The next session is an expanded fireside chat with many members of management of Intra-Cellular Therapeutics. Just as a reminder, if you have questions, you can type into your laptop, and I'll see them on the tablet here. Or if you're on the webcast, you can do the same thing. So it's my great pleasure to have with me Sharon Mates, CEO. Welcome. Mark Neumann, Chief Commercial Officer. Sanjeev Narula, the Chief Financial Officer. And I'm missing one person. Suresh Durgam. Hi. And your title or your role at the company is? Chief Medical Officer. The what? Chief Medical Officer. Chief Medical Officer. Got it. Okay. Nice to meet you. Okay. So maybe we could just start with the high-level just summary of the company's key assets, some of the key catalysts in the next three to four quarters, and then we can dig into the pipeline. Great. Thanks a lot. It's great to be here, so before I start, I should say that today we'll be making forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, and that actual results may differ, and I refer you to our website and our SEC filings for continuous updates on the company, so with that, let me give you a little background on us. We started the company in 2002, and that was to take technology from the Greengard Laboratory at Rockefeller, who Dr. Greengard had just won his Nobel Prize for showing intracellular signaling pathways in the brain, saying, "Don't just look at those receptors on the outside of cells, but look downstream of the receptors." And we started the company to take that technology out of his lab and set up a platform whereby we could screen drugs and create molecular signatures of drugs based on their downstream signaling from the receptor profiles. So we did that, and we call it CNS Profile. And we use that as a tool in the company to help us identify differences between molecules. Let me fast forward. We used that tool while we were developing lumateperone, which is now Caplyta, to be able to just help us define actions at different molecular sites for what is now Caplyta. We received approval for Caplyta, our first product for the first indication. That was for schizophrenia in December of 2019. We launched the product in March 2020, which, if you remember, March 2020 is when the world shut down. March 13th, actually, because that was the day, if I remember correctly. Okay. Well, all I remember is that we were going to be on our way to our national sales meeting and to launch the product. And people were coming back from right around a little later than March 13th. But they were coming back sick from a Biogen meeting. And we said, "What are we doing? We're flying 500 people out to Arizona. We're not going to do that. We're going to do a virtual launch." So we quickly switched. And I think we were certainly one of the first, if not the first, to do a fully virtual launch of a first product for a company. And the launch went well, considering that it was a virtual launch. But we actually did very well. And for two years, we had Caplyta for treatment of schizophrenia in the marketplace. And then in December of 2021, we received approval for a label expansion for the treatment of bipolar depression. And we were really off to the races then. First of all, offices were opening up. Still, you had these hybrids, open-shut places. But our trajectory for the sales of Caplyta has been very robust, increasing steadily. Last year, we did $462 million in revenues on Caplyta. And this year, we've guided you to between $665 million-$685 million in revenues. So the trajectory has been very good. We recently, over the summer, got the results of our studies in adjunctive treatment in major depressive disorder. And those results were extremely robust and were the basis for an sNDA that we just filed very recently. So to tell you, there's a big difference between these patient populations. Schizophrenia has a patient population of about 2.6 million patients. Bipolar has a patient population of four to five times the size of schizophrenia, which is about 11 million patients, and MDD has an even larger patient population, and I'm sure we'll talk about. You're referencing the U.S. numbers. These are all U.S. numbers only, and we've launched in the U.S. only to date. Okay. So just to step in there with a basic question, just in terms of the order, how did you make sense you started with, I guess, the smaller indication and moved to the larger one? Was that intentional, or did you just have some good early POC and schizophrenia that led to the approval there first, and then bipolar, and then the last one you mentioned? Right. Major depressive disorder as adjunctive treatment. Caplyta is an antipsychotic. And the antipsychotics have all started with schizophrenia. And the reason is to be able to get a handle on how the drug works in a patient population with psychosis. And that helps guide you in your dosing for both schizophrenia and other indications. Our other indications are in what's called mood disorders, which are much, much larger than the psychosis. And I mean, we believe we're becoming the leader and hope to keep that position as a leader in the treatment of mood disorders. There are a lot of antipsychotics on the market. Generics is a big, long list. What's the pitch as far as your differentiation? Is it an efficacy argument? Is it a safety argument? Is it a not gaining weight argument? All of the above. However, I should tell you that those antipsychotics are approved for schizophrenia. Most of them are not approved for any of the mood disorders, for bipolar disorder, or for major depressive disorder. So you are correct. There are many generics that are approved, I think 20-plus, like 22, 23, for the treatment of schizophrenia. But then it's a much, much lower number who have treatment in bipolar depression is only four or five. And the same thing for adjunctive treatment in major depressive disorder. Much, much lower numbers. The other little thing I know about these neuropsychiatric markets is there's a lot of running up, trying one, cycling to another one. Then that one doesn't work. Then you go to this one and then you're back in a circle. That's exactly right. And that's why in schizophrenia, it is actually part of the disease. It's called a lack of insight. So patients believe they're better. They believe they don't need a drug. They stop taking the drug. They relapse. They then are put on another antipsychotic. Or they say, "I don't like this drug. I'm not taking it." So they cycle through these drugs, very much so in schizophrenia, much less so in bipolar, and less so in major depressive disorder as well. Which sort of leads to my question for Caplyta. Caplyta, yeah. Caplyta, sorry. Is that no longer the case? There's a better persistence of duration of therapy, less cycling? We do have, well, again, for schizophrenia, part of it is the disorder. So whatever drug you give, you're going to still see they stay on the drug longer than if they were having all this weight gain or metabolic disturbances. But still, they cycle through these drugs. We do have very good persistence in bipolar disorder. And we're not approved yet for MDD. Okay. And then in terms of how psychiatrists approach the treatment decision, what% is of the new to therapy for both for the markets where you're approved? Do they go right on Caplyta, or they have to go through a whole series of generics before their insurance will? Certainly not a series of generics, but maybe I'll ask Mark to describe. Yeah, sure. It varies across the different channels, and it varies by payers, so there is a substantial amount of unrestricted availability for Caplyta, which means that a physician can prescribe for any indication for any patient that they'd like. There are others who employ an electronic step edit, which is almost as good as unrestricted because they don't have to do anything different. They prescribe the product as long as the patient's already been on a generic. The prescription goes through. And the vast majority, for the reason that you mentioned before, the hallmark dynamic in the antipsychotic category is this churn of patients because they try one after another. And even when there's a prior authorization in place, they're not onerous prior authorizations. Usually, they just want to make sure that the product is being used according to label. If it is, then those go through as well. We should also tell you, though, that it's also the payer dynamics are different amongst these different disorders. So schizophrenia is about 85% in the public markets, Medicaid, really Medicare/Medicaid dual eligibles. To a lesser extent, it's probably half and half, half public, half private, commercial markets for bipolar. And then MDD is even more commercial. How does your pricing look compared to, say, your competitor, Karuna, Bristol? Yeah. All of the oral antipsychotics are essentially in the same range. So price really isn't a factor in the prescribing decision. What about some of these other indications, for example, like Alzheimer's, dementia, or Parkinson's disease, psychosis? Are those areas that you would explore or have got some preliminary data in? Or is the mechanism not really suited for those? No. The mechanism is suited. We do have a large program in generalized anxiety disorder and in psychosis and Alzheimer's and in agitation and Alzheimer's, but not with lumateperone, which is Caplyta, but with a deuterated form of lumateperone that is called, yeah, that's called 1284. So these are large studies. They're all at least 700-plus patients, and those studies are ongoing. Is that an IP to deuterate or to just extend IP? Or is there some physicochemical reason for the deuteration? We think that there is a reason for doing the deuteration, and that is lumateperone has metabolites, and we deuterated all around the molecule. And the one that we chose to move forward was because, based on preclinical data, we saw that, in fact, we thought there were advantages from a PK standpoint. You have more parent expressed, which we think contributes to the efficacy, and as well as we did see in it was a small patient population in a phase I study in elderly patients, less somnolence. So we think that there may be some real advantages that we're waiting to see if it pans out in our larger studies before we go. Now I'm remembering my P-Chem from grad school because the carbon-deuterium bond is shorter than the carbon-hydrogen bond, I believe, if I remember my NMR, which may have some advantages in terms of the lack of metabolic activity, maybe. Maybe. Okay. Interesting. Now, do you break out sales in the different indications or no? We don't specifically break out our revenues. But generally, what you find with the antipsychotics is the mood disorders that Sharon mentioned, either bipolar depression or major depressive disorders, are the major driver of antipsychotics revenues. So from a patient population perspective, 2.6 million schizophrenia patients, 11 million bipolar, 21 million MDD. And if you look at it from a prescription basis, in 2023, there were about 68 million prescriptions for oral antipsychotics. About 30% of them, the largest indication was major depressive disorder, which we just submitted for. Second largest is bipolar depression at about 26%-27%. So those two are very close. And then schizophrenia is a distant third and then some of the other indications that you were talking about before. So when these products these days become blockbusters, they become blockbusters based on their performance in MDD and bipolar depression, less so in schizophrenia. Right now, the majority of the growth in the brand is coming from the bipolar segment? That's right. That's right. Right. Okay. And then once you get the other one approved, the mood disorder, then that should take over? MDD. Well, we will be expanding base. So over time, MDD adjunctive treatment, we would expect to become larger. But bipolar, new patients have been being diagnosed. It would not surprise me if we see a big expansion in the bipolar patient population as well. If you think about the Venn diagrams of these indications, are we talking about non-overlapping? For example, I mean, for the MDD overlap with the bipolar, I can't believe there's zero overlap, right? I mean, there must be some. That's a good point. In fact, that's one real beauty of Caplyta. We're approved in bipolar depression, not only for what's called bipolar I, but a much more difficult to diagnose and difficult to treat bipolar II. Those patients are for years misdiagnosed, often as having major depressive disorder. They're given SSRI after SSRI after SNRI, and none of them work. Here, a physician doesn't have to make the choice. What do they have? Do they have bipolar I or bipolar II or MDD? Because right now, we are approved for both bipolar I and bipolar II. They can say, "Oh, I don't have to try and figure out what they have. They have bipolar I or II. Let's just give them Caplyta, and then with an approval in MDD, they'll be able to do even more broad diagnosis of, 'Is it bipolar I? Is it bipolar II? Is it MDD?' I can use Caplyta for all of them. It's also the ease of administration. It's a once-a-day drug, and there's no dose titration, which is most of the antipsychotics. It's not just a single dose. You have to titrate them up because they can cause adverse events, primarily movement disturbances, and so in them, others have other adverse events. So here, you give them the effective dose on day one, and they can stay on that dose. Okay. Would you venture even further into some other peripheral psychiatric indications, like some of the personality disorder indications or OCD? Are those relevant? Suresh, do you want to address any of that? Yes. In terms of venturing into other indications, there's a possibility of venturing into other indications. And for 1284, we will likely announce that later on about venturing into other indications. In terms of personality disorders, you're specifically mentioning there's an interesting concept. But again, those trials are very difficult to do. And also, success rates are less. So we have to take that into consideration. Okay. So we've been talking about the U.S.. What's the lay of the land? You have global rights. What's going on in the other major pharmaceutical markets, Europe, Japan, China, maybe? Obviously, we know Karuna is partnered there with, or now Bristol's partnered with Zai Lab for their drug. So can you talk about the footprint ex-US? Sure. So all of our studies are global. We do think that Caplyta and our other products in development can certainly help patients worldwide. To date, we have not applied for an approval ex-US yet, but we will over time, and so stay tuned. That was done intentionally because you got the first approval in 2019. So now it's basically five years later. Was there a reason you decided to wait? Yes, because we wanted, first of all, we wanted to have more indications than just schizophrenia, just a first indication. And then this is not, no pun intended, atypical. This is not atypical for the antipsychotics, that it takes several years before you venture into the ex-US countries from the US. Okay. You want to talk a little bit more about the pipeline? You mentioned one of them. 1284. In terms of the pipeline, we have 1284, the deuterated lumateperone, so we have started studies that are ongoing right now in generalized anxiety disorder, both as adjunctive therapy and as monotherapy in patients who did not respond to generalized anxiety disorder medications. We also have ongoing studies in psychosis with Alzheimer's and also agitation with Alzheimer's. All these are phase II studies, but they are powered as phase III as can be used as registration studies if they are positive, so for agitation, I'm sorry, for generalized anxiety, we have two studies ongoing. If they are positive, that can be used for filing. Those would probably be our next filings that we would expect the company to be doing. How do you approach the question, which is a challenge not just for you, but for all the companies that are in the neuropsychiatric space, some of the sort of perennial challenges with good clinical trial design, meaning managing the risk on the placebo effect, which is the way it is in this indication. Obviously, it occurs in other areas too, but it's particularly notable in neuropsychiatric. And then the aspect of "professional patients" that seem to show up again and again and again. How do you manage those risks to make sure that you because obviously, we saw what happened with AbbVie the other day, right? Yeah. This is a good question. And placebo response for psychiatric trials is a huge issue. And one thing is I would say, first, starting with the compound, the compound should have good properties for differentiating itself. And once that is done, then looking at designing the protocol and also ensuring that the right kind of patient enters into the trial. When I mean right kind of patient, it means they actually have the diagnosis under study if you're talking about generalized anxiety, making sure that they really have generalized anxiety disorder. So for that, we use different things in our studies, adjudicating each patient that enters into our studies, and also looking at consistency of data across different scales that are in the trials. Also ensuring for professional patients, there are several things we may ensure that there is within our databases and other databases that the patients are not participating in the trial simultaneously and also that they are not repeatedly going to clinical trials for this. We do address that also. Well, there should be enough patients to not have to have repeat customers, right? Unlike some rare oncology where there's only 800 patients in the United States. But that professional patients is happening. Yeah. It is happening. Okay. Okay. Understood. Now, talk a little bit more about the commercial, the marketing. What sort of novel methods are you using, for example, social media or even some of these "influencers"? Do you involve them in any way in the marketing message, use of AI or machine learning to drive the sales to the right clusters? Yeah. So we have a very comprehensive marketing mix in the promotional activities behind Caplyta on both to professionals, physicians, nurse practitioners, etc., as well as the consumer side. So on the consumer side, bipolar depression and in the future, MDD both lend themselves to being the types of markets and the types of patients in which direct-to-consumer advertising is an effective means of educating the population about the disease and also educating them about the potential benefits of Caplyta for them so that they can have that discussion with their healthcare practitioner. We also are active across a variety of mediums in digital advertising, social media channels, etc. On the professional side, the main forms of promotion come from our sales force. We have a sales force of about 530 individuals. We have a target audience of about 70,000, predominantly psychiatrists and the nurse practitioners that support them. However, in the Q3 of this year, we stood up a 150-person primary care sales force, which we've also said that we will expand next year in preparation for MDD. Primary care plays a significant role in the treatment of bipolar depression. They account for about 25% of the total prescriptions in the market for bipolar depression. Psychiatry and the nurse practitioners account for 75%, but primary care plays an important role. When we get into major depressive disorder, that's closer to 50/50. So primary care plays an even more important role in major depressive disorder than in bipolar depression. We have a very comprehensive medical education program that we employ, sampling on the product, as well as digital advertising to healthcare professionals as well to the sites that they most often visit. So it's a very comprehensive marketing mix and comprehensive program to make sure that we're driving brand awareness of Caplyta as well as product choice. Now, I know Sharon was saying for schizophrenia, it's just endemic part of the disease, the pathology of the disorder that you keep cycling around. But for MDD or for bipolar, what's the expectation as far as Caplyta's duration of therapy? Is it expected to be just chronic, or would there be a point where you would expect the patient to not be on therapy anymore? How are you thinking about that? I mean, from a revenue perspective, if you think about the cash flow per patient over time. Yeah. Maybe Suresh, from a clinician, as a psychiatrist, perhaps maybe Suresh can provide the background on how clinicians think about treating their patients with bipolar and MDD, and then maybe I can add some commentary around the commercial implications. Sure. In terms of the patients with bipolar and MDD, each patient is different. So there are several patients who would need treatment for a long term. And that also depends on where they are in the stage of the disease. So if they are initially started for either bipolar or MDD, the recommendation is to wait to continue the drug for at least about a year and then reevaluate. And sometimes when they stop the medication, there is a relapse in bipolar, and then they put back on the medication. And then once they have a relapse, then the recommendation is to continue them for a long term. And for depression, it's very similar. But in depression, there are a lot more people who try for some time, and then they're okay for several years, and then they may get back on the medication again. You mentioned MDD. There's one other one I just thought of, manic-depressive. Is that? Yes. That's part of bipolar. That's part of bipolar. Okay. Bipolar has two poles. One is the manic pole and the depressive pole. Between these two poles, a patient spends generally about 80% of the time in the depressive phase of the illness, and they spend about 20% in the manic phase of the illness. Gotcha. Okay. And then, as far as talk a bit about the funding. I mean, at this point, you're generating cash. You're cash flow positive. No, we're not cash flow positive. Okay. Where are you on the path to profitability then on the P&L? So we are well capitalized. We have a $1 billion cash, and we have no debt. So we're well capitalized in terms of investing. So we are investing in the business. Profitability is important and is an important goal for the company. Right now, with the priorities that we have in maximizing on Caplyta, whether it's the existing indication or launching for MDD and investing in the pipeline, as we talked about, including 1284, our priorities are to make sure we have enough investment, and we get to a goal of sustainable profitability. So once we get profitable, we remain profitable. And I think we'll provide more guidance next year when we give that. But clearly, our focus is on sustainable profitability. You haven't given a specific time frame when you're going to get to the break-even? We have not. But we are providing guidance on the revenue. We are providing guidance on the expenses and OpEx. So if you look at that, you can get this. But when we provide 2025 guidance, we'll give you a kind of a range of options in terms of where we are investing and when we get profitable. Okay. Gotcha. Did you want to say something? Sorry. And then as far as other capital allocation, are you at the point where you would start to think about other things like buybacks? You're not there yet. I think it's, as I said, right now, I think the priority is to invest in the business, and we'll continue to do that. We're looking at all the other options. And it's only a matter of time when we get the cash flow positive. Clearly, all the options will be tabled. But I think we got enough on the table with investing in the business, both on growing commercially and then investing in the R&D. Okay. We're going to have to cut it a bit short because the team has to get back to the airport to head back home. So thank you all so much. It was a fascinating conversation. I learned a lot, and we'll talk soon. Great. Thank you so much. Thank you.