Okay, welcome everyone to our next session. I'm Brian Abrahams, Senior Biotech Analyst here at RBC Capital Markets. We're very pleased to have our next featured company, Intra-Cellular Therapies. We have on stage with us, Sharon Mates, their CEO, Suresh Durgam, their CMO, and Mark Neumann, their CCO, Chief Commercial Officer. So Sharon, Suresh, Mark, thank you guys so much for for being here to give us the latest updates. Thanks for having us. Great to be here. Great! Well, maybe we start off with lumateperone in major depressive disorder since you guys are coming off some recent very positive data. Can you maybe just start by putting that data- putting those data into context? I guess, you know, how meaningful should we think about this 4.9-point MADRS reduction, and where do you see this drug potentially differentiating in the MDD space versus what else is out there? So I'll ask Suresh to take that question, but before we do, I do wanna just remind everyone that we'll be making forward-looking statements here, within the meaning of the Private Securities Litigation Reform Act of 1995, and actually, results may differ. I refer you to our website and to our SEC filings for continuous updates. With that, Suresh, would you like to answer it? Sure. In terms of the data itself for MDD, our studies are an adjunctive treatment for MDD. That's adding on lumateperone on top of antidepressants. So typically, the clinical meaningful usually ranges from two to four points, four for being for the monotherapy studies and around two for the adjunctive therapy studies. Here in 501 study, which we have reported recently, we have seen robust results both in total MADRS score, which was a primary, and CGI-S, which was a key secondary, and also in a patient-rated scale, quick depression inventory scale. So in all three, we have seen very significant robust results. And we have seen drug placebo difference of -4.9 in the total MADRS score. That is generally... we have not seen that level of improvement for an adjunctive treatment. What do you. So that definitely is a very robust study. If you compare with the, you know. Again, you can't compare head-to-head, but again, with the data you have seen out there, it's a very robust. What do you attribute that to, with regards to lumateperone's receptors? I would say I would think so with the receptor profile of the receptor with the certain inhibition by 5-HT2A antagonism. Yeah. Also, we've been telling from the, you know, about the contribution of the AMPA and NMDA receptors indirectly acting through the D1. So all that plays a role. And also, you know, we were able to very successfully able to mitigate the flexible control in this particular study, so that will help a lot in, you know, any study that we can if you can do that. So I know we're now only a couple of weeks away from the second phase III MDD study. Can you talk about your level of confidence in that second study? And then maybe, I guess, along those lines, remind us some of the key similarities across the two studies and any differences that we should be thinking about, things like sites or maybe conduct in the way that placebo effect may be managed, or the type of placebo effect you might expect in the population you're seeing enroll in this study versus the first one? Yeah. In terms of the similarities, the studies are almost exactly the same in terms of the study design. It's a nine weeks, approximately nine-week study, with two weeks of screening period, six weeks of double-blind, and one week of safety follow-up. The inclusion criteria, exclusion criteria, were exactly the same, and the endpoints also were same. The one difference that, if you see from on the clinical trial on Gov and in the, the protocols, we have also included in the second study the sexual dysfunction scale, looking at sexual dysfunction. That was the only difference between these two. Nothing else has changed. Everything else is exactly the same. In terms of the sites, we have all our studies are global studies. We generally enroll about 30% of patients from U.S. and the rest from other, from other parts of the world, and this study will be similarly... is very similar to 501 in that aspect. In terms of the sites itself, we cannot have same sites doing two studies because then we will not be able to complete our recruitment for many, you know, another couple of years. So usually we, we have similar sites which we have worked with in the past in other programs. If you look at our bipolar programs or other programs, we have used the same sites. So it won't be same sites as 501, but the sites we have used in 502, we have experience. Okay Of using them in the past. Is there anything different about the way those sites are in terms of the patient populations they tend to enroll? Are there sort of different socioeconomic backgrounds or ethnic backgrounds or different, right, slight, any subtle differences? Yeah In the way doctors are administering these endpoint scales at these other sites? Sure. Sure. So in terms of the sites itself, there is no change even in terms of execution and the patients that are coming into the trials also. Because for each patient that goes into the trial, we adjudicate every patient that goes into the trial. We look at the screening forms, making sure that all the criteria, severity, both from CGI, from the clinical impression, as well as from the total MADRS score, all of them are meeting the criteria, so we adjudicate every patient that goes in. So no, no differences from that aspect, from 501 and 502. Okay. That's really helpful.... Initially, you had run three bipolar studies. Right. And then you had pivoted that third bipolar into the, what ended up being the mixed features study, the successful mixed feature study. Do you have any preliminary thoughts on how you might choose to pivot your third MDD study that's ongoing, should the second one read out positive and you have two positive phase IIIs? I know that's getting a little ahead of ourselves. Yeah, that's what, you get ahead of it. Yeah, we're of the belief that the second phase III is more likely than not to work. We will wait for the results, and we have some ideas what we want to do. At this time, it's just a thought. We have to see what the 502 shows, and then based on that, we will be able to figure out what we want to do with the 505 study. Okay. Basically, wait for a few until before the end of the quarter. Okay. I know you get asked this a lot, but would love to hear your latest thoughts from a regulatory standpoint. Can you maybe just characterize your latest regulatory interactions and what you believe is the FDA's amenability to reviewing an application with a single positive phase three study in MDD, plus supportive evidence from additional studies, such as in mixed features? And maybe in addition to your own interactions, kind of how that would tie into how you might interpret regulatory flexibility from what the FDA is showing in terms of leniency towards other antipsychotics in MDD. Yeah. In terms of the regulatory, how a regulatory will think, of course, we have to wait what they will do. But from our perspective, generally, they look at the totality of the data, of the package, of all the studies in depression. So we have depression studies that are now, you know, 501, 502. We also have studies, supportive data from our mixed features. So all that as a package, we have to wait and see. So it will be too premature to say how, what they will say or not, what they will do or not do. But I think we are confident that with the overall package, that it's we are in a good position. What do you think you'd need to show from the second phase III to support approval based on the totality of the data you've generated to date? Yeah. The mixed features data plus the very robust efficacy you've got in the first study. So even that is, you know, difficult to tell, because also we have to see what the 502 study does. If it is exactly like 501 or is it, you know you know, successful, or if it's missing, we have to again see that. But there are precedents where you have the totality of the evidence that was good, then in that cases, there are, you know, indications or at least precedents that they were able to approve based on the totality of the evidence. Going back to the mixed features data, do you see any path forward for mixed features as, I guess, sort of like a standalone indication or for the use of lumateperone monotherapy in some form of an MDD indication, just given the data you have to date, or is it really primarily to support adjunctive use in filing? Right now, it is mainly to support the adjunctive use in filing, but again, that will be a discussion we'll be having with the FDA, how that package can be used and what can we do with that, data. And again, that will all come when we have the full package. Okay. I guess I'm sort of wondering if there were populations who, you know, may benefit from monotherapy, and who couldn't... Maybe they can't take an SSRI or an SNRI for some reason, but could still benefit from lumateperone as a monotherapy. Yeah, there could be. Yeah. But again, for this program, it was adjunctive MDD program. How we use that, in the study we did with the mixed features, which included both bipolar depression and MDD, that MDD portion, how we will fit into this package, that's a matter of discussion with the FDA. Okay. All right, so we'll stay tuned. A lot of data and future regulatory discussions coming up. We cannot prejudge what they will say with that. Okay. Good. I want to shift gears a little bit to the commercial side of things. Sure. Maybe starting with the existing indications. Mark, can you elaborate on your recent commercial successes that you've had with bipolar and schizophrenia? Which aspects of the drug's profile are you guys seeing resonate most with physicians and with payers, and where do you see or are there segments of the population where you see the most potential future growth going forward? Yeah. So I'd say as excited as we are about the potential for MDD, we're very pleased with how well CAPLYTA is performing in the marketplace with its current indications of schizophrenia and bipolar depression. We continue to see new all-time highs across all of our prescription metrics. In fact, yesterday, when we got the new-to-brand weekly new-to-brand prescriptions, we hit a new all-time high, both in volume and market share. So we continue to gain share, continue to penetrate that market. We're growing the business steadily, and schizophrenia and bipolar depression is still growing very robustly. We're adding many new first-time prescribers of CAPLYTA, averaging in between 3,000 and 4,000, and getting close to about 40,000 physicians who've now tried CAPLYTA since the launch. We're really seeing usage across all segments of bipolar depression, and by segments, I mean bipolar one, bipolar two mixed features. We're seeing it used as monotherapy. We're seeing it used as adjunctive therapy. We're getting switches, both from generic products as well as, branded products.... So essentially it's being used exactly as the label is laid out. And as you know, we have the broadest label in bipolar depression. And the message is resonating, to your question, what they see is they see robust efficacy, they see a very favorable safety and tolerability profile. Whether you're talking about the metabolic side or the movement disorder side, CAPLYTA is comparable to placebo, and that's a profile that, to them, is best in class. You have a dosing regimen that allows for the patient to start at the effective dose and stay on the effective dose without having to titrate up to get to that point. So that package of benefits that CAPLYTA has to offer those patients, physicians have really grabbed onto, and their experience, their experience with the product is very similar to what Suresh's clinical trials produced, and that's always a good thing to have that kind of match when you're launching a new indication like that. And then, as you think about the potential launch in an MDD indication how are you planning to resource and scale the commercial activities? You obviously have even more resources now in terms of balance sheet, which could give you flexibility there. But how much of the existing bipolar infrastructure and schizophrenia infrastructure can be leverageable for an MDD launch? And how much additional investment do you want to put in to to potentially capitalize on what could be a large market opportunity? Yeah, I think it's fair to say that all of the existing infrastructure that we have for schizophrenia and bipolar depression can be leveraged in MDD. And what I mean by that is we currently have a call universe for our sales force of about 43,000 physicians, mostly psychiatrists and the nurse practitioners that support them, but also primary care, which plays an important role in bipolar depression. All of those 43,000, who are high prescribers of branded antipsychotics in bipolar depression, will also be high prescribers, for MDD as well. MDD is a very large indication, with a large patient population, and so, those 43,000 physicians will have a very high awareness level of CAPLYTA by the time we get to a potential MDD launch. They will have had experience with the product, and so we would anticipate that that group of physicians, there would be a very rapid uptake in MDD because of the favorable experience that they've had thus far with the brand. Where the expansion would come in is for us to go deeper into primary care, because there are many primary care physicians who are comfortable treating bipolar depression. There are even more that are comfortable treating MDD, but don't see a lot of bipolar depression. So it would be for those physicians that we would expand our sales force to give the appropriate coverage in educating those physicians. And beyond that, I think it's fair to say that MDD would be very amenable to a DTC campaign. As you know, Brian, we're out there with a bipolar depression campaign. We would anticipate continuing that and also looking at MDD as an opportunity there as well. If you look at what Rexulti and Vraylar are doing today, they're both very active in that space with their MDD campaigns. From a commercial standpoint, how much of a halo effect should we be thinking about with regards to MDD? I, I guess, how much of a growth driver could MDD be in and of itself, versus the idea of having MDD on a label, and sort of CAPLYTA as almost being a one-stop shop for many different mood and, and psychotic disorders? How, how do you think about that? How should we think about that halo, potential halo effect for the other indications with an MDD approval? Yeah, no, it's a good question. I think that both represent significant opportunities for the brand. Certainly, MDD in and of itself a s a new, new indication, large patient population, accounts for about 30% of the antipsychotics prescriptions. There's 68-69 million prescriptions each year of antipsychotics. About 30% of them are for MDD. It's the largest segment of all the indications, and for the branded antipsychotics, it's the fastest-growing segment, so that alone offers a tremendous opportunity. I think you make a good point, though, as especially with these products, as you build more and more indications into the label, the new indications and the experience that physicians have in that new indication does give them even more confidence in the brand, and they find more bipolar depression patients who might be appropriate for CAPLYTA, more schizophrenia patients who might be appropriate for CAPLYTA, and you do get that halo. So I think you'll see that as well. Sharon, can you just take a moment to remind us about the IP protection for lumateperone and your level of confidence that market exclusivity could potentially extend beyond the early 2030s? Sure. So we have Orange Book protection. I don't know if you noticed, we did just get another patent added to the Orange Book that goes through 2040. And we're very confident in that protection. Our patents in the Orange Book cover lumateperone in all shapes and forms, in all, composition, formulations, et cetera, as well as we have patents outside the Orange Book to what's called build a picket fence. So we're very confident in our protection through both Orange Book listings as well as through our broad patent protection outside of the Orange Book. Great! And then if we could talk a little bit about the rest of the pipeline, and I'm gonna maybe keep this question more open-ended. As you think holistically about Intra-Cellular and the state of the pipeline, what are the next steps? What future programs are you guys most excited about internally? What are the pipeline programs that you think are gonna really start to mature and get de-risked over the next year or two? Just before we get to the pipeline I would like to just add in, our pediatric program which is a very robust program. And we have open label studies, we have double-blind studies, and maybe do you want to describe those studies? Sure. Yeah, our pediatric program, we have started the schizophrenia pediatric program, which is an open label study for safety data. And we also have completed the PK extrapolation between adults and adolescents. That study was done, and we showed comparable efficacy—sorry, comparable exposures, so only we, we are required to do just the safety study for that, and that study has already started. We also have started the bipolar depression study in children 10-17 years of age, and that has started last month. We are going to start the irritability in autism program soon. That all of these will result, if studies are positive, will result into indications in those populations. Just to tell you, there are about 55-60 million people in that age range and about 6% of them have any o ne of these. disorders that Suresh just mentioned. So, we are devoting significant resources to this, and we're excited about it. Okay, so now I see we only have four minutes left, but to get to the pipeline. Well, we'll count that as pipeline. Which way? Okay, it is, it is pipeline, but it's still LUMA. So, of course, we have the 1284, which is our deuterated lumateperone, which we're very excited about, and several indications that we've told you about, and other indications which we are first working through to bring into the clinic. And what is starting in the clinic now is the generalized anxiety disorder, or GAD, as adjunctive treatment. We think that is a very important patient population. There are over 10 million people with GAD, half of whom are not treated, or insufficiently treated. So we think there's tremendous opportunity there. We also are going to be starting very shortly after that, studies in psychosis in patients with Alzheimer's disease and in agitation in patients with Alzheimer's disease. So that's 1284. We have a long-acting injectable program of lumateperone that is also. We've done a phase one study. We are looking at additional formulations, and those additional formulations will be starting soon. We have a whole platform of phosphodiesterase one inhibitors, and these are very unique. It's a very unique platform. We find we're always investigating this whole platform. What we're investigating is the anti-inflammatory effects that you see with these molecules. We're looking at it in a Parkinson's phase II program, where we're looking at movement disturbances as the primary endpoint, but we're measuring biomarkers to look at, to look at benefits with PDE1 inhibitors. And then we also have a separate molecule within the PDE1 inhibitor space that we're looking at for cancer, for certain cancers, and we're also right now looking at that in normal, healthy volunteers, just for dose-finding studies. So, we have a couple of other programs as well, but I'm not sure we have the time. 333, which is a mu-opioid receptor partial agonist for substance use disorder. And then, of course, my favorite one, or I shouldn't say my favorite, 'cause they're all my favorite, but 1549 is the non-hallucinogenic psychedelics where we have, with our deep knowledge of serotonin biology, created in-house molecules that are, built on 5-HT2A cores that, we've shown in many preclinical models, benefits in anxiety, in social anxiety, in depression, and that is working its way through to go into the clinic next year. Great. Maybe just with the last 30 seconds, I wanted to ask about business development. On the first quarter call, you mentioned keeping an open mind about BD. Can you maybe just clarify that a little bit more, and maybe talk about how you're thinking about prioritizing capital relative to Caplyta commercial efforts versus the internal pipeline versus external innovation? Yeah. So 98% of our activities go to building the CAPLYTA franchise, to investigating our present pipeline, to... We have an amazing group of chemists who have really discovered molecules that we believe can be very beneficial to humankind, and so our primary focus is to our in-house programs. We do always look at what's out there. We do investigate. Of course, if we could bring something in that Mark and his commercial group could capitalize on, we think that would be wonderful. But I think you should be thinking about our internal programs primarily. Okay. Good. Well, certainly a lot, lot going on and a lot to look forward to in the coming months. S thanks again. Okay. Really appreciate it. Thank you. Thank you. Thank you very much. Great.