Good afternoon and welcome to Intra-Cellular Therapies virtual event, which will feature presentations on the company's pipeline, including lumateperone, ITI-1284, the PDE1 inhibitor platform, and ITI-333. There will be two question and answer sessions during today's program. Questions can be submitted throughout the presentations. To submit a question, type it in the box provided and hit the submit button. I will now turn this call over to Dr. Mates. Thank you, operator. Good afternoon, everyone. I'm Dr. Sharon Mates, Chairman and Chief Executive Officer of Intra-Cellular Therapies. In today's virtual event, we will be sharing highlights of our development programs. Joining me today from Intra-Cellular Therapies are Dr. Suresh Durgam, our Chief Medical Officer, and Dr. Robert Davis, our Chief Scientific Officer. They lead our clinical development and research efforts. Dr. Durgam is a psychiatrist with nearly 25 years of clinical research experience in neuropsychiatric drug development. He has led clinical programs and FDA drug approvals in several conditions, including schizophrenia, bipolar disorder, depression, and pain. Dr. Davis has over 40 years of drug discovery and development experience, including the areas of schizophrenia, bipolar disorder, Alzheimer's disease, Parkinson's disease, and pain. We are pleased to also have a distinguished group of KOLs joining us today. Dr. Christoph Correll, Dr. Andrew Cutler, Dr. Thomas Kosten, Dr. Roger McIntyre, and Dr. Ira Shoulson. We've assembled today's event to highlight several of our R&D programs. To begin our discussion, Dr. Durgam will provide an overview of our lumateperone and 1284 programs. Suresh's program presentation will be followed by a panel discussion with Doctors Correll, Cutler, and McIntyre. They will discuss these programs with an emphasis on the medical needs in mood disorders. This will be followed by a Q&A session. There will then be a short break prior to starting the second half of our program, where Dr. Davis will provide an overview of our phosphodiesterase one inhibitor program, and Dr. Shoulson will discuss current medical needs in Parkinson's disease. We will finish with a discussion of ITI-333 by Doctors Davis and Kosten, and then we will have Q&A from the audience. As per operator instructions, please submit your questions throughout the presentations. This will allow us to address them during the Q&A sessions. To remind you, today we will be making forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Actual results may differ, and I refer you to our website and our SEC filings for updates on the company. Let me start with a brief overview of our company. We founded Intra-Cellular Therapies in 2002 using technology based on the Nobel Prize-winning science from the laboratory of Dr. Paul Greengard on intracellular signaling. Our company's mission is to develop innovative treatments to improve the lives of individuals with neuropsychiatric and neurologic disorders in order to reduce the burden on patients and caregivers. We have been true to our mission. Today, we are a fully integrated biopharmaceutical company with strong CNS research and clinical development capabilities, complemented by an experienced commercial organization. A quick snapshot of where we are now. We had our first product approval in December 2019 for CAPLYTA, for the treatment of schizophrenia in adults. We successfully launched CAPLYTA last year. We are pleased with our launch, especially taking into account COVID-related disruptions in schizophrenia patient care. We are very excited about the potential label expansion for CAPLYTA to include the treatment of bipolar depression. As you know, our supplemental new drug applications are under review with PDUFA date on December 17th. In addition to bipolar depression, we are advancing the development of lumateperone in other depressive disorders. Suresh will tell you more about our development program. We have a robust pipeline with multiple platforms that we will be discussing today. This chart summarizes the programs we will be discussing, including ITI-1284, our phosphodiesterase one inhibitors, and ITI-333. We look forward to a very productive day and your engagement during the Q&A sessions. With that, it is my pleasure to turn this over to Dr. Suresh Durgam. Thank you, Sharon. It is a pleasure to be here to share our progress. I would like to remind our audience to submit your questions during our presentation. I will start with lumateperone. Lumateperone is a very exciting novel compound with a pharmacological profile, including unique interactions with serotonin, dopamine, and glutamate systems. Based on our understanding of the pharmacology of lumateperone, we have pursued a clinical development strategy across a broad range of major neuropsychiatric conditions. Today, we have made major progress in pursuing this strategy. Lumateperone is already FDA-approved for the treatment of schizophrenia in adults and is currently under FDA review for the treatment of bipolar depression. We also have an ongoing program in other depressive disorders, including phase III program in major depressive disorder, as well as in mixed state features. Let us take a moment to review CAPLYTA's profile in our first FDA-approved indication for treatment of schizophrenia in adults. CAPLYTA's proven efficacy is complemented by a favorable safety profile, including changes similar to placebo in extrapyramidal symptoms, weight, cardiometabolic parameters, and prolactin. Based on the feedback we have been hearing, the patients' and physician real-life experiences are in line with what we have demonstrated in clinical trials. Moving on to our next major indication, bipolar depression. As we mentioned earlier, the lumateperone PDUFA date for the treatment of bipolar depression is December 17th of this year. Our sNDA are supported by 2 phase III studies that are positive in evaluating lumateperone in adult patients with either bipolar I bipolar II disorder. Study 404 was a monotherapy study, and Study 402 was an adjunctive therapy study with lithium or valproate. In these trials, treatment with lumateperone resulted in a substantial reduction in depressive symptoms on both primary and key secondary endpoints. In fact, the data from our phase III monotherapy pivotal trial was recently published in The American Journal of Psychiatry, the most prominent journal in our field. The favorable safety and tolerability profile in our bipolar depression program is consistent with what was shown in our schizophrenia program. The most common adverse events were somnolence, dizziness, and nausea, which were mild or moderate in severity. The rates of discontinuation for these adverse events were less than 2%. Patients with bipolar disorder are particularly concerned with side effects including weight gain and movement disorders. Importantly, EPS-related adverse events were generally similar to placebo. In terms of metabolic parameters, lumateperone was also similar to placebo for changes in fasting glucose, total cholesterol, and triglycerides. Similarly, changes in weight were similar to placebo in the placebo-controlled trials. Following the efficacy and safety profile I just described, we believe lumateperone has the potential to be important option for patients with bipolar depression. lumateperone was successfully evaluated both as monotherapy and as adjunctive treatment. There are only a few FDA-approved treatments for bipolar depression, and currently, no other drug has been extensively studied across this broad range of adult patients. Pending FDA approval, we look forward to helping patients with bipolar depression. As I indicated earlier, two disorders, we have ongoing phase III clinical trials in adjunctive treatment for major depressive disorder, as well as large study in mixed features. Let me share details of our phase III program in adjunctive treatment for major depressive disorder. We have patient enrollment in 3 global studies, Study 501, 502, and 503. The first two are phase III double-blind, placebo-controlled, six week studies evaluating lumateperone 42 mg as adjunctive treatment to antidepressants for patients having an inadequate response to antidepressant therapy. The primary endpoint is change from baseline versus placebo on the MADRS total score at week six, and CGI Severity is the key secondary endpoint. Study 503 is an open-label rollover safety study to assess safety for six months. We have strong clinical evidence from our bipolar depression program and in patients with schizophrenia with comorbid depression to pursue lumateperone as an adjunctive treatment to major depressive disorder. Mixed features is depressive disorders, is another important program because these patients have greater symptom severity, have higher risk of suicide attempts with high comorbidities and respond poorly to antidepressants. Roughly one-third of patients with major depressive disorder and bipolar depression have mixed features. At the American Psychiatric Association annual meeting earlier this year, we presented the data from a post hoc analysis of Study 404, showing that lumateperone significantly improved depression symptoms in patients with bipolar depression exhibiting mixed features. Our ongoing Study 403 is a large, well-controlled, randomized, placebo-controlled clinical trial evaluating antidepressant effects of lumateperone in patients with bipolar depression or major depressive disorder who exhibits mixed features. We expect top-line data from this study in the second half of 2022. Wrapping up lumateperone, we have a long-acting injectable formulation for the treatment of schizophrenia. This formulation is designed to maintain therapeutic levels of lumateperone for at least one month. Our phase I single ascending-dose study evaluating the pharmacokinetics, safety, and tolerability of lumateperone long-acting injectable in patients with stable symptoms of schizophrenia is ongoing, and we have not seen any safety signals in the study. We anticipate initial results by end of this year. These results will inform the dosing strategy for the multiple ascending-dose study and the efficacy study needed for FDA submission. We also have other formulations in development, which will allow for treatment beyond one month. I would like to switch gears and talk about ITI-1284-ODT-SL. It is a deuterated form of lumateperone, a new molecular entity formulated as an oral disintegrating tablet for sublingual administration. Our completed phase I program found that ITI-1284 was rapidly absorbed into systemic circulation, was metabolically stable, and resulted in high systemic exposure. In our phase I studies in healthy volunteers and healthy elderly volunteers, there was no reported serious adverse events in either age group. Initially, we plan to develop this molecule for the treatment of behavioral disturbances in dementia, psychosis in dementia, and depressive disorders in the elderly. This compound, based on its pharmacological characteristics, is well-suited to study in this important patient population, including the elderly. This is an interesting program which we can discuss further, but in the interest of time, I want to start our discussion with our panel of experts to share their expertise on the opportunities, including unmet needs, as well as their impressions on the lumateperone profile. Let us start with the introductions. Dr. Correll is Professor of Psychiatry at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell in New York. His expertise is in psychopharmacology and clinical trials. He has authored over 700 journal articles and has also contributed extensively to clinical practice guidelines, including the American Society of Clinical Psychopharmacology Task Force on Expert Consensus Guidelines. Dr. Cutler is Chief Medical Officer at Neuroscience Education Institute and is Associate Clinical Professor in the Department of Psychiatry at SUNY Upstate Medical University in Syracuse. He has been a principal investigator on over 400 psychiatric and medical clinical trials, including lumateperone. Dr. McIntyre is Professor of Psychiatry and Pharmacology at the University of Toronto and Head of Mood Disorders Psychopharmacology Unit at the University Health Network in Toronto. He has published over 700 articles and manuscripts on mood disorders. In addition, Dr. McIntyre has also contributed extensively to clinical practice guidelines and is lead author of Florida Best Practice Psychotherapeutic Medication Guidelines for Adults with Major Depressive Disorder and Bipolar Disorder. Their disclosures are on these slides. Welcome, and thank you for joining us. I have a few questions to get us started. Potent than to D2 receptors, that difference between 5-HT2A to D2 is larger than with any other currently approved antipsychotic. Furthermore, the D2 affinity is similar to the affinity to SERT, a serotonin reuptake transporter, and D1. Those are all hit at the same affinity level. On the D2 receptor side, it has a unique profile in that presynaptically, where the break of the dopamine system is, it seems to be a partial agonist, stimulating partially the break. Postsynaptically, it is an antagonist. Since the break is stimulated at the currently approved dose of 42 mg, there is only a 40% postsynaptic D2 occupancy. That is a low occupancy that is only achieved with clozapine otherwise and translates into very few postsynaptic dopamine blocker-related side effects. All other antipsychotics currently approved are both antagonists pre and postsynaptically or partial agonists pre or postsynaptically. In addition to the serotonin reuptake inhibition that would translate into antidepressant activity, there is also a D1-related effect that translates into ultimately an increase in AMPA and NMDA glutamatergic transmission, which could be potentially helpful for the treatment of negative and cognitive symptoms, although obviously this would need to be tested in future studies. The side effect-related receptors, histaminergic and cholinergic receptors, are bound to with very low affinity, which then translates into very few side effects related to either weight gain, related to dry mouth or anticholinergic side effects, and also the sedation and anticholinergic-related brain fog that some patients report when they get antipsychotics. All in all, this is a medication that has a unique pharmacologic profile that can translate into beneficial efficacy signals, both in the antipsychotic but also in the mood disorder sphere, as well as in relatively low side effect profile. Thank you, Dr. Correll, for the explanation of the pharmacology and its therapeutic relevance. We'll switch gears now and go to a topic for Dr. McIntyre. Dr. McIntyre, can you describe us the bipolar treatment landscape and where lumateperone fits in the landscape? Be happy to, Suresh. The landscape as it currently exists with respect to the pharmacology for bipolar depression is a landscape that's comprised of 4 FDA-approved treatments. They are quetiapine, lurasidone, cariprazine, and the combination of olanzapine/fluoxetine. We know there's a larger number of medications that are approved by FDA for the treatment of acute bipolar I mania or mixed states. That being said, the most common presentation of bipolar disorder for those who live with the illness is one of depressive symptoms and episodes. In addition, depressive symptoms and episodes are what's called the index presentation, the initial presentation, along with being the most common presentation. Why it's so relevant for us to have treatments for bipolar depression that are newer and safer and better tolerated is because the most common reason a person who lives with bipolar I disorder bipolar II disorder would visit a healthcare provider is because they're experiencing depression. There are separate lines of evidence that indicate that the morbidity, that is the impairment in function, the loss of quality of life, the inability to in fact fulfill one's role, as well as mortality in depression, either due to unnatural causes like suicide, but maybe even natural causes, are in part related to depression. Taken together, depression is the primary therapeutic target and the unmet need. Important to also underscore, Suresh, that we look at the landscape, the four treatments that I enumerated for bipolar depression currently FDA-approved. Only one of those treatments, that is quetiapine, is currently approved in a way that included both bipolar I bipolar II disorder. bipolar disorder is a group of disorders. The DSM 5 codifies bipolar I bipolar II disorders separately. The remaining treatments, cariprazine, lurasidone, and olanzapine/fluoxetine combination, were not studied in the area bipolar II depression. In addition to having relatively few treatment options for the most common presentation of bipolar depression, we have even fewer, just one other treatment that has in fact been studied in adults with both bipolar I bipolar II disorder. Thank you. Dr. Cutler, can you tell what types of patients should physicians consider using lumateperone? Also, can you shed some light on your own experience using lumateperone? Absolutely, Suresh. Should be happy to. This is a very important question. When a new medication comes out or a medicine gets a new indication, one of the very common questions that we get asked is, what kind of patient would fit for this medicine? Certainly, in the clinical trials, sometimes we don't get a granular look at a specific patient type. In other words, you'll get approved for adult patients with schizophrenia, if you will. What we use a lot of times is the symptom clusters, the symptom presentations, and try to match up what we know about the pharmacology or the effects, or very often the side effects and risk profiles of these drugs we might match to the individual patient. That being said, whenever a new medicine comes out, I'll be very honest, where prescribers often use them or try them and is in their patients who haven't responded to other medications, or so-called we call them train wrecks, which is not fair. Of course, that's a place where lumateperone has been used, and I've certainly seen patients do well with lumateperone who didn't respond to other medications. I think where I really think about it being guided by the data is in patients who have responded to another antipsychotic. This is for schizophrenia, by the way. Patients who have responded to another psychotic but have developed weight gain or metabolic problems. The data really suggests that switching to lumateperone can be an extremely effective way of mitigating or managing those kind of issues. Patients who've experienced drug-induced Parkinsonism or akathisia, both of which are really troubling to patients and are reasons that lead to discontinuation of medication. This profile, as we heard, I think Christoph did a great job elaborating the pharmacology, which in my mind predicts antipsychotic and antidepressant efficacy without a lot of the risks that we usually associate with other atypical antipsychotics. We associate them with either weight gain, metabolic disturbance, maybe sedation, or else EPS, akathisia kinds of issues. You don't see that. In another group of patients that I definitely think this is appropriate for are patients who are early in their career, if you will. You know the old saying, you only get one chance to make a good first impression. Well, if patients develop side effects, nobody wants to take psychiatric medicines, right? If you develop a side effect, that gives somebody a good reason to not take the medicine. I like to use a medicine like this that might be safe and well-tolerated. Looking at the data further, of course, the antidepressant signal. Patients who have depressive symptoms with their schizophrenia, which is quite common actually, might be another place. There was another subscale that was studied in the schizophrenia trials called the prosocial subscale, which measures social interaction and social appropriateness. Patients with schizophrenia who might have that kind of complex of symptoms, that presentation, maybe some negative symptoms, is another place where I've definitely used it and seen some utility. On the bipolar side, first of all, as Roger said, and I'll be very honest, I have been using this medicine off label for mood disorder patients and find it to be really a good niche for this medication. As Roger said, bipolar II patients is another natural place where I'm going to use this medication because it actually has data, and the only other alternative, quetiapine, which is a very effective medicine, is really hampered by weight gain and metabolics and a lot of really antihistamine sedation, which as Christoph said, is more that fog sedation rather than the milder sedation that was seen in the clinical trials of lumateperone. Thank you for describing and talking to us about your experience with lumateperone. Dr. Correll, I would like to come back to you and what we just heard from Dr. Cutler regarding how often are the side effects considered and also the equal importance given to side effects with efficacy. Why is that people should consider side effects when making treatment decisions? Yes, that's a very important question. Thanks, Suresh. We need to balance efficacy and safety. It is clear we give the medications to have efficacy, but it can be undermined by problems with side effects. Especially when patients feel better and they have benefits from the treatment, but there's a lingering problem through the side effects, they are less likely to continue taking the medication and see value in the medication. Non-adherence has been linked quite a bit to safety and tolerability issues. When asking family members what side effects might lead to low quality of life the most when they take medication and have schizophrenia, they say sedation, weight gain, and cognitive problems. They don't talk much about sexual side effects because, I mean, patients don't talk much to their parents about sex, and they don't talk to clinicians much about it either unless they are being asked about. I would say that's a fourth dimension that is relevant. When you ask patients, they say weight gain, sedation, cognition. Let's face it, when you have either some improvement or very much improvement, but there's something that impedes your ability to function well, either mentally or physically, then why would you want to continue with the medication? Via the non-adherence, you can undermine efficacy, but you can also undermine with side effects functionality. If there is brain fog, if patients have a problem with restlessness or stiffness, slowing of the body and the brain, that's the postsynaptic dopamine blockade, you will have less functionality. Data show now very much that about 50%-60% of patients feel that their quality of life, well-being, but also their functionality is really impaired by lingering side effects. It could also be insomnia, the opposite of the sedation. We have some agents, as Andy was saying, that are more activating and have maybe the restlessness and the insomnia. We have others that are more sedating and have weight gain. We have yet others that block dopamine very strongly and have prolactin elevation and sexual side effects and stiffness. So far, each of the medications we have has at least one Achilles heel, and many have two or three. Lumateperone, through its unique pharmacology, it's very low in terms of side effects. The only one that came up with morning dosing was sedation, but that can be actually exploited at night when you help people sleep and give them a better rhythm for their day. Other than that, since there's little postsynaptic dopamine blockade, there is no appreciable issue with extrapyramidal side effects or akathisia and prolactin elevation. There is also very little weight gain or metabolic abnormalities, and there's also relatively little interference with daily functioning due to lingering sedation, especially when the medication is given at night. In that sense, it's really helpful to consider that side effects need to be put into the treatment algorithm. I would also say that in addition to weight gain shortening life potentially, and the metabolic parameters also when you have dyslipidemia, glucose abnormalities, there are now data to suggest that weight gain also translates into reduction in cognition. When you have metabolic syndrome, that reduces cognitive functioning, something that's already a problem in people with schizophrenia. We must keep the body and mind, and we must keep also side effects as part of the balancing act to make the medication even more efficacious. Here, lumateperone has a unique position in having very few side effects and robust efficacy. Thank you for that explanation of letting us know why side effects considerations are important in treatment decisions. Earlier I have talked about in my presentation about the development program for lumateperone as an adjunctive treatment for major depressive disorder. There are only a few antipsychotics that are approved for this indication for adjunctive treatment of major depressive disorder. Dr. Cutler, can you elaborate on your thoughts on the potential use of lumateperone in this area? Yes, I actually see a very big role for lumateperone in this specific indication. According to the National Institute of Mental Health, over 17 million people in the U.S. will suffer from depression. This is quite a common illness, and data from the STAR*D study, which was a large study sponsored by the National Institute of Mental Health, looking at the effectiveness of various treatment options. In the first line of treatment in response to our very standard effective antidepressant, an SSRI, only about 49%, less than half of patients responded, had a response to frontline treatment. Less than that, only a third got to full remission, which is really our goal here to maximize function, quality of life, make someone whole, if you will, return them to wellness. As you mentioned, there's only a handful right now of atypical antipsychotics that are approved, and those include olanzapine as a combination with fluoxetine, quetiapine, aripiprazole, and brexpiprazole. As we heard earlier, as Roger was elaborating, talking about bipolar depression, it's a slightly different stable of choices, but there's some overlap. They're plagued by some significant safety and tolerability issues, including weight gain, sedation, and possibly Parkinsonism and akathisia. What I find with patients with depression, with mood disorders in general, they tend to be a little more sensitive to side effects than those potentially with schizophrenia. They don't tolerate these things as well. They're often higher functioning. I think having another option here that does really look like it has antidepressant efficacy, and with this, as Christoph mentioned, this unique safety and tolerability profile really adds to our armamentarium of options. What it might do, certainly one of my hopes for this, is that a medicine that is better tolerated and safer from the point of view of weight and metabolics might overcome some of the reluctance of prescribers to prescribe atypical antipsychotics as augmentation. Despite the clearest and best efficacy data that we have for any augmentation strategy, various ones are used. People have been very reluctant to use these medications. As a matter of fact, of the patients who get an adjunctive or augmentation treatment, only 10% of those are getting an atypical antipsychotic. Talk about an unmet need and huge potential to expand the use. I think that really helps us understand the potential role here, and I'm personally very excited. The other thing I would like to mention is to have what I call a pan-depression indication to potentially have bipolar depression approval, both 1 and 2, and augmentation for unipolar depression, possibly even in the future, a mixed depression indication. I think that's going to be extremely helpful, particularly in a primary care setting, which is really where the bulk of depression is first managed and treated. I think it might give people a little more comfort because they're not as good at parsing out the different kinds of depression a lot of times. Perhaps it'll give them more comfort level in starting a medicine like this. Thank you. Now we're coming to the last question, and I think you touched base a little bit about the mixed features. Dr. McIntyre, there are no drugs approved for mixed features in major depressive disorder or bipolar depression. Can you describe the patient population and the presentation of mixed features and the medical need for these treatments in this patient population? Be happy to, Suresh. To pick up on some of the comments that Andy was speaking to, that being the spectrum of mood disorders or the group of mood disorders. I think it, in fact, begins with really a definition. What are mixed features? Frankly is not abundantly clear to everybody, but certainly is receiving a lot more attention because they are so common. Mixed features during a depressive episode are defined as the presence of hypomanic symptoms during that depression, and there is a specific number minimum, that being 3. For some people, it's a bit of a scratch my head kind of reaction. How can you have hypomanic symptoms and depressive symptoms at the same time? It begins with, first of all, we've often, in fact, described hypomanic symptoms as a mood disturbance, which is what it is. It's more than that. It involves also levels of activity. In fact, overactivity is a central feature of mixed features. What does that mean? People who have depression and mixed features will often present to their care provider, and they will report paralyzing anxiety, agonizing agitation, extremely difficult to focus and pay attention. Their partner or their friend, their family, the people they live with, will describe the tremendous irritability, the dysphoria, the anger, and no doubt this is contributing greatly to their interpersonal as well as work-related dysfunction. This description of depression that's woven with these symptoms that I described, Suresh, is what clinicians often encounter. How frequently? Well, we've looked at it. Others have looked at it. Mixed features during a depressive episode as part of major depression bipolar II or bipolar I affects between 25%-75% of people, that's a lot of people, depending on how it's defined. What's also important to underscore, Suresh, is not only how common it affects people, but how often it affects people who go to their healthcare provider, and it is a staggering percentage, with in some studies, more than half of people having these mixed features. The challenge, Suresh, as you know, is that clinicians have instinctively, especially in major depressive disorder, have prescribed antidepressants like Andy made mention to, for example, an SSRI. It turns out, however, that when you prescribe a conventional antidepressant, such as an SSRI, to someone who has major depressive disorder and mixed features, the outcomes seem to be very poor. People don't tolerate these treatments. They often, in many cases, will report an amplification of their distress and their symptoms, and they will frequently say, "The heck with it. I'm not taking this treatment." Last year, 2020, the Florida Medicaid guidelines provided an algorithm for individuals with major depressive disorder and mixed features as part of their clinical practice guidelines. In there, in the Florida Medicaid guidelines for major depression and bipolar depression I and II, what's underscored is that perhaps avoiding an antidepressant is recommended. Perhaps using a second-generation antipsychotic would be the preferred way to go. We know from other lines of research, and also my own clinical experience, that patients often benefit from second-generation antipsychotics during depression with mixed features as part of major depressive disorder. As both Christoph and Andy have summarized very well, the limitation with the existent treatments, the available treatments, is that there's too many side effects like sedation that's impairing sedation, the weight gain, the metabolic problems, and the risk for so-called extrapyramidal side effects. As Andy accurately cited, less than 10% of people will vote with their feet and say, "I want to take these treatments," because of the side effects. They're open to taking them. Side effects have been a deal breaker. Mixed features are very common. One of the most common presentations in both major depressive disorder and bipolar disorder. We've had very few treatment options that are acceptable to patients and are effective. We now know, based on available evidence with lumateperone, yes, it's effective in bipolar I bipolar II depression. That is a point of differentiation from most other psychotropic agents FDA-approved across all phases of bipolar disorder, focusing on depression. We're looking forward to seeing the data, Suresh, as it relates to major depressive disorder with mixed features. As you know, Suresh, we have, in a post hoc way, looked at mixed features in adults with bipolar I bipolar II depression, and we were pleased to see that the treatment was not only safe, well-tolerated, it was also very effective. I think we clearly have unmet needs in major depression, in bipolar I and II depression. Speaking to clinicians across the country and around the world, they say that their needs are especially acute as it relates to these commonly encountered patients with mixed features. Thank you. Thank you for your insights, for all of the panel. Let me turn over the call to Sharon to moderate the question and answer session. Thank you. Thanks everyone for participating today, and again, to our first day of talking about our development pipeline. We have had a lot of questions come in. By the way, this is Sharon Mates again. We've had a lot of questions come in, and so I'm going to start with some questions about lumateperone. We've had several questions, asking about I'm going to start with schizophrenia and CAPLYTA, just to give a frame to the conversation. We have some comments about the weight metabolic profile of lumateperone is very good. What makes you confident this profile will hold as more patients are exposed to the drug for longer periods of time, and can you share your perspectives on going forward and on your experience in your clinical trials with bipolar disorder? I have put a few questions together there. I'm going to actually ask, maybe Christoph to start on the metabolic profile and then have Dr. McIntyre chime in, and then Dr. Cutler chime in, and Dr. Correll, if you would start, please. Thanks. Great. Thanks for this important question. Obviously, cardiovascular risk is a very important part of psychotic treatment and also of the treatment of the mentally ill, who come with a higher risk anyway, and also with poorer healthy lifestyle. One of the big strengths of lumateperone, as I see it, is the consistent low body weight gain and metabolic burden. We have to bear in mind that although weight gain accrues over time, and that was one of the questions, long-term effects, it actually announces itself early. Early weight gain predicts later weight gain. That there was no difference from placebo in the six and four week trials is really comforting because that means that the weight gain will most likely remain low. Obviously, the metabolic effects can go up over time, but also in the open-label studies, we have seen rather a decrease in cardiometabolic risk compared to patients who are treated with currently available treatments. I and the time that lumateperone's cardiometabolic safety will hold up. Yeah, I'd agree with that. From the point of view of the future, always difficult to predict, it certainly is predicted by the near term. The near term being in the first four to six weeks. That gives you a great forecast as to what the weight gain liability will be like later. We have no reason to believe things will change six months, 18 months, three years later. This is such a critical question, not only from the point of view of cardiovascular risk, which is a major cause of morbidity and mortality in schizophrenia and bipolar, but the end user. A survey was conducted just a couple of two years ago at DBSA, Depression and Bipolar Support Alliance, the largest advocacy group for people who have bipolar and depression in America. We asked our constituents, "What are your priorities in bipolar depression management?" What came up first was, "We don't want treatments that cause a lot of weight gain." It's important from the point of view of absolutely the metric of their weight, and that's not acceptable as an outcome, as a side effect. The end user, the person who lives with schizophrenia or bipolar, they prioritize that in their treatment decisions. Finally, the Florida Medicaid guidelines, which are the most up-to-date guidelines informing treatment decisions for schizophrenia and bipolar In America, circa 2020 last updated, explicitly state that treatment selection in schizophrenia and bipolar should prioritize weight gain and metabolic liability in the sequencing of antipsychotics in both conditions. Yeah, I certainly agree with my colleagues. I would just add one quick thing, and that's mechanistically, the mechanism of action really doesn't predict a lot of risk for weight or cardiometabolic. The affinity, particularly for the histamine H1 receptor is very low, virtually non-existent. It doesn't have any affinity for 5-HT2C, which is another receptor, serotonin 2C. I would certainly agree with my colleagues. My experience up till now has been consistent with the clinical trials. Great. Thank you. I'm going to switch gears and go to MDD and go to mixed features in MDD and bipolar. We have a bunch of questions there, too. I'm going to start out with a question from Sumant Kulkarni from Canaccord. For the KOLs, do you think bipolar depression is diagnosed appropriately? What is the risk that misdiagnosis might mean that patients are prescribed standard antidepressants first, even if a medication like lumateperone may be approved and available for bipolar depression. Differences in some studies, they aggregate to about, depends on the study, between 2% and 3% of the population. What's important to highlight is that both conditions, of course, you have to have mania or hypomania for BP1, BP2 respectively, are really in fact conditions of depression. Depression is the most common initial presentation, the most common longitudinal presentation, I mean across time. Here's the part that's so critical, it's the most common reason people go to healthcare providers for treatment. The question around diagnostic accuracy and timeliness is well taken. We do know still in 2021, there are in fact less than optimal detection and diagnosis rates. We don't think that this is a fait accompli, it has to be this way forever. There's plenty of evidence to show that education can actually increase detection and diagnosis accuracy, if you will, in healthcare providers. The reality is, we know this from recent pharmacoepidemiologic evidence in America, that antidepressants continue to be prescribed very commonly in people with bipolar I bipolar II, and that's not in keeping with clinical practice guidelines, with the science or FDA recommendations. Having an indication in bipolar I bipolar II disorder will allow further knowledge transfer and education of care providers and will provide another opportunity, another touch point, if you will, for those persons who see the patients, the healthcare providers, to be learning about what is the state-of-the-art and how you would disambiguate, how you would separate major depressive disorder from bipolar disorder. One final comment is mixed features. My colleagues and I at Cleveland Clinic reported on this. We found that 25%-35% of all people with major depressive disorder have mixed features. They're very common. That is, having these hypomanic symptoms, even though you don't have bipolar disorder, and they don't respond very well to conventional antidepressants. The Florida Medicaid guidelines explicitly state that second-generation antipsychotics with minimal weight gain liability should be prioritized in the treatment of major depressive disorder with mixed features, as well as, of course, in bipolar disorder with mixed features. Thank you. I'm going to now combine some questions from Ashish Verma of Bank of America and Ami Fadia from Needham and they're asking about the use of CAPLYTA, first as a monotherapy or, I guess, off-label, they're saying. I'm just going to say as they wrote, adjunctive treatment. I guess let me rephrase that as your experience with the use of CAPLYTA, and if you have any hurdles in using CAPLYTA. I'm going to start with Dr. Cutler on this one. I assume we're talking about bipolar. I wasn't clear what indication we were- No. We're talking about schizophrenia. Oh, okay. Oh, adjunctively with other medicines. Okay, I see what you're saying. Yeah. I take it that's what they're asking. Yeah. Yeah. In schizophrenia, it's interesting. The regulatory pathway, typically people do monotherapy studies. There's far fewer studies of adjunctive treatment, certainly of registration quality, as opposed to bipolar, where there are these studies. Basically, anything we say about augmentation or additive to another antipsychotic, for instance, is off-label. We all certainly do it commonly. It's a very common question I get asked when I'm doing CAPLYTA talks is, can I add it to X, Y, or Z other antipsychotic? We do this in the real world, and I think mechanistically, again, I go back to mechanistically, it's a very reasonable thing to consider because you're not layering on additional D2 blockade necessarily. You're maybe adding other mechanisms of action. Certainly, I have seen it done. I have done it occasionally myself. The one that would be most interesting, of course, would be what happens if you use it with clozapine, which is a medicine that has a huge metabolic and other burden, and would that allow me perhaps to lower the dose, which would be risk mitigation, harm reduction? Again, we don't have data on that, but certainly I've done it. I think the fact that there's not a whole lot of pharmacokinetic interactions, and there's not a lot of pharmacodynamic drug-drug interactions here to worry about. You don't have additive anticholinergic or antihistamine properties, for instance. Certainly, that makes sense. I think a lot of the use, as I go around talking to other doctors in the real world, is adjunctively added to other antipsychotics. Particularly, any new drug is going to get used often in patients who haven't responded as well to something else. Certainly, that does get done. Anybody have anything else to add? Well, just this sort of anecdote that I'd share is that. I think the question's well taken. I think we all are aware that there is an epidemiology showing that more than one antipsychotic is prescribed in people with schizophrenia. It can range from 25% to as high as 50% in some surveys. Yeah. What I'm hearing is that when CAPLYTA is introduced, when it's added to a preexisting antipsychotic, what we're hearing is that not only does that provide the opportunity to stop that previous antipsychotic, but also many of the other psychotropic medications. Yeah that people are prescribed. For example, antidepressant medications, anxiety-reducing medications. There's a bit of a Velcro effect that occurs where people just get more and more medications tagged on. There's an opportunity to simplify regimens, and I'm hearing that quite commonly across the country. Yeah, I agree. The other one is to be able to minimize the anticholinergic burden, because adding this, which doesn't have much of a signal for movement disorders, you can, again, lower the dose of an offending agent and be able to get rid of the anticholinergics. Yep. Good point. Yeah. This is kind of a catch-all question, and it's from Charles Duncan at Canaccord. I think we asked it in different ways a little bit, but have you been hearing any concerns from physicians regarding somnolence sedation as a side effect? Are there any indications that it may be a greater concern than other drugs? Is it a bigger issue potentially for bipolar depression population? I'll ask Dr. Correll to start, and then ask both Dr. Cutler and McIntyre to comment. Can you hear me now? Sedation is a funny animal. Sometimes when there's so little, you want it so that people can fall asleep. When there's much, you throw up your arms in the air. I think CAPLYTA has a profile that is quite positive because although we saw 23% of people have sedation in the schizophrenia trials, registration trials, this was morning dosing. Open label studies where it was given in the evening, it was below 10%. In the bipolar studies, it was also below 10%. In a way, especially in depression, sleep problems are quite big, and having something that might ease people falling asleep is okay. I haven't heard much about a carryover effect during the day, which would make it harder to function. Patients seem to light up quite a bit when they go to lumateperone, and that might be partly also the antidepressant effect. I'm interested in hearing what our other colleagues will say. Yeah. Go ahead, Andy. Oh, excuse me. Okay. Yeah, what I would say is it's not unusual to hear this question. In my mind, clinicians always want to ascribe something bad or negative to every medication. How can I get in trouble is kind of the thought process. I think the one thing that stands out here, interestingly, as opposed to some of the more serious safety concerns, is sedation. That shows up in 20% or so. I think Christoph's point about it's really not been an issue clinically for me. I tend to give it in the evening, and it's not antihistamine. Again, I go mechanistically. It's not antihistamine sedation, which can really be quite impairing, cause foggy headedness, and difficulty functioning. I think it's probably coming from some of it undoubtedly is a high affinity for 5-HT2A, which, if anything, has been shown to improve certain aspects of sleep quality and sleep architecture. In a nutshell, it hasn't been a big concern for me and not from other clinicians that I've talked to. Yeah, I agree, Andy. I've heard much of the same across the country. It's just simply not been an issue. We had a bit of vote of confidence with respect to the fact that the dropout rate in the studies due to somnolence was actually a couple percentage points. It was very low. Yeah. That has translated clinically in the natural habitat of clinical psychiatry. The other point, though, to that question that came up, Sharon, is around bipolar depression. I think our colleague has tapped into something which I think is very insightful in the sense that on average, people who have bipolar disorder, on average, function at a higher level than people with schizophrenia. Certainly, tens and tens of thousands of patients later that I've provided care for, they are more likely to vocalize concerns around sedation, somnolence, or other types of side effects that encroach on their quality of life, their function, et cetera. Certainly what we could say is that based on the science that's there and the anecdote we've been hearing across the country, it doesn't seem as though it's been actually an issue for patients as well. They're more likely to vocalize it. No, it hasn't been a case in bipolar depression. Yeah. Great. In the interest of time, I'm going to ask one more question on Luma and then go to an LAI. I apologize for not calling out specific questions. I'm going to group together several questions on MDD. These questions go from, why do you think this is a good drug for MDD as adjunctive treatment, to what is the mechanism that should be at work here for MDD? I think we can go around everybody. Let's start with Dr. Correll again, and then we'll go to Dr. McIntyre, and then we'll go to Dr. Cutler. Okay. Thank you, Sharon, and thanks to whoever asked the question. I think it's pretty clear from the pharmacology that the selective serotonin reuptake inhibition built into the molecule is basically one of the big mechanisms of action that will help depression. We've been able to see that in the bipolar depression data, but also in the schizophrenia data in the subgroup of patients who had depressive symptoms, although patients were not selected for that condition or symptomatology. We now have seen it in several studies, and I would think that it's pretty expected that this will carry over into the MDD portion. The 5-HT2A blockade has also been associated in some studies mechanistically with antidepressant activity, and since there's a 60-fold tighter binding than D2, that would give us some additional confidence. We don't have too much D2 blockade that can actually counter the antidepressant effect that postsynaptically has been a problem at higher doses, even for drugs that are approved as augmentation for bipolar depression. For unipolar depression, sorry. Very good points, Christoph. There's aspects around the pharmacodynamics of lumateperone that give us the reason to believe it would be helpful in depression and major depressive disorder, as I understood the question. The key symptoms that are negatively affecting health outcomes, that is quality of life and function. For example, it has more of a kind of a fine-tuning effect on dopamine, as well as indirectly affecting glutamate. Really the enemy of the state in depression is problems with cognition and problems with what we call reward or anhedonia. Pharmacodynamically, this is in fact really calling out indication in depression at the clinical level. The other part is, which is I think worth mentioning, is that when we look at the prescription of second-generation antipsychotics across America for individuals who would be candidates, that is, have had an antidepressant or two, and they haven't had a good outcome or sufficient outcome, what we see is that lots of room for growth. In fact, only about maybe 10% of people who would be candidates actually get them. When we look at the data at a granular level, what emerges very clearly is an attitudinal barrier supported by science. Many clinicians would say, "I know the evidence shows that the antipsychotic works in depression, but I have a lot of concerns about weight gain, and I have a lot of concerns about diabetes. I have a lot of concerns when I have alternatives that are not associated with that. Historically, we've not been able to provide for them an FDA-approved or treatment that they could use safely in that regard, because typically we're talking about longer-term exposure. Along with the theoretical reason to believe around the pharmacology, there's a real-world barrier that is modifiable, and that is adverse events, and those adverse events are the very adverse events that lumateperone doesn't have. I think that the balance of the factors that I just described, I think it's going to be favorably reacted to in people who have major depression. It's probably also why we're hearing about some off-label uses, but that's a different story. I certainly agree with my colleagues. Mechanistically, there is absolutely a reason to believe, as we have heard, including the activity of the D1 receptor, which intracellularly affects glutamate, AMPA, and NMDA receptors. The clinical evidence Christoph mentioned, this drug is emerging as having a clear antidepressant signal, which not all atypicals do, at least not to this degree. Finally, I would say clinically, it would be a huge deal, and I think I mentioned this earlier, to have a pan-depression indication across unipolar MDD and bipolar depression. I think this gives us a lot of confidence. The only currently available medication that already has that is quetiapine as monotherapy, as opposed to olanzapine/fluoxetine combo. Both of those, of course, are plagued by this weight gain and metabolic issues that we have been talking about. I think some of the reluctance, as Roger said, to prescribe also comes back to the risk of EPS and especially the scourge of tardive dyskinesia, which this drug tends to be very favorable on the movement disorder side of things and doesn't elevate prolactin. For all those reasons, I think it would be a very big deal and very clinically important and useful to have that indication as well. As Roger said, it's already being used off-label for bipolar depression and as adjunct for unipolar depression. With success, I might add. Thank you. I was going to go over the LAI now, but since we also have so many questions on the deuterated on 1284, and since you have all discussed the pharmacology, I'm going to start with first a question from [Robert Hazlett] on 1284, and then try to combine some questions from Brian Abrahams of RBC and Jess Fye from J.P. Morgan on 1284 as well. First from Robert Hazlett, does deuteration materially change the unique pharmacology surrounding 5-HT2A, dopamine D2, D1, SERT, and potentially others of lumateperone described by Dr. Correll? If so, how has it changed? I'm going to ask Dr. Durgam to comment on that, and then I can chime in as well, and then we'll go to the next questions and ask all of you to opine. Yes. ITI-1284 is a new molecular entity. We believe it is well-suited to study in elderly patients based on its unique pharmacological characteristics. In our recently completed phase I program, we found that ITI-1284-ODT-SL was rapidly absorbed into the systemic circulation, was metabolically stable, it resulted in high systemic exposures. Also, we have seen that in both the single ascending dose and multiple ascending dose studies, in both healthy volunteer patients and healthy elderly patients evaluated for safety, tolerability, and pharmacokinetics of ITI-1284. We have seen there were no reported serious adverse events in either age group. Also in the elderly cohort, the reported adverse events were very infrequent, the most common adverse event was transient dry mouth. These formulations will have a benefit in certain elderly populations and the indications we are pursuing initially. To follow on to that, Brian Abrahams from RBC asked, how does deuteration impact the receptor profile, bioavailability, and biodistribution relative to lumateperone, and how do you expect these different properties to play out clinically? He asked the book here. How does the patient profile differ between elderly and younger healthy volunteers? It was generally safe and well-tolerated in both. How do you think about optimizing tolerability in elderly patients? I am going to stop there and I am going to ask Christoph to start on that one. Basically, the differences between deuterated So we know- Yeah. Sorry. Yeah. We know from other drugs that deuterating a medication really doesn't change the pharmacodynamics, the molecules at the receptor level. What it does is that the breakdown is typically slower, and you need less frequent dosing, and some agents that are given more than once a day. You have a less peak-trough variation, and basically better tolerability that way because the pharmacokinetic profile is smoother. In this sense, we wouldn't expect any worse side effects or any change in the pharmacodynamics with the deuterated form, and it's more suited for the elderly because those at the extremes of age are more vulnerable to even slight peak elevations with the medication. Although lumateperone is very safe already, it would only be safer that way. I think following on from that, Jessica Fye asked, how did we decide to advance the deuterated form of lumateperone in behavioral disturbances, and why not advance it for adjunctive MDD? I think we've answered that already, that we know that it's generally safe and well-tolerated. We know it's a very stable molecule. I think, does anybody want to add anything to that, or are we good here? Yeah. Sorry, go ahead. No, please go ahead. No, I was just going to put a fine point what Christoph mentioned. I think the whole point of deuterization is, in fact, to bring a certain kind of predictability to the kinetics. We have a lot of variability to kinetics. This is a way of smoothing it, and that often translates, not always, but often translates into improved tolerability. When you get into special populations like the elderly, this is a point that takes, I think, an additional sort of point of emphasis. For me, changing the question slightly different, if asked, if you have deuterization, what are the populations you'd want to start with first or prioritize first? It certainly, for me, would be the elderly. Great. I'm going to switch gears a little bit again and go to the LAI, because I'm very cognizant of the time here. We have many questions. I'm going to start out with some questions from Andrew Tsai from Jefferies, who's asked about our Sorry, I thought I turned this off. Who asked several questions, and I'm going to start with the program, the LAI program. He's asked us to talk about the single ascending dose study and what we hope to accomplish from that. What would we want to see in the single ascending dose study data? Then he asks a question about why are we looking at the LAI's drug release profile only out to six weeks? First of all, let me start with that, and then I'll ask if Suresh wants to comment on the clinical design at all, and then if anyone else wants to comment on LAIs in general. We started out with a four week formulation. We do have several formulations in development. This is our first, and if successful with the [SAD], we know it's safe and generally well-tolerated. We don't know other information yet. We will proceed to a multiple ascending dose study. The reason we're hoping this is a four week drug for the first one, and then following this, we would go to longer injections, a two month injection. I think the first things first, and it's to see how a one month formulation looks. I think then he has a question about in the big picture, what does the LAI landscape look like. I think, and would we in the future want it to be monthly, bimonthly, three times a year, or even six times a year, he says, and the competitive landscape. For that, I'm going to turn it over to whoever wants to take on this. I know everybody on this call has done studies with LAI, so maybe we'll start with Dr. Cutler, then go to Dr. Correll, and then go to Dr. McIntyre here. Well, I'm heartened to see that the market share of LAIs in patients with schizophrenia has been increasing recently. It had been about 10% of the market a couple of years ago. I saw more recent data that we're up to about 12%-13% of the market. It is a growing market. I think it's a very attractive option. Unfortunately, our currently available options are either haloperidol, predominantly the ones that are commonly used, or risperidone, haloperidol-based, or are aripiprazole-based. All three of those are plagued by the weight metabolic issues we've talked about, especially movement disorders, risk of tardive dyskinesia, and then prolactin elevation for the first two. Here we have a very attractive option vis-à-vis the others that are currently available with respect to not having a signal on any of those. I can tell you that already, as I've been going out, speaking to colleagues, giving talks, one of the first questions I get asked often is, "Is lumateperone going to be available as an LAI?" I think there is a certain degree of hunger for something out there, even though we do have several options. I also think the fact that you could potentially be developing a subcutaneous or an IM and/or an intramuscular could be a very big deal to give us those kind of options as well. I'm very sanguine about this. I think this would be a very important development. Yeah, I strongly agree. What we see is also that the guidelines are expanding in terms of earlier use of long-acting injectables. Yes. Even as an alternative to oral treatment in people who are currently adherent, because we know that nonadherence creeps in, particularly the people who are early in their illness stage are at highest risk of discontinuing. Multiple studies are showing this. Those are the folks that have the most to gain and the most to lose but are also sensitive to antipsychotic side effects, where lumateperone in the early phase would be attractive. Having more options and more formulations available will make also the use increase for lumateperone. I'd like to comment here, and why we are developing a long-acting injectable is for a couple of reasons. One is so that patients can have an option to take lumateperone as either an oral or as an injectable, and also for those patients who are non-compliant to help them in compliance. We do believe that an oral product will remain important in the marketplace as well. To that, we are developing, as you know, a sub-Q formulation for LAI, and a question just came in from Ashish Verma, Bank of America, on sub-Q LAIs. I guess he's asking, do you think sub-Q injection is good? Or he says that there are fewer sub-Q injections and that IM is where most of the products are. He thinks is the fact that IM has done better in the marketplace because there aren't more sub-Qs, or is there something about a sub-Q injection? Is that good or bad? Christoph, you're shaking your head, or Dr. Correll. It's a history that we did not have any sub-Q available, basically. That's why the market is dominated by IM. To destigmatize the medication in terms of intramuscular injection and also to remove some of the fear and resistance of prescribers as well as patients, having a sub-Q available, I think, is key and much of an advantage because you can liken it to a flu shot or other things. I think it's great to have a sub-Q available, and I'm not sure that 10 years from now there will be that much in terms of deep intramuscular as a formulation for LAIs. The only currently available sub-Q is risperidone-based, so I think that's another thing that's limited the uptake to some degree. If you just think in your own life, which would you prefer? A deep intramuscular injection or subcutaneous? I think the answer is obvious. I want to just pick up on what Andy just said, and this is an important point about the atmospherics and the future. In fact, Andy, you were citing a slight uptick in the percentage market share. Medicine's changed, and it's certainly changed a lot the last two years with COVID. There's going to be legacy of this, not only telehealth and more democratization of the knowledge around treatments, but what's really being emphasized now is more shared decision-making with patients at point of care. What that really means in English is that patients increasingly are being asked to play a part in what the choices are. Certainly one of the learnings, in fact, a light bulb moment for me, has been that attitudinally, IM, sub-Q, long-acting injectable broadly has historically been for patients who are very tertiary, very ill, often non-compliant. However, what we've learned in the last five years using LAIs, we've got lots of very high-functioning people who are very compliant, who prefer to take LAIs, but never heard of them before. I think that the culture of shared decision-making, which is going to be increasingly emphasized in the future, implicitly has a dashboard discussion. You're going to have more LAIs on that because optionality is the key word here. When you put those options on the dashboard, I suspect people are going to say, "I never heard of that before. I've tried so many drugs. What is an LAI? Oh, this is once a month. One decision a month versus 30 decisions a month. Why have I not been told this before?" This is what we hear at the grassroots level. To quickly emphasize that one of the first patients I ever recruited for a second-generation LAI study, when I presented this to him, said, "I'd much rather do that than take a pill." He said, and this is amazing, "Taking a pill every day is a daily reminder that I'm crazy." This was a very compliant gentleman. I think that you're right, Roger. Yep. I'm being told that we're over time, that's okay because I'm going to end on one question for all of you to opine on. I'm going to rephrase the question as it came from Marc Goodman at SVB Leerink. I'm going to say, the reason I'm rephrasing it is because we're not going to name any other brand of antipsychotic. Again, I think it's just, can you tell us where do you think CAPLYTA fits into the armamentarium for physicians? First for schizophrenia and then for bipolar depression, then further out for adjunctive treatment in MDD, and then mixed features. Start with anybody. Maybe I'll start off with bipolar depression. Well, this is actually just picking up where the guidelines left off in Florida last year. We have relatively few treatment options in bipolar depression to begin with, and then we start to filter the treatments as a function of side effects that are frankly not acceptable to patients right out of the gate, like weight gain. It's apparent that lumateperone will be a first line, be a first choice. The notion that it's been shown to be effective as monotherapy and adjunct in BP1 and BP2 is truly differentiating this product from what we've seen in this area without the burden of the side effects. In major depressive disorder, we've talked about that. There is an appetite. There's an appetite for next step strategies in people who've not benefited sufficiently with conventional antidepressants. The barrier has been side effects, side effects, and side effects that matter most to patients. There has been a clarion call to identify an effective treatment that doesn't have side effects that patients say no. I've never had a patient in my life say, "Hey, Dr. McIntyre, can you make me overweight, please?" People don't speak like that. They obviously are very real world. They want real-world concerns addressed. It's going to be first line, first choice in bipolar depression across BP1 and 2 with so few options. Only quetiapine's been shown to be effective in BP2, and it's got a limitation with the weight gain. In major depressive disorders, Andy, you mentioned this will be a unique situation of sorts in the sense we don't have the weight gain problems with a potential second-generation add-on in depression. Yeah, I would certainly agree. I think just quickly, if you're looking at the data for schizophrenia and bipolar depression, the data is quite impressive, and the magnitude of response is exactly what you would expect and looks a lot like other agents. We have evidence of efficacy clearly here. Again, as I mentioned, not all atypicals have a prominent antidepressant signal. We do have that here as well. I think what's truly differentiating, as we've been alluding to this whole time, is tolerability and safety both. They're two slightly different things. I think especially, as I mentioned, doctors want to know how do I get in trouble. With atypical antipsychotics, there are a number of ways, as we've elucidated, that you can get into trouble. Boy, there just seem to be a whole lot less of those risks with this medication. Great. Thank you. Obviously different factors play into the choice of medication. Now, since this is branded, there might be other choices that need to be made first. That's not a problem, especially in schizophrenia, because switching is so common and even early in the illness phase, because people either don't tolerate the medication, have side effects that impair their functioning, or don't really respond as well. In that sense, even though lumateperone should maybe be given very early and can't in some phases, in some payment and payer environments, it can still be given early since there are these changes that happen over weeks and a couple of months. Okay. Well, unfortunately, we could go on and on here. I think that this was certainly a stimulating conversation. I feel like I'm running a race here, trying to keep up with all the questions as they're coming in. Thank you guys very much for. My pleasure. your- Thank you. Thank you. answering questions. I think we may see you again later after the next one. Okay, thanks so much, guys. Thank you. Thank you. Thank you. Bye-bye. Bye-bye. Welcome back. I'm Robert Davis, Chief Scientific Officer at ITCI. I will be presenting on phosphodiesterase or PDE1 program, including the physiology of PDE1 and the effects of PDE1 inhibitors in animal models and early clinical studies, including Parkinson's disease. I will be joined today by Dr. Ira Shoulson. Following my presentation, Dr. Shoulson will provide a presentation covering the unmet therapeutic needs in Parkinson's disease. Dr. Shoulson is a well-known and eminent physician scientist who has devoted his career to the study of movement disorders. Dr. Shoulson is currently a professor of neurology in the Center for Health and Technology at the University of Rochester and is an adjunct professor of neurology at Georgetown University. He is also founder and principal of Grey Matter Technologies. In 2016, he was the recipient of the Michael J. Fox Foundation Pritzker Prize in recognition of his leadership in research and education for Parkinson's disease. We look forward to hearing Dr. Shoulson's insight later in this session. On to our phosphodiesterase program. Phosphodiesterases, or PDEs, are important drug targets because of their unique distribution, structural properties, and functional properties. PDE inhibitors can enhance physiological processes by influencing pathways controlled by the important second messengers, cyclic AMP and cyclic GMP. These act to prevent the degradation of cyclic AMP and cyclic GMP, restoring signaling in an affected pathway. This process is depicted in the figure on the right-hand side of this slide and is exemplified by the phosphodiesterase type 1 or PDE1 enzyme. PDE1 is a unique phosphodiesterase because it's the only PDE whose activity is tightly regulated. What this means is that under normal conditions, the PDE1 enzyme is turned off and is unable to degrade cyclic AMP and cyclic GMP. However, in certain pathological states, this enzyme becomes uncontrolled and highly active, shutting down signaling in selected pathways, often to the detriment of the affected tissue. PDE1 inhibitors act to restore signaling in these pathways, reestablishing normal function. We refer to this process as on-demand control of PDE1 activity. As a unique enzyme, PDE1 has several characteristics which are important for understanding its contribution to disease. As noted, PDE1 is maximally active when cells are stimulated, but not active when unstimulated. PDE1 has three major isoforms, PDE1A, B, and C, that are distributed across different signaling pathways. Importantly for this discussion, one of these isoforms, PDE1B, is highly expressed in the brain and immune cells, including macrophages and microglia. Specificity of PDE1 inhibitors is achieved based on PDE1's tissue distribution, neurotransmitter and hormonal specificity, and selective pathway regulation. The importance of these characteristics is highlighted in the next slide. Four potential disease targets are exemplified here. Parkinson's disease, cardiovascular disease, cancer and inflammation, and vascular disease. The target tissue for these diseases are basal ganglia, cardiac muscle in the heart, immune cells in tumors, and vascular smooth muscle. The pathways are activated by dopamine, adenosine and glucagon, purinergics, and nitric oxide. The isoforms differ across diseases and are PDE1B for basal ganglia and immune cells, and PDE1C for the heart and vasculature. The affected cyclic nucleotide is either cyclic AMP or cyclic GMP, depending upon the affected pathway. The elicited responses are dependent on activation of the DARPP-32 pathway, calcium mobilization, VASP or vasodilator-stimulated phosphoprotein pathway, and guanylate cyclase pathways. It is thus possible to target a particular diseased tissue without altering function in normal tissues. To address these multiple diseases, we have developed a broad portfolio of PDE1 inhibitors. lenrispodun or ITI-214, I will be using these terms interchangeably throughout this presentation, is the most advanced compound in our portfolio, having completed multiple phase I and phase I-B/II-A studies in humans. All of our PDE1 inhibitors under development are extremely potent and highly selective. The chemical structure of ITI-214 is depicted here. This program has delivered multiple PDE1 inhibitors, which are currently in various stages of development. In the following slides, I will highlight a few of our preclinical findings that support our clinical efforts. We have shown that ITI-214 reduces neural inflammation by directly modulating intracellular signaling pathways in microglia, the brain-resident immune cells. These effects have been demonstrated in multiple brain regions and in microglia isolated from the inflamed brain. By way of example, the effects of ITI-214 on inflammatory biomarkers in the basal ganglia of mice treated with lipopolysaccharides or LPS, a bacterial endotoxin that induces brain inflammation, are presented graphically in this slide. ITI-214 reverses the effects of LPS on the pro-inflammatory cytokines, IL-1β, TNF-α, and IL-6. ITI-214 also augments the effects of LPS on the anti-inflammatory cytokine IL-10 and reverses the effects of LPS on the chemokine CCL2, a chemoattractant for microglia. Together, these data indicate that ITI-214 can lower inflammation in the brain. Thus, these data support the further study of our PDE1 inhibitors to reduce neural inflammation in neurodegenerative diseases, including in patients with Parkinson's disease. The ability of our PDE1 inhibitors to alter microglia activity generalizes to other immune cells, including macrophages. These findings have led us to explore the impact of PDE1 inhibitors in other tissues, including certain cancers. While we will be discussing our oncology program in future presentations, here are a few highlights. We have shown that PDE1 inhibitors can inhibit the recruitment of immune cells into tumors. By regulating tumor recruitment of immune cells into tumors, our PDE1 inhibitors suppress tumor growth in certain mouse cancers, particularly when combined with other immunotherapies like PD-1 checkpoint inhibitors. This ability to modulate the activity of immune cells may be useful across a broad variety of tumor types. These data are planned to be presented in future scientific meetings. I will be reviewing several pre-clinical studies that support our clinical efforts to treat Parkinson's disease. These studies are based on our many years of studying the PDE1 enzyme and its impact on brain function. In animal models of Parkinson's disease, inhibitors of PDE1 restore normal function by potentiating motor improvements of suboptimal and optimal doses of L-DOPA without causing dyskinesias. Non-motor symptoms of Parkinson's disease may also be improved by PDE1 inhibitors. For example, cognition may be enhanced, and daytime sleepiness may be reduced. Further, PDE1 inhibitors may be disease-modifying by decreasing neuronal inflammation. Our PDE1 inhibitors augment L-DOPA-induced improvements in motor performance deficits in animal models of reduced basal ganglia function. In this model, dopamine is severely depleted on one side of the brain in the basal ganglia of a mouse. Animals stop using the affected limb in favor of the non-affected limb, as shown in the second bar. The affected limb is not paralyzed, and function can be restored in this model by administration of L-DOPA or other dopamine replacements. As shown here, when administered alone at a subtherapeutic dose of L-DOPA of 2.5 mg/kg, limb use is not restored. See the third light gray bar. When this suboptimal dose of L-DOPA is administered in combination with a PDE1 inhibitor, partial use of the affected limb is restored. See the fourth red bar. When administered at a therapeutic dose of 5 mg/kg of L-DOPA, limb use is incrementally restored, depicted in the fifth gray bar. When this dose of L-DOPA is administered in combination with a PDE1 inhibitor, use of the affected limb is completely restored, as shown in the last red bar. In data not shown here, these effects of PDE1 inhibition are manifested without producing unwanted dyskinesias. Thus, these preclinical data support the combined use of our PDE1 inhibitor and dopamine replacement therapy to improve motor function in patients with Parkinson's disease. Shifting gears to cognition. We use the novel object recognition task to evaluate drug effects on recognition, memory, and rodents. This test is based on the spontaneous tendency of rodents to spend more time exploring a novel object relative to a familiar one. In this task, a mouse is presented with two similar objects during the training session, T1, and then one of the two objects is replaced by a new object during the retrieval session conducted 24 hours later, T2. The amount of time spent exploring the new object during the retrieval session on T2 provides an index of recognition memory. If a memory is retained, the mouse will remember what object is old and not novel, and therefore will spend more time exploring the new object. Conversely, if a memory is not retained, the mouse will spend equal amounts of time exploring both the old and the new object. Drugs can be administered before the acquisition phase at T1, during the consolidation phase when memories are being stored, and before the retrieval phase at T2. ITI-214 improves memory retrieval regardless of when administered relative to training and memory retrieval testing. ITI-214 improves memory retrieval, whether it's administered before the acquisition phase when memories are acquired, during the consolidation phase when memories are stored, and before the retrieval phase when memories are recalled. These data support the study of our PDE1 inhibitors to improve cognition in patients with Parkinson's disease. I will discuss our clinical studies that have evaluated ITI-214 in humans. We have completed 6 phase I studies and 2 phase I-B/II-A studies, 1 in Parkinson's disease and 1 in heart failure patients. Pharmacokinetic evaluations indicate once-a-day dosing. Safety and tolerability have been demonstrated at doses up to 300 mg. As just noted, we have completed a phase I-B/II-A study in patients with Parkinson's disease, which we call ITI-214-105. This study was designed to determine the safety and tolerability of ITI-214 in patients with Parkinson's disease. This was a randomized, double-blind, placebo-controlled, multiple ascending dose study in patients on stable dopamine replacement therapies with stable idiopathic Parkinson's disease. Cohorts of eight patients were randomized in a 6 to 2 ratio to receive ITI-214 or placebo orally once daily for seven days. 5 cohorts were planned and completed using ITI-214 doses of 1, 3, 10, 30, and 90 mg. Included in this study were multiple exploratory endpoints to assess effects on motor symptoms and non-motor symptoms. lenrispodun was well tolerated with a favorable safety profile in this study. No adverse events were reported. No patient discontinued treatment with ITI-214 or placebo because of adverse events. The most frequent treatment emergent events were dizziness, hypotension, and somnolence. All treatment emergent adverse events were mild. No clinically significant changes in ECG parameters or other clinically significant findings were reported. Clinical signs related to improvement in motor function were seen. Together, these data inform a dose range for future clinical studies. I will now pass this presentation over to Dr. Shoulson to provide his insights on the unmet therapeutic needs in the treatment of Parkinson's disease. Dr. Shoulson? Thank you, Dr. Davis. I welcome this opportunity to inform you and update you about Parkinson's disease, and particularly unmet therapeutic needs. A lot has been learned about Parkinson's disease in the past few years, and particularly what patients report directly about the problems that bother them and how it affects their daily functioning, which is obviously relevant to the experimental therapeutics of this disease. The next slide is a thumbnail summary of Parkinson's disease, and just wanted to highlight these points. First of all, Parkinson's disease is the fastest growing neurological disease worldwide, and this has been noted, and I will show you some data on this, but it continues to grow, possibly related to environmental factors. The prototypical Parkinson patient has onset of Parkinson's disease about age 60, and then experiences progressive disease and illness and disability in the next 20 years of life or so. The first 3 quarters of life is relatively unaffected, or seemingly unaffected. In the last decade or 2 of life, after some transient improvement with dopaminergic therapy, these progressive symptoms are related to motor and non-motor functions, especially cognition. The motor functions most disabling are related to postural instability, and the two most intractable features of Parkinson's disease therapeutically are postural instability and cognition. Indeed, dopaminergic treatments do ameliorate the symptoms, at least temporarily. The excess mortality due to Parkinson's disease prior to the advent of dopaminergic therapy has been greatly lessened and functions improved. Unfortunately, these benefits are not enduring, and Parkinson's disease remains a major source of progressive disability and still excess mortality. Next slide shows you the worldwide data on Parkinson's disease. Currently, about 7 million individuals, 6.5 million individuals worldwide, are affected by Parkinson's disease as a prevalence figure. It's expected, at the current rate, that in the next two decades, that this will double to about 13 million individuals. If you look on the next slide around the world as to the prevalence of Parkinson's disease, you can see certainly it's a worldwide disease. The high prevalence that one sees, particularly in North America and other places, is due to very good diagnostic ascertainment. The lower prevalence is in part related to less diagnostic ascertainment, very striking in Africa, also parts of South America and parts of Asia. This will, with increased diagnostic precision, that the prevalence will continue to increase. Next slide shows an interesting calculation about in the U.S., that if one looks at the two major neurodegenerative diseases, Parkinson's disease and Alzheimer's disease, that one in 10 Americans over the age of 60 have either Parkinson's disease or Alzheimer's disease based on these assumptions here, which I think are pretty reasonable, that there's 74 million people in the U.S. over the age of 60. Assuming that nearly all those with Alzheimer's and the vast majority of Parkinson's disease are over the age of 60, then a conservative estimate is one in 10 Americans are affected by these neurodegenerative diseases. Again, to emphasize that Parkinson's is actually growing at a faster pace than Alzheimer's disease. Next slide. I wanted to share with you a remarkable data set that we have been involved in with the support of the Michael J. Fox Foundation and their online Fox Insight research study that invites research participants self-identified as having Parkinson's disease to enroll and share their information about what they feel and experience about their disease. This is unique because the participants report their symptoms, one, verbatim, and technologies, including natural language processing and machine learning, are applied to analyze this and classify them into symptoms. It's also remarkable because it's the participants or the patients who decide the priorities of their problems, what bothers them the most, second most, third most, up to the fifth most. In contrast to traditional approaches where severity is gauged either by the patient or by the clinician, in this case, it's a priority that the patient determines by himself or herself. One looks, we have this data set includes more than 21,000 individuals. This is as of a data cut we did in 2020. This entire population is up to about 40,000 now, really a testimony to how rapidly patients come online and share their symptoms, and a large proportion of these individuals have now been followed up to three years, so there's longitudinal data. Looking at the data, these are the symptom classifications that are reported by the patients. The first four bars here are the motor symptoms, comprising tremor, rigidity, bradykinesia or slowness, and postural instability, including gait problems, balance, falling, and freezing types of symptoms. The colors show the priorities to the patients. The blue color at the bottom of each represents the highest priority of problems, number one, the orange bar, the second priority, the green bar, the third, et cetera. As one could see on the motor symptoms, by far and away, postural instability and the symptoms of gait, balance, falling and freezing really predominate even more so than tremor, which perhaps is the most conspicuous feature of Parkinson's disease, at least to the outside observer. What's also remarkable is how common non-motor features are of Parkinson's disease. Indeed, these constitute at least half of the symptoms that patients report and a large proportion of the symptoms that represent the highest priority to patients. These include problems with sleep, fatigue, cognition, mood, pain, and a classification related to autonomic dysfunction, such as constipation, urinary problems, blood pressure control, et cetera. If you look also at something like cognition, which like postural instability, is the predominant feature, in this case, of non-motor features, one can see that also this applies to the primary priority of these patients. Again, it's really striking, this type of distribution reported directly by patients. Just to point out that postural instability as a motor domain and cognition as a non-motor domain remain the therapeutically intractable features of Parkinson's disease. We also have interesting longitudinal data that can be applied to online therapeutic trials. Next slide shows the history of therapeutics and a way of approved therapeutics in Parkinson's disease. Most of the therapeutics, I think, in summary, can be related to dopaminergic therapies, either in the form of levodopa or those that affect the dopamine receptors, particularly the D2 receptor. A variety of other drugs have been used and are approved for Parkinson's disease, again, largely affecting the dopamine system. Of course, there are some non-motor therapies that have been introduced that treat psychiatric problems such as dopaminergic-related psychosis or confusion, to treat autonomic dysfunction. The acetylcholinesterase inhibitors, used primarily for Alzheimer's disease, have also had some limited application as approved drugs for cognitive impairment in Parkinson's disease. The message here is that little has changed in the past 2 to 3 decades since the advent of these types of therapies. Even though there's some newer ones, they've had really just marginal effects. Again, it remains a progressive disorder with therapeutically intractable problems, particularly postural instability and cognition. The next slide is a summary of the potential applications of a drug such as ITI-214 that is especially affecting the phosphodiesterase systems. As Dr. Davis pointed out, here is a drug that in non-clinical studies in a 6-hydroxydopamine mouse model and also in a rodent model of cognitive remembering, that the drug exerts beneficial effects in terms of efficacy. In the human phase IIa studies, the multiple ascending dosage studies over seven days, it's been, in this context, shown to be safe and tolerated. Based on what we know from non-clinical studies from the pharmacology of the drug, that it would be predicted to, in human studies more long term, to improve motor and cognitive performance as an adjunct to dopaminergic therapy or possibly as monotherapy in Parkinson's patients. This is a novel approach and certainly an opportunity in the setting of the many unmet therapeutic needs in Parkinson's disease. Thank you. Thank you, Dr. Mates. In summary, based on the accumulated evidence, we believe that lenrispodun has the potential to treat motor and non-motor symptoms that accompany Parkinson's disease. Our PDE1 inhibitors may expand the therapeutic utility of existing treatments in patients with Parkinson's disease, and may also provide a standalone treatment early in Parkinson's disease when sufficient endogenous dopamine is available to support synaptic activity. Our program goal is to study the drug's ability to satisfy the unmet needs of patients with Parkinson's disease by improving both motor and non-motor symptoms, including cognition, through restoring neuronal function in affected brain regions. The next presentations cover our final platform for today, ITI-333, a novel approach to the treatment of opioid use disorders and pain. As you may be keenly aware, we are in the middle of an opioid use epidemic. The number of drug overdose deaths each year are horrifying. It is of paramount importance to provide new treatments for substance use disorders, particularly those related to the intended or unintended use of opioids. This problem has been recognized. The Helping to End Addiction Long-term initiative, or NIH HEAL Initiative, was established to speed scientific solutions to stem the national opioid public health crisis. We have been fortunate to collaborate with the National Institute on Drug Abuse, or NIDA, to advance the development of our compound, ITI-333, for the treatment of opioid use disorders. Dr. Kosten will join us today. He will present an overview of the nature and causes of this opioid use epidemic. I will present the preclinical and early clinical data that support the use of ITI-333 as a novel approach to the treatment of opioid use disorders and pain. I remind you that at the end of these presentations, we will take questions about the PDE1 inhibitor and the opioid use disorders program. Dr. Kosten is recognized for his extensive experience in the treatment of substance use disorders. He is currently the J.H. Waggoner Chair and Professor of Psychiatry, Pharmacology, Immunology, and Neuroscience at Baylor College of Medicine. He is the past president of the American Academy of Addiction Psychiatry and the College on Problems of Drug Dependence and is on various substance abuse commissions for the National Academy of Sciences, the FDA, and Department of Defense. We are glad to have Dr. Kosten with us today. Dr. Kosten. Thank you for that introduction. Yes, I will be talking about the opioid use disorder epidemic in the United States, where the extent of it needs to be carefully recognized that there are 10 million people with opioid misuse, which is almost 4% of the population. 93% of the opioid use disorder is the result still of pain medication misuse. This is not something that's gone away. The types of drugs that are misused still include hydrocodone, oxycodone, and fentanyl, of course. This is the fentanyl that's produced in the illicit market. The bigger problem is the illicit fentanyl, which is, of course, continuing. Overprescribing of opioids is not something that's gone away. The heroin use population, which is a group that we are, in fact, quite concerned about, that there's 341 is a conservative estimate of those who are using it alone. There's at least another 400,000 that are using pain relievers plus the heroin. Next slide, please. What are the consequences of this? Nearly 50,000 people in the U.S. died from opioid-involved overdoses in 2019. Which is more than 130 people a day die from opioid-related drug overdoses. The total economic burden of prescription opioid misuse alone in the United States is almost $80 billion a year. Next, please. The evolving opioid use epidemic has been coming in waves. The prescription opioids, then the fentanyl, then the fentanyl plus stimulants, which is the latest epidemic that's involved. What you can see in this graph below is the lines that are put in for prescription opioids, which is the blue line that starts the epidemic off in around 2000 or so. You see fentanyl up there, which is the brownish line, and you can see that the synthetic opiates, fentanyl in particular, led to the very abrupt rise in this epidemic around 2015. What you see are the stimulants. That is the yellow line that's there. The stimulants are all of a sudden increasing now, in part because of their combination with fentanyl. That fentanyl and stimulants are now going together in a variety of ways. As you can see, this is a very significant problem for us as we move into 2022. Next slide. These are the overdose deaths from fentanyl, specifically from 2015 through 2020. It's now, of course, combined with stimulants. That combination began at around 2016, 2017. It has continued to go up with the significant portion of it being the combination of fentanyl with stimulants. Some increasingly being that people think they're buying cocaine or think they're buying methamphetamine. In fact, what they're buying is a mixture of cocaine and methamphetamine with fentanyl, in part because the manufacturer of fentanyl or the illicit manufacturer of fentanyl is relatively inexpensive. A very tiny amount of fentanyl will in fact greatly increase the drug effect of either cocaine or methamphetamine, even when those cocaine or methamphetamine are not pure. Next slide. Amphetamines are increasingly being mixed with fentanyl. There's a new rising mortality from amphetamines. It's due to fentanyl being disguised as amphetamine or mixed with the amphetamine. The amphetamine mortality rate is rising at twice the opioid mortality rate due to this fentanyl adulteration. Amphetamines' fourfold mortality rise has required only five years. In these last five years, it's a fourfold increase. For opioids to increase fourfold, it took 10 years. This combination is particularly lethal and suggesting that any treatment that we develop for opioids, particularly for fentanyl, will be very much needed in other populations of abusers, and those populations are in the millions. Next slide. What is needed? New and better ways to prevent opioid misuse, to treat opioid use disorders, and of course, to manage pain. The particular medical advances that would be needed are safe, effective, non-addictive treatments to manage chronic pain. This has been a goal of actually what was one of the first commissions of the National Academy of Sciences, formed back in the 1920s, early 1920s, and continues now 100 years later in search of this, you might say, magic bullet. New innovative medicines to treat opioid use disorders. There's no question about that these would be very useful and very helpful, not simply another lookalike opioid. Chronic treatments for relapse prevention. Once we get people opioid-free, we have to get them then so they don't relapse back. The ability to mitigate or reduce withdrawal symptoms is certainly very important. There's also protracted withdrawal symptoms, which can continue for months and lead to a relapse. Of course, this fentanyl, which will override most of our available treatments. That is methadone, buprenorphine, or naltrexone can be overridden with fentanyl. Improved overdose prevention, reversal interventions to save lives and support recovery, particularly focused on this rise in fentanyl misuse. What we have right now is not sufficient to manage fentanyl, either in an overdose situation or to prevent abuse of that. A new medication that thinks about and targets the kind of part of the receptor, which you'll hear about more, of course, and that is really a very big and immense need at the moment. Thank you, Dr. Kosten, for the extremely informative presentation. I will now provide an overview of ITI-333, the lead molecule in our opioid use disorder and pain program. Our ITI-333 program is focused on addressing the unmet needs in opioid use disorder and pain. As Dr. Kosten just highlighted, there is a pressing need for safe, effective, non-addictive treatments to manage chronic pain, new innovative medicines to treat opioid use disorders, improved overdose prevention, and reversal intervention. ITI-333 has the potential to meet these needs based on its novel mechanism of action and demonstrated pharmacology. ITI-333 uniquely combines interactions with serotonin and opioid receptors. At the μ-opioid receptors, ITI-333 is a partial agonist signaling through G protein pathways but acts as an antagonist at β-arrestin pathways. At serotonin 5-HT2A receptors, it behaves as an antagonist. The serotonin and μ-opioid receptor interactions are synergistic and may drive the pharmacology of ITI-333, increasing both potency and efficacy while reducing liabilities. Importantly, after ITI-333 administration in animals, there is no development of dependence or withdrawal reactions, and no decreases in GI motility or pulmonary function. ITI-333 has high potency interactions with the 5-HT2A, D1, and μ-opioid receptors, with no significant off-target activity, including no interactions with other opioid receptor subtypes. It is orally active with excellent pharmacokinetic properties and has desirable brain penetration. Agonists of seven transmembrane G protein-coupled receptors, including the μ-opioid receptor, can signal through two distinct pathways, a G protein-coupled pathway and a β-arrestin pathway. The beneficial effects of opioids are thought to be mediated through the activation of G protein signaling pathways, while many side effects are mediated through activation of the β-arrestin signaling pathway. Opioids like morphine and heroin appear to activate both pathways and thus are balanced agonists. Newer agents have emerged which exhibit a relative bias towards G protein pathways. Still other opioids, like fentanyl, exhibit a relative bias towards the β-arrestin pathway. Unlike these other drugs, ITI-333 is an agonist at G protein pathways and an antagonist at β-arrestin pathways. This is one of the unique aspects of the mechanism of action of ITI-333. The mechanism of action of ITI-333 is further detailed in this slide. ITI-333 is a partial agonist at mu opioid G protein signaling pathways and an antagonist at mu opioid β-arrestin signaling pathway. The graph on the left depicts the intrinsic efficacy of the full agonist, [Pancuronium], [DAMGO], the high-efficacy partial agonist, buprenorphine, and the low intrinsic efficacy of ITI-333. While partial agonism is a somewhat difficult concept, this means that ITI-333 will act as an antagonist in the presence of high levels of mu opioid G protein receptor signaling and as an agonist in the presence of low levels of mu opioid G protein receptor signaling. At the β-arrestin pathway, ITI-333 not only has no agonist activity, it actually is an antagonist, blocking the effects of fentanyl and other arrestin agonists. This biased pattern of activity is important for understanding ITI-333's pharmacological actions, which are outlined in the next slide. ITI-333 is not self-administered by animals, suppresses heroin-mediated relapse in rats, mitigates physical signs of opioid withdrawal in mice, does not precipitate withdrawal in opioid-dependent mice, is a potent and efficacious analgesic in acute and chronic neuropathic pain models, and has 5-HT2A antagonism, reversing DOI-induced head twitches. Additional preclinical studies demonstrate the safety of ITI-333 and its lack of abuse liability. After administration of ITI-333, no physical signs of opioid tolerance or dependence were seen in rats in a 28-day study with one-week withdrawal. ITI-333 also is not self-administered in rats or non-human primates trained to self-administer heroin. The pharmacological safety of ITI-333 also has been established in rodents and non-human primates. Unlike other opiates, ITI-333 does not increase locomotor activity, reduce GI motility, or decrease respiratory function. Unlike heroin, as I just mentioned, ITI-333 is not self-administered by non-human primates. Opioids like heroin have strong rewarding properties. As shown here, non-human primates will work to self-administer heroin. See the first black bar. In contrast, these same monkeys will not work to self-administer ITI-333 or vehicle. These data indicate that ITI-333 lacks the rewarding properties of a full opioid agonist like heroin, whose rewarding properties drive opioid use. ITI-333 also suppresses heroin cue-induced relapse responding in a model of opioid relapse prevention. Relapse occurs when a person returns to drug use after a period of abstinence. Exposure to environmental cues previously associated with drug intake often provokes relapse to drug use. It is not uncommon for those recovering from opioid use disorder to relapse. Many view relapse as a significant stumbling block to recovery. In this model, a rat is trained to press a lever to self-administer heroin in the presence of cues. The cues gradually take on the rewarding properties of heroin. This response is extinguished by not providing heroin or cues. The animal learns to stop pressing the lever. The response is reinstated by providing just the cues and no heroin. Vehicle-treated animals continue to respond, but ITI-333 treated animals do not. ITI-333 reduces the reinforcing properties of cues paired with heroin administration and may be useful in preventing relapse of opioid use after a period of abstinence. ITI-333 also reduces somatic signs caused by naloxone-precipitated withdrawal in oxycodone-dependent mice. Oxycodone-dependent is first established. Naloxone is injected to precipitate abrupt withdrawal, and somatic signs are elevated. See the black bar in the graph on the right-hand side. ITI-333, when administered before naloxone injection, blocks the somatic signs of withdrawal. See the purple bars in the graph on the right. ITI-333 may be useful in reducing symptoms of withdrawal following abrupt cessation of opioid use. I will discuss the analgesic effects of ITI-333 in animal models of acute and neuropathic pain. ITI-333 elicits potent naloxone-sensitive acute analgesia in the mouse tail flick assay. In the tail flick assay, a high-intensity beam of light is aimed at a rodent's tail. The beam of light produces a mild, painful heat sensation, causing a reflex that moves the tail. Opiates like morphine increase the time before the animal reflexively removes its tail. See the black bar in the figure on the left. Like morphine, ITI-333 potently increases the time it takes for the animal to move its tail, demonstrating its analgesic effects. See the purple bars in the left-hand figure. The effects of ITI-333 are blocked by the new opioid antagonist naloxone, demonstrating dependence of this effect on opioid receptor activation. Not shown are data demonstrating that the robust analgesic effects are maintained after 14 days of chronic once-daily dosing of ITI-333. ITI-333 also reverses chronic neuropathic pain. Neuropathic pain is an exacerbation of pain in response to both innocuous and noxious stimuli. Current treatments are limited but include gabapentinoids or local anesthetics. In animal models of neuropathic pain, ITI-333 at doses of 1, 3, and 10 mg/kg reverses allodynia or neuropathic pain across multiple sensory modalities. As shown in the graph on the right, non-diabetic rats perceive the cold stimulus as innocuous. See the clear bar. Diabetic rats perceive the cold stimulus as painful. See the green bar. At all doses tested, ITI-333 reverses allodynia or neuropathic pain to the cold stimulus, purple bars. Not shown here, these effects generalize to other sensory modalities like touch and pressure. Together, these data indicate that ITI-333 has analgesic properties in models of both acute pain and chronic neuropathic pain. In animal models, we have shown that ITI-333 is an effective, non-addictive treatment for reducing multiple forms of pain. I will briefly discuss our ongoing clinical studies and plans for future studies. We are conducting a single ascending dose study and will soon be starting a multiple ascending dose study and a brain receptor occupancy study. These three studies will inform the conduct of several planned studies to assess human abuse liability, potential to precipitate opioid withdrawal, and 2D- Determine the ability to treat the non-motor features as there is the motor features. If somebody comes in with Parkinson's disease and they're slowed down or tremulous, there are some therapeutic options, and most of that is a preoccupation of therapeutic intervention. On the other hand, non-motor features, one, not recognized yet by clinicians how common they are and how problematic they are for patients, and not having tools at hand, therapeutic tools to intervene. I think it speaks to the mismatch between what patients say and what doctors hear, and what doctors are able to do in the therapeutic realm. Thank you. Due to the interest of time, I'm going to rapidly go through some of these. The next one is from Brian Abrahams, RBC. Can you walk us through some of the key factors you were thinking about for the larger Parkinson's trial? Are you planning to focus on UPDRS or on-off time, and are there any key secondaries, any sense of potential timelines, potential for combination therapy? I'm going to ask Dr. Durgam to address that question, please. Thank you, Sharon. Regarding the study designs, we are still in the process of finalizing the study designs. The endpoints typically will include the UPDRS, also the on-off mechanisms, on-off timings, and also a cognitive endpoint. As we put the timelines on ClinicalTrials.gov, we will be sharing the details later on, once the enrollment begins. In terms of the adjunctive treatments, we are going to be looking at patients who are on other Parkinson's medications. This will be adding on to the patients who are already on other medications. I'm going to go to our next question, also from Brian Abrahams with RBC. You mentioned other potent and specific molecules you have developed out of PDE1 platform. How do these compare with 214, and would any be more amenable to the heart disease or oncology indications rather than the neural site where 214 is targeted at? Brian, you are correct. 214 is targeted to neural site. We do have other molecules that are moving along the development pathway for other indications, and you will be hearing more about those pretty soon. I think, Bob, did you want to add anything to that or are you good? I think I would just like to add that these are all mechanistically similar, but they have different characteristics. They have different distributions within the body, and they're being fine-tuned for different indications. As Sharon said, there are multiple compounds coming forward, and we'll tell you more about where they're going in the future. Sticking with mechanism, we have a bunch of questions on mechanism. I'm just going to put them all together and ask you a few of them, and this is for you, Bob, please. Can you further explain why the PDE1 enzyme is not active in the unstimulated state? Does this add some comfort about the safety of PDE1 inhibitors? That's a good question, and it's really one of the key features of this enzyme, that it is in the off state and unable to degrade cyclic nucleotides in that state. It is only when it's active, and this is performed by the structural modification that occurs when in the active state. It goes from an off state to an on state. For tissues that are not being stimulated or not being affected by disease, the inhibitors will not do anything. They can't access the active site, and they can't degrade cyclic AMP. On the other hand, in a disease state or a diseased tissue that is being stimulated or is activated, these compounds will be very effective. From a safety perspective, this provides you a great deal of safety in the sense that you're only affecting the diseased tissue and not other tissues. Again, to mechanism, from Jessica Fye at J.P. Morgan, do we know if ITI-214 has any higher, lower affinity towards any one of the PDE1 subgroups, PDE1A, PDE1B, or PDE1C? Maybe, Bob, you can take this, and you can also discuss the importance of A, B, and C and what that means for different disease states. All of our inhibitors are pan inhibitors. That means that they have equal affinity for all 3 of the isoforms. The isoforms, as I mentioned, are distributed differentially throughout the body. For example, PDE1B tends to be higher in the brain, in microglial macrophages. PDE1C is the isoform that's in the heart. What that means is that they have different abilities to degrade either cyclic AMP or cyclic GMP. That understanding that role, and how each one of those isoforms and which isoform is activated in a disease, is important for designing your molecules for these diseases and then picking the indications. Dr. Shoulson, I'm going to put you on the spot here a little bit. We have a question. What aspect of lenrispodun attracts you the most, the potential to improve motor symptoms or non-motor symptoms? Well, I'd answer that by saying the potential to improve symptoms. Let's begin with that, what the patients say bothers them is a really great opportunity that's not necessarily captured right now. That is something because we understand now the emergence and evolution of symptoms in Parkinson's disease, not only as a snapshot, but longitudinally over time. The amelioration of symptoms is at hand and something that can be done. Of the motor symptoms, as I mentioned, certainly postural instability and the symptoms of gait, balance, and falling are really important. Also in the cognitive domain, particularly, maybe this recognition memory that was attended to in terms of the non-clinical rodent studies, but also the executive function problems that bother patients with Parkinson's disease and many other patients who have subcortical features of cognitive impairment. And this again has been intractable and not addressed, except at the margins by acetylcholinesterase inhibitors that are used primarily to treat cortical dementias such as Alzheimer's disease. That is really interesting. From a mechanistic point of view, what's interesting is all the therapeutic effort in Parkinson's disease has been focused on the nigrostriatal synapse, that dopamine synapse with, and when I say preoccupied, I mean preoccupied figuratively and also literally with transmitters and agonists and the like. Here's an opportunity to look at intracellular signaling beyond that synapse and to modify it. I think from a mechanistic point of view, this novel approach is also very appealing, taken together with the ability to detect actual symptomatic effects, both motor and non-motor. Thanks. I think that is one thing that really excited us about the PDE1 inhibitors is going beyond the nigrostriatal pathway. Bob, did you want to just say anything about that or are you good? Well, I'll just add to Ira's comment is that this is different than any of the other agents that are out there and any of the agents that are under development. So we're really excited about the possibility of actually understanding how changes in intercellular signaling in a disease like Parkinson's disease can be affected by drugs like our PDE1 inhibitors. I'll say one other thing is that this is not only a dopaminergic activation, so the drug works outside of the nigrostriatal system. That may be important, for example, for improving cognitive symptoms. Yep. Great. Again, I feel like I'm asking these in lightning fashion here. I have a couple of questions about inflammation, and so I'm going to try and put them together with a question from Sumant Kulkarni from Canaccord. He's talking about lenrispodun and its wide range of indications. He asks about, he says, some inflammation can be a good thing. How good could lenrispodun be in modulating the inflammatory effects, especially in the neuro setting? Along with that, maybe I'll try and put a couple of other questions into that. If you could just talk about the effects on inflammation, and on reducing infiltration of macrophages infiltration into tumors, so maybe we should split them up. Let's first address Sumant's question about modulating inflammatory effects in the neural setting. That's a good question, and it's an important question. Our PDE1 inhibitors work very differently than classical anti-inflammatory agents. They are immune modulators. We discovered the ability of these molecules to modulate a very specific pathway in both macrophages and microglial cells. What they do is they prevent the activation of these immune cells, both in the brain and in periphery. There's another feature in the peripheral system where these molecules are important for the transition from monocytes to macrophages. Again, the key feature of PDE1 inhibitors is that once you reach a normal state, the enzyme shuts off. We will only be addressing the hyperimmune state that occurs when there's an inflammatory event or where there's chronic inflammation. As long as this system can be activated, I think we'll have no problem. Do you want me to go on to the tumor? Yeah, please. Emanating from our understanding of what these molecules do, we know that in certain tumors, the tumor environment is populated by macrophages. In fact, they can account for almost 40% of the cells in the tumor in some tumors. What appears to be happening in these tumors is that they take on an anti-inflammatory phenotype such that the immune system no longer can recognize the tumor, and the tumor can grow unimpeded. What we do is we change the proportion of the macrophages and microglia, if it's in a glioblastoma, such that the innate immune system can become activated again and recognize this tumor. Really to push the system even further, if we use a checkpoint inhibitor like a PD-1 inhibitor, we can charge up the T cells and the other tumor-killing cells. The combination together of our reducing the macrophages in the tumor microenvironment and stimulating the ability of the T cells leads to, in multiple models in animals, an inhibition of tumor progression. We think that's important. I guess one other feature is that when you give a checkpoint inhibitor, sometimes you get macrophage stimulating syndrome, which is called a cytokine storm, and we believe that our compounds will be able to quell that storm so that you can have a more effective inhibition of the immune system. As we go forward, we'll be talking a lot more about compounds for oncology indications. Unfortunately, due to the time, I think I'm now going to switch to ITI-333. I'll start with several questions coming from Andrew Tsai at Jefferies, and he asks us to please talk about existing treatments for opioid use disorder. Dr. Kosten, these are directed to you. I'm not stopping here. He has many questions here. I'll try and put a few of them together. Okay, talk about existing treatments for opioid use disorder. Do they include methadone, buprenorphine, naloxone? If so, what kind of benefit do these drugs give patients, and what are their limitations? Other than having a novel mechanism that enables ITI-333 to be non-addictive, are there any favorable attributes we should consider for ITI-333? Could it also benefit comorbidities associated with OUD, depression, anxiety, and sleep? What evidence is there, and do other drugs for OUD benefit these comorbidities? I'll stop right there, and I'll get to the other ones after you, if you have time, after you answer these. Okay. Well, my apologies if I give more of a lecture than hoped for, the 3 main treatments are indeed methadone, buprenorphine, and naltrexone, which is a long-acting form of naloxone. The limitations of all 3 of those treatments are multiple for each one, but the most fundamental limitation is none of them block fentanyl. Fentanyl is the drug that's on the streets that's killing people. That has been true since at least 2016, and the epidemic is quite profound. The fentanyl itself is not only found in opiates now, it's an opiate-like drug, but it's being imported from Mexico, mixed inside of drugs that look like Xanax, drugs that look like Percocet, and drugs that look like Adderall. That people who think that they're buying stuff on the street that are these other brand name drugs are, in fact, getting a hefty dose of fentanyl in them, and the fentanyl causes the respiratory depression and kills them. What ITI-333 does, and it's the only drug that I know of that comes close to this, is it is a partial agonist for the β-arrestin pathway that's part of the opiate receptor. All the others go through a G protein type pathway as Dr. Davis had elucidated for you. This, in fact, can be a groundbreaking intervention to deal with an epidemic that's gotten, I would say, totally out of control. In that way, there's a great deal of optimism that I think I certainly have, and I think that the National Institute on Drug Abuse feels about this. This could be a medication that can essentially block fentanyl, block overdoses, block abuse of fentanyl, and could also be used for both detoxing from fentanyl, which is when people are dependent on fentanyl, the usual approaches we use with clonidine, with lofexidine, with buprenorphine, simply are not working. They're not reducing the withdrawal symptoms. This medication could do that. The third thing, of course, is that in an acute situation where you have someone who's basically stopped breathing, the doses of naloxone one has to give are quite large and frequently don't work. This would be a medication that could reverse those overdoses, could be life-saving. All of these are, of course, optimistic views, and this is early in the development of this medication. This is the only one on the shelf right now that looks anything like this. I would say that its mechanism is profound. Needless to say, there's other areas outside of addiction, including, as a partial agonist, buprenorphine has been very helpful as a pain medication because you can't overdose on it. This similarly could be a pain medication like a fentanyl derivative, but it couldn't overdose because it's a partial agonist. That's not been an important part of this presentation yet, but there are very large number of uses, and this could be an extremely useful medication. I think you had another question. I probably lost track of it by now. I think that's quite comprehensive and good. Yes, we agree. These are early days, but we do have preclinical data that we're very excited about. As everyone here knows, we're in a single ascending dose study, and we're looking forward to that data, which is PK data and safety and tolerability data, later this year. In the meantime, Bob, I think Dr. Kosten mentioned, and I know in your talk you mentioned the β-arrestin your slides. You mentioned the β-arrestin pathway and the G-coupled protein receptor involvement. Would you just explain just very briefly how ITI-333 acts in that milieu and what's different about ITI-333 from other agents? Surely. What most people think about opioids, they think about heroin, morphine, oxycodone. Those molecules are what are called balanced agonists. They are agonists at both the G protein-coupled receptor and the β-arrestin receptor. Newer agents have come about that only are G protein receptor agonists and don't do anything to the β-arrestin pathway. It's thought that by going through the G protein receptor pathway, you get the beneficial effects of opioids without some of the adversities like respiratory depression. As Dr. Kosten has said, fentanyl is different. It seems to like the β-arrestin pathway better than the G protein pathway, and it is associated with severe respiratory depression and other activities. Unlike all of those other agents, ITI-333 acts as a partial agonist at the μ-opioid G protein receptor, but it is an antagonist at the β-arrestin. It will block the effects of opioids at the arrestin pathway. That is thought to be the interaction that drives the adversities of the μ-opioid compounds, including fentanyl. Great. Thank you. With that, I think we're going to have to wrap this up with only one more question, which I'm going to try marrying two questions. Well, let me first ask from Sumant Kulkarni again. On ITI-333, is there any reason to believe the product might work differently when it comes to fentanyl? I know you addressed this, is there anything else you want to say, which is seeing increasing rates of abuse versus the classically abused opioids. Along with that, from Ami Fadia, again, on with what we know about its potential clinical profile, where would you see this drug being used in the real-world setting? Given the low price of an opioid, they may continue to be used extensively, and use of newer mechanisms, which are more expensive, limits to select patients. Where would you see ITI-333 fitting in? I guess that ties in with the fentanyl story. Would you like me to try to address that one to start? Please. Yeah. I think that the major thing to recognize is fentanyl is very inexpensive to make, that there are hundreds of varieties of fentanyl that can be made. All of them are quite toxic. The one carfentanil that you've probably heard of is now restricted to be only given to elephants because tiny dosages of that will kill any other creature. That it is fentanyl that is the peculiar drug. Fentanyl is a very useful drug. It's a very short-acting drug in many places. We have nothing that has been specifically would be a blocker of fentanyl. There was quite a bit of research done on this about 20 years ago, and this is remarkable that something's turned up like this. Yes, this is a medication that conceivably would need to be given to every drug abuser for whatever drug that they abuse, other than alcohol, because they haven't figured out how to mix alcohol and fentanyl together. fentanyl is now mixed. It's a white powder. Tiny amounts go a long way, and it is being mixed by illicit distributors, mostly from Mexico and China, to look like the standard medications that people like to abuse, such as Xanax, such as Percocet, such as methylphenidate, such as Adderall. They look just like the pills, but they've got fentanyl in them. This could have quite a broad range of applicability to basically millions of people here in the United States and, of course, around the world. I'm sure that's far too optimistic to make the company feel comfortable. Nonetheless, this is truly a breakthrough. Right. Well, thank you for that. Obviously as the sponsor, we have great hopes, but I do remind everyone these are early days for developments of these compounds. Then to tell you that in fact, that was the purpose of this meeting today, certainly the second half of the meeting, to introduce you to our earlier stage programs. This was our first ever event focused on talking about our earlier stage programs, and we really appreciate everyone's having joined and also both Dr. Mates and Dr. Kosten for participating. I promised the analysts that we would be off the phone prior to the market close so they could go focus their attentions elsewhere. I think that with that, we can conclude our meeting today and I think that ask everybody to stay tuned for further updates as we progress with the development of all of our programs. Thank you. Operator, you can disconnect.