Biotech analyst here at RBC Capital Markets. Our next featured company is Sage Therapeutics, represented by three members of their senior management team: their Chief Business Officer, Chris Benecchi, their Chief Financial Officer, Kimi Iguchi, and their Chief Scientific Officer, Mike Quirk. So, Chris, Kimi, Mike, thank you guys so much for joining us. Thanks for having us. Great. Thanks for having us. Thank you. Well, I'll maybe kick things off with a bigger picture question. How are things going with the Zurzuvae launch? What have been the really some of the biggest surprises that you guys might be seeing on the positive side, and any unexpected challenges? Maybe if I could just kick it off, Brian. First of all, thanks very much for having us. Thanks for being here. At this conference today. We appreciate it. But for those of you who aren't familiar with Sage, Sage is a company who's been focused in the area of brain health. We did that by really honing in on the GABA and NMDA mechanisms, and have been able to build a really prolific and differentiated pipeline by focusing there. As you mentioned, Zurzuvae Zurzuvae is our first approved, it's the first approved therapy for women with postpartum depression, that we launched at the end of last year, and things are off to a great start, and I know Chris will elaborate in great detail on that. In addition to Zurzuvae, we also have a great year with regards to our pipeline. We have a lot of catalysts that we'll be seeing in both dalzanemdor and SAGE-324, so. It's a big year. It's a big year for Sage, and I'm happy to say as the CFO that we do that with a strong financial foundation, so a strong balance sheet to take us through all of those key readouts. So, looking forward to continued progress and continuing to update you. And with that, maybe I'll turn it over to Chris so he can drill into the Zurzuvae. Yeah, so you get the question answered. Yeah, so just to get started, I think, as Kimi said, we're off to a strong start, you know, at the quarter we announced $12.4 million in collaboration revenue, more than 1,200 prescriptions, more than 700 shipments, which are from the SPs to the patient's home. All of that reflective of what we really saw as strong demand from patients. I think as we were getting ready to launch the medication, you know, Zurzuvae, we heard the bear thesis, and the bear thesis was OB-GYNs were not writing this medication. Payers were only going to allow access to this medication through step-through, and there was uncertainty about the degree to which patients' real-world experience would actually match what we saw in the ROBIN and SKYLARK studies in phase III. What we're really excited to talk about is that the OB-GYNs have really leaned in. They're on the forefront of prescribing, and we can get into that maybe in a little bit. But, specifically, what we're seeing is the majority of prescriptions are actually coming from OB-GYNs. The payer ecosystem is responding well to Zurzuvae. You know, we see that now more than 65% of commercial, of patients that have commercial coverage are now under contract. two of the three PBMs now are online with Zurzuvae. Medicaid, in and of itself, has, you know, nearly half of the states now provide access to Zurzuvae. So that's not access with a step-through. That is without onerous prior authorizations, without step edits, enabling first-line access to Zurzuvae. And then in the real-world setting, what we're seeing is that the patient experience is matching what we saw in clinical studies with what you would expect from the label. Women are taking the medication who have PPD. They're seeing after just a couple of doses the onset of efficacy. They're completing their 14-day course. They're going through the full 42 days, and the safety profile, again, is matching what we saw in clinical studies and what we have in our label. So we're off to a very encouraging start making this medication available as a first-line therapy for all women, regardless of access and affordability. And can you elaborate more on the types of PPD patients who are starting on the drug? I've always sort of wondered if there's sort of a backlog of patients who've been struggling with PPD, waiting for a new therapy, who, you know, may or may not have been through SSRIs or other treatments unsuccessfully. Or are there a lot of patients that you're seeing come onto therapy who are newly diagnosed and that the sort of yeah, how should we think about that going forward? So we now have a full quarter of patient-level data. So what we see now in terms of what that's telling us is that the patients that are coming through represent the breadth of what you would expect from women that are suffering with the signs and symptoms of PPD, similar to our label. So there is no specific subset of PPD patients that we see. OB-GYNs, psychiatrists, PCPs are really leaning in, identifying women with PPD, regardless of severity, as being viable candidates for this important therapy, Zurzuvae. So that's been really encouraging for us. I think that, in terms of how you see the prior experience with medication, nearly half of patients who are coming through have not had the medication, an antidepressant, in the preceding 12 months. So the read-through on that is that, in large part, we believe that those are monotherapy first-line patients who don't have another medication. Regardless of whether a patient comes through with another medication or is a monotherapy patient, we just want to see women with PPD get treated as effectively as possible, and specifically with Zurzuvae because there is the potential to use it as a first-line therapy, again, without onerous PAs and step edits as we go. We didn't really experience a bolus of patients. I don't think OB-GYNs largely were holding back care until this medication was approved. But certainly, when the medication was approved, they jumped on it as well as psychiatrists and primary care physicians. Can you talk a little bit more about the implications of OB-GYNs being such early adopters to the therapy? It would seem that they're the most sort of boots-on-the-ground physician type that would be seeing PPD patients early on. But how much education would they need to navigate the and any sort of complexities in the insurance or prior auth process? I mean, it sounds like that's not a huge hurdle, but I guess I'm sort of wondering how much education you're needing to impart to the OB-GYNs versus the psychiatrists who may be prescribing this. It's exciting that OB-GYNs have really leaned in with this medication. For so long, I think in the absence of a medication that was FDA approved, they would suspect, detect, and refer. Now with a medication that is FDA approved that they have comfort with and experience, we're seeing them really lean in and identify women within their practice and treat them rather effectively rather than referring out to a psychiatrist or a reproductive psychiatrist. You know, that that in and of itself is a really, really positive sign. These are practices that are very sophisticated. They have other medications that are flowing through those practices where they're familiar with the complexities of navigating the payer ecosystem. Given that the payer response has been the degree to which it's been favorable, they aren't having to navigate onerous prior authorizations and step edits, enabling them at the practice level to really get this medication into the hands of women as possible. So what we effectively see is a change, a paradigm shift that's happening in the management of women with PPD that we are really excited about. And with Zurzuvae at the forefront of that, we're certainly going to continue to lean in. Well, that was always the hope. So it's great to see that that's playing out initially. There's a lot of different metrics that have been reported and that some of us glean from third-party sources, wondering how we should be thinking about putting all those together, right? And how do we tease all the different inputs and outputs, the third-party prescription trackers, free drug inventory, to get a sense of what the initial launch curve is looking like here and, you know, how we can expect demand to evolve as like, should we be thinking about reported sales in the second quarter to be higher and that should continue to steadily increase? Should we be thinking about an inflection? How are all these inflection how are all these metrics fitting together as we try to kind of project out what what are your guys' expectations based on what you're seeing? There's a lot in there, Brian. But first, I think. Well, I mean, launch trajectory. Yeah. Yeah. So what I would. Launch trajectory. Yeah, launch trajectory. What I would start with is what Chris talked about earlier: strong demand, strong revenue, great prescribing patterns. Access is going really well. So all those things are showing a really. Key fundamentals are there. Strong launch, right? So, you know, too early to really talk about trajectory. But let me just comment on a couple of things that you brought up. So number one, on the inventory front, let's talk about that. You know, what we said about inventory was that the net revenue in the first quarter was, you know, went towards both wholesalers shipping product to patients as well as wholesalers stocking inventory in anticipation of the increasing demand, right? So they're seeing the prescription. So they're understanding that demand. So that's one thing on the inventory front. I think, another point, and this comes up quite a bit, is on the IQVIA data, which tracks the shipments from specialty pharmacies to patients. What we're seeing right now is that there's a lot of variability on a week-for-week basis. And what that's really coming from, we think, is around the fact that they don't have all the specialty pharmacies. In fact, we know that there's one specialty pharmacy that is blocking their information. And they also are not picking up our free good program, which is a really important program for us to make sure that we can get Zurzuvae in the hands of patients as quickly as possible. So they're not picking that up as well. So you have that variability. And so again, I would say to you that, it's, you know, IQVIA right now is not the best source to look at for tracking the Zurzuvae launch. Okay. And then that was one of my other questions as well. I was on the free drug. Can you elaborate on how free drug and gross-to-net dynamics might evolve over the course of this year? Yeah. Yeah. So again, the free drug program, an important part of our strategy to make sure we get Zurzuvae to patients as quickly as possible. That's out there. That's working. You know, what we did say, though, was that the majority of the shipments that happened in the first quarter were paid for. And we do expect, as you know, access comes on board, as everyone becomes more familiar with the system, that the free goods program will decline over time. With regards to gross-to-net, you know, what we've talked about is the fact that, because this is the first approved oral therapy for PPD and the novel nature of the drug, that we don't anticipate the kinds of discounting that you see on other branded ADTs or recent ADTs. So you don't see that. Anyway, the typical components that you'd expect, there's discounts. There's the patient assistance programs. So the typical things you'd see in gross-to-net. But we don't think we'll see the same kinds of pressure on the discounting that you see with the more recently approved one. Just another point to make is that the free goods are actually go through cost of revenues. They're not included in the gross-to-net. Got it. Can you talk more about commercial messaging? I guess I'm curious what specific messaging initiatives that you and your partner have undertaken to communicate the drug's benefits to prescribers. How might these strategies evolve as the launch progresses? What are you going to be looking towards to determine potential additional investment in salesforce and sales infrastructure, or reprioritization of resources towards different aspects of the launch? Yeah. Maybe I'll cover the first part if you want to cover the investment piece as we go forward. That may be helpful. Yeah. So, in terms of how we're thinking about the launch, we recognize, based upon our experience over the first full quarter, that this is a highly promotionally sensitive marketplace. And certainly, we do a considerable amount with the sales force that we have out there. And they are calling on, as I noted, OB-GYNs, psychiatrists, and primary care physicians. It's also really important that we round that out with omnichannel efforts, you know, whether it's digital or potentially in the future DTC or DTP, giving you the depth and breadth or the extension of reach and frequency that you need because you can't call on every clinician that needs to hear this message with a sales force. So you have to really balance that. So given the performance that we've seen in the first quarter, we continue to invest in things like peer-to-peer and digital initiatives that are going to enable us to, again, broaden that reach and deepen that frequency. You know, peer-to-peer efforts are expanding. We now have our dot-com HCP website, our dot-com consumer website. Those, in effect, also have attached to those search engine optimization, display ads, banner ads, and the like, enabling us to really, again, get out and deliver that important message in a promotionally sensitive market to clinicians and to also make sure that patients, as they go in and they engage with their clinician, they have the information that they need to have an informed discussion about Zurzuvae as we go forward. So that collaboration has worked really well with Biogen. I think the alliance is working very well in that fashion. We'll continue to be partners with them in this process of making sure we get the word out and impacting the marketplace. And we're also very aligned in the investment philosophy around how we thought about the commercialization of Zurzuvae. And so from our philosophy was really around starting very focused in the launch, sort of a precision launch, if you will, and looking at the metrics over time, be it prescriptions, prescribers, all the different metrics to say, when is the right time for us to actually increase our investment? So we took a very tempered approach that way to not get ahead of ourselves and to right-size the investment in the launch. And we're already increasing our investment in some of the marketing and nonpersonal promotion because we're seeing the impacts it's having. And then we'll continue to look at the other metrics to decide and determine when is the appropriate time to increase the investments in other areas, like salesforce or DTC or other other areas. Is that something that will be kind of reflected on this year, potentially? Or is that sort of a 2025 or later assessment? Well, what I'd say to you is that, you know, given the progress that we've seen so far, if that were to continue, I'd say there's a good likelihood that we would increase our level of investment. But it's still a little early. And we want to make sure that those metrics continue to track in the same way. So we're again, we'll continue to look at those metrics. Makes sense. Maybe a couple more before we get to kind of the pipeline. Our most recent check of the FDA's adverse events database suggests that the AE profile of Zurzuvae looks pretty in line with what's been seen on the label. And it sort of aligns with what you said earlier, Chris, that there's not what the real-world experience is mirroring the clinical trial experience. How has safety looked during the early part of the launch? What's physician perceptions and patient response to the box warning? And how have you managed through some of the safety points around things like driving? Yeah. I can start. And Chris, maybe you can layer in from the field perspective. Well, clearly, you know, our number one priority is making sure that we have safety and the safety of the drug. And I think we have been encouraged with what we've seen to date that, as Chris said, the data is in line with what we've seen in our clinical trials in terms of both the efficacy and safety profile. You know, we do have a box warning around things like driving. But this is also a physician population that's very experienced, administering and prescribing drugs that have similar types of warnings from that. And so I think that the general perception would be that with a robust label, it's been a good tool for having the right conversations with patients to understand the benefit-risk. I think that's been what we've been seeing playing out in the field. So, when we hired our neuropsych account managers, we went out. We specifically looked for individuals who had established relationships and experience in neuropsychiatry and OB-GYN practices. In effect, we were looking for not just seasoned representatives but credible voices in a practice setting who, when they had to deliver the messaging around the safety and the efficacy of the product, could do so credibly. And we find that they are obviously well-trained and prepared. We have well-trained and prepared them to have these conversations, ultimately for them to have informed dialogue with clinicians to best advise patients about, you know, the right path to take when there's an opportunity to potentially choose Zurzuvae. So, you know, we'll continue to do that as we go forward. Great. And beyond PPD, there's obviously other indications where the drug could have benefits. I'm curious if there's anything you might be able to tell us about your latest sort of regulatory conversations or views on the potential for Zurzuvae in MDD. Are there perhaps any plans to further evaluate it in this indication? Or, you know, how are you thinking about even other indications such as bipolar or refractory mood disorders where, an effective and acutely acting drug could potentially, have a benefit? Or should we really just be focusing on PPD? Yeah. So, Brian, the answer to that is focus on PPD. So what we've said is that, we're, you know, both Sage and Biogen are very focused on making sure that we make Zurzuvae successful in PPD. And so that's what we're doing. We are having ongoing conversations with the agency. But, until we have something to provide more information, we will. We're not making any incremental investments in MDD. So again, full focus is on successful PPD launch. Okay. Any timing on when we might see an update there? Or is it on just on sort of the regulatory discussions and go forward? It's hard to say. It's hard to say. Okay. Understood. And then maybe shifting gears to the pipeline, maybe with SAGE-324 what are your expectations for the upcoming KINETIC 2 data, specifically regarding the suitability for essential tremor in an elderly population? And how do the upcoming study results fit into sort of the broader development mosaic and strategy for the drug? Yeah. So just to take a step back for a moment there. So for those who might not be familiar, SAGE-324 is our another one of our GABA receptor positive allosteric modulators. It's also partnered with Biogen. And as you alluded to, its lead indication is essential tremor. This is an area that there's been very little innovation over the last 50 years. I think there has been 50 years since the last approved product. But it is an area that, as a company, we've been heavily invested in since the earliest days. We were actually doing some early essential tremor studies with brexanolone as an IV, more as a proof of principle to understand, was there a signal there so that we could then invest in our oral molecules? And that experience in essential tremor has been very valuable because what we've learned from that is that there is a direct relationship between drug exposure with the GABA receptor, PAM, and the ability to reduce tremor signals. And so when we went into the program with SAGE-324 the first major study we did, the KINETIC trial, was looking at we purposely went to a high dose, a 60 mg dose, that we were dosing during the daytime because we wanted to understand for SAGE-324 what the exposure response profile looked like. And by dosing in the day, it allowed us to make measurements of drug exposure without waking up patients in the middle of the night and really measure that time course. What we saw in that study was, we saw the expected effects of a reduction in tremor amplitude, significant reduction that was correlated with activities of daily living, which gave us some insight that it was a meaningful reduction and not just a statistically significant reduction. But we also saw degrees of somnolence that made us think that the 60 milligram dose with daytime dosing was not the best one to take forward into phase III. So KINETIC 2 really leveraged those learnings. It's a classic phase II signal finding study where we've made a number of changes from KINETIC 1. So, first of all, we're dosing for three months instead of 28 days. We switched to nighttime dosing, which we think is actually the appropriate time to administer the drug given the somnolence profile of the molecule. And we're also using multiple doses. So we're testing 15 milligrams, 30 milligrams. We also have the 60 milligram dose. But we're titrating up to that. And the goal of the KINETIC Study is, at the end of the day, to be able to see a dose that appropriately balances efficacy signal on tremor reduction but also has a tolerability profile that not only would allow us to move forward into phase III, but we think would be a commercially viable profile as well from that perspective. And so that really is what success looks for, is being able to identify that dose or doses that that generate that window. And we are looking forward to having the data from the KINETIC 2 in the middle of this year. And we define middle of this year as Q2, Q3. Great. Well, looking forward to that data, to those data. You recently then maybe shifting gears to 718, dalzanemdor. I have to get used to that name. What did you see coming out of the first study, the PRECEDENT trial, in Parkinson's disease? Obviously, it's a tough population. What do you think some of the specific factors were that contributed to the lack of efficacy there? And can you talk about the potential for the drug to have a stronger mechanistic rationale in Huntington's? Yeah. Yeah. So, dalzanemdor, or SAGE-718, is our wholly owned NMDA receptor positive allosteric modulator that is looking at improving cognition across a range of neurodegenerative conditions, including Alzheimer's, Parkinson's, and Huntington's disease. As you mentioned, we recently reported out on the first of the studies that we expect to have this year, the PRECEDENT Study in Parkinson's disease. We were disappointed to not see a signal that would allow us to move forward in that population. But we've always believed that Parkinson's was not predictive of the other patient populations, the Alzheimer's and Huntington's population. While there is recognition that NMDA receptors could be dysfunctional in that patient population, the pathophysiology is very distinct. It's a much more complicated population in terms of, you know, on-off periods in terms of motor disorders. And so we really don't expect there to be much read-through there. We are very much excited by the Huntington's and Alzheimer's trials reading out this year. So we have two Huntington's studies, the SURVEYOR and the DIMENSION study, SURVEYOR reading out middle of this year, DIMENSION later this year, which is Q3 or Q4. And then we have a classic sort of signal finding study in Alzheimer's disease, the LIGHTWAVE study, maybe just focusing on the Huntington study. So the DIMENSION study is the robust placebo-controlled study, looking at the HD-CAB. This is a composite cognitive endpoint that was designed by the leaders in the field to really capture those domains of cognition that are most impacted in Huntington's. And we believe there's a very strong mechanistic rationale of why we would expect to see an improvement with SAGE-718. And this really comes from the work that we've done showing that there is a reduction in the endogenous modulator, 24-hydroxycholesterol, that happens right around the time that patients start showing robust cognitive change. The SURVEYOR Study is a much smaller study. It's not designed to show statistical significance between drug and placebo. It really is around providing information that helps contextualize the data from the DIMENSION Study and provide the grounding on what a cognitive, clinically meaningful change could be like in that patient population. So very exciting time across both of those studies. Good. Well, we're out of time. So thank you guys so much. It should be an exciting year. We look forward to the data readouts and to following the continued launch of Zurzuvae. Yeah. Thank you. Thanks very much. Thank you.