Annual TD Cowen Healthcare Conference. I am Joe Thome, one of the senior biotech analysts here on the team. It is my pleasure to have with me today the team from Intra-Cellular Therapies. We have Chairman and CEO Sharon Mates, CCO Mark Neumann, and CMO Suresh Durgam. Maybe just to, to kick things off, Sharon, congrats on the continued progress of the company. Maybe if you want to start with just a high-level overview of some of the, the key points from 2023 and maybe what investors should look for throughout the duration of 2024. Great. Well, thanks for having us here, in the first place. And then secondly, before we start, we do have to tell you that our comments today will contain forward-looking statements, and actual results may differ, and we refer you to our website and our SEC filings. Okay. Having said that, I think you and most people in this room know that we started the company in 2002, and we had our first product approval, being CAPLYTA for the treatment of schizophrenia in December 2019. We launched and did well, even in the face of the pandemic. And then in 2021, in December, we received approval for an expanded indication for the treatment of bipolar depression, both bipolar I and bipolar II, as a monotherapy and as an adjunctive therapy, with lithium or valproate. So, bipolar depression has four-five times the number of patients of schizophrenia, and so not surprisingly, we saw a very rapid increase and a rapid trajectory of increase to our scripts. And last year, in 2023, we had an 85% increase in scripts over 2022 even, so and with revenues reaching $462 million. So we're very pleased with that. And on our last earnings call, we on our last quarterly call, I should say, we gave guidance for our earnings to be between $645 million and $675 million for 2024. So we're very pleased with how things have been progressing with CAPLYTA. And very importantly, the product has played out in the marketplace exactly how it played out in our clinical studies, which sometimes is not the case because your clinical studies are well controlled. So I know we're going to talk a lot about clinical development, etc., but I should say that we believe that lumateperone has a real place in treating mood disorders. And to that end, we are in phase three development in our pivotal studies for the treatment of adjunctive treatment of MDD. That first study should read out very shortly. We announced in April, and the second study will read out later, late in the quarter. We also have other studies ongoing. We have a very rich pipeline that I hope we get to, including a long-acting injectable for lumateperone and also a platform called 1284 for the treatment of GAD as well as agitation in Alzheimer's and psychosis in Alzheimer's. We have a PDE1 inhibitor program, which is in phase II development for Parkinson's disease, as well as we're very excited about this platform because of its ability to treat neuroinflammation and, in fact, be anti-inflammatory, both in the CNS and outside the CNS. Then we also have a program called 333 for substance use disorder. Lastly is our preclinical program that are in non-hallucinogenic psychedelics that, I think we'll talk some about that we're very excited about. That's a whirlwind tour of ITCI. No, that's great. You did mention the $645 million-$675 million guidance for Caplyta. I guess what are sort of some of the key execution steps to achieve that guidance? Is it continuing what you're doing right now, or are there other things that investors should be looking for that you're doing from the commercial side to make sure you're hitting those goals over 2024? I say continue doing what we're doing, but Mark can expound on that a little bit. Yeah, no, and largely that's true. I think our 2024 guidance is reflective of the high degree of confidence that we have that our robust growth is going to continue. Two of the metrics that we follow very closely are the breadth of our prescriber base, so how many new first-time prescribers of Caplyta are prescribing the drug, and then the depth of prescribing, which is across that prescriber base, how many prescriptions on average do each of those physicians, right? We're now in our ninth quarter since the bipolar depression launch, and every quarter we've had very significant gains in our prescriber base, 3,000-4,000 new first-time prescribers of Caplyta every quarter. And the depth of our prescribing has been increasing quarter-over-quarter at about the same pace since the first quarter of our launch. So, those two metrics are very healthy, and that gives us the confidence to provide the kind of guidance that we did. And as Sharon said, a lot of it is just really focused on execution. So make sure that our sales force is executing very strongly. We have a very robust DTC program consisting of a national television campaign along with social media and digital advertising. We'll be rolling out a new creative campaign in the second quarter of this year, so keep an eye out for that. And that all sits on top of what we consider to be very strong market access. So, we have very broad access for CAPLYTA in Medicare and Medicaid. Over 99% of patients are covered. In the commercial channel, it's about 90%, so we have very broad coverage so patients can access the drug as well. 2024 is really just about executing as strongly as we can and as we have been since we launched. It was mentioned on the fourth quarter call, that the two large Medicare Part D accounts moved to unrestricted status for CAPLYTA. I guess what does that mean for the franchise going forward, I guess both in terms of access but then also for revenues? Is that a large impact? Yeah, so it'll be significantly more volume through those two payers now with unrestricted status. Prior to that, both of those payers had a prior authorization with two generic steps before you could get to Caplyta. Now we have unrestricted status, which means the physician can prescribe Caplyta for whichever patient they deem appropriate without having to fill out a prior authorization or step through other therapies. So we saw some impact of that in the fourth quarter. These things take a little bit of time to work through the system. We expect the full impact of that this year. Then maybe moving to the upcoming phase three trials in MDD, maybe just to set the stage a little bit, what level of clinical impact would you like to see from these trials? Obviously, it is an adjunctive study, so a lot of investors are used to seeing monotherapy benefits on MADRS of, you know, four+ points, but with adjunctive, it tends to be maybe toward the lower range of that two-four area. What would you view as success there, and if you could give us a hint at the powering assumptions for the phase threes? These are Suresh's studies? Well, let Suresh address it. Yes, thank you. Regarding the studies, we have two phase III studies ongoing, and the first two studies will be reporting pretty soon. The primary endpoint is MADRS total score. And in that, as you said, the generally two-four-point difference is clinically meaningful for monotherapy on the higher end, for the adjunctive therapy on the lower end. If you look at other approvals, they are in the same range for mono for adjunctive therapy. In terms of the powering, typically we power most of our phase III studies, pivotal studies, at 90% power. Obviously, placebo response has been a big, I don't want to say concern is a bad word, but, but concern for neuropsychiatric studies. I guess what has the company learned from prior studies in the neuropsych space to control placebo response? Maybe what are some of the, the top things that you're doing for these phase III studies to make sure it's consistent? Yeah. Yeah, placebo response in psychiatric trials in general and in particular with MDD, it's even higher. So we implement strategies in terms of adjudication, having the right patient into the trial, right kind of severity, and also severity looking at different aspects, not only from MADRS, from the clinician perspective, and also from CGI perspective, who comes into the trial. So we take that into account, and also mainly the adjudication of individual patient into the trial. We did see the phase three data for mixed features patients in the first half of last year. Maybe just at a high level, if you could review those data and do those data have implications and give you confidence in the currently running phase IIIs for adjunctive MDD? Sure. The mixed features data is the study 403. In that study, we had patients both with MDD with mixed features as well as bipolar depression with mixed features. So the study was designed to look at the overall combined population of both and also to individually look at individual subgroups. And all three were considered primary. So all three individual subgroups were considered primary. So we have separated again, the primary endpoint there also was MADRS total score, and the secondary endpoint was CGI-S, the Clinical Global Impression-Severity scale. In that, we have seen the overall combined between MDD mixed features with bipolar mixed features. We have shown MADRS and CGI separate, and there was a five-point + separation, but with effect sizes in the six-seven range, depending on how you look, which study, which subgroup. Also we have shown robust results in MDD with mixed individually as well as in bipolar depression with mixed. In the same study, we also looked at a pre-specified population of anxious distress. That is, patients who had. This is a post-hoc analysis, but it was pre-specified population looking at MDD, mixed features as well as having anxious distress. There we saw effect sizes even higher in that population. Maybe on that anxious distress population, I guess how important is showing benefit there, I guess in terms of differentiation if, if the therapy obviously is expanded to MDD but even with the current indication of BPD? Yeah, again, most, you know, with the comorbid anxiety is very high in patients with MDD. Again, this is a post-hoc analysis, so any data that is available to the clinicians is helpful that it treats those conditions if somebody has comorbid as well. And this is also looking at within that patient, anxious distress was also a new specifier that was added in DSM-5. So previously there was different names, anxious depression, you know, things like that, but this was more codified within the DSM-5 as a separate entity. They are different from the GAD and other social anxiety disorders, but this is within the MDD space and the bipolar depression space. Maybe just. Just to be clear, the mixed features in bipolar depression and in MDD were pre-specified and controlled for multiplicity. So this was a very, very rigorous, robust assay, and we had told you that we were going to be going to the FDA and talking to them. So for bipolar depression, we know we have a very broad label, and it's already encompassed within our label. So nothing more needs to be done for mixed features in bipolar depression. The question that we went to the FDA with was what do we now need to do for MDD? We have no label in MDD, right? So what do we need to do in order to move forward there? And we had a very good meeting with them. I think that we've discussed the design of first of all what a label within MDD could look like and what we need to go there. And so I think stay tuned. We're working through that right now, and I think that we were very pleased with our meeting. I think you maybe indicated on the last quarterly call you'll have the minutes from that meeting towards the end of this quarter. I guess what should investors expect on from the company in terms of when that path might be a little bit more clear, really? Well, I think I just described what happened, and we did literally just get those minutes, and I just told you what happened in it. So, we'll be unrolling a design of a study and more as we go forward. Investors obviously question whether both studies need to be statistically significant in the upcoming MDD adjunctive study, or obviously we have seen other applications with, you know, one study maybe just missing but obviously showing a clear trend. Can you talk maybe a little bit about your expectations for what you would need for the SNDA for the adjunctive MDD label expansion, and maybe just overall interactions with the FDA using the totality of the data that's generated in their decision? Yeah. Yes, that's true. You know, generally you require two studies. Having said that, if you see most applications, there is, you know, how the data reads out, if there is one study that is very strong and one that is a little bit not that, that strong. So then they took a also look at the overall data that we have in the MDD space itself. And again, if you look at MDD, even if looking at data from within our depression space, either in bipolar depression, which also is a major depressive episode, and this study we are currently undergoing and looking for the results is an adjunctive setting. So they will look at the overall package. So when we put together, again, there is different combinations and iterations how that could go. So we had to wait for the data to say how we will approach that. Maybe can you just talk a little bit about the overall expansion opportunity maybe into MDD? Are you currently seeing any sort of, I guess, quote-unquote, "off-label" use in MDD with the current label that you do have, or what level of expansion would this, label expansion bring you? Yeah, so as you know, once a product is on the market and approved, physicians can write for whatever they deem appropriate for the patient. So we do see some off-label use in MDD and other areas. I think what to expect from this is that we would expect to see another very significant inflection as we did with our bipolar depression launch. Like bipolar, MDD is a very large patient population, even larger than bipolar. A very significant unmet need remains in this area for an effective and safe and tolerable agent. I think the success that AbbVie has had with VRAYLAR this past year launching an MDD is really validation of what we already believe to be true, that there remains a very significant unmet need in this area. And so we would expect to see a similar kind of inflection. Perfect. And then in terms of what you would need from the commercial sales force expansion for MDD, can you touch a little bit on what are the call points that you're hitting on right now, and what would you need to expand in order to get the best use out of that expanded label should it come? Yeah, we would expect a significant expansion in our salesforce with a MDD approval. To give you a little bit of context, right now our target audience is about 43,000 physicians. The majority of those are psychiatrists and the nurse practitioners that support them. That's primarily who treats bipolar depression and schizophrenia. We do call on a segment of primary care, but it's not the majority of primary care. There are some primary care physicians who are comfortable treating bipolar; they don't treat schizophrenia, but they are comfortable treating bipolar depression, and they are high-volume prescribers of antipsychotics in those patients. But again, the majority of primary care physicians aren't comfortable doing that. With MDD, that changes. Primary care physicians are much more comfortable treating MDD adjunctively with antipsychotics. It would be for that group of physicians that we would expand our salesforce to provide, you know, the opportunity to optimize our growth in MDD for CAPLYTA. As we get a little bit closer to launch, we'll come back to you with more specifics about that. It'll all depend on how deeply into primary care we go and how quickly we go there. We'll come back to you with more specifics as we get closer. Perfect. And obviously the muscarinic class has gotten a lot of attention in the schizophrenia space, and now it looks like maybe two of these agents will be potentially marketed by large pharma in the coming years should they be approved, and these deals go through. I guess do you see an impact, from the muscarinic class on your existing CAPLYTA schizophrenia revenue opportunities, or maybe how do you expect that to play, together in the sales? Yeah, sure. We don't expect a significant impact from the launch for a couple of reasons. First of all, as we were just talking about, the vast majority of our business now and growing comes from bipolar depression, and with a successful MDD trial, that would be even more skewed towards the depressive, the mood disorders. And less and less of our business would come from schizophrenia. And even within schizophrenia, we've never seen a particular agent dominate the schizophrenia. It's not how that works. The dynamics are these patients really churn through multiple different antipsychotics. Most of them have safety and tolerability issues that cause the patients to discontinue their therapy until they find one that's tolerable for them and is effective. And we would see if the muscarinics are approved there, them slotting into that dynamic. For patients, it's good news. Any new product that comes to the market, especially in schizophrenia, is good news for patients, and we would welcome that. Perfect. And maybe, Sharon, you did mention the long-acting injectable formulation development work. Maybe if you could just highlight, where that stands right now, and how do you see the importance of a long-acting injectable, to the schizophrenia patient population? So I think the schizophrenic population is really a unique one. We do think a long-acting injectable offers two things. One is for those patients who are noncompliant. You can have a court order for them, or in some situations where they can be convinced that they want to take it, that they do. The other thing is just, you know, for ease of use for that patient population. Some patients might like it better. So we think that it is an option for patients. We've seen good uptake in schizophrenia with lumateperone. We don't have the side effect profile that you see with many other antipsychotics. They don't have the movement disorders. They don't have the weight gain. They don't have, as you see with some of these muscarinics, etc., they don't have any gut issues. So, I think that lumateperone oral is fairly widely accepted. Now, having said that, we do think that it is an important option for patients, and we are developing both a one-month and longer, and the longer being, we hope, two-month formulations, of lumateperone. And we have developed four different formulations, and we did test one formulation, a subcutaneous administration of 1-month duration. We think that's not the optimal formulation to use, so we've developed four other ones, and that testing we're going to be doing them simultaneously should start pretty soon. Perfect. And then you also did mention the deuterated lumateperone, the 1284 molecule. Maybe can you just highlight what the supportive data are for the compound that led you into the three phase II studies that are ongoing right now, and maybe how the profile could be differentiated for better use in some of these indications? Yeah, if we talk about the profile for why we went into these three indications, the indications we are pursuing are the GAD, and also, psychosis in Alzheimer's and agitation in Alzheimer's. Looking at the profile with the action on serotonin for 5-HT2A, SERT inhibition, and the dopamine, D2 action, and also the D1 indirectly through glutamate, all these play a role in these mechanisms. Plus also for GAD, we have information in the sense from the mechanistically, it makes sense to go into that, and also there's an unmet need in that space, especially as an add-on therapy. And then in terms of the agitation and psychosis, clinically also there is evidence, right? There is a lot of antipsychotics that are being used off-label in clinical practice for many, many years now. And also you have seen recently with the approval of brexpiprazole in agitation, the path forward has, you know, at least been laid for that indication. There's also for psychosis, clinically it's used, and mechanistically it makes sense, and also it's an unmet need with the safety profile of a compound with very less liabilities, potentially less liabilities in movement disorders like akathisia or EPS, metabolic issues, no issues with weight gain, and also no prolactin issues that will, you know, play out well in that patient population. We think that from the PK data we have in our early studies with 1284, there are some beneficial aspects to 1284, especially in an elderly population over lumateperone. So that's how we went with 1284 for these indications. Perfect. And you did mention that there's, you know, some initial indications or therapies actually being approved for these indications, but they still seem a little bit newer, in terms of the overall drug development cascade, sort of these neuropsych associated with, you know, neurodegenerative disorders. Can you talk a little bit about patient finding for Alzheimer's psychosis, Alzheimer's agitation? We've obviously seen some companies, you know, push their, their data back a little bit. So how easy is it to find these patients? Yeah, these are patients that are in clinical practice, yes, very almost anybody who sees patients in this population will encounter these patients almost on a weekly basis, having that is in clinical practice, but enrolling into the studies because then you had to make sure that the patients are enrolling in the studies, stay in the studies for a long time. These are difficult to get those patients. That's why the studies are mostly global studies where you go out and reach for a different wide variety of network of patients from across the globe. And also if you look at the studies that have been completed with brex and other things, you will know these studies took quite some time. And that's why most likely these studies will be global studies. At least our studies will be. Yeah, yes. Then in terms of uptake in this patient population, when we think about agitation and psychosis, I guess are these symptoms of the disease that would require chronic therapy, do you think, or is this more of a you, you treat it when you have an event, or how does that work overall? So it depends, but there are right now the chronic therapies, especially there are some patients who have, you know, these come very often. And that's again, there is you can treat it as episodic or this one, but definitely chronicity because it's sometimes once the disease has progressed, you have them very frequently. So then anticipating when it occurs may be difficult, but there may be some areas where it that can be done. But right now the path generally we are taking is the chronic because of, you know, it comes quite often. Last question on these. When do you think we might be able to see some initial data from the phase two programs? Yeah, so that one, once we start the studies, once we figure out the exact timings, we'll post it on clinicaltrials.gov. But at least wait till we start the studies before we give the. The clinical enrollment in the studies and put them on ClinicalTrials.gov. Then you did mention last year, I believe it was at the ACNP meeting that there was a lot of interest in the non-hallucinogenic compound, the psychedelic program that you do have. Maybe if you could just get a high-level talk about the program in general, and maybe what we should expect from data updates on that one preclinically. You want to? Yeah, sure. Yeah. So that is, as you said, we have announced about the 1549 molecule, a nonhallucinogenic psychedelic. So right now those preclinical studies are ongoing, and they are all IND-enabling studies, which will require for us to open an IND. That compound has 5-HT2A agonistic activity, and also we believe that based on the experiments we have done so far, in terms of it is beta-arrestin selective, so it requires both beta-arrestin and also the G-coupled pathway to activate it. Selectively activating through beta-arrestin and not through the G-coupled helps with not the hallucinogenic effects. That means we'll not have hallucinogenic effects. And we have seen that we have this is called head twitching in animal models. We have shown that. And once we finish up our IND-enabling studies, we'll progress into our first- in-man single ascending dose studies. We'll be looking for that data. Perfect. The company does expect to report some phase II data from the ITI-214 program for Parkinson's in the first half of 2025. Maybe at a high level, what should we expect from those phase II data? What would give you confidence to maybe move forward with that? Yeah, so the phase II study that is for ITI-214, we are looking at in Parkinson's disease as add-on therapy to levodopa. In that, this is a four-week study we have designed where we are looking at the Hauser diary, looking at increase in on-time without troublesome dyskinesia as the primary endpoint. We also have UPDRS Part II, which talks about the daily living, as a secondary endpoint. We also have multiple other endpoints in cognition, as well as also we're looking at different biomarkers, inflammatory biomarkers, in that study. Once we see the data from that, we have depending on how we want to go based on the inflammatory biomarkers data, we also have a second compound that we are looking for in oncology indications and other indications for that. We had to look for the data to make sure that based on and also for the cognition, how the data will look, will depend on how we design our next studies. Parkinson's has proven to be a little bit of a challenging commercial landscape for several other companies in the space, obviously launching new therapies. I guess how is that a consideration? Obviously, you touched on what you want to see from the clinical package, but how does the commercial potential, I guess, kind of factor in? I'll talk mainly about, you know, what we are looking at in terms of that you're right. That has, you know, we are aware of that, that this is a difficult market in terms of the Parkinson's. That's why we have included other areas where we want to look at the whole totality. Maybe if you talk about the movement space itself may be crowded. That's why we have introduced the cognition. We have introduced the bio-inflammatory biomarkers tending to look at it and see which is worthwhile to go into in future. Perfect. And obviously, you have a lot of different agents in the pipeline. What about the several years you are going to be generating some cash, obviously, through Caplyta's growth? How do you feel about BD external opportunities? Do you want to expand the pipeline, or are you happy with what you have right now? We're always looking. Anybody has any great ideas, we'd love to hear them. We look at a lot of things. So far, we haven't seen anything that we think would displace some of our own internal because there's only a certain number of dollars to go around. But we do always look, but we do think that we have a terrific internal platform, and, and we have a robust research group who continues to generate new platforms. So, we're, we're open to all of the above. Perfect. Well, with that, we're at time, so thank you very much for a great discussion. Sure. Appreciate it. Thank you. Thank you.