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, CMO Suresh Durgam, and CCO Mark Newman. Welcome. Thank you. Thank you. So for those who may not be as familiar with Intra-Cellular, can you provide a brief introduction? Sure. Thanks. It's great to be here, and we're very excited to tell you about all of the progress that we've been making at Intra-Cellular Therapies. Before I start, though, I should tell you that we will be making forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, and that actual results may differ. So I guide you to our website and to our SEC filings for continuous updates on the company. Having said that, let me just give you a brief overview of where we came from, where we are, and where we're going. So we started the company in 2002 to take technology out of the Greengard lab at Rockefeller. Dr. Greengard had just received his Nobel Prize for intracellular signaling pathways in the brain. And we set about to set up a platform whereby we could look at the actions of different drugs in the brain and compare them to each other. So to compare known drugs with our new drugs. And we successfully did that. That platform is called CNS Profile, and it is a tool we use to look at new chemical entities and their actions in the brain. Now, let me fast forward and tell you about CAPLYTA, which we received our first approval in December of 2019 for the treatment of schizophrenia. And we launched that first product into the eye of the pandemic in March of 2020, and even with the pandemic, we were very successful in our launch. So now again, fast-forward to December of 2021, and we received our first label expansion for lumateperone, which is CAPLYTA, as its brand name. And we have had a very, very successful launch, which is still ongoing, for CAPLYTA for the treatment of bipolar depression. Our label for bipolar depression is a very broad label. It is for both Bipolar I and Bipolar II, both as a monotherapy and as an adjunctive treatment, so, with lithium or valproate. So we are very, very pleased with the hockey stick trajectory that we've seen with the introduction of CAPLYTA for the treatment of bipolar depression, and that makes a lot of sense because the population of patients with schizophrenia is about 2.4 million adults, and for bipolar, it's 4-5 times that size, with about 11 million adults. We've been very pleased with the trajectory and with patient testaments of how CAPLYTA is helping them. Last year, our revenues on CAPLYTA were about $462 million, a little bit over. And we have guided to this year for between $650 million and $680 million. In the first half of this year, we saw a 50% increase from the first half of last year on our revenues. We think that we're well on our way to establishing CAPLYTA as a treatment in mood disorders. To that end, we have had an ongoing phase III program, registration program for adjunctive treatment in major depressive disorder, which again is an even larger market than bipolar. So, we, a couple of months ago, read out two very, very successful robust studies with lumateperone, or CAPLYTA, as an adjunctive treatment in major depressive disorder. And I'm happy to say that we recently had our pre-sNDA meeting with the FDA, and we are on track on our filing with our sNDA for the treatment of major depressive disorder as an adjunctive treatment later this year. So additionally, we call it lumateperone before it's an approved product, and then once it's approved, it's CAPLYTA. So with lumateperone, we have many ongoing programs. We have several pediatric programs. We have other adult programs in bipolar disorder as well, and I'm sure in the Q&A, Suresh can speak more about that. So then, if I could just switch gears a little bit, just to tell you a little bit about our pipeline. We have a very, very robust pipeline. We have ITI-1284, which is a deuterated form of lumateperone, that we are in several phase II studies, but they're powered as registration studies. They're powered and sized as registration studies, and should they be successful, we will use those studies in our registration endeavors for ITI-1284. First one is in GAD, in generalized anxiety disorder, and again, in the Q&A, Suresh can go into more detail. We also have started our studies in psychosis, in patients with Alzheimer's disease, and we'll soon start in agitation in patients with Alzheimer's disease. We have a platform called PDE1, and that platform, again, is very broad. We're in a phase II study for patients with Parkinson's disease, looking at movement disturbances and also looking at cognition in those patients. We also have another molecule within PDE1 platform, where we're looking at certain cancers. So two other platforms I want to talk to you about just a little bit. One is our long-acting injectable for lumateperone, where again, I'm pleased to say we have started a new clinical study looking at several different formulations, looking at both one- and two-month formulations for this LAI. And then lastly, our earliest stage program is the ITI-1549 series, which is we're very excited about, and these are molecules that don't cause hallucinations and delusions, and for the treatment of mood disorders. They're called neuroplastogens. So we're very excited about that program and all of our other programs, and I'll stop here so that we can get to your Q&A. Great. No, thanks so much, Sharon. That, that was very helpful. You talked about how CAPLYTA guidance, you've raised that to $650 million-$680 million. What factors do you think will influence whether you land at the bottom or the top of that range? Can you just talk a little bit more about that? Maybe I'll ask Mark if he- Yeah, sure. As Sharon mentioned, we've been very pleased ever since the launch of CAPLYTA, and in particular, with the bipolar depression launch. We've seen very consistent, very robust growth that we believe is going to continue well into the future. So we have a high degree of confidence in the guidance that we've provided. All of the fundamentals for the launch are in place and all going very well. We continue to increase both the breadth of our prescriber base, as well as the depth of prescribing on average by those physicians. And so I think, Jeff, it's just a matter of, you know, how strong will the trend continue to be, and that takes you to one end of the range or the other. I can't say that I can point to anything specific that would take you one direction or the other, but we do our trending. We see very consistent trend lines, and that results in the kind of growth that you've been seeing at the brand. What do you estimate is the current revenue mix between schizophrenia and bipolar depression? Yeah, the vast majority is coming from bipolar depression, which is not a surprise, for the reasons that Sharon actually mentioned. When you look at the size of these patient populations, schizophrenia is about 2.4 million adults in the U.S., bipolar, about 11 million. And when you look historically at the antipsychotics, as an antipsychotic adds a mood disorder indication to schizophrenia, whether that's MDD or whether that's bipolar depression, the vast majority of the prescriptions come from the mood disorders. And so, we're very much following that track. That's where the real explosive growth you've seen in CAPLYTA are coming from. And I think longer term, if you look, a good analog is VRAYLAR. VRAYLAR now has schizophrenia, bipolar depression, and MDD. With approval with MDD, we would continue to see that skew towards the mood disorders. And for reference, for VRAYLAR, schizophrenia represents less than 10% of their prescriptions now. So you see the vast majority is coming from MDD and from bipolar depression. And, I guess on a quarterly basis, like, you know, how many-- about how many new prescribers do you have? And then, I guess, what have you seen in terms of what kind of potential impact that has on TRxs? Yeah, this is, this has been a really encouraging metric for us to follow, particularly with the bipolar depression launch. So at the end of the second quarter, we had over 43,000 unique prescribers of CAPLYTA since launch. And each quarter, quarter over quarter, we're averaging between 3,000 and 4,000 new first-time prescribers of CAPLYTA. So for the second quarter, we added 3,600 physicians who wrote CAPLYTA for the first time since launch. And that's really been consistent quarter- over- quarter. So again, we don't see that diminishing at all over time either. Great. And can you just give us an overview of the current sales force and the DTC campaigns, and what kind of sales impact or increase in brand awareness have you seen with those initiatives? Yeah, both have been very successful. We track our ROIs on all of our investments. Our investment in the sales force with physicians and our investment in DTC, in TV, as well as the digital efforts that we have, all return a very positive ROI. Right now, our sales force, before the recent expansion that we announced, that we're in the middle of now, stood at about 370 representatives. Their primary promotional focus is on psychiatrists and the nurse practitioners that support them. Although we have had a small segment of primary care that we've been calling on. These are the very high volume prescribers of antipsychotics as primary care physicians, who do see a lot of bipolar depression patients, and that's a trend that's been increasing over time. And those 370 representatives call on about 43,000 physicians, again, predominantly psychiatrists and nurse practitioners. And all of the metrics that we track on our sales force are looking very good. And the feedback, in addition to the ROI calculations that we do on our investments, the feedback that we get on the DTC program in its efforts to raise awareness of the brand, to have patients decide if that could be a medication for them and ask their physicians about it, have all been very positive as well. Can you talk about the differences in goals for the 150-person sales expansion this year versus the second sales force expansion in 2025 for MDD? And would this mean that the 2025 expansion would be smaller in size? Not necessarily, and we've said we'll come back to you with the details of the second phase of the expansion as we get a little bit closer to the potential approval and launch, but the 150 that we're in the middle of right now, the decision we took was to go deeper into primary care for our base business of bipolar depression. We've been tracking a trend over time that suggests that primary care is playing an increasingly important role in the treatment of bipolar depression. Primary care accounts for about 25% of all the bipolar depression prescriptions written for antipsychotics, so psychiatry still dominates. That's the predominant specialty, but primary care plays an important role in bipolar depression, and that role has been increasing over time. So we felt that, in the context of the fantastic MDD results, that I'm sure we'll talk about later, that came out of Suresh's clinical trials, that gave us an even greater degree of confidence in the long-term prospects for CAPLYTA, and that allows us to invest even a more significant amount in our current business in bipolar depression today. So those 150, they'll be focused on bipolar depression. They'll be focused in primary care, new targets for us. It takes our target audience from 43,000 up to about 70,000. And as I mentioned, for the second part of the expansion next year, we'll come back to you with the details of both the size of that as well as the timing of that. And with the sales force expansion, can you just talk a little bit more about the dynamics of that in terms of, you know, how the psychiatry setting can be leveraged for acceleration, of a potential MDD launch? Yeah. The great news is. If I go back to the 43,000 physicians that we've been calling on up until this point, we call on them for bipolar depression and schizophrenia. Virtually, all 43,000 are also high-volume prescribers of patients with MDD as well. So we'll immediately be able to leverage about five years of brand awareness and experience with CAPLYTA in a new indication in MDD. So we would expect that will really help with a rapid uptake in MDD. Similar, honestly, to what VRAYLAR has seen in their MDD launch, which has been very successful. And again, for us, we see that as a validation that there remains a very significant unmet need in MDD for antipsychotics that have robust efficacy and a good safety and tolerability profile. We feel with the results that we've seen in Study 501 and 502, that that could represent a best-in-class profile for us. Just to emphasize, we are presently, prior to the expansion that Mark is just completing right now, we have been addressing the primary care market with those high-volume prescribers. So. Now, as we're going from 370 to over 500 sales reps, we have the opportunity to broaden our reach within the primary care market. Okay, great. Maybe focusing on adjunct MDD for Studies 501 and 502, you reported compelling efficacy on those two studies. Can you just give us an overview of those results? Yes. For the adjunct MDD program, we had several studies, the 501, 502, and 503, and 505. We have read out the first two studies, the efficacy studies. Both are 6-week double-blind studies, and with large effect sizes. We have read out the positive studies with the primary endpoint being MADRS total score, secondary endpoint, CGI. We have seen drug placebo difference, in the range of -4.9 to -4.7, and effect sizes of 0.61 in one study and 0.56 in the second study, and also, the same thing was replicated in CGI, which is the clinician-rated scale, and in this particular program, we also included what is called QIDS. That is the patient voice into the clinical trials. We have also seen the same level of significance that is comparing to the MADRS total score, CGI-S, and QIDS. So from three different perspectives, from a rater perspective, from a clinician perspective, and patient voice, we have shown consistency in both trials. And also the 503, which is the long-term safety study, that also we had good patients who were into the trial. And the data in all these trials have shown that in terms of the metabolic issues, the glucose, triglycerides, and cholesterol, as well as prolactin, weight, they were similar to placebo. And we are, you know, looking now, busy with putting the sNDA together. Can you talk about what the feedback has been like, following the two top-line results? You know, any areas of the data that were particularly well-received, either by physicians or key opinion leaders? Yeah. The feedback was very positive. Talking to the KOLs and prescribers, the results, again, in terms of the... Most of the KOLs has been talking about the breadth of the studies and also the effect sizes that usually in adjunctive treatment studies for MDD usually you see a two to four point difference in separation between drug and placebo. The higher for the monotherapy trials are around, you know, in the lower end for the adjunct trials. In this particular, with this particular compound, lumateperone, we have seen, you know, the drug placebo difference was in the higher ranges. So that was something that most people are, the KOLs I have talked to are impressed about that. And also, the safety profile from schizophrenia, bipolar, we have seen consistency that has panned out even in MDD program. Then for Study 503, can you just talk about what aspects of the safety profile that regulators might be focused on most? That this is a long-term, 6-month study, so one would be interested in making sure that whatever you have seen in the 6 weeks is continuing for long term. That will be the main thing they'll be looking at, and we have seen that it's an open-label study, so if that same profile is also continuing in the long term. And then what steps are you getting until approval versus what can be done now ahead of the sNDA submission? Again, I think Sharon was mentioning, we had a successful pre-sNDA meeting with the agency, FDA, and it was very successful, and they agreed with our package, what we are submitting. And now putting together and submitting it. Okay. And then how are you thinking about messaging the differentiation of CAPLYTA to providers? If you can just talk about that a little bit. I can talk from a clinical point of view. From a clinical point of view, one of the reasons, you know, having a good effect size that makes sure that the drug is efficacious, that's one thing. And second important thing is the side effect profile. Patients usually discontinue medications because of the side effects. So for antipsychotics, the more common things that people look at is the metabolic profile. That is, if there is increases in glucose, and also from a long-term, you know, hemoglobin A1c, increases insulin resistance, triglycerides, cholesterol, all that. And for prolactin is another, for some of the medications, increase in prolactin and weight gain and EPS are all the common things that people generally switch medications because of the side effects. In the major issues that with antipsychotics in this program, what we have seen with schizophrenia and bipolar, the same thing was also seen here in MDD, where in the drug, in the double-blind studies, we have shown that they were all similar to placebo. So the same profile that is in our label for schizophrenia and bipolar has panned out also in the MDD program. I think from a commercial perspective, we're very excited about the potential for an approval in MDD, partially because of the reasons we were talking about before, because of the great unmet need and the success that other antipsychotics have had there. But also because of the results of the studies, which we believe show a best-in-class profile in MDD. So you have CAPLYTA with very robust efficacy results, a safety and tolerability profile that Suresh described, that is very favorable, that it's been essentially replicated from schizophrenia to bipolar to MDD now. And you have a dosing regimen that is simple and convenient, once a day, single 42 mg dose. The physician can start the patient at the effective dose and maintain them on that dose. That, that's a really powerful package of attributes that the drug has, particularly in MDD, which upon approval, would be where our focus would be from a commercial perspective. And additionally, as Suresh mentioned, in the MDD studies, we added the patient voice. And the patient voice is extremely important because if the patient doesn't, "like the drug," they're not gonna stay on the drug. So the patient voice was very robust and matched both the clinician's voice and the rater's voice. So we're really pleased that our belief that CAPLYTA should be the drug of choice across mood disorders is being demonstrated to be true. And so we're very excited about that and look forward to a potential launch for adjunctive treatment in MDD. I would add one. Sorry, I missed that point, that in both studies, we were able to show the drug was efficacious as early as week one, when we measured it, and it continued throughout the study. Great. You mentioned about VRAYLAR earlier, and, you know, we've seen reports of heavy ad spend for VRAYLAR. Can you just talk about why growth for this product class is so sensitive to promotional initiatives? Yeah, I think it actually relates to what Sharon was just saying. The patient voice in treatment decisions is very important in each one of these categories, and particularly in MDD. These patients are sensitive to the potential safety and tolerability side effects that they've seen in previous antipsychotics. And with CAPLYTA, that's really where CAPLYTA shines in terms of its safety and tolerability, with all of the important parameters being comparable to placebo, as Suresh was talking about. And so I think whether you're talking about on the physician side and all of the different promotional activities we bring to bear there. We are on the consumer side with our DTC activities. It is a very promotionally sensitive market, and it was one of the underlying reasons for our decision to expand further into primary care at this time, and then further again next year. How do you think about potential competitive pressures from genetic VRAYLAR? Sorry, generic VRAYLAR, like later in the coming years, later this decade? Yeah, we don't foresee it to be a significant impact on our business. If you look historically at what happens in the antipsychotic category, as brands go generic, that brand gets impacted, but the remaining branded products really aren't affected. The most recent example of that, 'cause we had these questions a year and a half ago with LATUDA, we were told: "Well, your business is really gonna be hurt when LATUDA goes generic." It hasn't at all, and we didn't expect it to be because that's not what happens in this category. So we don't expect that the VRAYLAR going generic will have any significant impact either. Okay, great. Maybe looking at mixed features in study 43, you know, how are you thinking about the label? You know, do you need to have adjunctive MDD and MDD with mixed features in the label, or is adjunctive sufficient for unlocking that addressable MDD market? In terms of adjunctive, the program that the filing we are doing is mainly the indication we are looking after is adjunctive treatment for patients who had inadequate response to one-to-two antidepressants. So that is the focus of this particular application. Again, any positive data in the package is going to be helpful in getting that indication. And specifically in terms of what we're going to do with mixed features, of course, we are going to. We are presenting the data at different conferences. We are also going to be publishing it soon. And in terms of additional studies and all those things, we are discussing right now, and once we finalize our plans, we will let you know on that. What would you estimate is the overlap between adjunct MDD and mixed features? I would say in general, if you talk about MDD space, MDD has about 25% of the patients with MDD have mixed features. So irrespective of monotherapy or adjunctive, the same thing will carry over. So I would say 25% of adjunctive treatment will likely be mixed features patients. What's important is other antipsychotics don't necessarily treat these mixed features. Patients don't respond. We do know that with lumateperone we had very good responses, and it's encompassed within our Bipolar label already. Great. Maybe moving to your early stage programs, you mentioned deuterated lumateperone earlier, ITI-ITI-1284, and other indications. Like, how do the differentiated features with ITI-1284 lend to better indications, or lend better to the indications that you're targeting? In terms of the top, what indications we are targeting, basically looking at the mechanism of action from, again, it's a multimodal mechanism with a D2 partial agonist, you know, presynaptic partial agonism, postsynaptic antagonism, with 5-HT2A antagonism, as well as the glutamate system with the indirect activation of AMPA and NMDA receptors. We have picked, at least initially, we have started three programs. One is the adjunctive, sorry, the generalized anxiety disorder program. We have already started the adjunctive treatment program. That's also in patients who did not respond to one or two anti-anxiety medications. And we are in the process of starting also a monotherapy program in the same patient population who did not have response to two anti-anxiety medications. And then the second program is the psychosis in Alzheimer's. That program has started. It's also a phase II, but powered as phase III, if successful, can be used as a registration study. And shortly, we are going to be starting another program that is the agitation in Alzheimer's, which also is being powered as a phase III trial. And then for the other indications, we will let you know as we make our progress. We are planning a few other indications in that. Why would you expect an efficacy benefit in Alzheimer's disease psychosis? You know, other atypicals have not shown much of a benefit there. Yeah. So multiple lines of evidence. One, in terms of the mechanism itself, you know, it lends well in, for psychosis. And then in terms of clinical use, you know, right now for psychosis, there are different clinical trials being pursued. But clinically, antipsychotics have been used for treating psychosis in Alzheimer's for many, many years. Of course, it has black box warnings and all those things. In spite of all the black box warnings, clinicians, when patients and patient caregivers are stuck with difficult situations, the prescribers are prescribing psychiatrists in the, in the nursing homes and other areas, they are prescribing this. So from a clinical, there is an evidence that antipsychotics do help with those patients. And now we're studying this in this patient to make sure that they're safe and effective, and prove that this actually works, it's our job to do that. And then for generalized anxiety disorder, what do you need to see, I guess, to move it to phase III? This is powered as a phase III. It's powered as phase III. So if these two studies are positive, t hat will be the application. That will be the package. Okay. If I could just add on, the differences between the deuterated form of lumateperone and lumateperone is, you do have the same profile from the metabolites. However, they're different in the way they're expressed, and we express much more parent in the deuterated form. And we showed in a small cohort, but a cohort of normal, healthy elderly, we did see some benefits to the deuterated form, and there are other pKa values that we've seen that we think are beneficial, and we're looking to see if that pans out in larger studies now. Great. Sharon, you mentioned this at the beginning, but can you just talk a little bit more about ITI-333 and the rationale for the long-acting injectable? Okay. The ITI-333 is one program, and our long-acting injectable is another program. The long-acting injectable program that we have is with lumateperone. The ITI-333 is for opioid use disorder. Let me first emphasize the lumateperone long-acting injectable program, and we're very excited about that. We had looked at one formulation that we thought could never be developed for longer than a one-month formulation. So we went back to the drawing board, and we've got several programs, both preclinical and now clinical, looking at several different formulations of lumateperone. And the ones that we've just started now, again, are for both one- and two-month formulations. And ITI-333, again, that's in PET studies right now, and a multiple ascending dose study for substance use disorder. Okay, great. Well, looks like we'll leave it there. Thank you so much for your time. Okay, great. Thank you. Thank you.