Great, thanks. Good afternoon, everybody. It's my pleasure to be hosting this panel with Barry Greene, CEO of Sage, who I've known for a long time, and we did a bunch of panels in his Alnylam days. So, Barry, thank you for making the time. I really appreciate it, man. Maybe we can start by just having Barry give a quick snapshot of Sage, talk about how the zuranolone launch is going, and talk about the 718 and ET studies just at a high level, and then we can drill in deeper. So thank you again, and take it away, please. Yeah, Paul, I appreciate you having us here. These are important discussions. So, you know, we at Sage are focused on brain health. We believe that we are the leaders in brain health, and have an opportunity to build a top-tier biopharmaceutical company. That stems from our deep understanding of our neuroactive steroid and oxysterol chemistry platform, which we've applied to our learnings in the GABA and NMDA pathways, where we look for natural endogenous metabolites that regulate these pathways and then use our chemistry knowledge as a drop-off to then design new chemical entities to target those. That's evidenced by Zulresso, zuranolone, dalzanemdor, and SAGE-324 reading out this year. So, very exciting time at Sage. We have a catalyst-rich year, as you're well aware, with the launch of Zurzuvae in PPD, as well as the number of data readouts across dalzanemdor, which I know we'll talk to, in Huntington's, Parkinson's, and Alzheimer's, as well as SAGE-324 in essential tremor. So kind of big year ahead of us for Sage. Okay, awesome. So let's start with PPD. You had this nice start in December where, you know, there's clearly a bolus of demand in just 10 days. What have you seen since, and what are some of the more interesting trends that are kind of starting to play out now that you've got three months or so behind you? Yeah, Paul, we can say it. And clearly we'll, you know, we'll give a full quarter update at our quarterly call. We'll give the data. But as you said, we made Zurzuvae for women suffering from PPD available in mid-December. There were roughly 10 days where patients could access healthcare providers. So reflected about 10 days, we saw, you know, over 100 scripts, 120 scripts, 50 shipments went out the door. And importantly, the majority of the shipments are being paid for. So payers are responding very well as we get medical policies and contracts in place. We saw prescribing not only from psychiatry but also from OB/GYN and primary care, which we should talk about. And, you know, for as stigmatized as PPD has been, we've seen people step up and want to get treatment. So, you know, if you think about the opposite side, sort of the bear thesis, there was a concern that payers wouldn't pay, OB/GYNs wouldn't prescribe, and moms wouldn't reach out. We sort of disproved that in the first 10 days. The color I can give you is that the launch continues to go very well. We've continued really robust conversations with payers where we're hearing that they understand that PPD is a medical condition, not a moral failing, that the attributes of Zurzuvae, a 14-day oral medicine, the first oral medicine ever approved for PPD, where patients start feeling better based on clinical data in as few as three days, is a valuable package for them, that they largely believe that women suffering from PPD should get. We continue, for the most part, to hear that they want to make sure that Zurzuvae is given in PPD. So a kind of light touch physician attestation will be required, which makes sense, but they don't think that step-throughs make sense. In if you think about it medically, you know, why make a woman suffering fail a therapy that might take 4-8 weeks to work when the first and only oral medicine specifically approved for PPD is there and they could be feeling better in 3 days? So the dynamics of OB/GYN, psych, PCP prescribing, the positive payer dynamics, and the positive anecdotes we hear from, you know, from women and their families after taking Zurzuvae have all continued very close to what we saw with the clinical data we're hearing anecdotally from real-world experience. Yeah, I mean, the point you made about OBs and PCPs, I think, is really important because, you know, there's probably going to be—or not probably—at launch, right, there's a group of patients that have already been seeing a psychiatrist, but, you know, over time for kind of new patients, right, the time to actually getting an appointment with a psychiatrist can be a real lag. So I guess to that point, what else can you say, Barry, about the TRx split between OBs and primary care, and from a commercial perspective, like how much of your outreach is focused on those groups? Yeah, look, what I said, I mean, you kind of nailed it, Paul, with Zurzuvae, which is why I say that I think Zurzuvae is the key to unlock the blockbuster potential in PPD, allowing us to help many, many women suffering from PPD. If you think about the before Zurzuvae versus after Zurzuvae dynamic, if I'm someone with a history of depression, and I'm being seen by a psychiatrist or a primary care and I get, you know, postpartum depression, I'm likely to get that appointment, get in and get help because I'm seeing someone. The ones that are naive or newly diagnosed in the world before Zurzuvae, and OB/GYN, frankly, just didn't have the time to screen diagnose because what are they going to do? If they prescribe an SSRI, SNRI, they know that four or six weeks is the time it might take to work, and that mom and the baby are already out of their practice group. Therefore, they have to refer. They've got to get them into a good place. Well, the dynamic we're seeing with Zurzuvae is that if I diagnose depression, I'm going to diagnose. I'm not going to suspect depression and refer. I'm going to diagnose and treat. And that diagnose-to-treat paradigm shift from suspect and refer is a huge paradigm shift that we're already seeing. So if you think about the patient journey, the mom that goes through pregnancy may or may not have a history of depression, is not currently under the care for depression by a psych or PCP, that mom's likely to get diagnosed and prescribed by their OB/GYN, which is great, picking up right away early in, you know, third trimester or early in the weeks after giving birth. Those that are under the care of a primary care or psych will likely get their next depressive therapy from them. And in our case, you know, it's the desire to make Zurzuvae frontline. Yeah, okay. Makes sense. I guess when you think about this year, right, not to be myopic, but like for year one, what's a realistic goal? Like you guys obviously have been giving guidance. You look at street models, they're just all over the map, right? Some people have this a tiny opportunity, some people have a huge, it's challenging, right? There aren't any great analogs. Like what do you say to people who ask, you know, what's a, what's a good outcome, what's a great outcome, and how do you kind of differentiate between the two? Yeah, as Paul, as you said, we haven't given guidance, so I can't give you kind of a numerical answer to that. And you're right, street models are all over the place. And as we get multiple quarters, hopefully those models will come closer together. But what I'm looking for from a street perspective is quarter on quarter script growth, shipment growth, revenue growth. We're looking at, you know, shipments going out kind of ASAP, and we're heading in a good direction with our specialty pharmacies there. And we're looking for tremendous satisfaction, broadened equitable access to Zurzuvae by all moms that want it. So when a script's written, that script's filled. We're looking for awareness to continue to increase among OB/GYNs and psychs. And we're looking for all those payer policies to come in with very positive coverage. In our mind, positive coverage is, you know, physician attestation prior auth without steps. Got it. You know, if all that's in place and we see that quarter-to-quarter growth, we've got a really important trajectory going into next year. Yeah, okay. We talked about this briefly when we were offline, but I think it's important to kind of clarify. What should we make of the IMS data? Which I did point out to you, Barry, is weirdly like exactly 50 for December. You know, how accurate are these data and how much do they inform our expectations for the upcoming quarter? Yeah, so what IQVIA is picking up is they're picking up, using a methodology they use, not a 100% count. They're picking up shipments from specialty pharmas to patients. That's what IQVIA is picking up. And as we've said before, it's directionally correct. So as you see growth, it's directionally correct but not complete. For example, they might miss some specialty pharmas and they might miss things like free goods shipment because of their methodology. So yeah, the fact that December, as you said, was 50 is an anomaly. It's a good directional tool to use, but you really have to wait to the quarterly updates to get the precise numbers. Yeah, okay, okay. Fair enough. And the one last question I wanted to ask on PPD, and this is one metric that I'm really focused on, and I want you to tell me maybe talk about this metric, and I also want you to tell me if I should be focused on it or not. I think the time to getting drug is one of, if not the most important variables with this launch outside of just scripts and revenues themselves. And the reason why is one thing we've heard from some doctors who are more comfortable with using an SSRI in this population is, you know, what they say is, look, an SSRI usually has functionally very little out-of-pocket cost, and you can get it usually within an hour or two at a local CVS or Walgreens, right? So it's really important that for Zurzuvae, you know, this isn't a 4 or 5-day wait, right, that this is something you can get relatively quickly. What can you say about that and what you're seeing on the ground today, and how much am I, you know, on point as it relates to a variable that is like really key here from a commercial perspective? Yeah, you know, given the value proposition of an oral pill you take every night and you feel better rapidly in two or three days, of course, the sooner that woman suffering from PPD takes Zurzuvae, the sooner they feel better. That's the benefit we're looking for. So, so clearly, time from scriptment to, you know, swallowing the first pill is important. There's a bit of a fallacy on the SSRI and SNRI side. You know that the data suggests that, that, you know, people suffering from depression generally, including PPD, will work through two to and a half SSRIs in the course of a calendar year for those that, that continue treatment. And the median time on an SSRI, SSRI is only seven weeks. So many people stop taking it because of side effects before the potential efficacy kicks in. There's a pretty large abandonment rate in terms of, okay, here's a script, go to your pharmacy. They don't go to the pharmacy. So there's a bit of a fallacy that every patient I give a script to gets that drug in an hour. That's, frankly, just not what the data says. So it is important, but it's not every patient that's getting a different drug in an hour or two. And, you know, a drug that you get delivered to your home in three days, it takes three days to work. We're still in better shape than something that might take four to eight weeks to kick in. Yeah, okay. Fair enough, man. All right. Anything else we can kind of highlight here? I know at the end of the day, we just got to kind of wait for the next report. Yeah, look, we got to wait for the next quarter. But, you know, as I said, we, you know, with a challenging drug, we've been in the PPD market for a long time. And, you know, we really do think that Zurzuvae is the key to unlock this market. And anytime you're building a new market, which we're doing in PPD, I know it's a show-me story, but I'm pretty confident that based on what we've seen early in the launch, this is going to be a very important medicine commercially. Yeah, okay. All right. Well, we look forward to seeing more there. Let's switch gears to SAGE-718, which I understand you have a generic name now that I have not practiced saying yet, so forgive me, but. Dalzanemdor, let's practice it. Dalzanemdor. Dalzanemdor. All right. I think I got it. Do you want to walk through the various studies that you have ongoing? And, you know, I guess the question really sort of within this program is, you know, why should we be confident that this mechanism has relevance outside of Huntington's where you have almost like a PPD-like hypothesis in Huntington's, but in Alzheimer's and Parkinson's, it seems a little bit less biologically obvious? Yeah, well, maybe, maybe we can start there and then maybe then let's walk through the studies just to put it in that order. So, you know, as, as I started upfront, one of the, the skill set of, of Sage is, is looking at, natural metabolites that regulate GABA and NMDA pathways. So what, you know, when we, when we're looking at NMDA, we know that NMDA hypofunction is associated with, learning and memory issues, executive function issues. So those, those areas of cognition that are kind of the higher order areas. That's known. There's lots of literature. It's very well documented. Our observation in Huntington's patients, and, and we and our collaborators were the first to observe this, that 24(S)-hydroxycholesterol is downregulated, led to that the pharmacologic insights there led to the discovery of dalzanemdor. It's not, it's not that metabolite. It's the pharmacological observation. So what we know is in a kind of naturalistic way with dalzanemdor, we're positively allosterically modulating NMDA. The early data suggests, and they're open label, so it's not the gold standard, the early data suggests that we're seeing similar results in Huntington's, Parkinson's, and Alzheimer's that we saw in the ketamine challenge study in terms so it gives us lots of reason to believe. And it's this NMDA hypofunction that we're addressing. So it's not a replacement of a metabolite. It's an allosteric modulation of NMDA. So that's sort of the basic mechanism of action. Now, where you're right is if you think about homogeneity versus heterogeneity, clearly the Huntington's patients are a bit more homogeneous. Then comes Alzheimer's, then comes Parkinson's, which is the most complicated patient set. But that's, you know, that's the reason to believe. You know, we'll have data this year. In terms of the studies, what we've said is that the Parkinson's study PRECEDENT will read out early 2024. When we use early, that's Q1, Q2, mid Q2, Q3, and latest Q3, Q4. PRECEDENT early, SURVEYOR in Huntington's mid, and then LIGHTWAVE in Alzheimer's disease and DIMENSION in Huntington's late this year. Let me provide some color. The Huntington's package has been designed in a way that if, if positive and, and data matter here, we've said that a lot, that, that we think with DIMENSION, we have a large placebo-controlled study that's been powered to show a difference in the primary endpoint of HD-CAB. The SURVEYOR study midyear is not powered or designed for statistical significance, but rather to show the difference between healthy Huntington's patients and, and drug. It's really there to confirm HD-CAB so that any new learnings from SURVEYOR, we can then apply to the stats plan for DIMENSION, which reads out at the end of the year. So it's been designed that way. The PRECEDENT and LIGHTWAVE studies are your classic phase 2 studies where we're looking at a number of different endpoints with a goal of understanding what works best that gives us data then to work with regulators to design the phase 3 studies. Okay. For Huntington's, I think one thing I'm a little bit confused by is the reliance on HD-CAB. You know, another company in this space basically got feedback from the FDA that they didn't like this measure only a couple of years ago. What do you guys make of that? Like why, why, why rely on this scale and why, why not try to look at something else or, or get better regulatory alignment ahead of time? Well, look, we have worked with regulators and there are, you know, anytime you have a composite endpoint, this is general across divisions, there's skepticism on composite endpoints and what are all the components we need. Look, we're using HD-CAB as a primary endpoint, which provides a battery of cognitive tests that's been developed by the HD community. So we do have patient advocates on our side, and it evaluates changes in this population. You know, an executive function is an important component of that. So, you know, when I said data matter here, obviously the data matter, the components of the data. But let's step back. We have seen good regulatory flexibility in orphan diseases and particularly something here where there's nothing for people suffering from cognitive issues in Huntington's disease. We think we've got a number of primary and secondary endpoints to demonstrate an effect here. Look, when you have nothing and you show that a drug works, there's typically a much, much better discussion. Yeah, right. Yeah, right. But don't you think that precedent was a little odd, right, with Vaccinex and their conversation with the FDA and them wanting to focus on different measures? Do you think that might not be relevant here? Yeah, I mean, the you know, regulatory precedent is relevant, but you know, our conversations are going well. And again, if we have really good data here, I think we've got a good shot at the next step. Totally. Okay. Fair enough. Of course, it's all data-driven and. All data-driven. Yep. Makes sense. So you want to actually switch gears a little bit to the Parkinson's and Alzheimer's studies? Because I guess like that's an interesting conversation that's come up in the investor community is the endpoints here. You know, in Parkinson's, right, there's nothing approved in cognition and PD. And in Alzheimer's, right, I think in the investment community is accustomed to things like ADAS-Cog, CDR. You know, the measures you guys are using, again, don't really have much precedent. So can you speak to the measures you're looking at, the thought process, what you think is kind of most relevant to focus on? Yeah, I mean, look, rather than break down every individual endpoint we're looking at, you know, as you said, we're looking at a battery of cognitive tests. Yeah. And in Parkinson's, it's the WAIS-IV, which is the Digit Symbol Substitution Test to understand all aspects of where we might be impacting. The important part is for both Parkinson's and Alzheimer's, we've set these up as classic phase 2. So we're measuring a lot of different cognitive measures at various time points. We're doing run-in for these studies to kind of wash out any learning effect because we know there may be some learning effect with these kinds of studies. And they're phase 2. So we're going to look at all the endpoints. We have primaries just to look at the study, but there's a whole bunch of secondary endpoints that we're going to look at. Right. And then, you know, we'll see what works well, what doesn't work well, and we'll sit down with regulators to, to map out what the right, what the right phase 3s look like. And given the large population for both Parkinson's and Alzheimer's, it's likely that, you know, we'll have to do a phase or a couple of phase 3s. So we'll map it out. But these are really learning studies. Look at a lot of endpoints, a lot of measures. Where does it work best? And, and then go forward from there. Yeah. Okay. All right. Fair enough. And Paul, when you're paving new pathways like we do, there's just no precedent to rely on. So you've got to create a forward-looking way of doing it, which. Yeah, no, I totally get it. I guess maybe just to ask one thing is, you know, in Alzheimer's, why not look at something like ADAS-Cog given the established precedent with that? Oh, we have that. We have them in phase 2. You have ADAS-Cog as it? I thought you didn't. Okay. Okay. All right. That'll be interesting to see as well. All right. Great. Anything else to add? So we'll get Parkinson's data here relatively soon, right? And then the smaller Huntington's study and then the bigger Huntington's and Alzheimer's trials in the back half. Is that correct? Yeah. Yeah. It's PRECEDENT early, which is first or second quarter, SURVEYOR mid, which is second or third quarter, and then LIGHTWAVE in Alzheimer's and dementia late 2024. So that's the guidance. Okay. Okay. Sounds good. Be super interesting. Do you want to talk about tremor briefly? Because that's also a pretty big catalyst for you guys. Maybe you can speak to the data in the prior trial and the sort of key questions you're trying to answer as you've moved into this phase 2 big. Yeah. So phase three to four is our GABApam that's been designed for chronic administration, partnered with Biogen for movement disorders, and we're starting an essential tremor. You know, I think you're aware there's about 7 million adults in the U.S. that have essential tremor. Very few of those diagnosed because there really hasn't been any innovation in years. And we talk about essential tremor. This is a disease that challenges people with activities of daily living. They can't eat. They can't button their shirt, get dressed. So many require caregivers. And it really is a very significant unmet need. What we were asking in KINETIC, the previous study is that phase three to four given in the morning at a fairly high dose over one month or 28 days, do we see a change in tremor amplitude? Do we see a change in activity of daily living? What's the tolerability profile? So when we read out KINETIC 2 at that 60 mg dose, we saw statistically significant improvement in a sense in tremor amplitude as well as activity of daily living, with, you know, enough patients that stayed on drug for the month to reach that sig at day 28. We lost some people toward the end more than we wanted. So the next question is with KINETIC 2, given phase three-four over three months, what's the right go-forward dose to achieve improvement in tremor amplitude with a chronic dose that people will take at night every day? The big change we made to KINETIC 2 is we moved from morning dosing to evening dosing. We did morning dosing because we wanted to get PK. And when if you do PK at night, then patients will report in the morning that they're tired because everyone woke them up to get blood draws. So, we moved it to evening dosing, and we, you know, changed a couple of features of sites and studies to pick the best sites. So we'll see midyear, you will see the readout. And the view is that we have a drug that works well in terms of activity of daily living, tremor amplitude improvement with the right dose that will become a dose for chronic administration. Okay. Makes sense, Barry. From a safety perspective, have you guys done the work here with 3-4 to kind of understand, you know, chronic tox, risk of withdrawal, risk of tolerance, things like that? Yeah, we have. And, you know, phase 3 to 4 from all those perspectives is pretty clean. The thing we're battling with is the classic kind of GABA PAM. It's the somnolence and sedation that we saw at that high dose given in the morning. You know, obviously we saw, you know, we saw a bit of that with Zurzuvae. So the question is, you know, what's the right therapeutic, what's the dose with the right therapeutic index so that, you know, despite adverse events with people suffer, the adverse events are not severe that causes dropout. Dropout's really the key. It doesn't, you know, people can have 100% of something, but if it's not so severe that they stop taking their medicine, you know, you don't want adverse events, but it's acceptable. The real key here is do we have a chronic dose that people will take? Yep. Okay. Okay. Makes sense. And from a regulatory perspective, are we comfortable that the endpoints you're looking at, and the way you're adjudicating tremor, because I know there's been different ways to kind of either do it site rate or central rate, are we comfortable that there's alignment with those? Well, so, so again, this is a phase 2 study. And, and, you know, yes, we met with the agency and yes, there's general alignment, but we haven't had the, you know, do we do the tremor amplitude as primary or do the activity of daily living as primary discussion yet? And we'll, with these data in hand, we'll have that discussion. The good news is that if they want activity of daily living versus the TETRAS upper limb scale as a primary endpoint, at least based upon KINETIC, we have those data to size a trial on and we can do that. Yeah. Okay. Okay. Great. I know we're up against time here, Barry, but we covered a lot. Is there anything else you'd like to highlight? I think, yeah, you asked all the right questions, Paul. I mean, the thing we don't have time to now, but we will later in the year is, you know, we've got an exciting early stage pipeline emerging as well, which we'll talk about. And again, it's just a very catalyst-rich, exciting year for Sage. Looking forward to the months to come. All right. Best of luck. Thank you, Barry. Appreciate it. You do.