Good afternoon, everyone. I'm Dr. Sharon Mates, Chairman and CEO of Intra-Cellular Therapies. I would like to welcome you to today's webcast. Joining me today is Dr. Suresh Durgam, our Chief Medical Officer, and we are pleased to have with us Dr. Roger McIntyre, Professor of Psychiatry and Pharmacology at the University of Toronto. Dr. McIntyre is an expert on mood disorders. First, Dr. Durgam will provide an overview of our lumateperone programs. Dr. McIntyre will follow with an overview of mood disorders and share a psychiatrist's perspective on the need for additional treatments. He will share highlights of our lumateperone presentations from this week's American Psychiatric Association annual meeting. Following their presentations, we will open up the conversations for questions. To submit a question, please type your question in the box located right below your video player. Please submit your questions throughout the presentation, and we will address them at the end of the presentation. Before we continue, we will be making forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Actual results may differ. I refer you to our website and to our SEC filings for updates on the company. This webcast is very timely. Yesterday, we announced our supplemental NDAs for lumateperone and bipolar depression were accepted for review by the FDA. The PDUFA action goal date is December 17th, 2021. With that, I'll now turn the podium over to Dr. Durgam. Thanks, Sharon. As you can see on this slide, we have a broad development program in place for lumateperone. Lumateperone is FDA-approved for treatment of schizophrenia in adults. It is also in development for other highly prevalent psychiatric conditions, including bipolar depression and major depressive disorder, or MDD. There is a significant need for effective, safe and well-tolerated treatments for these conditions. Given lumateperone's efficacy, safety profile, as well as its pharmacological profile, we believe lumateperone will be an important treatment option in these patient populations. As Sharon mentioned, we have just announced FDA acceptance of our sNDA filing for bipolar depression. The submissions were based on studies 404 and 402. These two positive phase III trials support label expansion for the treatment of bipolar depression. Both studies demonstrated robust efficacy and a favorable tolerability and safety profile, consistent with the findings in all the previous studies. In addition to bipolar depression, we are advancing lumateperone in other depressive disorders. We have begun our adjunctive MDD program and anticipate enrolling patients in two phase III studies evaluating lumateperone as an adjunctive treatment in MDD later this year. Study 403 is a large proof-of-concept study evaluating antidepressant effects on lumateperone in patients who exhibit mixed features in both bipolar depression or in MDD. This trial is ongoing, and Dr. McIntyre will explain more about this condition. We are pleased to be joined by Dr. McIntyre. He 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 more than 700 articles and manuscripts and has edited several textbooks on mood disorders. In addition, Dr. McIntyre has also contributed extensively to clinical practice guidelines and is lead author of the "Florida Best Practice Psychotherapeutic Medication Guidelines for Adults with Major Depressive Disorder and Bipolar Disorder." You can see his disclosures on the slide. Dr. McIntyre will be sharing with you an overview of mood disorders, including bipolar depression and mixed features, as well as share highlights of lumateperone presented at the APA. I will now turn over this webcast to Dr. McIntyre. Suresh, thanks for doing so, and thanks for introducing me. Good afternoon to all of our colleagues who are joining us. I'll have the next slide. Really, what I'm going to try to do is sketch a portrait. I want to sketch a portrait of mood disorders more broadly, but we'll sort of be focusing in on what is the most prominent part of bipolar disorders, that being the depressive phase of the illness. You're going to hear me mention words like common, complex, severe, but you're also going to hear me emphasize the predominance of depression in the portrait of bipolar disorder. We'll come back to that in a moment. This slide really provides a starting point in the way we organize the mood disorders. You can see that they're along a spectrum. What we in fact recognize is that across America, many people, in fact, estimated at about 17% lifetime, will experience a major depressive disorder to the far left. That is, someone has major depressive episodes. That's the defining feature of major depressive disorder. Bipolar disorders are traditionally thought of as falling into two categories, bipolar I and bipolar II. Let's start with bipolar I disorder, which is defined by the presence of mania on the very far right. Bipolar II disorder, which we'll say a few more words about in a moment, is defined on the basis of alternating periods of hypomania and depression. So far, I've already introduced a vocabulary that probably deserves a bit more attention, mania and hypomania. Mania and hypomania have exactly the same diagnostic criteria. What's different is that hypomania, at least in cross-sectional time, is not as severe as mania. The person wouldn't have psychosis. In other words, losing touch with reality. They may not require to be hospitalized. They may not be severely impaired in their day-to-day life. It's milder in its cross-section but not milder longitudinally, and I'll come back to that in a moment. We're going to talk about mixed features, mixed are a little more complicated. That's why I like to use the word complicated, because it is complicated. This is when someone has a bit of hypomanic symptoms and depressive symptoms at the same time. Mixed features can actually affect people with either bipolar I, bipolar II, or someone with major depressive disorder. That's why I like this slide, because it really conceptualizes mania at one end, depression at the other end, and then you have that confluence of the rivers right in between denoting mixed features. Next slide. With respect to thinking about the criteria, the DSM-5 was introduced into our landscape in 2013, at that time, the American Psychiatric Association was of the view that mixed features were not just an aspect of mood disorders that was common, but was an aspect of mood disorders that really was severe. These persons suffer greatly, they were not, in fact, receiving optimal treatments, therefore more attention was required. Simply put, what it refers to is when someone is fully depressed, at the same time they have three or more hypomanic or manic symptoms. What percentage of people are affected? It's estimated between 25%-35%, maybe 25%-40% of people with either bipolar depression or major depressive disorder are experiencing mixed features. This is clearly a very common subgroup. The really important aspect in the call to action of why we need better, safer therapeutics is that conventional antidepressants, like the Prozac type drugs, have never been shown to be effective in mixed features. They have been shown to worsen mixed features. Persons become more unstable during those times. This would be so far academic if we didn't actually really emphasize a point. Bipolar disorder has one of the highest rates of suicide in all of psychiatry. It's recognized that mixed features especially identify a person who's at greater risk for suicide. Along with having this terribly tragic outcome, suicide, mixed features also identifies a group of people who are more likely to have what we call comorbidities, additional problems like drug and alcohol misuse, anxiety disorders, and many, many others. Taken together, mixed features are common. They are codified in the DSM-5. It represents a very severe, complex, and poorly treated group of individuals who are quite significant in their percentage across both major depression and bipolar depression. Next slide. When we think about the overall portion of bipolar, the title really emphasizes it. To say it's complex is true, and it certainly is a lifelong and chronic disease. The percentage of people affected by bipolar I and bipolar II disorder is approximately the same, although there's a suggestion bipolar II is more common than bipolar I. That translates into about 11 million people in the United States affected by this condition. Now, when we look at the lifespan of people who have bipolar disorder, there's been a whole host of studies that have looked at this with really a concerning finding that on average, people lose about 10 - 20 years of life if they have bipolar disorder. It's also in part because of the 20-fold higher rate of suicide. It's also in part because of the staggering rates of cardiovascular disease in this population, and that's in part because they have so many risk factors like obesity and diabetes. Hence, it's so important for us to have treatments that treat their mental illness but don't leave them burdened with weight gain and metabolic problems, which unfortunately has been very common in this space for the past two decades. Taken together, the disability is staggering, not just at the individual level, but at the societal level, with striking levels of disability, especially early on in life. In fact, I often press the point that when it comes to human capital loss, it's estimated that bipolar may have the greatest loss of human capital with respect to somebody's education attainment, but what they're currently doing. In other words, these folks are often not able to work in whatever role that they had hoped for themselves or their family had hoped for them. Next slide. When we talk about BP1, BP2, again, defined on the basis of mania in the case of bipolar I, BP2 is defined as alternating hypomania and depression. Taken together, however, when you look at these lifelong conditions, both of them have a lot in common in the sense that the majority of the time that these individuals are unwell, they're unwell with depression. In fact, about two-thirds to three-quarters of the time someone with bipolar I disorder is unwell, they're experiencing depression. Bipolar II disorder is closer to 80%-90% in many cases. In fact, my experience in over 20 years of working with people with bipolar disorder is entirely in accordance with this report, that being the predominance and really the perniciousness of these depressive symptoms leading to terrible functional problems. Taken together, although mania defines BP1, hypomania differentiates BP2, it really is the depressive symptoms that are contributing to the decreased quality of life, the terrible impairment in function that these individuals experience chronically. Next slide. When we think about bipolar disorders, and we think about BP1 and BP2, this is an area where the field is beginning to become a bit more contemplative. Historically, bipolar II disorder has been characterized as a less severe form of bipolar I disorder. That would be true insofar as hypomania is less severe than mania, for the reasons I mentioned earlier. However, when we think about bipolar, it's a lifelong condition. 75% of people who have BP1 or BP2, bipolar I, bipolar II, declare the illness, that is, it's apparent before the age of 25. This is very early in a person's life. We take a more of a life trajectory look at bipolar I, bipolar II. Bipolar II is as, if not more impairing than bipolar I, in the sense that depression, as I emphasize, is especially predominant. What's also predominantly more often seen with BP2 is comorbidity and a suggestion suicide rates are higher. When we look at the portrait of BP1, BP2, both are severe, both are complex, chronic, lifelong conditions. Frankly, both have staggering morbidity and mortality, but BP2 is worth as much of our attention as is bipolar I. Next slide. When we talk about the depressions of bipolar disorder, this is a part of the, or a phase of the illness where the field of psychiatry, and more narrowly, the world that I've worked in for over 20 years, mood disorders, has become much more contemplative about. What we have learned is despite the definitional requirement of mania in BP1 and hypomania in BP2, it really has been the depressions that have really ruined people's lives, have really made it difficult for them to fulfill their role inside the home, outside the home, and as I mentioned earlier, have also predisposed self-harm and suicidality. I bring that up because historically, drug development and treatment discovery and development broadly in bipolar really focused on mania and hypomania. That wasn't so much misguided, it just wasn't fully informed. Over the years, as we've learned more and we've been able to refine with granularity the symptoms of bipolar and what really impairs people's lives and function, our attention has shifted to the depression. Taken together, it is an unequivocal view that the unmet need in bipolar disorder I and II today is trying to treat these depressive symptoms. Of course, we don't want to induce hypomania or mania. We don't want to burden patients with terrible side effects like excessive weight gain and diabetes. When you look at the drop-down menu, in other words, the treatment options for bipolar depression, they still remain highly suboptimal relative to the treatments that we have for mania. For the person who lives their life with bipolar, depression is what's ruining their life, and the treatment options for BP1, BP2 depression, frankly, have just been suboptimal. Next slide. When we talk about the unmet need from a more public health perspective, I want to also bring this point up around detection and diagnosis. There's no question that bipolar disorder is a condition that can be challenging to diagnose on more times than we would like to count, quite frankly. For example, it's known that a majority of people who have bipolar disorder, when they visit a healthcare provider, not just once, not just twice, even three times, the diagnosis is often missed. Said differently, the bipolar presentation that often leads the patient to go to the healthcare provider typically is the depressive symptoms. People are more likely to go to their care provider in a state of depression than they are in hypomania or mania, for a variety of reasons. When the healthcare provider who, like the rest of us, is time poor and has a very short window to assess the patient, they're often seeing the patient in depression. When people with bipolar disorder seek out care, not only is it depression that they're seeking out care for, but they're often, in fact, having repeat visits because of depression. This is a critical area for us in the education world to educate our colleagues to be thinking about and screening for bipolar. Many endeavors like that are going on across the country. It really also emphasizes or really presses this point yet again, that the depressive symptoms are not just predominant with respect to the longitudinal presentation of bipolar, but they're the principal reason a patient will go to a healthcare provider and the principal reason why they are prescribed medication for their illness. This is not academic to get this diagnosis timely and accurate. We've learned from other lines of research that bipolar disorder is a progressive illness. Progressive in this context is defined as the illness changes over time. It becomes more malignant, no different than many other diseases like heart disease or diabetes, that over time become more and more difficult to treat. With timely and accurate diagnosis, we do the individual a great service by reducing their suffering. We also do a great service to the longitudinal trajectory, the illness trajectory, because if we can treat that depression effectively and safely now, the long-term course for that person can be one that's very optimal, in fact, live a flourishing and happy life. Next slide. We talked about the treatment landscape. This is really interesting. We've had antipsychotics and lithium. They have remained the foundation of treating adults with bipolar disorder across America. A report came out in August of last year, 2020, wherein it was reported that across America, antipsychotics are the most frequently prescribed class of agents for adults who have bipolar disorder. When one looks at the column of treatments, the agents that are approved for mania, and you juxtapose, you put that next to the list of agents approved for depression, it certainly passes the eyeball test very quickly that that column for bipolar depression is very, very small, to begin with, and very small relative to mania. What we need in the field is newer treatments for depression, for the reasons I stated, but also, in fact, for the future, we need treatments that can be effective and safe but don't cause the harm that we've seen so often with weight gain and diabetes, given the fact that cardiovascular disease is the most common cause of premature death in this group. Now, one of the observations that I've made, many have made, been reported in many different epidemiologic studies, is that conventional antidepressants, the Prozac-type drugs, continue to be prescribed frequently in people who have bipolar disorder. In part, this is because depression is so common. Secondly, this is because clinicians are being asked to treat depression at the point of care. Thirdly, it's because clinicians are not entirely sure what to give these patients a lot of the time. Frankly, we haven't given clinicians many solutions. Only recently now do we have newer treatments for bipolar depression. It's bad enough that people are using antidepressants. I want to press this point that antidepressants are not FDA-approved for BP1 or BP2 depression. For many people, antidepressants could destabilize patients. They have their own set of side effects associated with them. Unique to bipolarity is the destabilization of the actual illness. One of the liabilities of many of the other antipsychotics, I talked about weight gain, metabolic problems, unfortunately, very common with many of them. For others, so-called neurologic side effects called EPS or extrapyramidal side effects are common. We really need treatments that provide the efficacy in depression but don't burden them in these ways, given the high rate of discontinuation due to side effects. Next slide. We think about, to summarize this, and I have to say, after over 20, close to 25 years of providing care and researching mood disorders, I continue to find this spectrum of major depression, so-called unipolar depression at one end, and bipolar depression to be intriguing intellectually. Really, in fact, clinically, what we often see, whether the patient has major depression, which is not my focus, but more my focus, bipolar I, bipolar II depression, is depression. Depression is the predominant presentation, and many of these people also have so-called mixed features, and I had mentioned that mixed features also observed in people with major depressive disorder. The seriousness, the complexity, the chronicity, and the lifelong nature of bipolar are well reported with a shortened lifespan, but that's not a fait accompli. That's not something that needs to happen. With good treatment that is timely and accurate, efficacious, well-tolerated, people can expect to live a normal lifespan and a flourishing and high- quality of life lifespan. There are preconditions. The treatments have to be effective, and they have to be acceptable to the end user, the patient, and they certainly don't want, nor does anybody want, their quality of life really eroded by depression and side effects like weight gain, sedation, metabolic problems, and EPS. Against that background, I wonder if I can now have my next slide, and we're going to, if we could, look at some of these posters that were presented at the annual meeting of the American Psychiatric Association. Lots of language here. I'm going to keep it pithy and short. We're going to go through a study that looked at adjunctive lumateperone. That's our first study. Adjunctive meaning added to lithium or valproate. We will have the next study. This is lumateperone added to either lithium or valproate in adults who have bipolar I or bipolar II depression as part of their bipolar illness. We have 529 subjects were entered into the study. They had a moderate to severe depression, which is commonly encountered in clinical practice. They're randomized in equal ratio, 1:1:1, to either placebo added to lithium or valproate. The lithium and valproate were at good levels, so-called therapeutic levels, or lumateperone 20 mg or lumateperone 42 mg. The primary endpoint in this study, which is a common primary endpoint, is the change from the baseline to the endpoint in the total MADRS, the Montgomery-Åsberg Depression Rating Scale score at week six. Next slide. When we look at the results, you can see them here. You're looking at the top. I want to just orient you to the slide first. On the top, we're looking at the primary outcome, which is the MADRS total score. At the bottom, we're looking at a key secondary outcome known as the CGI, the Clinical Global Impression. Let's look at the primary outcome first. This is showing you data for placebo, 28 mg and 42 mg of lumateperone added to lithium or valproate. You can see that the 42 mg per day dose adjunctive to lithium or valproate met its primary endpoint of significant improvement at week six on the MADRS relative placebo. The effect size of 0.27 is identified. That would be considered clinically relevant. What I find really clinically relevant to me as a practitioner is the global impression of the patient. The CGI is what it calls itself. It's the Clinical Global Impression, a gestalt of sorts with respect to how is the patient really doing, and frankly, this is what clinicians do reflexively when they see their patients. Is my patient better? Is their patient mildly ill, moderately ill? Using the CGI as a key secondary outcome in this adjunctive study, you can see whether we're looking at the overall CGI or the CGI bipolar depression sub-score, there is in fact significant improvement for the 42 mg of lumateperone relative placebo. We have the itemized depression scale, the MADRS primary, and the global impression, both showing significance and clinical significance, not just statistical significance. Next slide. The safety results are here, and I want to underscore this area because after treating close now in my program, about 100,000 people with mood disorders, this is in fact what preoccupies clinicians and patients is tolerability. Most of the adverse events that we're seeing were mild to moderate, somnolence, dizziness, and nausea. The key point is relatively low dropout rate due to side effects. There's two types of side effects, side effects people have, and side effects leading to dropout, and the second part leading to dropout is what's most critical, and we saw really no difference here significantly between groups. I want to also talk about weight. Lumateperone in this program, I'm going to focus on the 42 mg. You can see there's no mean change in body weight and the 7% difference, that is the clinically significant threshold, not different, not greater than placebo, actually. There were no notable changes on metabolic parameters or some of the neurologic side effects as measured by the Barnes Akathisia Scale, the Abnormal Involuntary Movement Scale, or the Simpson-Angus Scale. I just want to pick up on that because throughout my career, those are the areas that are deal breakers for patients. In other words, too many of our medications cause metabolic disruption and weight gain, and the patient says, "I'm not taking these medications." The patient says, "I've got movement of my arms, my legs, and I don't know where this is coming from." They stop the medication. Those two last bullets are extremely relevant to people who have bipolar disorder. Among other roles, I serve as the Scientific Advisory Chair for the Depression and Bipolar Support Alliance, which is an advocacy group for people with bipolar and depression across America. We've done surveys of people who live with bipolar disorder. This is exactly what they prioritize. We don't want treatments to cause these side effects. I think that's really patient-centric. Next slide. We move from that to the conclusion. We have efficacy. Now, two studies supporting the basis of this sNDA for the treatment of bipolar depression, that the 402 study, which is, in my world, better known as the adjunctive study to lithium or valproate, along with a separate 404 study, which is the monotherapy study, and this aligns with clinical practice. Clinicians will sometimes see patients who are not on anything right now, so monotherapy data is important. Other patients are already taking lithium or valproate, and the clinician may add something to it. Those are two paradigms that are commonly encountered. 42 mg a day shows tolerability and safety, and the most common adverse events were there with placebo-level adverse events across the parameters that I had mentioned. The potential is there that this treatment, lumateperone, can offer help to a large number of people whose needs are currently not being met in this space. Next slide. Next poster. We're going to quickly look at mixed features. Again, these are people who have bipolar disorder, next slide, who have now been put into two different categories, or I guess in conversational speak, two different buckets. These are people who have bipolar depression, and these are individuals who were enrolled in the so-called 404 s tudy, the monotherapy trial. What we did here in these 376 patients, we put them in two separate categories or buckets. Those who had mixed features. Remember we talked about that? While depressed, there is elements of hypomanic symptoms despite the fact they're depressed, and the other group did not have mixed features. Let's have a look at the next slide. It turned out when we did this, about 41% of people with bipolar depression in the monotherapy trial met our criteria for mixed features. We had what we call a proxy definition of mixed features. That's in keeping with what we see in the real world, where about 25%-40% of people have mixed features. I was really interested in this analysis because these patients are common, severe, not well-treated. They often receive antidepressants to their peril. Antidepressants make life worse for these people, often exacerbate hypomania and mania. In contradistinction, what we see with lumateperone within these two subset analyses on top, you're seeing people, the overall population. At the bottom figure, you're seeing those with mixed features. You're seeing, in fact, efficacy. You're seeing efficacy of an effect size that's clinically relevant without treatment-emergent hypomania. The efficacy clearly valued, but we don't want to harm the patient, which so often happens because they often end up on conventional antidepressants. This is extremely important data from the point of view of public health in providing care for people with bipolar and mixed features, and probably has some degree of extrapolation, not the focus of this poster, into Major Depressive Disorder as well. Along with the improvement in the depression scores, we also found improvement on that Clinical Global Impression. It's not just a symptom outcome, it's a global impression, which we also value. Next slide. Taken together, I've said a lot about mixed. It's a very significant subpopulation, very severely ill, higher rates of self-harm and suicide, and certainly a much more unstable illness with, frankly, an underwhelming list of treatments that we can offer. It was mentioned when Suresh introduced me that I was a contributor to the Florida Medicaid guidelines, and in those guidelines, we said that there could be a role for a second-generation antipsychotic to treat mixed features in bipolar as a standalone treatment. We recognize how serious this problem is and how, frankly, underwhelming the options are until recently, what we're seeing here with this post-hoc analysis from the 404 data. This is, again, promising, not just for depression, but more widely for mixed features in BP1, BP2. Next slide. The third of four posters, we're just sort of rounding the bases here. This was a pooling. We love to pool data together, pooling 401 and 404. These are two monotherapy trials. The design was very similar, allowing to pool. By pooling, we increase our power. Looking at 42 mg of lumateperone as monotherapy versus placebo once daily in the evening to treat bipolar depression. The usual primary outcome around depression and usual safety and tolerability parameters are evaluated. Because these studies were similar in not just their design, but also in their demographics and baseline characteristics, that lent itself organically to pooling. Next slide. What you can see here is you can see the more common adverse events that were noted in this program. What you can see here is that somnolence, nausea, and dizziness, we've seen this before, were the most common adverse events. What I want to come back to is the rate of adverse events that lead to discontinuation, which was not really significantly different for most of these side effects. You can also see that the tolerability profile showed that it was similar to placebo, whether we're looking at EPS, that's those neurologic side effects, weight changes, or some of the metabolic, and then prolactin, which is a hormone that's raised by other types of antipsychotics and can be a problem for some patients. Again, that safety and tolerability profile aligns with the adjunctive program, the component studies in bipolar depression, as well as in the study done in schizophrenia. Next slide. Okay, final slide. This is depression symptoms in schizophrenia. The next slide, please. Just a couple of comments. We know schizophrenia is primarily a psychotic illness. Anywhere from about 25% up to 60% of people who have schizophrenia also have clinically significant depressive symptoms. Like people who have bipolar disorders, the rate of suicide and self-harm is higher in this population, people with schizophrenia, and self-harm is associated with depressive symptoms. We don't have really a lot of treatment options for depressive symptoms. We have not seen an FDA-approved treatment specifically for depressive symptoms. Given the pharmacodynamic profile of lumateperone, given its role now in treating bipolar depression so robustly in replicated studies, we wanted to look at what is the effect on depressive symptoms in a person with schizophrenia. The opportunity was afforded by the study, lots of numbers here, sorry, Study 303. This was really, more descriptively, a long-term study. It was open label, where people were receiving treatment for up to a year, lumateperone 42 mg. Again, that 42 mg, easy to remember, and they were followed forward after stopping their antipsychotic. They go on to lumateperone followed forward. Really assessing the effects of lumateperone on depression. What's the scale? It's called the Calgary Depression Scale and is often used in people who have schizophrenia to measure their depressive symptoms. We have benchmarks for what denotes the presence of significant depressive symptoms. It turned out that 80 people met our criteria within this larger program of having sufficient symptoms of depression that we can then evaluate lumateperone's effects. Let's see if we can just look at the next slide. The demographic characteristics were similar between those who were taking and those who were not taking antidepressants. It turns out that 28 of the 80 people were taking an antidepressant, and 52 were not taking an antidepressant. They have schizophrenia. They all have significant depressive symptoms. It turns out that lumateperone was associated with an improvement in depressive symptoms in both groups, the 28 who were taking antidepressants and the 52 who weren't. The full sample is 80. Whether you're taking an antidepressant or not, lumateperone significantly attenuated depressive symptom severity over a period of one year. That has tremendous implications for people who live with this condition and has tremendous implications for the acceptability of the treatment because depressive symptoms of schizophrenia is another reason why people often stop their treatments. This is certainly an important finding. Next slide. Okay, just a quick summary. Went through a lot of data there very quickly. We have positive results now for lumateperone 42 mg in two phase III bipolar depression studies. We have the monotherapy; we have the adjunctive to lithium and valproate. We have these studies really replicating significant statistical and clinical efficacy at the 42 mg, whether the person has bipolar depression or whether we subgroup that into those with and without mixed features. That's extremely clinically relevant. In stable schizophrenia, when people switch over to lumateperone, there's an improvement in depressive symptoms. There's that replication. We want to see replication. This is replication of that antidepressant effect without the baggage or frankly, the tolerability problems of weight gain and metabolic changes, extrapyramidal side effects, prolactin. The rates are all similar to placebo, which frankly is not something I've said before in 20, 25 years of working in this area. Extremely promising. I'm even going to say the word hopeful, very hopeful for people. Gives them a tremendous line of sight forward, where they can forget being so consumed with side effects and inefficacy and focus on getting their lives back, something of which every person who lives with these conditions lists as the therapeutic objective number one, getting my life back, this gives them a chance for that. I think that's our last slide. I'm going to go back to Sharon, I think from here. Thanks, Roger. We have been getting a lot of questions, and I think rather than go question by question, since many of them are a variation on a theme. I apologize if I don't say the name of the person asking the question, because I'm going to try and group these, and then when we get to the one-off questions, then I'll try and address them to the particular analyst who mentioned them. First, there are a lot of questions about bipolar I and bipolar II, and what are the differences? Why doesn't everybody study bipolar II in their studies? That's why, if Bipolar II is important, why doesn't each study look at it, and do Bipolar II patients seek treatment less? In fact, one of the comments, and this one was from Ash Verma of BofA, said, "Based on his KOL feedback, my understanding is bipolar II patients" Wait a minute. My computer just jumped around. Oh, here. "Bipolar II patients seek diagnosis treatment at a much lower rate than bipolar I patients. Why is that?" Then I'll go on to the rest of this question. Yeah, those are great questions. Let me just maybe just address kind of a couple of themes there. Bipolar I and bipolar II have a lot in common. They're both part of the bipolar collection of disorders. Both are predominantly depressive illnesses. Both are highly disabling, and both are associated with premature mortality. That is certainly a list of commonalities that really draw our attention, our urgency to both of them. There are some differences by definition. Cross-sectionally, hypomania is milder than mania. The person's not as severely impaired. Again, the portrait of bipolar disorder is such that hypomania, although defining BP2, is a relatively brief excursion relative to depression. Depression is the predominant presentation, and pound for pound, the depressions of bipolar II are much more chronic, much more malignant, much more difficult to treat. Taken together, BP2 has just as much, if not in many cases, more morbidity than BP1. There's a lot in common. One other aspect about this which came up is how often are they studied? One of the reasons why most organizations, not just academic but sponsors, have not studied BP2 is that BP2 historically has a higher placebo response rate than BP1 for a host of reasons. In other words, it's a tougher phenotype or a tougher subgroup to show signal in studies. It's the nature of BP2. On the issue of diagnosis, it's a really interesting point that Ash brings up. I can tell you that at our center in Toronto, it really cuts about 50/50. In fact, maybe 55/ 45 in favor of BP2. BP2 does in fact utilize healthcare services as much as BP1. Some might even say even more so. It reminds me of that phrase that, I didn't see what I didn't believe. Unless you're thinking about it, you don't see it. People, in fact, who've sat in clinics, have systematically sat down with patients in the waiting room who are there to see their care provider, it turns out BP2 is as common, if not more common than BP1. Admittedly, given what I've said about BP2, and I have seen tens of thousands of folks. I like to say I'm doing a perfect job at diagnosing it. BP2 does have some challenges. Mania, the person's severely ill. Often, they lose touch with reality. They're functionally very unwell, and one doesn't need to have a health science degree to say, "This person's not well." It's obvious to everybody. Hypomania is not as severely ill cross-sectionally, and there's clearly a change in their behavior, but it becomes a little tricky to know, is this part of this person? Is this just who they are? Is this maybe just related to the fact that they may have had some comorbidity, like drug and alcohol misuse? Clinicians often scratch their head, not certain whether the hypomania is representing "pathology" or is this part of who they are. Because patients come to the clinic while depressed, they don't have the luxury always of seeing that person while they're hypomanic. There are some diagnostic challenges with BP2, more than BP1. They're not challenges that can't be met, and we can make a diagnosis, but there are challenges, no doubt. No, BP2 is as common as BP1 when you take a more structured evaluation to the patients. Okay. Thank you for that. I'm going to switch from BP1 and BP2 questions for one second, because I also have the questions that, if antidepressants are not approved and not effective in treating BP1 and BP2, why are they used so much there? There's a number of reasons why. First is that depression is just so common in BP1, BP2. It's why they go to the care provider. Secondly, is that clinicians are doing their best to try and help their patients, and they don't know what to give them. Clinicians are intuitive. They're saying, "Okay, if an antidepressant works in major depression, well, my goodness, it must work in bipolar depression." That's a completely reasonable set of thoughts, and to connect those thoughts. It turns out that they don't work as well in bipolar depression, and that's a highly replicated finding. I think that there's a different dynamic, and there's a whole literature on this. When patients go to a prescriber, they have an expectation. The expectation, I'm going to leave with a prescription. Even when the care provider says, "You shouldn't get this antibiotic for your viral infection," the patient will rate that encounter very negatively. There's that dynamic as well. I'm just saying that there's expectations that people have when they go to the care provider. The big reason is depression is common, depression is why they go to the care provider, and they're scrambling to find something for the patient. That's simply put why they're more common. Not FDA-approved, not proven effective. I alluded to a study, Sharon, that was published last year that showed that antidepressants across America not only are widely prescribed, but really the trajectory has been just slowly going up and up. Again, speaking, I think, to the unmet need in bipolar depression. I'm going to switch gears to mixed features in a minute because I've just been getting several questions on that. Before I do that, I would like to address, I'm going to try and put together a few questions asked by Brian Abrahams at RBC. His question is, unipolar depression patients tend to be higher functioning and more sensitive to AEs than schizophrenia or bipolar patients. Is there anything to suggest that the AE profile may be different across the different psychiatric disorders, or that patients may be more aware to low-grade AEs such as nausea and somnolence, and is there any way to mitigate this? First, do you agree with that statement, and then do you have any comments there? Brian, I love your question. I agree with what you're asserting. Let me just add to it. There's no doubt about it that people who have a psychotic disorder, when they're put alongside people with a mood disorder, people with mood disorders, broadly, both major depression and bipolar disorder, are more likely to report adverse events than people with schizophrenia that would compromise their willingness to stay with the treatment. That's an important point to just finish with. You could conjecture that, because on average, people with, for example, bipolar disorder, are higher functioning than people who have schizophrenia. Perhaps they have a reference effect, if you will. They can reference how the drug side effects is affecting them negatively more than someone who's lower functioning. That's just intuitive. That's true. What's also true, Brian, is that within the population, the willingness to tolerate side effects is very different the longer things go on. Let's use COVID-19. Were you willing to tolerate staying at home for two weeks last March? How if I said to you, "Stay at home for 14 months." That's a different calculation. It's no different with side effects. People are much more willing to tolerate side effects for a week or two, but not for two months, not for three months, not for six months. When patients come to see me, and they've been prescribed medicine, they start gaining weight on, they say, "Look, I'd rather not take this medication. I'd rather just take the risk of getting sick again. I do not want to take this medication." For me, frankly, as a clinician and as an advocate, as a person who's been supportive of patients in this area, it's been really frustrating because we're trying to treat their depression. I want them to stay on treatment, but I get it. They don't want weight gain and metabolic problems. Yes, your assertions are true. I would put MDD and bipolar closer together, but they're different than schizophrenia for sure. The side effect willingness to tolerate is certainly more the case over the first two to three weeks of treatment than it is after two or three months. That's why it's so critical. With lumateperone, and this is an important point, I've studied weight and metabolism in bipolar disorder and major depression for 25 years as a scientist, and I can tell you that this is a very, very critical issue, not just from the point of view of patients taking it, but also to the long-term negative effects it has. Obviously, it causes worse scores on your physical health ratings, but also your mental health ratings. The fact that lumateperone is neutral right across the board in this regard, it's not heard of, and it's a profound observation for people who are making choices. Not just choices, what am I going to take for the next 2-3 weeks, but what am I going to take for many years of my life? We're going to jump around a little bit again, and we're going to switch to mixed features, and then I think we'll come back to some specifics about some questions on a couple of our presentations. A few questions put together, and then one succinct one from Sumant Kulkarni from Canaccord, who asks, "The DSM-5 has been around for several years now, so why is it that industry has not focused on developing products for mixed features? And what is it specifically about lumateperone that makes it potentially a good treatment for mixed features? Great questions. I think, sorry to quite get that name, it was Sumani. If I'm not pronouncing your name right, my apologies. Sumant. Yeah. Sumant. My apologies. Sumant, it's an excellent question. You're right. We've had the DSM-5, circa 2013, so that's eight years and counting. Where did time go? Mixed features was a new construct in the DSM beginning in 2013. Part of this, it's still kind of a newer kid on the block, so to speak. There has, in fact, now been recognition within the field of bipolar disorder, that is the academic and scientific community, that this is an area that we need to study. I think, in fact, that until you had a consensus within the scientific and more specifically the bipolar community, unless that consensus was there, I think you're not going to see sponsors willing to come to this area in droves. We all recognize it's an issue, but we need to have consensus on what is the criteria, how should it be operationalized, what's the outcome measures? Now recognizing that mixed features cuts across both bipolar and major depression, there's a consensus we need to focus on this. We are, in fact, also aware that the FDA, which needs to also be aligned, the FDA obviously is aware of mixed features, and I think until recently, there was less clarity about the regulatory pathway forward. There seems to be a bit more clarity on how that pathway might look. It's not just scientific. Obviously, there has to be a regulatory framework that gives a line of sight, and I would say that that line of sight now is closer to 20/20 vision than it was five years ago. You have to line these stars up, and that's what's happening right now. To carry on with that theme, Brian Abrahams from RBC asked, "How often do you see patients with mixed features? Is this something that you would assess prior to starting treatment or more when one realizes they're not responding well to treatment? Is this more of an academic distinction rather than something that affects the treatment paradigm in the community? How can broader awareness and diagnosis be improved? Brian, that's fabulous. I appreciate the question. Brian, it is a critical clinical issue. Let me just say a bit more about that. First, I did a study, a study was done at my center in Toronto with colleagues at the Cleveland Clinic. What we decided to do was something very simple. Very simple question we wanted to address, which would inform your answer. We asked how common are mixed features in people with depression as part of bipolar, walking into Cleveland Clinic in downtown Cleveland or coming to the University of Toronto Hospital. It turned out it was around 35%-40%. In fact, that's quite similar to what we saw in the lumateperone program. Now, as you know, mixed features has a definition. You have to have a certain number of symptoms. We used a more rigorous definition that was aligned with the DSM-5. As you might expect, many patients have symptoms of mix, but it might not reach the full threshold, the full number that the DSM requires. If you open the goalpost wider, you get more field goals. In other words, if you widen the criteria, you get more people meeting the definition. The DSM-5 definition that we used was around close to 25% - 40%. If we broaden it to include symptoms that the patients are agonizing over, if it doesn't quite reach the threshold, it's up to 45%- 50%. It's common. It's not just academic. Just to substantiate my assertion that it is so clinically relevant, for the last five years, I have participated in the Medicaid Guidelines that are published in the state of Florida. You can find them at medicaidmentalhealth.org. These are guidelines that are authored not just by academics and clinicians like me, but also primary care providers, people who live with the condition, people in policy. It's really around the table, all stakeholders that are relevant to this space. We have a separate algorithm in the state of Florida on how to manage mixed features. This is not actually just something academic. We all recognize mixed features are harming our patients' lives. They keep getting the wrong treatments, like antidepressants. Clinicians need a guideline on how to treat this. This is job number one, and there's a guideline for that's in the state of Florida. It is extremely clinically relevant. I'm really pleased to see that the company is doing this from the point of view of patient experience, because this is just agonizing for patients. I mentioned in passing that people who have bipolar disorder have one of the, and in fact, in many studies, the highest suicide rate in all of psychiatry. When we look at people postmortem who died by suicide, we find out that they're almost always in a depressive state and very often experiencing mixed features. That distractibility, the anxious agitation, the mood instability. This, along with depression, is a very combustible mix. It is a very serious clinical matter. Great. Now I'm going to go back to bipolar I and bipolar II, and we have six or seven questions. I'm sorry, I'm not going to read every one of them. They all go to how difficult is it to discerning the difference between bipolar I and II, and what is the treatment plan for each of these. Let me just see if I can add a few other things. From at least three of the analysts, we got the questions of what percent of your population is bipolar I versus bipolar II, and within that, to whom would you anticipate prescribing lumateperone. Greg, I can never pronounce your last name, Graig, I'm sorry, Suvannavejh from Goldman asked, in years one, in years two, and in years five. It's a lot of questions. It is. Let's talk about differentiating BP1 from BP2. In a perfect world, I would say differentiating these conditions is easy. I can do it in three seconds. That would not be true. Differentiating BP1 and BP2 is fairly straightforward most of the time, but not all the time. On its outer perimeter, with the severity, if someone's severely ill, removed from the workplace, significant relationship, marital problems, getting themself into all kinds of problems related to impulsive behavior, that's obviously very severe, and that's fairly straightforward from differentiating from hypomania, which is BP2. Most of the time, not a problem, but that's not all the time. I would say, frankly, about 1/3 of the time, it's a bit of a challenge, because that line that differentiates hypomania and mania is qualitative in some ways. It's severity. Some people, because of a variety of reasons, their family, their friends, their own skills at being able to mask the illness, it's sometimes a little tricky. Most times, we can make that differentiation by taking a good history. With respect to the question. Let me get this right now. It was a question around lumateperone. There was one before that. Sharon just remind me again. I've forgotten. Anyways, I'll answer the lumateperone. Oh, the percentage of people in my practice that have BP1 versus BP2. Right. Yeah. I can answer that empirically. It's 1/3, 1/3, 1/3. I run a very large by volume mood disorder center in Toronto. I started it 20 years ago. It's very busy. The way Toronto is, we're the only medical school in the Toronto area. Toronto is very metropolitan, so it's a big volume. Over the years, approaching 100,000 people who've come through. A lot of these for consultation, et cetera, referred by primary care psychiatry. About 1/3 d have BP1, about 1/3 have BP2, and about 1/3 have major depressive disorder. What they all share in common, 95 x out of 100, is that they're depressed. They come to see me because they're depressed. People say, "Oh, hey, Roger, you run a bipolar program. What's that like?" I say, "Well, everyone's depressed." I would never have known that when I started the clinic up. It is a depression clinic, but the portal of entry is BP1, BP2, major depression, 1/3, 1/3, 1/3. We've actually looked at this. That's why I have those percentages fairly tip of the tongue. Now, for lumateperone in bipolar depression, let's say a few words about that. When it comes to managing people with bipolar illness, you've heard me probably to the point of over-repetition, it's about depression. When it comes to what patients prioritize, we've done this work at DBSA, it's depression. When I look at the roster of treatments that I have, it is underwhelming. In the U.S., the FDA has approved olanzapine in combination with fluoxetine. No patient has ever come to me and said, "Dr. McIntyre, can you do me a favor? Can you make me really overweight?" No, they don't say that. They say, "Don't give me any medications that cause weight." I'm on board with that. Olanzapine is not happening. Quetiapine is a very effective agent in bipolar disorder, depression. However, it is not going to be an option because of the weight gain and the sedation with that particular medication, which can be quite treatment-limiting. For that reason, in the Florida guidelines, we have put a bit of an asterisk next to quetiapine and olanzapine. Yes, they have the approval in bipolar depression, but there are serious treatment-limiting side effects. These aren't just cosmetic side effects. These are serious with respect to people's health. We have lurasidone in bipolar depression, but lurasidone's not been studied in bipolar II depression. It was studied in bipolar I depression. We said that it's almost an equal ratio, BP1, BP2. Cariprazine we have in bipolar depression. Cariprazine and lurasidone are two drugs that have FDA approval in bipolar depression. Cariprazine is like lurasidone. It doesn't have the efficacy data in BP 2. Taken together, just to summarize that, there are three pharmacologic options in bipolar depression that are evidence-based, safe, and effective that are without weight gain liability. They are LATUDA, VRAYLAR, and now lumateperone. Only lumateperone has been studied in BP 2, which represents half of the bipolar patients coming to seek care, not just at a university center, but also in a primary care center. Because of the tolerability profile, the safety profile, short and long term, it's obvious, again, speaking as an academic and someone who creates clinical practice guidelines, CPGs, it would be a first-line, first-choice option, not based simply on my opinion, just simply based on what you would imagine. Patients want what you and I want. I wanted my life back. I don't want nonsense side effects. I don't want the burden of all these things. I just want to feel myself again. That universal human expectation will make lumateperone a first-line, first-choice treatment. Great. Thanks. Again, I'm going to consolidate several questions, and I now figured out why the questions keep jumping around. Sure It jumps around. I'll try and do it before another one gets added. Sure. I'm going to use as the lead a question from Charles Duncan at Cantor Fitzgerald, and then I will add in several other questions that came through as well. The effect sizes in 402 and 404 are notable, given only seen over six weeks. Given the waxing, waning, or cyclical presentation of either BP 2 or 1 of depressive symptoms, could you see clinical benefit grow with time on therapy? I'd like to add on to that some questions that came around Study 402, which has the adjunctive treatment, which has a lower effect size than 404, which was a monotherapy, which had not only an extraordinarily robust effect size, as did 402 for an adjunctive study, but also we saw efficacy very early on with 404, I think it was at the first time point tested, whereas 402 is more gradual. Can you comment a little bit on adjunctive studies versus monotherapy studies and also answer Charles Duncan's question as well? Some of that consolidated question came from Marc Goodman at SVB Leerink. Thank you. I'll take Charles' questions first, then Marc. Charles, great question. What you're speaking to is what we kind of refer to in the business as the response trajectory. Bipolar depression, by its very nature, the symptoms are very fluid. Patients got better, you saw the benefit occurring very rapidly with treatment within a couple of weeks. We start to see significant separation between the two groups, placebo and lumateperone 42 mg in bipolar depression. One of the most replicated observations in bipolar depression, which would extend into other areas of psychiatry, we're going to focus on bipolar depression today, is that what occurs early is the best predictor of what's going to happen later. Said differently, as long as patients stay on treatment, which we believe that they will because of the tolerability profile, you can expect a further accumulation or accrual of benefit with time. I think a six-week window is certainly enough for what we call assay sensitivity because we want to show the drug can separate from placebo. That's rock number one. For clinicians and for patients, they can very reasonably expect three, six, nine months later, even further benefit. Absolutely, early is the best predictor of later with respect to the response trajectory. On the question about adjunctive trials and monotherapy trials, throughout my career, I've done many adjunctive trials in bipolar depression and many monotherapy trials, here is the observation that occurs 100% of the time. Not 50%, not 80%, 100% of the time. It's always more difficult to show signal of your new medication versus placebo when it's added to a preexisting treatment. I always say this conversationally. It's much more difficult to sit on the shoulders of another drug already shown to be effective in bipolar and prove that you're effective. Every single time we do this, the effect sizes in monotherapy are higher than the effect sizes in adjunctive. It's just a byproduct of the, we call the assay sensitivity. It's just harder to show signal, and that's always the case. Keep in mind that despite that, and frankly, I'm very open about this, I welcome companies to do adjunctive trials, but when they say to me, "Roger, we want to make sure that we just want to keep this simple." Well, simple means doing monotherapy. Adjunctive is really showing efficacy because you're showing efficacy on top of something else. That really is proving that there's an intrinsic action. Does the monotherapy, but all things being equal, it's so much harder in the adjunctive paradigm. What you saw in the adjunctive studies that we quickly went through, you saw a signal, a statistically significant benefit was seen on the primary and the key secondary. Now, the primary is what matters. That's what we're powered to. That's what the question is. The key secondary was also interesting. Now, when you start getting into response and remission outcomes, that's a bit of slicing and dicing the data, which we instinctively do, but that goes well beyond the primary purpose of the study. In an adjunctive paradigm, it's exceedingly difficult to show signals on a list of secondary outcomes because of the reasons I mentioned, and also because it's not the primary question. Thanks. We only have time for a couple more questions. I'm going to, again, try and consolidate them. I think you may have already answered this, but just for in case you haven't, this is from Andrew Tsai at Jefferies. He's asking, "What percent of your bipolar I patients, your bipolar II patients would you prescribe CAPLYTA to?" What percent of your patients would you prescribe it to? "Would you prescribe both adjunctive and monotherapy for both treatment naive and treatment experienced? Would you prescribe CAPLYTA" I'm not sure what this really means, but, "Would you prescribe CAPLYTA immediately? Yeah. I presume that means immediately upon approval. Okay. Exactly. The answer is, I would. First of all, we already have CAPLYTA approved for schizophrenia, we already have so-called real-world experience with this agent, obviously proven safe. It's effective. It's tolerated schizophrenia. My point is, I would clearly have no hesitation immediately prescribing it in bipolar upon approval. For the data reasons we've provided, also because we've already had a bit of a test drive, for lack of a better way of saying it, in the schizophrenia in the real world. We're reassured and say so absolutely. The question about what percentage of patients, it's always a tricky one to answer. What I would say is that this is a decision that's not just me making, it's a patient makes it. Patients are not some mysterious entity. Patients are no different than you and me. In many ways, if you walk through the process, when the patient comes in, they have depression. Clinician like me says, "You've got the diagnosis of bipolar depression. Let's review the treatment options. Do you want weight gain?" I mean, the question is obviously foolish. Do you want to have EPS? Do you want diabetes or cholesterol elevation? Clinicians are not expected to go through all side effects and tolerability concerns, but reasonably expected side effects, which include the ones I just mentioned. Already, I've already deleted a couple of the treatment options, and this is as frank as it is. In fact, we have patients, as I said, they come in with depression. VRAYLAR's going to continue to be a treatment option. LATUDA's going to continue to be a treatment option. They don't have efficacy in BP2, and they don't work for all patients. You're going to see, in fact, lumateperone's going to occupy first choice, first-line status. It's going to be unique in the sense of the BP2 without the weight gain liability metabolics. You're going to see a treatment that is, unlike VRAYLAR and lumateperone, does not have a signal greater than placebo on extrapyramidal side effects. It's always hard to predict the future, but as you can guess, it will be a significant percentage. There are genuine points of differentiation. They're not nuanced. They're genuine points of differentiation from VRAYLAR and LATUDA, which would be also considered first-line treatments in bipolar I depression, but not bipolar II depression. I'm going to have to cut off all the questions, and they keep coming in. I'm going to end with one general question. Several of the questions that have now been coming in are concerning really each of the approved products, and I don't think that we need to be discussing those right now on this call. Maybe the better question here is from Sumant again, saying, "Bigger picture question. What do you think needs to be done in terms of education for bipolar depression to be diagnosed better, and who do you think is best positioned to do that? Is it industry, the physician community, patient groups, or something else? Great question, Sumant. The unmet need in bipolar disorder across America, across the world, I just wrote a paper on this in The Lancet, the number one unmet need is get this diagnosis made. We've got to get people thinking about bipolar disorder at the point of care in all patients who present with depression. Full stop. That is a clear unmet need. There are campaigns underway right now to increase awareness and the dissemination of screening tools, which makes life easier in the waiting room, facilitates the efficiency of the patient journey in the clinical practice, getting that diagnosis timely and accurate. Secondly is that, who are the authors of this campaign? Who are the generals behind this campaign? It's everyone you mentioned. I do think that primary care, broadly defined, because it includes not just MDs, but nurse practitioners, PAs, physician assistants, et cetera. They are uniquely positioned because people with bipolar disorders 1 and 2 are high utilizers of primary care services. Obviously, psychiatrists as well, they're a smaller workforce relative to what I just described. There's certainly lots of precedent when we look at campaigns in major depression, because in major depression, which you would think is an easier diagnosis to make in primary care, there was a lot of concern that major depression was being missed, and it still is, for a long time. Campaigns around education at point of care show that you can increase not just the detection rate, but the correct detection. We don't want people having false positives. We want people to identify people who really have the condition. Public education of our colleagues has been shown to increase the detection and accuracy of major depression. We believe that would also extend over into bipolar disorder. Quite frankly, diagnosis. This is my final point. Diagnosis of mental illness is in tandem with the availability of a solution. Clinicians are less inclined, less motivated, to establish a diagnosis if they don't believe, and they don't have confidence that they can provide a solution. That's just human nature. If they have a solution that they like, the patients like, they have an additional inclination to really dig deep to find that diagnosis. It's just human nature, and that's exactly what goes on. We've just recently, for example, validated a new screening tool for bipolar that's going to almost every care provider across America, getting them thinking about it, getting them contemplating about it. All depressed patients in primary care have got to be screened for bipolar. Nice, simple message, and that's the campaign. We also need to make sure that we're diagnosing timely and accurate, and we now have solutions that the patients are going to be willing to take. I think that that is a zinger, that we have to have a solution that they're aware of and a solution that they're very satisfied with. Okay. Well, thank you very much, Dr. McIntyre. I want to thank everybody for all of your questions, and I know there are several that I did not get to. We will have an R&D day, and we will also have other opportunities for Q&A in the near term. If I didn't get to your questions, I'm sorry. I tried to group them all together, so to make sure we got a flavor of all of them. I want to thank everybody for participating today. Again, thank you very much, Dr. McIntyre, for your comments. My pleasure. As well as for your answers to your questions. I think, operator, we can now end the call.