Hello everyone. Thank you for joining us today. I'm Dr Greg Mattingly, and this presentation will explore the efficacy data of CAPLYTA, or its generic name, lumateperone. We'll be taking a closer look at the results of the clinical trials and the potential impact this treatment can have on treating the symptoms of schizophrenia in adults.

CAPLYTA is an atypical antipsychotic indicated for the treatment of schizophrenia in adults. As an important reminder, CAPLYTA should not be used for the treatment of elderly patients with dementia-related psychosis, as it has a boxed warning for increased risk of death in this population.

The clinical efficacy and safety of CAPLYTA 42 mg once daily were established in two 4-week, randomized, double-blind, placebo-controlled, multicenter US trials in adult patients with schizophrenia.

Let's start by taking a look at Study 1. In this trial, patients were randomized to receive either CAPLYTA 42 mg, placebo, or risperidone 4 mg, once daily in the morning with food. And CAPLYTA conveniently requires no dose titration.

CAPLYTA should be avoided in patients taking concomitant CYP3A4 inducers, moderate or strong CYP3A4 inhibitors, and UGT inhibitors. CAPLYTA should also not be used in patients with moderate or severe hepatic impairment. It's also important to note that, although risperidone was used as an active control, the study was not designed to compare the efficacy of CAPLYTA versus risperidone. In fact, risperidone was included purely for assay sensitivity.

The next study, Study 2, was a 1:1 randomization including CAPLYTA versus placebo.

Across both Study 1 and Study 2, the primary endpoint was the change from baseline to Day 28 on the Positive and Negative Syndrome Scale, or PANSS, total score. We also looked at some additional secondary endpoints and a post hoc analysis, which we will discuss later.

The PANSS is a comprehensive 30-item scale used to measure the severity of schizophrenia symptoms. As a clinician, I want to understand how a medication may impact symptoms. How does it affect positive symptoms, how does it affect negative symptoms, and how does it affect general psychopathology symptoms, the largest group of symptoms within the PANSS?

Collectively, these symptoms comprise the PANSS total score, with a higher score reflecting greater overall severity of disease.

In both Study 1 and Study 2, CAPLYTA was evaluated in a US adult population with schizophrenia. We can see that the baseline criteria were similar across treatment groups in both studies.

It is important to note that the average person who came into these trials was moderately to markedly ill. Mean baseline PANSS total scores in Study 1 and Study 2 CAPLYTA treatment arms were 88.1 and 90.1, respectively.

Now that we've reviewed the methodology and design of the key trials, let's discuss the results of these studies, starting with Study 1. Based on the primary endpoint data from Study 1, patients demonstrated statistically significant improvements in PANSS total score, which as we know, is comprised of positive, negative, and general psychopathology symptoms associated with schizophrenia.

So, to what extent did CAPLYTA improve symptoms? We can see that patients receiving CAPLYTA experienced a 78% greater reduction in PANSS total score at Day 28 compared with placebo. Specifically, patients in the CAPLYTA 42 mg and placebo arms had mean reductions in PANSS total score of 13.2 and 7.4, respectively, demonstrating statistically significant antipsychotic superiority for CAPLYTA vs placebo at Day 28. The 13.2 reduction in PANSS total score at Day 28 with CAPLYTA was 5.8 points more than the reduction seen with placebo at this time point.

And when we look at the results of Study 2, we can see that patients receiving CAPLYTA 42 mg experienced a 41% greater reduction in PANSS total score at Day 28 for CAPLYTA compared with placebo.

This was associated with a mean reduction in PANSS total score of 14.5 points with CAPLYTA, which was 4.2 points more than the reduction seen with placebo. Thus, CAPLYTA demonstrated statistically significant antipsychotic superiority over placebo at Day 28.

As we look at the data week by week, we can see that CAPLYTA began to separate from placebo as early as Week 1 and continued to improve over the course of the 4-week trial. It is important to note that the weekly time points prior to Day 28 were not powered for statistical analysis and should be considered descriptive only. Therefore, the results require cautious interpretation and could represent chance findings.

In terms of the secondary endpoints from Study 1, we can see the change in PANSS symptom domains in patients taking CAPLYTA or placebo.

Looking at the changes in the positive subscale, patients on CAPLYTA 42 mg experienced a reduction of 4.7 points compared with patients on placebo who had a reduction of 2.3 points. On the negative subscale, patients on CAPLYTA experienced a reduction of 1.2 points compared with placebo's 0.3 points. On the general psychopathology scale, patients on CAPLYTA experienced a reduction of 6.3 points compared with patients on placebo who experienced a reduction of 3.6 points. These are all Day 28 evaluations.

Now, it is important to understand these secondary endpoints were not powered for statistical analysis and should be considered descriptive only, so these results could represent chance findings and require cautious interpretation.

Study 1 also included a post hoc analysis which evaluated the change in prosocial symptom domain in patients taking CAPLYTA or placebo.

As a reminder, out of the 30 items listed in the total PANSS, 6 measure social functioning, which make up the prosocial symptom domain, including hallucinatory behavior, suspiciousness/persecution, emotional withdrawal, passive social withdrawal, stereotyped thinking, and active social avoidance. Each item is rated by a clinician on a 7-point scale, with higher scores indicating more severe symptoms. Some questions you can ask patients to assess these symptoms include asking if they feel engaged in their daily routine and lives, whether they want to go for a walk with their loved ones, whether they want to spend time with friends and family, or whether they generally choose to avoid them.

Patients in the CAPLYTA 42 mg and placebo arms were observed to have reductions in the PANSS-derived prosocial factor of 5.0 points and 2.5 points, respectively. Looking at the mean baseline scores for both treatment groups, we see they were 23.1 and 22.2 for CAPLYTA 42 mg and placebo, respectively.

It is also important to remember that this is a post hoc analysis, and it is considered exploratory. Therefore, the results require cautious interpretation and could represent chance findings.

Switching gears back to Study 2, seen here are data from the Clinical Global Impressions-Severity Scale, or CGI-S. Clinical global ratings are helpful in determining overall change from a clinical perspective and provide a clinician's view of the patient's global functioning prior to and after initiating an intervention. The CGI-S is a well-validated, easy to administer, 7-point, clinical outcome measure that is used in a variety of psychiatric settings. As seen here, based on the CGI-S data from Study 2, CAPLYTA yielded a statistically significant improvement.

Now, let's transition to the safety profile, which is based on data from pooled short-term (4- to 6-week) placebo-controlled studies. The safety of CAPLYTA has been demonstrated in 1724 adult patients with schizophrenia, including 108 adult patients who received the drug for at least 1 year.

The 2 most common adverse reactions that separated CAPLYTA from placebo were somnolence/sedation and dry mouth, at 24% and 6%, respectively. Somnolence with CAPLYTA was predominantly mild. Patients on CAPLYTA also experienced metabolic, EPS, prolactin, and weight changes similar to placebo.

It is important to note that antipsychotic drugs have been reported to cause hyperglycemia, diabetes, dyslipidemia, and weight gain. Blood glucose, weight, and lipids should be monitored periodically during long-term treatment with CAPLYTA. Antipsychotic drugs have also been reported to cause tardive dyskinesia. The risk of tardive dyskinesia may increase as the duration of treatment and cumulative dose increases, and it can develop after brief treatment periods or after discontinuation.

Another point to note is that no single adverse reaction leading to discontinuation occurred at a rate of >2% in patients treated with CAPLYTA.

In summary, CAPLYTA 42 mg once daily demonstrated improvement in schizophrenia symptoms across 2 double-blind, placebo-controlled clinical trials based on the reduction in total PANSS score compared with placebo. Somnolence and sedation were the most common adverse reactions. Somnolence was predominantly mild.

Overall, the decision to choose CAPLYTA for appropriate adult patients with schizophrenia can be based on its proven and effective clinical profile, coupled with its once-daily, titration-free administration.

Please listen to the following Important Safety Information.