All right, let's get started. Thanks for joining us at the Sage Fireside Chat at the 44th Annual TD Cowen Health Care Conference. I am covering analyst Ritu Baral and joining us from Sage today. We have CFO Kimi Iguchi to my left. After that, CMO Laura Gault, and Chief Business Officer Chris Benecchi. Chris, Laura, Kimi, thank you for joining us today. Let's start off. Kimi, if you want to give sort of state of sort of state of the union of Sage as you embark upon a commercial launch, but with a very, very active pipeline. Yes, yes indeed. Well, thank you so much, Ritu, for having us here. We appreciate it. Looking forward to it, looking forward to the discussion. For some of you who are not familiar with Sage, Sage is a company that's focused in the area of brain health. And we have really focused in on two mechanisms, the GABA and NMDA receptor systems, as, as, a way of getting there. And from there, we've been able to create a very differentiated and diverse pipeline, so, very robust pipeline. We have a we'll be talking a lot today about ZURZUVAE, our first launch, the first oral product launched for women with PPD. So we're very excited about that launch, and the launch is, is going very well, and I know Chris will spend a lot of time talking about that. But on top of that, we have this very rich, a catalyst-driven year across two major programs, dalzanemdor, which we're looking at in three different indications in Huntington's, Alzheimer's, and Parkinson's disease, as well as SAGE-324 in essential tremor. So a lot's going on at Sage, and thankfully we do that with a very strong balance sheet. We have a lot of cash in the bank, and we just received a milestone from Biogen for the first commercial sale of ZURZUVAE and PPD. So we have a good, strong balance sheet to get us through all those catalysts and to see the launch move forward. So we're very excited about the year. It's too soon. I can't call dalzanemdor. I can't do it more than once. We're going to hold SAGE-718 too soon. Let me start off with ZURZUVAE for PPD anyway. Maybe Chris will start with you on the care journey for PPD patients. As we talk to psychiatrists, as we have conversations with OBs, we get, it's like a tale of two cities where OBs will say one thing, psychiatrists are like, "Oh, all these women, you know, they have psychiatrists. They can just come see us." And the OBs are like, "No, they absolutely do not." Take us through the care journey as you see it now with increasing awareness of PPD through lots of things, not just ZURZUVAE, but, you know, what are we looking at in today's day and age? Yeah, I'm happy to take that question. Before I start, though, I want to share my excitement around the launch of ZURZUVAE. I'm a psychiatrist. I've treated women with PPD, and it really is an area that has been underserved for far too long. And it's exciting to me personally and as a member of Sage to really see this launch going forward, getting off to a good start, and knowing that we're at the beginning of being able to help a lot of women who are living with PPD. In answer to your question about the care pathway, I think there are a number of different ways that women with PPD can be identified within the system. And, Ritu, I think you raised the point that maybe there are slightly different patient populations seeing a psychiatrist versus an OB. Really, when you think about the type of person who will be diagnosed at an OB's office, it's probably someone that they followed through the pregnancy. They've probably been monitoring them with screeners, and then they at some point test positive on the screener and are evaluated and treated. If that person is not psychiatrically complicated, the OB will often do that diagnosis and treatment themselves. If at some point along the way, either before or after they make the diagnosis, they realize that the patient is complicated psychiatrically, then they may start a treatment but refer the patient out to a psychiatrist for further care, or they may refer. Laura, there are two things, I'd like to follow up on. You used the word screeners or screenings, plural. In my own experience, when I had my daughter, there was one at six weeks postpartum, and that was literally it. Has that paradigm changed? And then can you clarify what you mean by complicated? Sure. So, in terms of the screening tools that are used, they really are being used a lot more these days than they used to be. And it's really driven in part by interest from professional organizations. So the American College of Obstetricians and Gynecologists recently released a guideline, that really tells the physicians how often to screen, how to screen, what constitutes a positive screen, and what they should do as next steps. And that was released in June just ahead of our PDUFA date for ZURZUVAE. Once we had our PDUFA and our positive indication for PPD, they actually issued an update to that guideline within days that, you know, gave their members information about the benefit-risk of ZURZUVAE and how they could potentially use it in patients with PPD. So that's one example of how there's a lot more awareness of PPD as a disease and a willingness to screen for it. But ACOG is not the only professional society to do this. The American Academy of Pediatrics, I mean, these, these are physicians that don't even see women with PPD as patients, but they see a lot of women in that year postpartum because the women are bringing their children in for well-child visits. Constantly. And there's a recommendation from the American Academy of Pediatrics to screen these women and to refer them if they screen positive. So, you know, I see evidence from a lot of different professional societies, you know, including, as well, like the American Academy of Family Physicians, that are really all moving towards this, really strong suggestion to screen during pregnancy and in the postpartum period and are really providing practical guidance about how to treat these women. In addition, there's legislation that's been introduced and passed in many states that requires screening during pregnancy and in the postpartum period. And so you're starting to see that take hold in physicians' offices across the country. So I do think that screening has been picking up steam over the last few years. Certainly, with the availability of a drug like ZURZUVAE, that can be used easily to treat women with PPD, there will be more impetus to diagnose because now we have a treatment that's indicated for it and is, you know, easy for practitioners to learn how to use. And then the definition of complicated. Yeah. So a psychiatrically complicated patient, at least in the eyes of a psychiatrist, is a person who has more than one diagnosis, you know, psychiatric diagnosis. It was taking a number of different psychiatric meds. And in most cases, psychiatrists will feel very comfortable managing that patient, but a physician who's not a psychiatrist will often enlist the help of a psychiatrist. So, so if a woman goes to her OB and the OB says, "It looks like you have moderate PPD," I mean, obviously, if it's severe, they might get a little scared, but and they're not on any background meds or any this, any Xanax, whatever, you believe that they would feel comfortable making that ZURZUVAE. Yeah. I think Chris will speak to it in a little bit, but that's what we're seeing in the launch, that OB/GYNs are comfortable prescribing this. Can you describe that, that screening and diagnosis process right now in a little more detail, if it has evolved so quickly over the last few years? I don't think anybody's going to be familiar with it. Well, you're using standard tools like the Edinburgh Postnatal Screening Tool and, you know, looking for reaching a threshold. I think it's 10 for people to be considered screening positive. Once you have a screening tool that tests positive, that's not a diagnosis. You need to sit down and talk with the person about what they're experiencing, and you would make the diagnosis based on criteria that are outlined in the DSM. And at this point, physicians are very familiar with those criteria. And what are you seeing as that screening and diagnostic conversations increase, what prevalence are you seeing? Because I think we think of PPD as prevalent amongst 11% of pregnancies. Is that still the number that you're seeing with the increasing? So, what we see currently today is that 1 in 8 women will have symptoms of postpartum depression, and half of those will go on to be diagnosed with PPD. I see. So the 50%. So of those, only half actually go on to treatment. So there's a gap really at several steps along the way, both from, you know, onset of symptoms to diagnosis, from diagnosis to treatment. And this is the standard today. You know, I expect that we'll be seeing, with the availability of ZURZUVAE, that will drive interest in making the right diagnosis and treatment. Eventually, that we'll see more, more patients being treated. In your outreach so far, who has shown more familiarity with ZURZUVAE? Is it the psychiatrists or the OB/GYNs? Yeah. Just want to clarify. Yeah. So I would say when we spoke at our last earnings call, we talked a lot about the balance prescribing between OB/GYNs and psychiatrists, and we continue to see that well into the start of 2024. OB/GYNs and psychiatrists are both active and engaged in screening, diagnosing, and treating patients with ZURZUVAE, as well as PCPs. We do see a handful of PCPs as well. So we're really encouraged by that. I think a bear thesis that we heard as we were getting ready for launch was that, you know, frankly, OB/GYNs wouldn't write it, that there was a bottleneck in the psychiatric community. There just weren't enough psychiatrists to manage it. We're actually seeing quite the opposite. We're seeing, again, OB/GYNs very comfortable and confident screening, diagnosing, and treating, and psychiatrists as well, which is a strong telltale sign for the start. Among the OB/GYNs, are you seeing different populations? Are there you can track, I think, which doctors prescribe lots of, you know, sertraline or whatever. So are there a group of doctors who you can very clearly see are very, very comfortable prescribing antidepressants already, and then others, other OB/GYNs who just will not? Yeah. So it's been interesting because when you think about our sales force that's out there, obviously, when you launch a medication, where you start is typically with physicians that are already treating PPD and that have a large cohort of patients that, you know, there are to choose from. And in effect, we're seeing prescribing coming from that group of physicians. But what we're also seeing are non-called-on physicians that are being reached through omnichannel efforts, and whether that's digital promotion or it's the effectiveness of our broader communications campaign, we're seeing non-called-on physicians using the medication as well, too. Those tend to be physicians that aren't as adept at prescribing for PPD or that don't have large patient populations. It's going to be really important for us not only to call on OB/GYNs and psychiatrists and PCPs, but to use sales force and non-personal efforts, broader omnichannel, to reach the broader group of physicians. Because frankly, I think Laura hit on it, you know, one in eight live births, 500,000 or so women, half diagnosed, fewer than half of those screened. There's a lot of work to do to get the message out there about screening, diagnosis, and treatment as we go forward. We're going to need all of those channels in order to effectively do that. Can we talk about your field force? How many reps do you and Biogen have? How are they managed between that joint partnership? Yeah. So when I think about a sales force, we actually had a call yesterday with our entire sales force, and one of the neuropsych account managers, effectively our sales force, was talking about the number of launches she had under her belt, and the number was more than 12. And that vastly represents the sales force that we have in place right now. It's really a seasoned sales force of experienced individuals who have track records in CNS of launching innovative medications and bringing those innovative medications to healthcare. How many of them? We haven't communicated the exact number to date, but, you know, we're starting in a focused way, and our plan is to scale with success as we go forward. Can you say who you've hired them from without getting a seasoned assistant? Yeah. We can't say who we've hired them from, but when you take a step back and think about other blockbuster launches in the CNS space, we have many of them represented in the CNS space. Neuropsych launches. Okay. Got it. That's right. And that's really what we've drawn from, those types of individuals that are passionate, that believe in what we're doing, and those that you would really want in a launch like this where you're defining a space for the first time, the treatment of PPD with the first FDA-approved medication. How is this effort you've talked about scale for success repeatedly? How do you see that in the near term? Just last quarter, I think you said you had 120 prescriptions. I remember having this conversation with clients, in the November, December timeframe. You know, what would make people happy? And like, "100 would be great. 100 would be great." Come in at 120 with 10 days like, you did this in 10 days. You literally did this in 10 days, over the week of Christmas and New Year's, where I mean, I don't know how many of you were working between Christmas and New Year's, but I think that tells you something. You must be deploying at least some near-term scaling for success because that seems like at least some early success. What are you doing now? Well, maybe I'll start, Chris, in that. So So our philosophy, as you as Chris mentioned earlier, has always been to be very focused to start with and scale with success. So what that means is really looking at the metrics, things like sales, revenue, shipments, who's prescribing, where, where it's being prescribed. We'll look at the vast array of those metrics to decide when, where, and how to scale. And we'll just. But this feels like a little bit of success, so. Well, yeah. And so I agree with you there. I think what we would say is that, you know, based on where and how the launch is going, it feels like, yes, we would expand. I think it is a little early yet. And so what we want to do is take the time to see that trajectory continue, but we're already thinking about what it is and when, you know, when and how it will happen. Is this something you're going to assess quarter- by- quarter, or will it take longer than that? Over time, I think, you know, what we'll do is we'll step back again and really just gauge it to the metrics that we see and use those metrics to be smart about how we increase our investment. Can we talk about reimbursement? What are the challenges that you've seen thus far? I mean, Barry has mentioned the free drug program, for the near term, for as long as, you know, things are not on formulary and you don't want to keep patients waiting. You want to set up a best experience. Where are you in that process, and how are you deploying that free drug program? Yeah. So where we are today is in large part the result of about 2.5-3 years of work that have gone into this effort, you know, with payers over the vast amount of time. You know, we have been talking to payers for the last 2-2.5 years about unmet need in the marketplace. We've had the opportunity to present the data from ROBIN and SKYLARK, which we believe is compelling from both an efficacy and a safety perspective. And as we've thought about the commercial positioning of the medication, we've worked closely with payers to make sure that we understood what their needs are and they are as we go forward. So I think with that being said, right now, we are in a very positive position with payers because that conversation has gone well over time. We've said that we would communicate and we would see payer acceptance of the medication, commercially insured patients' plans in Q1 and Q2, and that government plans, mainly Medicaid, would come online in Q3 and Q4. We're on track for that. You know, we're seeing, again, positive progress with payers as we go moving forward. I think a telltale sign has largely been, at this point, the vast majority of prescriptions that we've seen have been covered prescriptions, whether they are commercially insured patients. Have you given the proportion? We haven't as of yet given the proportion, or Medicaid- covered lots. So again, I think there's a lot of inertia here for a very positive. Medicaid granted through exception? Medicaid through formulary exception. Who is who, who's leading the conversations with payers? Is it you, or is it Biogen? It's joined between Sage and Biogen. Could it just be you because maybe they shouldn't, maybe not in the best position to be talking to payers right now? What I can say is that between the two organizations, we have very seasoned, experienced professionals who have familiarity with many of these plans and the ability to effectively weigh in and have conversations that are to the benefit of ZURZUVAE. Okay. All right. You're not blocking Rx reporting, and I think a lot of us are looking at those numbers as they come in. How should we be framing those numbers as they're reported? You know, your opinion of the capture rate and what additional metrics can we expect as the launch matures? So on the data that you're seeing, that is shipments, right? So that's not prescriptions. I think some people have kind of gone back and forth on that. So that's the shipments. What you're seeing in that data as well are that does not include our free drug program. So it's only paid prescriptions that you're seeing from the IQVIA data. And I know Chris likes to say, "Looking at week-to-week numbers is probably not the best thing. You should be looking at the trending over time," right? I tell people within our own organization the same thing, so. Yeah. So, yeah. So that, that's what's in the IQVIA data. Got it. Let's see. We've got about 12 minutes left. Let's move to SAGE-718. Laura, can you review the mechanism of action of the drug? And then can you cover for us the biochemical rationale across the three programs? We'll start with Huntington's because that's what I love to talk about, but also Parkinson's and Alzheimer's. Yeah. Sure. So in terms of the mechanism of action for SAGE-718 that we now call dalzanemdor, it is an NMDA receptor positive allosteric modulator. And one of the things that Sage has been known for is understanding the neuroactive steroid space and developing drugs based on that understanding. And what we learned is that there's an endogenous neuroactive steroid, 24S-hydroxycholesterol, that binds to the NMDA receptor and increases the conductance of the channel when glutamate is bound. And so we designed a drug that mimics the activity of that endogenous neuroactive steroid in promoting the positive allosteric modulation at the NMDA receptor. So this is a drug that was discovered at Sage, and we're developing it alone without a partner. So the way that this works then is when glutamate is bound to the receptor and dalzanemdor is present, it increases the amount of current that is conducted through the channel. So it basically increases signaling through that pathway. And in that way, will lead to improvements in cognition. When you step back and think about the different disease areas that we're looking at, whether you're looking at Alzheimer's disease, Parkinson's disease, or Huntington's disease, what is true across these disorders is that they're all characterized by NMDA receptor hypofunction. So the NMDA receptor is not working as well as it should. And we know from our preclinical work that it almost doesn't matter how you hit the activity of the NMDA receptor. You can knock it down with autoantibodies. You can block it with things. But when you give SAGE-718, you can reverse that. While we understand that the mechanism that underlies the NMDA receptor hypofunction is different in these disorders, we believe the evidence suggests that we should be able to return the receptor towards normal functioning with dalzanemdor. Given that there are differences, however, in the disease processes and how patients present with the disease, you know, it's absolutely not the case that a positive or negative result in one of these studies is a perfect predictor of what will happen for subsequent studies. Can you walk through Huntington's in particular? Because from what I've read, there's an initial period of hyperactivity, and neurotoxicity from NMDA hyperactivity in Huntington's that then almost leads to NMDA receptor burnout. Did I interpret that correctly? So I am not aware of that data. What I can say is that we know from work that we've done and has been replicated in other labs that levels of that endogenous neuroactive steroid, 24S-hydroxycholesterol, are lower in patients with Huntington's at the beginning of the time when they start to show cognitive impairment. And so we believe that what we could be doing is sort of replacing the effect of 24S-hydroxycholesterol by modulating the NMDA receptor through binding to that binding site. Got it. You know, your first data from SAGE-718 is going to be from PRECEDENT in Parkinson's, early 2024. Can you walk us through that Wechsler primary endpoint? What does it measure, and, and what sort of delta are we looking for? Sure. So the primary endpoint for the Parkinson's study is the Wechsler Adult Intelligence Scale Coding. And it's actually a subscale to the WAIS test, which is an IQ test. This test has been used a long time. It is very similar to another test called the Digit Symbol Substitution Test that's also been used for a long time. And when I say a long time, I mean like 100 years. No, I'm not kidding about that. And so as a consequence of these tests having been around for a long time, we do have a lot of normative data in different age ranges and different types of populations. Unfortunately, there isn't normative data in Parkinson's or Alzheimer's or Huntington's that we're aware of. But the reason that we chose these is because we believe, based on our preclinical data and what we saw in our early open-label studies in each of these indications, is that dalzanemdor improves working memory or sorry, learning and memory and executive function. The DSST or the WAIS-IV Coding is a really good way of measuring that. Because we had seen signals in our open-label study, it made sense to then include that, to really improve signal detection in this study. I think at this point, it's important to point out that this is a true phase 2 study. It's a learning study. It's not intended to support an application, not intended to be a pivotal study. We've designed it in such a way that the primary endpoint is the WAIS-IV, but we've also included other measures of cognition that could be suitable as phase III endpoints, things like the SCOPA-COG, and MoCA. When we get the data, we'll be looking at the impact of dalzanemdor across all of these different measures, as well as on measures of function and global assessments. Got it. As we look at the Huntington's program, how do they differ? Can you walk us through how DIMENSION and SURVEYOR differ? And I wanted to spend a little time talking about the HD-CAB primary efficacy endpoint, and the other scales, the Hi-DEF measure that you're validating. Sure. Okay. So let's start with the overall Huntington's program. You know, I mentioned for the Parkinson's program, that's a phase II study. The Alzheimer's is, is that as well. When we thought about the Huntington's program, we designed it to be more flexible in that we have two studies in that program, the SURVEYOR study, which reads out earlier this year, and then the DIMENSION study, which will read out later in this year. And we designed it so that the SURVEYOR is our learning study, and we're using that to learn about how cognition differs in Huntington's disease compared to healthy controls, and also to understand how changes in cognition are carried through to changes in the other measures like function and global assessments. So it's a very different purpose than a typical phase II study. And even though we do have subjects who have Huntington's disease who are randomized 1:1 to drug and placebo, there are only 20 subjects in arm. And the intention of this is not to show a drug-placebo effect, but rather to understand these relationships and better understand our measures. Alongside this study, we're running the DIMENSION study, which is a much larger study, more conventionally designed to be a phase II study or potentially a phase III study. It's enrolling about 180 subjects 1:1 between placebo and active groups. And we're following those patients for 12 weeks. The HD-CAB, which was mentioned, is the primary endpoint. And the HD-CAB is the Huntington's disease cognitive. For both studies? Yeah. Well, actually, for the DIMENSION study, it is. For the first study that I described, the SURVEYOR study, it is included as a measure, but it's not the primary endpoint because, again, we're not looking for between-group changes. So for the DIMENSION study, that's been designed using the HD-CAB as a primary endpoint. And that is a composite measure that was, actually, put together by experts in the field so that it measures domains of cognition over time that are known to be impacted in Huntington's disease. So there's a lot of confidence in this measure. It's been validated for a lot of uses. And it made sense to include it in the Huntington's program as a primary endpoint. So that said, it is an endpoint that hasn't yet been used for regulatory purposes. One of the reasons that we're getting the SURVEYOR data is to be able to put the results from the HD-CAB in context and understand how changes on the HD-CAB would impact function and global function. Got it. And so are you correlating that well, you're correlating that with function. Is this one of those conditions where the FDA is going to come back and talk about activities of daily living? Where does Hi-DEF come in? Right. So we have not yet had those conversations with the FDA. And so it's at this point not possible to predict exactly what they will require. But I feel confident, based on how we've designed the program, that we have a lot of data to bring to bear to the conversation and we'll be able to identify a suitable path forward. Got it. The Hi-DEF that you mentioned is actually a patient-reported outcome that was developed by Sage in collaboration with the patient community. Essentially, what we did is we talked to a lot of patients with Huntington's disease who have cognitive impairment and asked them to share with us what challenges they faced. We listened for common themes and then put those into questions in several categories, like the performance at work, how things are going at home, driving, and communication. We developed a set of 47 questions that we then validated in a longitudinal observational study that involved 150 patients with Huntington's. So it's a pretty large study for a rare disease. We looked at this measure over time and better understood which of these questions was really measuring things that were important to the patients. At the end of that, we ended up with enough data to validate the endpoint. So we are including it in our future studies. We'll potentially be discussing that at the end of phase II meetings and with other regulators as well. As part of potential pivotal PRO? Well, as part of our overall data package. As part of the design in a pivot rather great. We have a couple minutes left. I want to make sure we hit SAGE-324 and your ongoing essential tremor study. What is the next update we're going to get? We have, and the other thing Athena and I have seen is other developers that are sort of modifying that TETRAS in various ways. Can you describe the variant of the TETRAS that you're using and the FDA buy-in to that? Sure. That's a whole lot of questions rolled into mine. So let me start with a little bit of background. 90 seconds. On SAGE-324. It's a GABA receptor positive allosteric modulator that we're developing in collaboration with Biogen. We've previously conducted a phase II study called KINETIC 1, where we looked at doses of 60 milligrams versus placebo. And in that study, we did see a statistically significant reduction in tremor amplitude. But we were also giving the drug in the morning, and it does have sedative properties. And so the degree of sedation and somnolence was higher than we wanted to see. And so we designed the next study, KINETIC 2, to look at different doses of SAGE-324 over a 12-week treatment period. So we're looking at a 15-milligram dose, a 30-milligram dose, and then a dose that's titrated up to 60 milligrams. We're also giving the dose at night rather than in the morning so sedative properties may actually be useful to promote sleep. So, what we're looking for there is evidence of a dose-response relationship and also using the data to identify a dose or doses that is that are efficacious and have the right risk-benefit profile that they would be suitable for chronic dosing in this population. So the endpoint that we're using as our primary endpoint in the KINETIC 2 study is the TETRAS Performance Scale. And this is a scale that really measures tremor amplitude in different parts of your body on both sides of your body, both, you know, both, right and left sides. And, you know, you can look at that and understand if your drug is having an impact by reducing the amplitude of the signal across these different measurements. And it's a good measure to use for signal detection. Not just your hands? You said all over your body? Well, yeah. If you can do hands, face, legs. So there are a variety of different limbs that are looked at for the TETRAS. It's a pretty standardized. It's so that you're using the standard version. No. Yeah. We're not doing anything spectacular. And, you know, our primary endpoint is actually the performance subscale that looks at the arms. But actually, everything is measured in the overall assessment. Got it. That timing at this point is? Timing. A timing for the data. For readout. The readout will be mid-year this year. Coming back to your question, we're using the TETRAS PS as our primary. We're aware that Praxis has gotten feedback from regulators that they like to see the ADL, the modified ADL. We are collecting that data, and we will have that data to have discussions with regulators. And if we get the same advice, we'll be well-positioned to be able to design a study on the basis of the data that we get from KINETIC 2. There would be a discussion on the far end of that mid-year data. Great. Correct. So an exciting year ahead for us. A lot going on with the launch and with the data readout. So we're excited. Yeah. So So the Parkinson's data first, then we have mid-year. We have SURVEYOR. We have the essential tremor data, FDA discussions, and then DIMENSION. And on top of that is all the launch. Exactly. The Alzheimer's study in there towards the end of the year. Yes. Towards the end of the year as well. Great. Well, thank you, guys. Thank you. You're very helpful. Thank you so much. Okay. Thank you. Thank you.