Okay, let's get started. Day three of the 36th Annual Piper Sandler Healthcare Conference. This is David Amsellem from the Piper Sandler Biopharma team, and we're delighted to have Intra-Cellular Therapies with us: Sharon Mates, CEO; Mark Neumann, Chief Commercial Officer; Sanjeev Narula, CFO. Thanks so much for joining us. Certainly, a lot to talk about, particularly with the recent submission of the sNDA for Caplyta in MDD. So maybe I'll just start off with a high-level question, Sharon. So you've commented previously that you envision Caplyta having a potentially $5 billion sales footprint or more over time. So I guess two questions over here. First, I guess, do you envision the majority of those sales coming from the MDD opportunity? And then secondly, talk about how other clinical settings, namely bipolar depression, fits into your aspirational target for the franchise. Great. Thanks a lot, David. It's great to be here. And just before we get started, I should remind you and the audience that today we will be making forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, and actual results may differ. We do guide you to our SEC filings and our website for continuous updates on the company. Having said that, we can get into a forward-looking statement on the $5 billion sales opportunity for Caplyta over the next 10 years. And maybe, Mark, do you want to start with if you can remember the question? Yeah, now I remember it well. No, so David, I think, first of all, as background, I think we always believed Caplyta was going to be a big drug, and the question was, how big could big be? I think when we saw the results of the 501 and 502 studies, our two studies in the adjunctive MDD, we viewed those results as a best-in-class result, but before we began to model that, we wanted to take that out and do some really rigorous quantitative market research to validate with prescribing physicians the same belief that we had about the profile of the product. To make a long story short, that's very much what we heard back, and so we utilized that data to model out MDD. We modeled out our bipolar depression business, which, as you know, has been growing quite robustly ever since launch almost three years ago now. And those two things together are both going to be very strong contributors to the $5 billion. And schizophrenia, to a much less degree, because the two big indications are MDD and bipolar depression. So they're both going to contribute very strongly to achieving the $5 billion. Yeah. And you talked about the $5 billion over a, I believe, 10-year period. So that sort of begs the question regarding exclusivity and how you're thinking about the exclusivity runway for Caplyta. And what gives you confidence in your exclusivity runway? And we could probably spend all kinds of time talking about IP, but just in a nutshell, can you talk to your confidence in the exclusivity runway? Sure. So our confidence is in our Orange Book-listed patents, which go out through December of 2040. We just recently had, I think it's three more patents added to the Orange Book. And we're very confident not only in the Orange Book-listed patents, but in what you build as your picket fence around those patents. And so we think that our patent position is very strong, and we look forward to a long, healthy run for Caplyta. So I'm going to ask one of these sort of big-picture vision questions. Just overall, your overall vision for Intra-Cellular looking beyond Caplyta, in other words, you have the pipeline, which we'll get into, both lumateperone-based and other opportunities. But beyond that, what's your appetite to bring in other assets, be it development stage or commercial stage, that further expands your neuropsychiatry footprint? As a founder of the company, I can tell you we started this company to bring better healthcare to patients to meet unmet medical needs. And I think we've done that with Caplyta. I definitely think we are helping patients, and it's very rewarding to get letters to see both patients and caregivers telling us testimonials. And so I find that very rewarding. And that is the mission of our company, to continue to do that, to keep building the company. I think we've hired a terrific team on the research side, on the commercial side, on the development side. And I think that is to both build from within. And then we also look to bring stuff in through BD. And we started by looking at commercial products that Mark's group and commercial could we take advantage of the sales force that we've built. To date, we have not brought in any commercial assets. We've gone earlier and earlier and earlier, and so we do. We have We have seen some very early-stage assets that we think are very attractive. They would not impact our balance sheet at all, though. So you would yawn. Our balance sheet, by the way, which is very robust. We have $1 billion in the bank, and we have no debt. So we can certainly support any of these early-stage BD opportunities that we would want to bring in. Okay, that's helpful. So let's dive into the opportunity in MDD. And so a few questions here. So obviously, with the body of data in hand, this is as good a time as any to talk about overall commercial positioning. And I'm trying to get a better sense of what your overall messaging will be to practitioners and patients. I mean, in other words, is the messaging ultimately going to land as being focused on, in part, on safety and tolerability versus the other atypicals that are approved and used in MDD? Is there other messaging that we should be thinking about? Help us understand your thinking? Yeah, so I think there's a whole package of benefits behind Caplyta and MDD. I think it starts with the unprecedented efficacy results that we saw in both 501 and 502. So very robust efficacy results coming out of those two studies. You mentioned the safety and tolerability. We essentially replicated in the MDD population the same favorable safety and tolerability profile we saw in bipolar depression and the same one we saw in schizophrenia. So on the metabolic side, those are comparable to placebo, whether you're looking at weight gain, you're looking at elevations in cholesterol or glucose. And on the movement disorder side, also comparable to placebo. So a very favorable safety and tolerability profile. That, especially, it's important in all indications, but especially in MDD. We think that's going to be very important. And then finally, from a dosing perspective, it's a very convenient dosing regimen. Single, 42-milligram dose for most patients. You can start the patient at the effective dose without having to titrate up. And that collection of benefits resonates very well with physicians in the market research that we've done. I would also say there's an overarching message now with Caplyta, because in bipolar depression, we have bipolar I, we have bipolar II, and now we have MDD. So if a physician has a patient in front of them who's having a major depressive episode, they don't need to worry whether it's MDD or bipolar II, because that's often misdiagnosed. They'll have the confidence that Caplyta is the right choice for both of those. And we really cover the whole spectrum of major depressive episodes. That's so important because in the Bipolar II patient population, which is a large patient population, these patients are very oftentimes misdiagnosed because their manic episode is a hypomanic episode, and it takes years to diagnose. They're put on SSRI after SSRI, and these SSRIs and SNRIs just don't work for them. But they're still loath to go off of them. It's really a cycle that you get into. Now the physician would no longer need to make those decisions of, "What do I have going on here?" I can just give them Caplyta, and it'll cover all of them. Okay. Another question on the MDD opportunity and the body of data. So are there any MDD patient subgroups that you've teased out or think you can tease out as being particularly appropriate for Caplyta and appropriate to detail to practitioners on? I mean, obviously, there's broad-based efficacy, but it's a vast market. So how do you think about that? I think that first, we're looking at the adjunctive treatment. There may be some patient populations for whom a monotherapy in MDD could be very useful. And we'll have more to say about that as we go forward. But there may well be certain populations, like TRD for one thing, or other patient populations within MDD for which a monotherapy might be helpful as we go forward. Okay, so there may be studies as monotherapy in the works. We look forward to the future. We'll update you as we go forward. Okay, fair enough. Okay. So kind of a question about the overall market. Can you talk about the overall footprint of atypical antipsychotics in MDD? Any color on atypical antipsychotic volumes, specifically in the MDD setting, and maybe what portion of MDD patients are on adjunctive treatment? This is sort of to set the overall landscape in terms of this market. Yeah, I guess the best way is to take a step back and to look at the calendar year 2023. There were 68 million prescriptions for oral antipsychotics that were written during that year. The single largest indication among those was MDD at about 30%. So 30% of those 68 million were written with an oral antipsychotic, the vast majority of that being adjunctive use, because that's where the well-established treatment algorithm is. Bipolar depression is not far behind. 26%, 27% of the prescriptions are bipolar depression. So by far, those are the two biggest indications. Schizophrenia is much less. And then you have a whole lot of other things that get mixed up in there. But MDD is the single largest indication. But the other dynamics are, for instance, in schizophrenia, there are many generics that are approved, and these patients cycle through all of them. In MDD, most of the antipsychotics have either not been tested or simply have been shown they don't work as adjunctive treatment. And so there are very few products that are approved in the antipsychotic space as adjunctive treatment in MDD. So the opportunity is very large. I think if I'm not mistaken, I think one generic that is approved is Abilify. Another is quetiapine. And quetiapine. And then there are two branded. And that's cariprazine, which is Vraylar, and Rexulti. So is it fair to say, I mean, I don't have the data, that Seroquel and Abilify are kind of the two, I guess, market leaders among the adjunctives for MDD? Yeah. Yeah. Okay. So let's talk about the commercial organization. Obviously, this gets beaten over the head, but got to ask the question. So in terms of the sales org and the launch in MDD, just walk us through the latest expansion of the sales force. And I guess ultimately, what does a right-sized sales force look like to fully support critical mass in MDD? Yeah. So up until the third quarter of this year, our main focus has been on the psychiatry specialty and the nurse practitioners that support them. We had a sales force of 370 individuals that called on about 43,000 physicians. Now, there was a smaller segment of primary care. These were the highest of the high-volume prescribers for bipolar depression. So we do have some experience in primary care with Caplyta, but not a lot. In the third quarter of this year, we finished standing up a 150-person primary care sales force that are now out in the field, up and running, promoting bipolar depression. That took our target audience from 43,000 up to 70,000. These were all brand new primary care targets for us. And what we have said is that we're planning a second phase of the expansion next year. We'll come back to you at the appropriate time when we give guidance for the year to fill in some of the details of the size of that second phase, the timing of that second phase. That will be another deeper push into primary care. Now, why is that important? Because primary care plays a very significant role in MDD. They play an important role in bipolar depression. About 25% of the prescriptions in bipolar depression are written by primary care. 75% come from psychiatry and the nurse practitioners that support them, but 25% come from primary care. And that's what we're focused on now for the next year. However, all 70,000 of those physicians that are targets today for bipolar depression, including the primary care targets, will all be MDD targets when we launch MDD and have the approval for it. So we'll have a year's worth of experience with these additional physicians raising brand awareness. They'll have experience with the product in bipolar depression so that upon approval with MDD, we think the uptake in that group will be that much more rapid. Our goal by the time we get the approval is to be right-sized so that we have a comparable share of voice in all the markets that we operate in. Just a quick follow-up question. So in bipolar depression, my understanding is that general practitioners have a greater degree of comfort managing MDD patients. But we are seeing more comfort in GPs managing bipolar patients. Is it your view that there's going to be a deeper GP audience in bipolar depression going forward? And is that part of the impetus for standing up the 150-rep sales force focused on GPs? We do. We've actually seen those trends over the last several years where primary care has been taking a more, and quite honestly, the mid-levels, the nurse practitioners that support the primary care physicians are taking a bigger role in that. Part of the reason is what Sharon was explaining before. These patients come in, they look like MDD patients because you miss the manic Phase. So then when they finally identify that, then they've got to treat that patient. You have a lot of patients coming in through primary care who look like major depressive disorder patients, but are actually bipolar patients. Those are the ones that primary care physicians are managing. It's also the way our healthcare is going in this country. And I think more and more we are seeing the GPs as the first and only line of treatment for patients. Most people are not having the luxury of being referred to a psychiatrist. In other words, if it's not acute mental illness, if it's not a psychotic break, if it's something that doesn't rise to that level, chances are you're going to be managed by your GP, not necessarily a psychiatrist. I think more and more it's going in the direction of general practitioners, which, as Mark said, includes the NPs. In fact, at this conference and the conferences that just happened in Miami, investors were coming up to me saying, "You know, I can't even get an appointment with my GP. I keep getting these NPs now. What is it?" And I think that's the way our healthcare system's going. Yeah. Interesting. So let's spend the next seven minutes or so we have left talking about the pipeline. And I'll focus a few questions on, I guess, all things lumateperone. Let's start with the long-acting injectable lumateperone opportunity. And I guess the question here is just talk to what you think is a commercially competitive LAI profile. In other words, does it need to be dosed once monthly? Does it need to be subcutaneous? And does that $5 billion you cited reflect any LAI contribution? Okay. That $5 billion does not reflect LAI at all. Okay. So we get that off the table. Our LAI strategy is we think oral lumateperone is incredibly well tolerated, and the real reason for an LAI is to give patients a choice or for those patients who will not comply and take an oral drug. And to that end, it would be very helpful to have both a one-month and at least two-month formulation. We don't think it's really necessary to have greater than the two-month formulation, but we are working hard to develop one- and two-month formulations. We're also looking at different strategies of IM and sub-Q. And we do surveys looking at IM versus sub-Q. And I think that story isn't completely told yet as to what is preferable there. However, we do have an ongoing study with four different formulations, all of which were developed in-house. And we're pitting those against each other. So over the course of the next year, we will have safety and PK data on those different formulations. And we fully expect two to three of those to fall out. And we would continue going forward with one of them. Additionally, we have other formulations with collaborators that are still preclinical. And on those formulations, should they be successful, we will owe a royalty on those. And we would like nothing more than to move those into the clinic as well. Okay. That's helpful color. So let's move on to 1284 deuterated lumateperone. And my question here is on just any early views on how you're thinking about differentiation versus Caplyta. I mean, my sort of general take is, okay, Caplyta is pretty well tolerated. So what can a deuterated form of lumateperone do above and beyond Caplyta? Okay. So the first thing about the deuterated form is our chemists deuterated the molecule all around the molecule wherever they could. And then the biologists did these preclinical studies looking to see if there were any benefits to the deuteration. And we found from behavioral aspects that there were many benefits to some of these deuterated sites. So we took the one that we thought was the best into the clinic. We did Phase I studies. Now, these are a small number of patients, but we did large mass balance studies that you should be doing, and we did. And there we saw, first of all, there's a big difference in exposure of the parent molecule. So how the molecule stays intact before it gets excreted from the body. And then when you form these metabolites, the metabolites that are formed are qualitatively the same as in Luma, but quantitatively different. So you express more parent, you express less of the metabolites. And we think that that provides benefits. We're testing out whether those benefits. So in certain indications, if it can be more beneficial in those indications, have further benefits than we think Caplyta would have had. But also what we did see, it was a small cohort, and we're looking to see if that duplicates in these larger populations. Is in the elderly, we saw less somnolence. Is just one example. And we saw other things, but we're a little cautious because it was a small number of patients. And so we want to see if that replicates. And then we'll scream it from the rooftops if it turns out to be true. Okay. And that leads to my next question, which is on your clinical programs, your Phase II in Alzheimer's associated agitation and AD associated psychosis. Just real quick, any color on timelines for readout? And then the second question here is I think there's some degree of white space here. There's one drug approved for agitation right now. I think it was Rexulti. I know you'll be led by the data, but wondering out loud of those two indications, what you think could be the more commercially attractive of the two? I think there are a lot of patients. In fact, some people believe that both psychosis and agitation are part of the same disease, just differences along the spectrum. The agency, the FDA does require you to do two separate studies on them. We're doing separate studies. I think they're both incredibly important. They are both slow enrolling studies for a variety of reasons. We have said that we don't expect these studies to read out next year. We think that this is really a later event, a 2027 event for readouts of these studies. We think they're both important. I don't think I would put, I think agitation, again, if it's along the same spectrum, then you really are not going to see any difference in the usage. But I think that at least one might suspect that agitation might have a slightly bigger audience. Okay. That's helpful. And then the minute we have left, I wanted to touch on the generalized anxiety disorder study of 1284. Again, same question, any color on the timeline to read out for that Phase II? And I guess with success here, I mean, this would be, I believe, the first antipsychotic approved for GAD. So I guess with that in mind, how do you think about that opportunity? Yeah. So we think the opportunity is huge in GAD. First of all, there are no branded drugs available now. There are four SSRIs that have been approved and one that's not an SSRI, but isn't really used very much. And they are not really very either well tolerated or if well tolerated, they're not really very effective in helping with the GAD. So hence we have the same strategy we had with bipolars. We have one adjunctive study and one monotherapy study. And we think both of those studies are important. They will both, one of them will finish enrolling. And we're guiding you towards 27 for both of those, although one may be slightly earlier. We'll see how the enrollment goes. And so while they are called Phase II studies, they are powered and sized as Phase III studies, and they would be registration studies if they are successful. So we're very excited about that. There are over 10 million patients with GAD, and we think it's increasing. Our lumateperone studies have really demonstrated a benefit in anxiety. And so we think that 1284 will only be better in that regard. Okay. Well. See we're done. Yeah. Lots to talk about. Wish we had more time, but I'll leave it there. Thanks, Sharon. Thanks Thanks Mark. Thanks, Dave. Thank you. Okay. Thank you, Nealy.