Welcome to the Morgan Stanley Global Healthcare Conference. I'm Jeff Hung, one of the biotech analysts. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. For this session, we have Intra-Cellular Therapies with CEO Sharon Mates and Chief Commercial Officer, Mark Neumann, and Chief Medical Officer, Suresh Durgam. Welcome. Thank you. Thank you. For those who may not be as familiar with Intra-Cellular, can you provide a brief introduction? Sure. I'm Sharon Mates, the Chairman and CEO of Intra-Cellular Therapies. We started the company in 2002, and we received our first approval for the treatment of schizophrenia with Caplyta in 2019. We launched the first product in 2020, in March, right as the pandemic was starting, and as our first indication with schizophrenia. That was an interesting time, and I think we did very well in spite of the pandemic. Importantly, in 2021, we received approval for our second indication, bipolar depression and bipolar disorder, and the trajectory of the sales of the product have been quite robust since then. I should tell you guys, I forgot to make our disclaimer statement about forward-looking statements, and so I will be making forward-looking statements, and I do refer you to our website and our SEC filings for updates on the company. Having said that, I'll now tell you that the trajectory of the product has been very robust. So much so that in Q2, on our earnings call, we increased our guidance to you to $445 million-$465 million for revenues of Caplyta for the year. We continue to expand the indications for Caplyta, and we have a Phase III program, a registration program, ongoing for adjunctive treatment of major depressive disorder. Those studies will read out next year in the first half, and we are looking forward to those results. We think that all of our studies to date have really demonstrated that Caplyta has utility across several different indications in mood disorders. To that end, we have recently announced results from a study called mixed features in patients with either bipolar depression or in mixed features in MDD, and I'm sure we'll get into that in the Q&A. Had very, very robust results in that study. We've also, I'm sure, we'll get into other indications that we are pursuing within the lumateperone scope. So I know I was asked to make this extremely brief. I'll just tell you, we do have a very broad platform as well with ITI-1284 for several indications, as well as our pipeline is pretty extensive, and we'll get into that as we go into the Q&A, I'm sure. Okay. Great. Thanks, Sharon. So how does Caplyta fit into the treatment landscape for schizophrenia and bipolar disorder? Do you wanna? Yeah. How does Caplyta fit into the treatment landscape for schizophrenia and bipolar disorder? Yeah. In terms of the treatment for schizophrenia and bipolar disorder, first, let's talk about schizophrenia. It's approved for schizophrenia, and we have done two studies, which was efficacious, and also the safety profile of the compound. With antipsychotics, there are common adverse events that are an issue, mainly the metabolic changes, weight gain, EPS, prolactin, are the ones that commonly are looked at. And in terms of all those common side effect profile that is common with antipsychotics, with lumateperone, they were very similar to placebo. So that what it makes a compound that is least useful in terms of using this compound compared to others because of its least metabolic liability. Coming to the bipolar space, depression space, we have shown that it works both in bipolar I and II, both in monotherapy as well as in adjunctive therapy. We have shown the same kind of profile which was seen in schizophrenia, also replicate in bipolar. Also, in the long term, because these are medications that are taken for a longer period of time, we have shown that in the long-term studies, both in schizophrenia and in bipolar, the profile was maintained. Hence, it will be a useful tool in the prescriber's armamentarium for using this medication for these indications. I don't know if you want to. Yeah, I can add a little color to that from a commercial perspective and what we're seeing in the marketplace. So we've been very pleased by the uptake of Caplyta, both in schizophrenia, especially in bipolar depression. And one of the most encouraging signs of the launch is that it's being used in a very broad range of patients, so it's not really being niched in any particular area. And when I say a broad range of patients, it's being used for newly diagnosed patients as well as existing patients in a switch setting. In this category, switches are much more numerous than newly diagnosed patients. But to us, the fact that it's getting used in newly diagnosed patients and that physicians actually prefer to use it as early on in the line of therapy as they can because of the favorable safety and tolerability profile, is a very good and encouraging sign to us. So it's being used in new, it's being used in switch, it's being used across all lines of therapies. Switches come from a wide variety of products, both generic products as well as branded products, s o it really is getting broad utilization, both in schizophrenia and in bipolar depression. As you mentioned, the broad utilization, what factors drive uptake in bipolar depression? Yeah, I think it all starts with the profile that Suresh and his team delivered in our clinical trials. Very robust efficacy, a favorable safety and tolerability profile, whether you're talking about the metabolic side, increases in glucose, triglycerides, cholesterol, etc., all comparable to placebo. Weight gain comparable to placebo, or on the movement disorder side, where again, Caplyta was shown to be comparable to placebo. We also have very broad market access, over 98% coverage in Medicare and Medicaid, around 90% in the commercial channel, with good utilization criteria as well. And the commercial team, our sales and marketing team is executing quite well, as well. I think all that together gives you the kind of performance that we've seen in the uptake of bipolar depression. Then I guess within bipolar depression, do you have a sense for how Caplyta sales breaks out for bipolar I versus bipolar II? Yeah. Again, another very encouraging part of the launch is that we're seeing the utilization of Caplyta pretty much consistent with how it's labeled. And by that I mean, it's being used in bipolar I and bipolar II, probably some differential use in bipolar II because we're one of only two agents that has a bipolar II indication. It's being used both as monotherapy and as adjunctive therapy. So again, all part of the picture of very broad utilization. Sharon mentioned that, you know, sort of raised Caplyta sales guidance. You know, what factors get you the lower versus the upper end of guidance? Yeah. So the way we arrive at our guidance, much like I'm sure, Jeff, you and the team do, is we look at the historical prescription trends. We trend that out over time. We layer in any expected disruptive market effects to get to the low and the high range. But I'd say predominantly, we've had a very stable upward trajectory in our prescription. That's given us the confidence to raise guidance as Sharon had said. And the range is just really variation around the mean. So it'll depend on the uptake of new patient starts and the persistency profile. Can you talk about your DTC campaigns, and what kind of sales impact or increases in brand awareness have you seen with those initiatives? Yeah. So as you know, at the beginning of this year, we launched an evolution of our Let in the Lyte bipolar depression campaign. We've been very pleased with the interest that it's drawn from patients and physicians alike, and the resultant requests for Caplyta by patients with their physicians. So we look at a number of different metrics, including ROI, and the ROI has been very positive, and we've been pleased with that, and so we'll be continuing our DTC efforts certainly for the remainder of the year. But we also look at other metrics. We look at the degree to which we're hitting the target audience with our messaging, and all of those metrics look very good. We know that prospective patients take action by going to the Caplyta.com website. When they're on the website, they tend to stay on the website longer, and they take what we call high value actions. They'll either download a co-pay card, they'll download patient information, et c.. It's a, we know we're hitting the right target, and they're not just visiting the site and leaving it, they're actually taking actions that indicate that they have an interest in it and that they'll be asking their physicians about it. All of the metrics that we look at, both the neuro metrics as well as our ROIs, are looking very good. Great. Let's move on to mixed features. Earlier this year, as you talked about, and you announced positive results from Study 403. Can you just remind us of what you saw? In terms of mixed features, let me talk about mixed features before I go into the data. Sure. Mixed features was a specifier that was added in DSM-5 as a sub-specifier within the MDD and also with bipolar disorder. Mixed features is patients who have subthreshold symptoms of mania or hypomania and who in an anchoring episode of depression. That's the patient population we have been studying. These are difficult to treat patient population. They don't respond to SSRIs, SNRI antidepressants. They also have more suicidal ideations and thoughts. These are the patients who also have more comorbidities and also cost more, cost more to the healthcare system. So we thought this patient population, since they are difficult to treat, we wanted to look at that patient population. The reason we looked at this was in our Study 404 trial, one of our pivotal trials, we looked at a post-hoc analysis where we saw a robust effect in the mixed feature population, where we used a proxy of YMRS more than 4. And coming to this trial, in this trial, we have had patients with both MDD with mixed features, as well as bipolar depression with mixed features. Our primary analysis was changed from baseline to MADRS score on week six, looking at three different populations: the combined population of MDD with mixed features and bipolar depression with mixed features, individual patients, patient population with MDD with mixed features, and bipolar depression with mixed features. In all these three primary outcomes, we have shown robust efficacy, and the effect size ranges from 0.64 to 0.67, and the same thing was replicated for the key primary, sorry, key secondary endpoint, that is CGI-S, and that is the data we have shown. Coming to the safety profile, what we have shown in the safety profile in terms of the metabolics, EPS, as well as the weight gain, was similar to what we have seen in our, the pivotal trials of schizophrenia, and it was very consistent. And then for the presentation of the results later this year, what additional data might we see that was not previously disclosed with the top-line results? Yeah. Recently, just two, three days ago, we have some presented at U.S. Psych Congress, the data, which included initially, we only talked about the, the top line present during the press release. We now released the, during our, the Psych Congress, we talked about the safety profile a little bit on the combined populations. You will see much more data about individual populations, more safety data, more, you know, individual safety data will be presented throughout the conferences as we come up going on. Okay. We also looked at a population called anxious distress, and this is another very difficult to treat population and very common population. And again, what all of these populations have in common is a major depressive episode. So either in bipolar depression or in the mixed features in bipolar, or in patients with MDD with mixed features, or even in our schizophrenia population, which is not a mood disorder, but those patients who had concomitant, they also had depression, and we were able to treat their depressive episodes. What all these patient populations have in common is a major depressive episode. So you'll see more data, again, on the ability of lumateperone to treat across these different patient populations, a major depressive episode, and it's what gives us a lot of confidence, even within our studies that are ongoing now for MDD of success because of the major depressive episodes. What kind of physician education is needed on mixed features, and what kinds of initiatives are you considering? Mixed features has been in DSM-5 for quite some time, so most prescribers are familiar with this. In addition, we are going to be presenting our data at all the conferences, and also we'll be doing, we'll be submitting a manuscript, on this sometime towards the end of this year, before the end of the year. And also we'll be doing a lot of activities, you know, in educating the, physicians. You've been working on the regulatory package and had planned to meet with the FDA to discuss the next steps. Any updates here on the regulatory front? Just we are planning. So we have two populations here under discussion. One is bipolar patient population, and one is MDD patient population, and we think that we now have our strategy going forward within these patient populations, and we are still, you know, preparing, and we'll meet this year with the FDA over these patient populations. How should investors think about the sales potential with a label expansion for mixed features? Well, obviously, I think our data is very robust and these are patient populations that truly have unmet medical needs. We think that educating physicians on the data is extremely important and will be very helpful for them in understanding their prescribing. I don't know if you had anything you want to add. No. Yeah. And Sharon, I would just add, these are significantly sized populations. The estimates, whether you're talking about MDD or you're talking about bipolar, is up to 1/4 to 1/3 of all patients with bipolar MDD have mixed features. So these are patients that our physicians see every day. And the ability, for example, as Sharon was mentioning, we have a broad bipolar indication, but the ability in a specific patient population like this to be able to share clinical data on the efficacy and the safety side in patients that they see every day, we feel is really going to help to further our penetration into the bipolar market and increase our market share in that area. Great. Maybe moving on to MDD, you have multiple studies ongoing. What gives you confidence for Caplyta in MDD? In terms of the confidence, several lines of evidence. First, talking about the mechanism of action. Lumateperone is a 5-HT2A antagonist. So based on that, the SERT inhibition, that is the SSRI action, as well as the action on glutamate, that is the AMPA and NMDA, through the indirect effects on D1. So mechanistically, it works in mood disorder space. And number two, if you look at our schizophrenia trials, where we have looked at patients with schizophrenia and comorbid depression, both in the acute trials as well as in the long-term trials, we have shown that in a subset of patient population, those taking antidepressants, are not taking antidepressants. Both those patients improved on a scale called CDSS, that's Calgary Depression Scale, that is specifically designed and validated for measuring depression within the schizophrenia population. So that's one of, one line of evidence. And then coming to that, next one is the bipolar depression, both in monotherapy as well as in adjunctive therapy. These patients, again, as Sharon was mentioning, has these are patients with major depressive episode in a bipolar disorder. So we have shown that it works both in a monotherapy setting as well as in an adjunctive setting. Adjunctive setting in the bipolar depression means patients taking lithium or valproate. On top of that, they showed improvement when giving lumateperone. Next, we also shown that in the recent trial with mixed features, we have shown that the combined population, both in bipolar depression as well as in MDD, that's major depressive disorder, we have shown robust efficacy. Recently, we have announced about the anxious distress. These are patients who met criteria for anxious distress, which is also a common specifier subtype within the MDD space and bipolar. We have then also shown both in these two populations, MDD with bipolar, with anxious distress, as well as bipolar depression with anxious distress. There was robust efficacy. All this gives us confidence, you know, that, that we have shown that, demonstrated so far, in mood disorder space, there is good efficacy with lumateperone. That gives us the confidence. Can you talk about your Phase III studies and what would be considered clinically meaningful? Clinically meaningful, usually in depression space, is about 2-4 points. 4 points being for the monotherapy trials and about 2 points being in the adjunctive trials. So there are examples of approvals where patients have, if you have one or two trials in the package, one trial they have shown there were drugs that have gotten approval with more than 2, and some had even 1.8 as meaningful clinical difference. This has changed from baseline on the MADRS. Yep. Okay, great. Maybe on some of your other studies and programs, you're planning to begin Phase I studies for several formulations of your long-acting injectable later this year. What would you like to see in the results next year? So what we'd like to see is, s o we've already looked at one formulation, and that was a one-month formulation. What we'd like to see, using different formulations, is looking at both one month and two months delivery, as well as looking at different, the first study we did was a subcutaneous injection, looking at other routes of administration, such as IM. So looking at IM versus subQ, looking at one month versus two months. Can you talk about the rationale for developing the long-acting injectable, and what are your expectations on patient adoptions of LAI? Sure. So, we think an LAI gives patients a choice. We don't think an LAI is going to take over the entire market by any stretch of the imagination. We think that in certain populations, in noncompliant patient populations, an LAI can be advantageous or in patients who simply don't want to take an oral drug every day. So, we think for patient choice, it's a good thing. This is a patient population that does not necessarily enjoy or embrace needles. So in no way do we think this is going to take over the patient population in schizophrenia, but we do think that it can be an important option for patients. I do think that the safety and tolerability profile of oral lumateperone is such that gives it a big advantage. And therefore, we think that patients can stay on a once-a-day drug that, like lumateperone, which doesn't require titration. They don't have to be going up in dose, down in dose, and it's very simple and the doctors like it. It's a single dose, so you don't have to be fiddling around with, "Should I give them this, or should I give them that?" So we think that the oral lumateperone is here to stay, and we think that LAI can be an important option for patients to have. You're also developing a deuterated form of lumateperone in other indications. Can you just talk about the rationale for developing the deuterated form, and how is ITI-1284 differentiated from lumateperone? Right. It's early days for the deuterated form. We know we have actually deuterated around the molecule at many different sites, and ITI-1284, we think, is the optimal compound. We have had it in phase I studies in normal, healthy volunteers and in a population of the elderly. There we've shown, what we see with lumateperone is, qualitatively, it is the same as Luma. However, quantitatively, it's different. We express more parent, and we think that's very important and can be very important in certain disorders. We are looking at different disorders with ITI-1284 than we have approvals in with lumateperone. We're looking at psychosis in Alzheimer's patients, agitation in Alzheimer's patients, and GAD, or generalized anxiety disorder, for a start. We think that there may be several advantages to ITI-1284, in the patient populations that we're looking at, and we're moving forward with those studies. What kind of overlap is there between agitation and psychosis in Alzheimer's disease patients? And, you know, how sensitive are patients to treatment for agitation versus psychosis? Yeah. So there is overlap, some overlap, but also the overlap is two different things. One, it could happen in the same patient but different time points. You may have an agitation at the same time, may not have psychosis. When you have psychosis, you may not have this one. And there will be a small segment of patients who will have both at the same time. So there is some overlap in those patient populations. And the treatments are different in the sense treatment measurements. How do you get to the approval is different. For agitation, you have different set of scales to demonstrate that you are efficacious in agitation. And for psychosis, there are different set of scales you need to show that this, you are able to demonstrate that improvement. And so while it's the same patient population, how you demonstrate is different. Great. I can't remember if you mentioned this at the beginning of the talk, but can you just remind us how much cash you have and how far that gets you? So we ended Q2 with about $550 million in cash. And we think we're very good with cash. Remember, we also told you, we gave you guidance on revenues of $445 million-$465 million. So we think we're just fine on our cash. Great. Let's leave it there. Thanks so much for your time. Great. Thank you. Thank you. Thank you.