtue of that engagement with payers and with physicians that we have a significant opportunity with zuranolone, if approved, based upon the ability to deliver that rapid and sustained efficacy with a very well-tolerated profile for that medication. So we'll continue to leverage learnings from our time with ZULRESSO in the market and offer an oral therapy, an oral short-course therapy that will advance care, if approved, for zuranolone for those moms that are suffering.

Yes. I guess, just to round that out, Tiffany, and it's a great question. It's -- we see in the course of commercialization of novel medicines that when something new, easy to access is available, and that we're going to lean into access here for patients, the numbers grow. It really is -- it's not the right answer for maternal health that only 75,000 women out of the 500,000 are treated. We think with an oral, easy-to-use drug like zuranolone, those numbers will greatly increase. And our opportunity is to approach that 0.5 million moms with PPD each year.

Our next question comes from Jay Olson with Oppenheimer.

Congrats on these results. Could you maybe provide some additional color on the unmet needs in the PPD market and maybe help us quantify the magnitude of the commercial opportunity, both in the U.S. and outside the U.S. for zuranolone in PPD?

Yes, Jay. Thanks for that question. And I'll start and turn it over to Chris for a little bit more color. So as Chris highlighted, epidemiologically, it's estimated that 1 in 8 live births results in a mom suffering from PPD. So the opportunity is huge. From a pharmacoeconomic perspective, and this presents [ why treat ] both in the U.S. and across the world, the costs are devastating. A mom with PPD not only gets attached to her baby, but can lead to generational impact, costing hundreds of millions of dollars to the health care system over time. It's pretty clear that treating women rapidly, having them attach to their baby helps them, helps their baby, helps the overall family. So there's lots of reasons to treat other than just [indiscernible] just getting a mom better with economic reasons to treat. Chris, do you want to provide a little bit more?

Yes, sure, Barry. So I think taking a step back, I think the message that you heard from us this morning based on the results of the SKYLARK data is that there's an opportunity to really change the way that we think about and treat depression, and particularly, postpartum depression. We highlighted that there is profound unmet need in this space, that currently there are no therapies that are approved for treating postpartum depression, except for ZULRESSO or brexanolone. And by the opportunity to provide zuranolone to physicians and to the moms that need therapy, we have the ability to provide a therapy that treats these patients with the urgency that they require, not only for themselves, but to continue to provide the care to their babies as well as to provide support they need to continue to maintain their family relationships. So we really see the impact and the opportunity for zuranolone as being significant by virtue of the profile that it demonstrates the ability to demonstrate both rapid and sustained efficacy through a short-course therapy as well as the safety profile that we've seen and the tolerability. So again, for that population of moms, the 1 in 8 moms that are experiencing postpartum depression, roughly the 0.5 million women, there's significant opportunity to not only provide them with the treatment that they need, but to continue to increase the opportunity to provide really positive and sustained effects over time.

Our next question comes from Ritu Baral with Cowen.

Congratulations on this top line data. I wanted to just ask a housekeeping question, my usual question. I want to make sure you guys didn't see any loss of consciousness events within this safety data set. And can you talk to the incidents of either severe sedation events or severe somnolence events, just given what a focus it was for ZULRESSO in that review cycle? And does timing of assessment of sedation and somnolence figure into the analysis at all? Barry, I know we've had this discussion, dose select before assessments early morning. But just given the somewhat irregular sleep-wake cycles of the postpartum period, I'm wondering if there are other kinds of assessments that are of importance to FDA.

Ritu, thanks for the congratulations. And just to emphasize again, we think the benefit/risk of zuranolone for depression [ EPC ] is very, very clear. You're right, the wake-sleep cycles of moms with PPD -- overall with moms and the moms with PPD are quite irregular. And we've highlighted that many moms actually have to use sleep aids, which disturb their ability to wake up when they're trying to care for babies. So we really believe we've got a great package here with zuranolone. Jim, you want to take some of the other aspects of Ritu's question?

Sure, Barry. Well -- and Ritu, just to answer the first question upfront, we have not seen loss of consciousness in the SKYLARK Study or indeed across the entire LANDSCAPE and NEST program for zuranolone. The vast -- and again, very similar to what we've seen in other studies, the vast majority of the somnolence, dizziness and sedation-related adverse events are mild to moderate. So quite consistent there, too.

Got it. And is there any differential analysis just on timing of when somnolence and sedation was measured?

Well, so what I would say there is we are consistent study-to-study on when those assessments are made, as you say, next day measures for the primary endpoint. But they're also measured routinely. And the other thing that I would say is, consistent in the study that we've seen in other studies as well, is that the majority of these adverse events are during the dosing period. Recall that the total duration of the study is out to 6 weeks. So many of these, not surprisingly, follow the pharmacokinetics of the drug, meaning you see most of these events relatively early and certainly the majority during the treatment period.

Our next question comes from Laura Chico with Wedbush Securities.

I guess I just had one quick follow-up on the difference between sedation and somnolence. I apologize if I missed it in the prior comments here. Just trying to clarify the distinction in definition. And I guess, I'll sneak one in, too. In terms of pricing, I guess, if there's any commentary you can offer here in terms of how you're thinking about pricing. Obviously, the MDD opportunity is substantially larger than PPD. But just curious how we should be thinking about that.

Yes. Laura, thanks a lot. Appreciate the question. So the adverse events are patients telling physicians what they experience and physicians kind of writing it down. So there's really not a big difference between somnolence and sedation. So on to your pricing question. So it's too early to talk about pricing per se. What I can tell you is that we're going to lean heavily to access, meaning we're going to do everything we can. If an MDD or PPD patient requires zuranolone, we're going to do everything we can to remove barriers to access. That starts with talking to payers on the value-based agreement front and sharing that risk, making sure that they have budget predictability and aren't fearful of allowing that script to go through. So we do everything we can. We'll get back on more details on pricing as we get closer to approval and understand what the label looks like. But again, we're going to do everything we can on the access front.

Our next question comes from Salveen Richter with Goldman Sachs.

How does this data impact the probability of zuranolone approval in MDD? Or is the division viewing the indications and packages as completely distinct here?

Yes. Salveen, thanks for the question. So when we met with the agency in the fall of last year after the positive WATERFALL data, we confirmed a couple of things. First, we confirmed that with a positive WATERFALL, we had a fileable package for MDD, recognizing that we had 2 outstanding studies at the time, CORAL and SKYLARK. So the agreement with the agency was to move ahead with a rolling submission for MDD, which we've started; include the CORAL data, which we reported and we had a very positive result; and then an associated NDA filing with the PPD data. And now given the positive SKYLARK data, we're thrilled to begin that associated NDA. As I've highlighted in the call a little bit earlier, the way the timing we hope works out is should MDD be approved, and we're going to file that to finish in NDA in the second half of this year, during the DEA review period, the 3-month period, we hope to get the approval, given the Fast Track for PPD, and able to launch both indications at about the same time. And of course, if one gets approved before the other, we won't wait for approval, we'll start helping MDD patients first if that's the first approval.

Our next question comes from Ami Fadia with Needham & Company.

This is [indiscernible] for Ami. Congratulations on the data. I guess I have a 2-part question. The first part is about the response rate that you see in day 15 and how will it change the [indiscernible] some color there? And the second part is it looks like that the numbers on both the placebo and the drug group are lower when compared to the ROBIN study. What would be the specific reason for that?

Thanks for the question. So as -- and I'll ask Jim to provide a few highlights here. But what we've seen with the SKYLARK Study is, as we've seen across now 3,000 treated patients, is a very consistent profile. We see change from baseline at day 3, day 15 and out days to be around the same major changes. Data are highly consistent. Now obviously, we saw a very robust effect relative to placebo. I will note that there were less assessment days, perhaps giving placebo patients less chance for that kind of white coat experience. So really robust results across the board. Jim, you want to add?

Yes. Barry, I guess what I would add to that is, as we talked about before, we had the study results. SKYLARK was really designed to be similar to ROBIN because we had a lot of confidence in the study design in ROBIN, but with a couple of key differences. So we've talked about the difference in dosing, so the 50-milligram dose for SKYLARK relative to 30 for the ROBIN Study. But we also did have a couple of additional differences in the studies beyond that. One is the size of the SKYLARK Study is the largest study that we're aware of that's been run for the treatment of PPD. And then I would also point to one other change in study design between ROBIN and SKYLARK, where we extended the period for women to enter the study. In the ROBIN Study, it was no more than 6 months postpartum. And in the SKYLARK Study, that's been extended out to 12 months postpartum. And as you can see from the results, which are quite similar to what we have seen from the ROBIN Study, that change hasn't made any significant difference, that it really is another learning from this study for the treatment of postpartum depression that we've got a wider window for women who are responding to the drug.

Our next question comes from Sumant Kulkarni with Canaccord.

Nice to see the SKYLARK dataset. Just sort of curiosity, was there any overlap at all in study participants between SKYLARK and ROBIN? I'm asking this to see if you followed ROBIN participants to see if PPD occurs after birth of another child and what the duration of effect or episodic retreatment potential of zuranolone may look like in the PPD patient population.

Yes, Sumant. That's a great question. Let me turn it over to Jim.

Yes. So good question, Sumant. There we actually do not have women who participated in both studies. We do have some -- a fraction of women in both studies who are -- it is a second or a third experience with PPD. But there are no women who are in both studies.

Just a note, Sumant. As we think about commercialization, what happens in the real world, we know, given the multiple years of experience we've had with ZULRESSO, these are anecdotes, we've heard back from moms that after their first child birth after being treated, they felt confident to have another child because they -- if, in fact, they suffered from depression again, they were telling us that they knew there was an approach to get them better. So we're pretty confident in, as we roll out this oral treatment, how it might be used in the real world.

Our next question comes from Vikram Purohit with Morgan Stanley.

Great. So one on baseline characteristics for us. Could you just provide us a bit more detail or whatever color is available on baseline characteristics for SKYLARK and how they compare to ROBIN, particularly with regards to what the baseline HAMD scores were and what portion of patients were on antidepressants coming into the study?

Yes. Great question. I guess I'll say that the SKYLARK to us reconfirms what we saw with ROBIN, which was rapid effect, sustained effects out through day 45 with highly similar profiles. As Jim has already highlighted, we used 50 milligrams versus 30 milligrams and have continued robust effects. Jim, do you want to talk about some of the baseline characteristics that Vikram is asking about?

Yes, absolutely. And again, I think probably the biggest message is similarity across trials. So in both studies, entry and the scores -- the entry criterion is 26 or above. It's -- the mean is going to be closer to 28 or something like that in the SKYLARK Study, so pretty consistent with the ROBIN study. And I think that's really the -- what I would say is the key message is, by design, the demographics are pretty similar across the 2 studies.

Our next question comes from Yatin Suneja with Guggenheim Partners.

Very robust results. Were you able to look at some of the other endpoints? Did you look at patients with anxiety versus without anxiety? I know that's one of the driving factors in a couple of the other previous -- a couple of the other studies. Just wondering what did you see. What about maybe sleep architecture and any comments there?

Yes. Yatin, thanks for the question. Look, this is -- we reported the top line data here. We look forward in future publications and conferences reporting the totality of data. But what we can say in both MDD and PPD now across 3,000 treated patients is a very consistent profile. That's rapid improvement in depressive symptoms, including improvement in anxiety without impact or negative impact to sleep, which is really what we want to see in treating depression. As we talked about before, we saw really robust results across MDD. We saw particularly strong results with MDD with elevated anxiety. And very often, PPD presents in moms with -- that have the darkened mood and the elevated anxiety. So really consistent results across reduction of depressive systems, anxiety without negative impact to sleep.

Our next question comes from Marc Goodman with SVB Securities.

This is Rudy on the line for Mark. So first, congrats on the quarter -- sorry, congrats on the data readout today. And I have a question regarding the use of the [indiscernible] practice for PPD. It seems like we're going for both monotherapy and add-on to existing antidepressants. Can you remind us what percent of patients are taking background antidepressants in both ROBIN and SKYLARK? And do you expect step added through generic antidepressant, even though there's nothing approved for this indication?

Yes. Rudy, thanks for the question. So let me start with this. Other than ZULRESSO, there aren't any drug specifically approved for PPD. So while antidepressants, they're not specifically approved for PPD. As we said on the call, we believe that with both ROBIN and SKYLARK data and the totality of the overall facts, including MDD, that zuranolone should rapidly become the standard of care for women with PPD. It really isn't appropriate to treat them with antidepressants, which can take 6 to 8 weeks to work if ever. And think about it, a mom detached from the baby 6 to 8 weeks is an absolute lifetime. So that's our goal. As we talked about before, we're going to lean into access to ensure that scripts that are written are provided. We really don't think it's appropriate medicine to give a mom an antidepressant, which takes weeks to work when we have a drug that has shown now repeatedly to work as little as 3 days.

Our next question comes from Douglas Tsao with H.C. Wainright.

I'm just curious, from a labeling standpoint, what your expectation is in terms of patients who potentially have some persistence of their symptoms? Obviously, the data is quite strong, but presumably, some patients who do have some continuation of PPD or even some recurrence. And what your expectation and interactions with what the agency might suggest you might be able to achieve?

Yes, Doug. Thanks for the question. So what we have seen in both SKYLARK and ROBIN is a consistent profile, rapid reduction in depressive symptoms out to day 45. And most of these moms report that the kind of the normative state remains for a long period of time, potentially to another depressive episode. Now we will have data in the SHORELINE Study on retreatment. And while that's not -- well, that's MDD. It is instructive in terms of what retreatments may need to look like. Most people get better and stay better. In SHORELINE, a majority of patients actually required only 1-, 2-week dose, and 80% required only 1 or 2 week doses up to 4 weeks of study. So if someone with depression PPD has another depressive episode, it could get diagnosed with PPD, it could get diagnosed with MDD, but we believe that zuranolone will be appropriate in those cases.

Our next question comes from Gary Nachman with BMO Capital Markets.

This is Evan Hua for Gary Nachman. Congrats on the data. Can you provide some more color on what the initial physician feedback has been on for SKYLARK data and how they might view that compared to the ROBIN data?

Yes, Evan, great question. Let me ask Chris to start and maybe Jim. Because I can tell you that the feedback is just outstanding.

Yes, I'll give it a start, and then I'll pass it over to Jim, as Barry suggests. So first of all, as you take a step back, as we're having conversations with physicians about unmet need in postpartum depression, as we talked about, today there does not exist something in the market that delivers rapid and sustained effects for moms that are suffering from PPD that can be administered through a short-course oral therapy. In fact, the only product that's currently approved, as I mentioned earlier, is ZULRESSO for women with postpartum depression. So the feedback based upon the interactions that we've had around ROBIN and SKYLARK has been highly positive around delivering on what that unmet need actually is for clinicians that are -- through the clinicians that we're communicating with. So again, the rapid and sustained benefits associated with the product, the tolerability profile, the ability to deliver it through a short-course oral therapy, that's really important to clinicians that really want to have the opportunity to treat moms who urgently need therapy. Right now, what they currently have at their disposal are SSRIs and other types of established therapies that for a mom that's showing up that needs effectively that urgent treatment, something that provides potentially relief after 4, 6 or 8 weeks, that's not doing the trick with respect to what it is that they're actually looking for to treat these moms. So we believe with the data that we shared through both ROBIN and SKYLARK, we're meeting a highly unmet need in this marketplace. And that also translates through to what we're seeing when we engage with payers as well. Payers also recognize that there's high unmet need in this space and that there's an opportunity to treat moms with PPD in a different way than they've been treated to date. So Jim, I'll pass it over to you.

Yes. So I think Chris said it very well. And when we talk to docs out there, there's a lot of enthusiasm and, honestly, a lot of excitement that there -- as Chris said, there are so many moms who are in urgent need, and that's just the situation as it exists today. We talked a little bit about the current ADTs are prescribed for postpartum depression. But frankly, the evidence is not great that it provides a ton of benefit. There's a -- we've seen some -- continue to see some really great results with ZULRESSO, brexanolone. But of course, for a lot of moms, access to brexanolone has been challenging. So the SKYLARK Study really reinforces the opportunity with an oral agent with this mechanism of action. And so that's what the providers are seeing. And I think there's a fair amount of excitement about it.

Thanks, Chris and Jim. And just to round that out, what we're also hearing is urgency to diagnose. What we see in depression and medicine in general is when a new tool presents that can help a patient, physicians have a lot more urgency to diagnose. So we do believe that with the introduction of zuranolone, we, in our education, will see the risk assessment tools that are generally available used much more and the diagnosis rates go up significantly.

Our next question comes from Vamil Divan with Mizuho.

Congrats on the results here. Just one question, just -- and this may be a little bit early. But when you think about labeling, there is some language in the ZULRESSO label around use in women or pregnant or during lactation. Looks like relatively benign information and more based on animal data than anything. But I'm just curious if there's anything else, would you expect sort of similar language in the label here in pregnancy and breastfeeding populations or anything sort of different that we should expect as you think about how the label might look.

Yes. Thanks for the question. Jim, do you want to take the lactation question?

Yes, absolutely. That one, of course, in the trial itself, we did not exclude breastfeeding mothers. But as has been done in earlier trials, participants agreed not to provide breast milk to their infants. We will be looking -- when we get to the label, as you point out in the case with brexanolone, we are actually measuring brexanolone levels in breast milk and they're quite low. We'll do the similar thing with zuranolone. And our expectations are that similarly the levels of zuranolone in breast milk will be low. But that's yet to be provided data. And of course, we'll have to get to specific labeling questions when we get to that point. But that's our expectation around the drug itself, that it would behave similarly to the way brexanolone behaves in breast milk.

That's right. And just -- let's all keep in mind that we're talking about a 2-week course of treatment. So unlike a chronic med, which provides challenges throughout the whole lactation period or breastfeeding period, this is 2 weeks.

Our next question comes from Neena Bitritto-Garg with Citi.

I just wanted to go back to some of the questions earlier around the rate of somnolence and sedation. I'm just curious in your regulatory discussions, either around brexanolone or around zuranolone, if there was a cap that FDA talked about in terms of the rate of those sorts of adverse events and even across comparing the data here to brexanolone. It seems like you do -- you have seen higher rates of somnolence and sedation than historically.

Thanks, Neena, for the question. Let me emphasize that the rates of somnolence and sedation here are actually not that high when you compare it to the labels of antidepressants that are out there. Everyone should take a look. They're used. They're safe. But I think the adverse event tables are not remembered. The second key point here, these are mild to moderate adverse events. And when you look at the discontinuation rate due to adverse events on the trial, it's extremely low. So in the overall benefit/risk, the key is that any adverse event doesn't negatively impact the patient to stopping drug or, in this case, dropping off a trial. We've seen dropout rates being extremely low. So we're highly confident in the benefit/risk here and the opportunity to help moms with PPD.

Our next question comes from Brian Abrahams with RBC Capital Markets.

My congrats on the data results as well. I'm curious maybe your latest mechanistic hypothesis on why you're seeing this work in both MDD and PPD, but seeing a larger effect size in the latter. And I guess along those lines, I know a full breakdown of HAMD subcomponents, we'll wait for the detailed data. But I guess, broadly speaking, I'm curious if you're seeing a mix of HAMD component effect that looks similar to what you see in MDD, but just maybe more robust across the board or if there are particular elements and subcomponents of HAMD where it seems like PPD patients preferentially benefit.

Yes. Thanks, Brian. So let me just emphasize again that we are seeing consistency of data in both PPD and MDD across 3,000 treated patients. When you look at change of the baseline at a 3, 15, 28 out to day 45 or 42 in the MDD case, so the drug kind of does what the drug does. It reduces depressive symptoms, anxiety without disruption to sleep in all of our studies. So it's really been consistent. I think a really important question on why a mechanism is critically important -- I'm going to ask Jim to explain it because that's a critical point of why we're seeing such robust results with zuranolone.

Absolutely. And yes, so I'd say the core hypothesis that we've had consistently is that what we think is happening is that in depression, you've got overactivity in key brain circuits. And that's not our work, there's a lot of work looking at -- for brain circuits that are overactive in depression. And so really what both brexanolone and ZULRESSO are hypothesized to be doing is calming down that overactivity. So as we think about it, the difference between populations may well be what triggers that change in brain function. In postpartum depression, of course, it's the changes in physiology associated with parturition and birth where it's going to be more variable in MDD. But the -- once that imbalance has been triggered, it's been triggered. And so that's why we think that the drugs are treating both patient populations. The only difference is really in the triggering.

Our next question comes from Tim Lugo with William Blair.

Congratulations on the results. Most of them have been asked, but I don't think I heard if there were any instances of suicidal ideation that's less than 5% rate. Obviously, I know that's an important event, given the class and the history of the class.

Yes. Tim, great question. And we don't. But Jim, do you want to comment more about what's going on here and why we don't?

Yes. I think that's the short answer, Barry. If you look at -- of course, we do track suicidality and we see no evidence for suicidality or suicidal ideation. We also routinely track for withdrawal with the physicians with a checklist. I don't see any signs of withdrawal in the study either.

Great to hear.

Yes. And Tim, what's important -- thanks for the question. This is working in a fundamentally different way, offering a new mechanism of action and innovation, which we haven't seen in over 30, 35 years is really exciting. But thanks for the question.

Our next question comes from Danielle Brill Bongero with Raymond James.

Congrats on the data. First, just a follow-up to an earlier question. Can you remind us how long post-treatment that breastfeeding restrictions would apply? And then also just curious if the baseline HAMD-17 scores were in the treatment of placebo arm.

Thanks, Danielle. Jim, do you want to take those?

So when it comes to breastfeeding, this is again for the -- in the trial. So they basically agreed to not breastfeed for until 7 days after the last dose of zuranolone. And the second question?

Just curious of the baseline HAMD scores for the placebo arm.

Right. The baseline HAMD scores were approximately 28 for each arm.

Very well balanced.

Our next question comes from Ritu Baral with Cowen.

Very quick one, given time. Barry, are you committed to having a different brand for PPD for zuranolone? Or is this something that is still on the table? I know this speaks a little bit into pricing considerations, but also potential sales force and sales force strategy. Can you speak to that at all?

Yes, Ritu. Great question. Look, we and Biogen are still in discussions about the way to commercialize. Zuranolone is a drug both for MDD and PPD. So it's highly likely that it will be the same brand and the same overall pricing strategy. What's important to us is people living with MDD and PPD get access to this drug, which is why we're partnering with payers to remove all barriers. And launching a new depression drug and seeing innovation in this space really for an oral drug for the first time in over 30 years is really exciting.

There are no further questions. I'd like to turn the call back over to Barry Greene for any closing remarks.

Thanks, everyone, for joining us this morning. We believe that completion of the SKYLARK Study is yet another important step towards our goal of bringing zuranolone to the market to help those suffering from MDD and PPD. As you've heard in today's call, these data meaningfully contribute to demonstrating zuranolone's potential to meet the needs of people with depression, including those diagnosed with PPD. I hope, in our voices and our comments, you can hear how thrilled we were with these data. We remain committed to making a difference in the lives of people living with brain health disorders, so they can thrive and get back to normal, healthy, independent life. Zuranolone, as well as the rest of our pipeline, is incredibly exciting. And we continue to build ourselves to be leaders in brain health and an opportunity to be a top-tier pharmaceutical company. That's where we're going. So thanks, everyone, and have a great day.

This concludes today's conference call. You may now disconnect.