SAGE (2019 - Q4)

Good morning. Welcome to Sage Therapeutics Fourth Quarter and Year-End 2019 Financial Results Conference Call. Currently, all participants are in a listen-only mode. 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 Matthew Calistri, Investor Relations at Sage. Matthew

Hello. And thank you for joining Sage Therapeutics fourth quarter and year-end 2019 financial results conference call. 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 related to today's call as well as the slides that contain supplemental details. I would like to point out that we will be making forward-looking statements, 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 Dr. Jeff Jonas, our Chief Executive Officer; Mike Cloonan, our Chief Business Officer; and Kimi Iguchi, our Chief Financial Officer. We’ll be joined for the Q&A session of the call by Dr. Steve Kanes, our Chief Medical Officer; and Dr. Jim Doherty, our Chief Research Officer. I will now turn the call over to Jeff.

Thanks, Matt. Good morning and thanks everybody for joining us. We're pleased to update you today on our mission to bring medicines that matter to people with brain health disorders. This morning, I'll provide an overview of our 2019 fourth quarter and full year progress, including advancements across our depression, neuropsych and neurology franchises. Then Mike will take a deep dive into the ZULRESSO launch metrics. And lastly, Kimi will provide an update on financials. In the last several years, Sage achieved a track record of success in an area of science known to have an unusual amount of failure and disappointment. Our success we believe was a result of our unconventional thinking in creative problem solving. That being said, the MOUNTAIN trial with SAGE-217 reminds us all that drug development at its core is difficult, and that innovation in the brain health space is not always straightforward. As we consider the MOUNTAIN data along with the bulk of the available clinical data for zuranolone, we believe it is clear that this is an active drug, having completed two prominent pivotal trials with tremendous potential for the treatment of major depression. This is what drug development looks like, we learn, we adjust and then we progress. Let me turn first to a discussion of the Depression Franchise. While the MOUNTAIN trial with zuranolone did not meet its primary endpoint at day 15, the effect size achieved within [ph] days was noteworthy, particularly in light of comparison to the effects seen with the current standards of care. We believe the data support a hypothesis that's zuranolone has a differentiated profile with the potential for a rapid and robust onset with durable effect. We previously stated we would meet with the FDA in the first quarter. Our goal is to find the most efficient pathway to bring zuranolone to patients as quickly as possible. We will not speculate on potential scenarios and we will announce next steps for zuranolone and the Landscape Program, once we evaluate the advice from our first quarter meeting with the FDA, including receipt of the meeting minutes. Mike will take a deep dive on the ZULRESSO, but let me quickly highlight three key areas where we have achieved progress since the launch. First, underlying patient demand is strong; Second, HCPs are diagnosing and referring for treatment; and third, payer coverage is exceeding expectations. Later in the call, Mike will provide more detail on the positive indicators. Turning now to our neurology franchise and SAGE-324, our next GABA PAM. Earlier in 2019, we announced positive results from an open-label single dose study with SAGE-324 in essential tremor. This condition is the most common movement disorder in the U.S. and affects an estimated 6 million people in the U.S. alone. What this open-label study has shown us so far is that SAGE-324 is a compound with the pharmacologic characteristics we believe are well-suited for development opportunities, not only in essential tremor, but also in epilepsy and Parkinson's disease. Our first step in advancing this novel compound is initiating a Phase 2 trial in essential tremor. We are on track to begin this trial with a dose of 60 milligrams during the first half of 2020. We've also made progress with the lead assay in our neuropsych franchise SAGE-718. We recently completed our Phase 1 program in healthy volunteers and in patients with Huntington's disease. And in open-label studies, SAGE-718 of 1 milligram was well tolerated, and patients demonstrated improved performance compared to baseline on assessments of executive functioning. These data align with our expectations of this molecule and are relevant to multiple disorders with impaired cognition, including Huntington's, Alzheimer's and Parkinson's disease. We are further interrogating these data to inform the advancement of SAGE-718 into one or more Phase 2a open-label studies, evaluating disorders in patients with impaired cognitive function. Results in these studies will inform the plan for advancement of SAGE-718 into further Phase 2 development, including Huntington's disease. We've also expanded our early-stage pipeline with 2 additional proprietary assets, both of which now have open INDs. SAGE-904, our second novel NMDA product candidate is currently being evaluated in a Phase 1 trial in healthy volunteers as a potential oral therapy for disorders, involving NMDA hypofunction. Additionally, we are evaluating plans to advance SAGE-689, an intramuscular GABA PAM into the clinic as a potential therapy for disorders associated with GABA hypofunction. As a company, Sage has made a decision to develop new drugs for the treatment of brain health disorders. We've taken an approach to drug discovery and development that we think is unique and is now being replicated by others. We believe the potential of our pipeline of novel compounds is unmatched in the neuroscience space. And now, I'll turn the call over to Mike to provide additional details about the launch.

Thanks, Jeff, and good morning, everyone. We are now two quarters into the launch and remain encouraged by the measurable forward momentum. And while the indicators are strong, as we've always said, breaking through on the predominantly hospital-based launch of ZULRESSO and the lack of urgency to treat for this medical condition that sits at the intersection of women's and mental health, is a challenge requiring trying to solve. For the quarter, we recognized product revenue of $2 million, which is a 33% increase over Q3. Full-year 2019 revenue since launch was $4 million. Similar to the fourth quarter, we are anticipating modest revenue growth over the next couple of quarters. We expect an increase in the revenue growth rate in the second half of 2020, based on plans to increase the number of treating sites, specifically larger hospitals, and drive increased volume at current sites of care. To drive revenue growth and increase patient access, our strategy in 2020 will continue to focus on increasing the number of sites that are treatment ready, increasing PPD patients and treatment volume in geographies with our treating sites of care through focused deployment of our resources, leveraging strong payer coverage and access, while increasing confidence in the reimbursement pathway, increasing the breadth and depth of HCP referrals and supporting patients, HCPs and sites of care through Sage Central. In the fourth quarter, there was improvement in all key metrics, as our deliberate and focused approach continues to make progress. Let me elaborate further. We had 300 additional start forms in the fourth quarter, a 50% increase from Q3, bringing the total since the launch to more than 500. We also doubled the number of referring HCPs to more than 300. From a site activation perspective, we ended the year with more than 175 REMS certified sites of care compared to the more than 140 as of Q3. We expect REMS certified sites to become less of a forward indicator in the future with treating sites of care being the more important metrics to drive revenue. We’ve made progress activating treating sites of care, with 29 sites having infused ZULRESSO as of the end of the fourth quarter, nearly triple the number for Q3. We have learned that it takes more time than anticipated to activate sites of care, especially the larger institutions. However, we continue to see positive momentum at larger sites as they move closer to becoming treatment-ready. We have also seen positive dynamics in payer coverage. At the end of the fourth quarter, 80% of total covered lives had favorable coverage that is no or limited restrictions. And Sage Central continues to be a valued resource for PPD patients, HCPs and sites of care, with more than 95% of patients utilizing our patient support. As I mentioned on our third quarter call and perhaps most importantly, we continue hearing stories from moms who have been treated, many who are seeing major benefits. I finally feel like myself again is a comment we hear often. We now have a full six months of learnings from this first of its kind launch. Based on these learnings we are taking several steps we believe will help us achieve accelerated revenue growth in the second half of the year. Specifically, we have seen that internal complexities of creating new protocols, operationalizing the REMS and identifying pathways to reimbursement have been barriers to patient access, especially in larger hospitals and healthcare systems. We now expect it could take more than nine months for the majority of sites that want to treat with ZULRESSO to become activated. And larger hospitals could take 12 months or longer to activate. To accelerate site readiness, we are sharing best practices from successful site activations, providing tools, supporting peer-to-peer education, and leveraging Sage Central to support hospital administrations’ efforts to accelerate the steps to becoming treatment ready. Enabling the treatment readiness of large hospitals will be critical to meet the growing demand and our expectations for ZULRESSO and in supporting all patient sites, both Medicaid and commercial. Despite securing broad and favorable coverage for ZULRESSO, sites are still often required to negotiate reimbursement amounts with individual payers under commercial coverage. Sites of care want direct reimbursement experience after infusing a patient and it can take time to receive payment from payers. What this means is some sites are becoming treating ready, administering to one or two women, but then pausing to wait and evaluate reimbursement outcomes. This treating pattern has led to a lag between site activation and revenue. Our team is focused on sharing successful reimbursement learnings from a number of active sites to help new and potential sites become more confident in the process. With approximately 50% of the PPD population being covered by Medicaid, we are also focused on improving access for these women. Medicaid reimbursement varies state by state, and often depends on whether the state treats the ZULRESSO infusion as an inpatient or outpatient administration. Through our efforts, we are seeing positive progress. We were granted a C-code in January, which provides hospitals an easier halfway to reimbursement in an outpatient setting. The C-code is being adopted by commercial and state Medicaid plans, and we anticipate activation by the end of the first quarter 2020, which could improve the reimbursement transparency. In closing, the indicators of success continue to be positive. We are leveraging learnings and we are focused on increasing patient access by increasing the number of treating sites of care, including larger hospitals. This is a unique launch in some very specific ways. Introducing the first ever healthcare facility based 60-hour continuous treatment for postpartum depression requires a high level of initial effort from several stakeholders within and outside the site of care. We are not just introducing an innovative treatment, we are establishing an entirely new treatment protocol in a system that is not necessarily designed for flexibility. And now, I'll turn the call over to Kimi to review our financials.

Thanks, Mike. 2019 was a transformative year for Sage. We received approval for the first ever treatment for postpartum depression, an important step in the treatment of women's health and mental health. ZULRESSO’s approval was also an important step for Sage, marking our transition to a commercial company. This year, we grew our workforce to support our commercial launch and the infrastructure to succeed as a commercial company with an expanding portfolio. Our R&D organization equally made great progress. This year, we advanced programs across all three brain health franchises and entered 2020 with five novel NCE candidates being evaluated over eight indications. I'll now walk you through the highlights of our fourth quarter and end-of-year 2019 financial results. Revenues were $2 million in the fourth quarter from the sales of ZULRESSO. That was compared to $300,000 for the same period of 2018. And that was a result of the collaboration revenues from Shionogi related to reimbursement of product. We ended the year recognizing $6.9 million in revenue. This consists of $4 million in ZULRESSO sales revenue and $2.9 million in collaborative revenues from Shionogi. We recorded $90.3 million in collaboration revenues from Shionogi for the full year 2018. Selling, general and administrative expenses were $85.1 million in the fourth quarter. We ended the year with $345.8 million in SG&A expenses, compared to $201.4 million for the same period of 2018. Our transition to a commercial company contributed to the increase in SG&A for 2019. The increase was primarily due to personnel-related expenses and corporate infrastructure costs to support expanding operations and the ZULRESSO launch. Research and development expenses were $91.3 million in the fourth quarter, consistent with the third quarter of 2019. We ended the year with $368.8 million in R&D expenses compared to $282.1 million for the same period of 2018. The advancement of the Landscape Program as well as the continued research and development efforts across our clinical and discovery pipeline contributed to the increase in R&D expenses for 2019. We reported a net loss of $168.7 million for the fourth quarter of 2019 and $680.2 million for the full year of 2019. That was compared to $158.4 million and $372.9 million, respectively, for the comparable periods of 2018. Finally, we continue to maintain a solid financial foundation, ending the year with $1 billion in cash, cash equivalents, restricted cash and marketable securities. As you've heard me say before, we take a deliberate approach to our investments. Looking at the year ahead, we’ll continue to invest thoughtfully to sequence assets we believe will create near, mid and long-term value for our stakeholders. I'll now turn it over to Jeff for closing comments.

Thanks, Kimi. Before we begin the Q&A, I want to remind everyone to contain themselves to one question each. Importantly, I also want to thank the teams at stage for their hard work, and emphasize that our focus in 2020 will be guided by perseverance, disciplined execution and rigorous prioritization to ensure an optimal pace of innovation for what we believe is the leading novel portfolio of NCEs, dedicated to treating brain health disorders. Okay. Let's open it up for questions.

[Operator Instructions] Our first question comes from Cory Kasimov with J.P. Morgan.

Hey. Good morning. Thanks for taking my question. My question is on SAGE-217 or zuranolone in this possible strategy of evaluating higher exposure levels to maximize activity. So, I guess, I'm wondering how confident are you that going to higher dosing could result in better efficacy? And are there preclinical, early dose-ranging experiments you can point to that would support this? Thank you.

I'm going to start and I'll turn it over to Steve. One of the things, like when you run these trials, or one of the things our team has been really good at is, looking at things like population PK, exposure levels, and also physiologic measures, say, such as beta EEG. And some of these data we don't make public but I can -- all I can say is looking at the average [ph] of brain profile and the population PK data, we're very comfortable that there is room for a higher dose for this drug, and that there is clearly room to believe that there will be potential larger effect size. I think, one of the takeaways from this and I've seen some speculations, is, this is really drug development sort of 101. You do your studies, you know you have broader exposure, you look at the popPK, and then you can make a determination. And that's what really is probative of what the exposure data looks like versus the effect. We're very comfortable we have room to go higher, and especially with the adverse event profile, we're very optimistic about it.

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

So, Jeff, I just wanted to probe a little bit about an observation that had made in the MOUNTAIN study, which we have consistently gotten follow-up questions on. What's your view about how to control better in any study that you're doing for compliance? So, is it really about choosing your site, is it about certain principal investigators that are better able to monitor patients? But what checks do you think you need to add into your trial designs in order to make sure that that's not a risk going forward, and any continuing or new studies that you do?

Yes. Thanks for the call. This is the Steve. The way that we look at this, is we look at all the procedures in the study, it will happen after whether study is positive or whether study hasn't met its primary endpoint, and look to see whether there is additional instructions we can give to the investigators and instructions to the patients that would additionally achieve compliance. We know that this is always part of the rigor related to the studies. But overall, the numbers we've seen is small. We've been talking about that as an element. As we understand the outcomes in the 301 study, mainly to point out that we continue to be confident in the activity of the drug, the profile of the drug, and what we've seen in terms of our overall profile. So, that's the way we think about it. And as we think about additional ways to sort of tweak the trials, will certainly do that, but that's how we think about this data.

Okay. Would you be able to provide any color, when you provide your update from your FDA meeting about any changes to protocol that would refer to this specifically?

What we'll do is, for things that are really germane to the overall sort of conduct of the study, we may make such comments. But those are the kind of things that we’ll share after we work through our strategy moving forward.

Our next question comes from Salveen Richter with Goldman Sachs.

So, with regard to the other MDD studies, so SHORELINE, RAINFOREST, and REDWOOD, some of these programs are still suspended in light of changes you may be making. Could you just walk us through whether the reads that were previously announced for this year, whether they're on track for readouts, just given the modifications that may be made?

Yes. Hi. This is Jeff. Some of them obviously being paused. We haven't determined final top-line data yet, based on what kind of feedback we've and our processing of feedback from the agency. I think that 303 is fully enrolled. That one, we may have some data by the end of the year. Again, this is going to determine overall based on what our pathway is with the agency and what studies they deem to be most valuable.

Our next question comes from Paul Matteis with Stifel.

I know, it's not the right place to speculate on what the FDA might want. But, Jeff, I'm just curious, how do you think about if the FDA wants more evidence of acute efficacy for MDD, as someone who's kind of planning going forward and thinking about risk mitigation, how many more shots on goal would you want to feel confident that you're really likely going to get another positive trial? In other words, would you want to start at least 2 or 3 more studies? And, how does the kind of path forward for PPD play into this, and whether or not you want to do another PPD study as well? Again, not from the regulatory perspective, but from your perspective, as it relates to risk mitigation and maximizing the probability of success. Thanks.

So that was a pretty clever way to get around my trying to talk about the FDA. However, let me just say it this way. I think for those of us who have lived with these data, who've looked at the population PK, who look at the data from the trial, again, some of which is trial management, we're very comfortable, this is an active agent, it really is. And we always remind people is that we're developing a new chemical entity, not a repurpose drug. That pathway can be more challenging. With that being said, we're very comfortable that this is an active agent. There are multiple potential scenarios and I specifically don't want to get into them. I think from a risk mitigation standpoint, what the risk is, is only going to be known once we understand what the potential pathways are for the drug. So, I really can't speculate beyond that. But, I think I'd leave it at that. I'm going to turn this over to Mike for a minute.

And probably just one of the things, from a portfolio perspective, right? So 217, clearly, we have to think about what your question is, risk mitigation, how many studies that will come. We are a company that has multiple assets, right, early stage pipeline, we want to continue to make the investments to drive long-term value and see. So, we will look at this overall as a portfolio approach but obviously developing our SAGE-21 strategy as well.

Our next question comes from Andrew Tsai with Jefferies.

So, just wondering, if you can help point to some precedence in the neurology space where the FDA has allowed a company to amend one of its pivotal trials midway such as adding a new dose or changing the enrollment inclusion criteria. And then, doing so, enable that company to get its drug approved. Just really wanted to get a better understanding of how common this is in the neurology space? Thanks.

The way that we think about it is the following. Well, first of all, ZULRESSO would be a great example where as we move forward, we took what were originally Phase 2 trials, and were able to discussions under breakthrough to agree in what ways we be able to collect data, handle them and use them for filing. So, there's nothing magic about this. It's really about thinking through what makes sense in order to demonstrate the efficacy of the drug and making sure that those are ultimately at the end of the day ones that we’ll be able to use for a filing. That’s the way we think about it. And it's one of the reasons why, as Jeff has said, [ph] speculate about how we might do it, it's really most important to understand what the FDA expects, put that through our own internal discussions on how to get there and then be able to talk about that more broadly.

Yes, I think the other point is, if we -- for example, we talk about amending, which again was acceptable, obviously with the ZULRESSO program where the Phase 2 became a Phase 3. So, there -- we clearly have precedent, not only in the industry, but as the company. The other point to remind you is that we are -- the first data set has already been locked. So, the issues of multiplicity really don't pertain. So, this will be a separate study. What we're taking advantage of is -- and it's really an advantage of operating leverage, is that we have sites that are still open. So, we don't have to go through the startup and training again. And so, all we're doing is taking operating leverage. And we are calling an amendment, but it's going to be an independent trial with an independent staff. So, it's -- you really have to look at it very differently. It's not technical -- it's an amendment technically but not in actuality.

Our next question comes from Laura Chico with Wedbush Securities.

I guess, just one on -- you were mentioning quite a bit on population, PK and amendment for 217. Have you elaborated at all in terms of whether there may be a potential food effect? And I guess, the reason I'm asking is, one, how that would impact future amendments, but also, secondarily, what does this mean or the implications for the prior studies? And I guess, specifically, I'm thinking about the bipolar study, which used a 30-milligram dose there. So any elaboration on how you're managing food consumption in subjects in the trials? Thanks.

Yes. So, Laura, there's a lot of speculation out there, I'll just sort of put that to rest. There's a food effect and the drug needs to be administered with food. That's pretty straightforward. As we've talked about before, we look at things like in clinical trials how to make sure that those instructions are as specific as possible. Getting to the other part of your question, remember that the bipolar study that was an open-label, initial signal finding study, and of course we use that for internal decision making to help us understand potential signals. So, I would separate those two out. Really the issue is, how best to instruct patients, assuming that we are getting to a filing on have best to take the medication to enhance the likelihood…

Our next question comes from Ritu Baral with Cowen.

My question is on, I guess, more previous FDA interaction and your impressions of the current status of guidance. I'm not technically asking about the recent interactions. But, suppose RAINFOREST should not yield the data that we want, can you talk about your confidence that a relapse prevention study, like REDWOOD would be enough to support the MDD NDA filing, by itself in the absence of a potential positive RAINFOREST data?

Yes. I mean, I think what you're really asking is what [technical difficulty]

Hello?

Hello?

Yes.

So, I hope that completes the answer.

[Multiple Speakers]

I think what you're asking Ritu is really what's our path forward for Landscape Program and where we might go. And of course, we're in the midst of that, and we've spoken to that point. But I can tell you right now is we've always said, we've needed data from SHORELINE, as well as from RAINFOREST as part of our overall filing. But, the real answer is the one that Jeff gave right upfront which is when we finalize our discussions with the FDA and sort that through strategically, we’ll share what the plan is forward. And of course, we're very -- we are continuing to be very confident in the overall profile of the drug. It’s opportunity to get patients well quickly. That allows us to have some -- along with breakthrough some discussions on ongoing way with the agency about how most efficiently bring this medicine to patients. It’s the way we always think about drug development, it’s what we'll be doing in this case as well.

Our next question comes from Akash Tewari with Wolfe Research.

So, given your disclosure today about potentially slower ZULRESSO center preparedness and including the higher dose arm potentially in SHORELINE, I wanted to ask maybe about your cash burn expectations for the upcoming year. And whether holding back on the ZULRESSO launch, just for a moment, is a possibility, if you're trying to optimize your pathway forward for 217? And how important is your current cash balance in kind of thinking about the development path for 217? Does that come up number one in discussion, or is the first consideration doing what's right for 217, and cash is kind of the secondary consideration? Thanks.

Akash, it's Mike. And I'm going to -- I’ll then turn over to Kimi. But, let me take the ZULRESSO piece and then I’ll turn over to Kimi to more broadly how we're thinking about resource allocation. So, your question about resource allocation and how much we're allocating to ZULRESSO. Let's just step back for a second how we think about resourcing ZULRESSO. If you step back and you think about first product ever approved in postpartum depression, shifting the paradigm, hospital based launch, right, covering a wide degree of OB/GYNs and sites, we resource this to really build this thing out. We knew it was going to take time. We said all along it was going to take time to get there. We know the product is having meaningful benefits to moms. And so, we continue to focus on driving sites of care, focusing on our strategy that we can continue to see that guidance that we gave. Modest growth for the next couple quarters, we expect an accelerated growth rate in the second half of the year. So, we will always look at our resource allocation for ZULRESSO, make sure we're deploying our dollars to the things that we think drive the most value and drive patient access. And we'll always fit that into the corporate context as well. But, I'll let Kimi kind of talk through.

Sure. Thanks, Mike. And Mike alluded to this earlier is when we think about how we resource our programs, and it's really about thinking across everything, so thinking across commercial and thinking across R&D. I mean, resource allocation is one of the most important things that we do as a leadership team and throughout the Company. So, we always think about the near, the mid, the long-term opportunities and are we balancing that and are we balancing risk? So, those are the kinds of things that we think about as we determine where we should allocate our resources. You also had a question on cash burn. And so, we haven't been very specific right now on cash burn. It's - a part of that relates to really we understand a path forward for zuranolone. But with regards to -- and that's from the R&D perspective. But when you think about SG&A, we did do a good deal of build last year in 2019 for the launch of ZULRESSO and preparing to be ready to really [technical difficulty]. Can you hear us?

Yes. I can hear you.

Okay. Yes. So, we don't expect that SG&A will continue to grow into next year.

Our next question comes from Danielle Brill with Piper Sandler.

Jeff, I'm just curious about how I should be thinking about the progression from the time FDA meeting minutes are received to when you'll update the Street on next steps. Should I anticipate an update shortly after the minutes or is there still work that will need to be done internally?

I think, it's a top question -- a top tier question, which is, it really depends on what -- how the final feedback comes to us. And as you know, sometimes -- I know you know, sometimes what you receive is very clear, and you can [technical difficulty]. Sorry. Sometimes we're having a little technical issue here. Sometimes there are -- it's hard to talk through N95 masks. Sometimes you have commentary that requires clarification in the call. So, as we said, we anticipate we’ll have the meeting and minutes completed in the first quarter. And once we process those and determine what a pathway may be, at that point, we'll be able to communicate.

Yes. So, as Jeff said, the meeting will be in the first quarter, will get the minutes, ultimately have internal discussions. The teams themselves are working through potential options, based on what we think may ultimately come through these. And as Jeff said, depending upon the outcomes of those discussions, we'll share those as efficiently as possible. We've always done that. And that’s what we intend to do in this case as well.

Our next question comes from Matthew Harrison with Morgan Stanley.

Hi. Thank you. This is Max Skor on for Matthew Harrison. A quick question. When can we expect derisking or proof of concept data for 324 and 718, specifically clinical evidence that these drugs are active in the disease state, beyond biomarker-driven data? Thank you very much.

Hi, Max. This is Jim. I'll take that question. Yes. I think the answer for both programs is, we are moving forward. In both cases, we're making good progress. For 324, I'll take that first. That molecule is our next GABA PAM. It’s got a profile that’s differentiated from the first two. But, it still has the same pharmacology as the first two. And so, as we move into the neurology space, our first patient population will be essential tremor. Of course, we already have data -- clinical data in essential tremor with small studies with both, ZULRESSO and then separately with zuranolone, showing acute effects in essential tremor patients. And in 2019, we had a small open-label Phase 1 study, replicated those findings with SAGE-324. So, the next step is to move forward into a Phase 2 study, placebo-controlled double-blind study, replicating the SAGE-324. So, I would say, we do have some clinical data already with SAGE-324 into essential tremor. In the case of 718, this is an NMDA positive allosteric modulator. So, the front end of our neuropsychiatric franchise and a different mechanism of action and the GABA compounds we've talked about quite a bit in the past. I would say there as well, although the focus in 2019 was on Phase 1 study, looking at safety and tolerability, pharmacokinetics and those sorts of things, we did also include work looking at patient results. So, in the fourth quarter, we announced results from a small Phase 1 open-label study in Huntington's disorder where we're able to show similar to what we showed earlier in the year in healthy volunteers, improvements -- huge improvements in executive functions and Huntington's disease. So that program will move forward in 2020. And instead of moving directly placebo-controlled study in Huntington's disease, these results are interesting enough that we really want to get a better sense of what other patient populations could also benefit from this novel mechanism of action. So, our next step is to broaden our investigations in small studies, looking for the same sorts of cognitive improvements in additional patient populations.

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

As we think about the inputs that go into selection of higher 217 doses on the backdrop of the evolving population PK info, I was curious, if you could tell us a little bit more about the consistency of drug exposure, patient-to-patient that you saw in MOUNTAIN. How much higher exposure may have correlated to HAMD response? And then, the range of exposures relative to those that you might expect to achieve would say a 40 or 50 mg dose? Thanks.

Hey, Brian. It's Jeff. I mean, I'll just be brief. We haven't disclosed a lot of those data, just to be clear. What I can tell you though is what I said earlier is that we believe there is a correlation between exposure and also some certain physiologic markers as well when we've done it. And we're very comfortable with that. So -- and again, as a key to this drug, and I think you all know is for that, it's like, looking at the population PK and understanding that dose response relationship -- dose exposure relationship, which we think we have established.

This is Steve. And the way that we do it is more than simply looking at correlations between popPK exposure and dose. One of the advantages now of having a program where we've had more than a couple of thousand patients who've been exposed is we're able to do more advanced modeling of these exposure response relationships. That's something that also goes into that decision making process. So, really be able to understand those relationships.

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

Hi. Since SHORELINE seems like the next big data point for zuranolone, talk about progress with that study and what you hope to see from it, what it will inform you about the activity of the drug. And if you end up adding another cohort to that study, could you still have data in 2020, or would it then likely be pushed out to 2021?

Yes. So, thanks for the question. It's an important one. SHORELINE is an open-label study, actually looking at the responses of patients who responded initially to 217 who we then follow on throughout a year. And the goal of the study is to look at how often patients need to be retreated, and what are those outcomes. So really, this is the largest cohort of patients inside of a development trial for depression that's ever been undertaken. And it provides some very fundamental information that we don't have to date for depression broadly and for 217 specifically. In other words, we'll be able to understand what patterns of retreatment are out there, potentially, whether there are differences in those patients that are able to be maintained for very long periods. We've already spoken about the fact that we've seen some patients within these trials being able to be maintain for very long periods without additional retreatment. So, it'll give us a lot of understanding, both of how the medicine is used best, what patterns of recruitment we might expect, and in whom. And, this is an open-label study. We're able to make use of those data in an ongoing way. If we are to change doses or increase doses in the cohort, then as Jeff said before, those may be handled as an independent group. But, we’ll still be able to have data on those patients that are fully enrolled as anticipated this year.

And one other, Gary -- this is Mike, to add on to that. One of the other important pieces of 303, the SHORELINE study is from a pricing strategy. As Steve said, we're going to get information on how patients are treated, how often that will ultimately help formulate what our pricing strategy is going to be on a per doses spaces for zuranolone.

Okay. And are there both, MDD and PPD patients in that study? Is it broad enough?

No, this is a study focused on the MDD program. Just like in ZULRESSO, long-term data has not been part of the PPD program. So, this is MDD focused trial.

Our next question comes from Marc Goodman with SVB Leerink.

This is Rudy on the line for Marc. So, I have two quick questions. First, can you talk about patients’ and doctors’ feedback so far for ZULRESSO’s drug profile and the ZULRESSO experience in general? And second, can you provide more color on upcoming essential tremor study for SAGE-324? And what data should we expect from the trial?

Yes. This is Mike. I'll take the first part on the patient and HCP feedback for ZULRESSO. So, as we said, the meaningful benefits that we're seeing in patients is mirroring what we saw in the clinical studies for ZULRESSO. It's been great to see. And in the real world, that's one of the first things you look for when you launch a drug is that the data that you saw in the clinical trial, does it get replicated in the real world. And so the patients who have been treated, they've seen meaningful benefits, which is really exciting for the team and motivational for the sites of care as well to kind of push through some of the steps to activate. On the HCP side, as you saw, we've increased the number of HCP referrals up over 300 in the quarter. The patient demand for the year was 500, 300 in the third and the fourth quarter, so a 50% increase. So, we've meaningful increase in both patient demand and HCP referrals. One of the points that’s probably important to note, consistent with what thought going into the launch, the HCPs are using this initially in the severe patient populations. But, as they gain more experience, we think there'll be an opportunity to move this forward in the treatment paradigm for PPD. I'll turn it over to Jim on the 324 question.

Yes. And so, for the essential tremor trial for 324, the study will be starting in the first half of the year. And the study is a Phase 2 placebo-controlled double-blind study comparing two arms, placebo relative to 60-milligram dose of SAGE-324. Primary endpoint is reduction in tremor, upper limb tremor, really the same thing that we did in our open-label study. And the goal of the study is quite simply to in a placebo-controlled blinded study to replicate the kinds of reductions in tremor that we saw with the Phase 1 work; the other difference of course being Phase 1 work was acute, this was a 30-day dosing study.

Our next question comes from Yatin Suneja with Guggenheim.

Just a couple. Could you maybe share your thinking about the path forward in PPD, based on current data set? What was the thinking for not seeking an approval in 2019 after success, if long-term safety was not the gating factor, is there a change in thinking now? And then, the second question is, if you were to test a higher dose, could you please help us understand the type of safety data you would need to build? Could that change the NDA submission timeline in any way versus a scenario where you don't have to test the higher dose? Thank you.

This is Jeff. I'll be quick. When we announced the breakthrough program, the original pathway was that we needed two depressions and 1 PPD, plus the safety data for an approval for both indications. Obviously, that's one of the many potential pathways that we're now considering and we'll have some -- so we can't really comment beyond that since that's -- that'll be something that will be up for discussion or has been up for discussion, or will be up for discussion with the FDA. So, that's it from that standpoint. With respect to dosing, we do have already a lot of -- several studies with higher dose exposures. And I think that we’re long with that. So, we're pretty comfortable -- very comfortable, we can go higher. With the turn of the overall database, we don't believe that safety for higher dose will be a rate limiting step for us. It's important to remember that while some of the stuff is not disclosed, as we move forward with higher doses, all these data go to the agency, the FDA, and they will have the opportunity to review it as we have. So, we don't think that safety around higher doses will be rate limiting, but again, this is -- all of this will depend on our final decision and pathways after whenever we receive the minutes after our first quarter meeting.

[Operator Instructions] Our next question comes from Jay Olson with Oppenheimer.

As you catch your learnings from the ZULRESSO launch to leverage for future programs, can you talk about any work you've done to evaluate economic outcomes for patients treated with ZULRESSO in terms of potential cost savings to the health care system? And how important this type of information will be for the uptake of ZULRESSO and PPD, and eventually for the launch of zuranolone in MDD?

Yes. Really important question. We've been working very closely with payers through our Health Economics and Outcomes Research. We actually do research and publish quite a bit. We had a recent paper doing an indirect comparison between ZULRESSO and available care, as well as looking at patient reported outcomes in our ongoing programs. And what we've seen are very dramatic differences between both, ZULRESSO and zuranolone as well as standard of care, based on this indirect comparison, both in terms of number needed to treat, as well as overall aspects of health related quality of life. So, we really -- we are really starting to understand what are the specific areas that payers are interested in around postpartum depression, meaning time back with children and so forth and the ability to fulfill appropriate roles, as well as what’s most important for patients with depression itself?

This is Jeff. I just want to point out we've actually published some of these analyses recently in CNS Drugs. And it was basically a [indiscernible] and it was in CNS Drugs. We can give you the reference later, which is a very nice med analysis, looking at indirect comparisons between brexanolone injection versus SSRIs. And that can actually give you some of the data analyses, some of which we've actually now methods that we’ve pioneered. So, I think that's well worth taking a look at, because that will give you a full picture of how we’re thinking about it.

This is Mike. Just to take it one step back. And your question was also going to learnings, right, from ZULRESSO to 217. And if you think back to learnings, I should go prelaunch, right? What we learned about engaging the payers early on was helping them understand what the unmet need was in PPD and what the burden of the disease was, some of the things that Steve was describing. So, to get the favorable coverage that we have now, the 80% favorable coverage that we have was the work that we did to educate the payers early on, which was the continuation of which we'll do with zuranolone, right, at the appropriate time. So, we want to continue to see ZULRESSO will real world evidence, both on the clinical side and the health economic side. We think the better value story we can tell, I think the more you're going to see sites lean into it because they're seeing the efficacy benefits, they want to see some of the health economic benefits as well.

Thank you. Our next question comes from a Vamil Divan with Mizuho.

Great. Thanks so much for the question. So, maybe just following up on the ZULRESSO commentary there. I appreciate the payer coverage comments you've made. My question is just around sort of the total out-of-pocket costs that patients have for a product like this? I know it's early and there's probably not a lot of data yet, but beyond the drug, I'm thinking about sort of facility fees, getting infusion, any fees on infusion or provider fees being in the center for 60 hours? So, do you have a sense, in terms of what's the range that patients are being asked to pay out-of-pocket for the total sort of procedure?

Yes. So, we're not giving range in terms of dollar amount. But what I can tell you is that's what Sage Central plays a critical role. We have Sage Central, we have financial assistance programs that are set up and designed not only to cover the costs, the co-pays and out-of-pocket for the drug, but also where we can and compliantly do it on the infusion cost as well. So, what I can say at this point is the out-of-pocket expenses for the patients have not been a barrier, right, in terms of their access to the treatment. And we'll continue to monitor our financial assistance programs but it's been a big part of our value proposition to the patients, to the health care providers that if there was financial assistance and we can provide, we will step in to support the patient.

Thank you. Our next question comes from Tim Lugo with William Blair.

Hey. This is Lachlan for Tim. Thanks for taking the questions. I was just wondering if you continue to interrogate the data from the MOUNTAIN study. Have you seen any differences between patients that were on a background therapy versus not, or any other baseline measures like anxiety or insomnia?

Well, the details aren't available for public disclosure at this point. We are continuing to look at the data to understand whether there's any differentiation within patients. The ones that we’ve talked about are the ones that we've been focusing on maintaining the appropriate -- make sure that patients are compliant and have the appropriate inclusion criteria. But, there was nothing else about the data that would give us pause today. Plus, we continue to interrogate that internally and that's what we do until we are approved.

Thank you. Our next question comes from Sumant Kulkarni with Canaccord.

So, given all the current evaluation with the 217 program and the ongoing interactions with the FDA, at a very high fundamental level, how’s your thought process evolved to maybe suggest that PPD could actually be a very different underlying disease versus MDD, which by its nature is a much more heterogeneous indication without a specific trigger, such as the birth of a baby, or is this simply a matter of PK/PD or dosing differences within these indications?

This is Jeff. I think, it's a good question. I think, if you look at what -- how we look at psychiatric disorders, and that has to do with validators of disease states. People with postpartum obviously have a different prescriptions. But if you look at their family histories, if you look at the course of the illness, if you look at symptom cross-sectional symptomatology, they're very similar with MDD. The major difference, of course, is that PPD, when it resolves and as it has with -- some of our ZULRESSO patients, if a recurrence occurs in a year and there is no childbirth, it's simply categorized as MDD. But, if you look at all the other typical validators response and antidepressants, whatever they may be, family history, things of that nature, they're probably part of the same effective spectrum. Whether women have a different underlying diathesis that makes them more vulnerable, I think that's something that none of us know yet.

Thank you. I'm not showing any further questions at this time. I would now like to turn the call back over to Dr. Jeff Jonas for closing remarks.

Well, firstly, thanks, everyone. And before I end, I want to thank the teams at Sage for their hard work. And for us at Sage, we feel like we're creating value with a market of product in an area of unmet medical need, a Phase 3 asset now with the large market indications, with two positive pivotal trials, which is a novel agent, the deep pipeline, and a really strong research engine, and not to mention that I think we're in a great financial position with about a $1 billion of cash to execute. With all that said, we're looking at some -- we have a broad portfolio, many of which -- which we think represent deep opportunity. So, our focus in 2020 is going to be guided by our perseverance, really disciplined execution and rigorous prioritization to really ensure an optimal pace of innovation for what we believe is a leading novel portfolio of NCEs dedicated to treating brain health. So with that, I want to thank everyone for their attention today and have a great day.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.