Hello everyone. Thank you for joining us today. I'm Amber Hoberg, Psychiatric Nurse Practitioner with Gero Psychiatric Associates of Central Texas, and this presentation will explore the short- and long-term safety and tolerability of CAPLYTA, or its generic name lumateperone, a treatment for adults with schizophrenia.

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.

Before we review the safety and tolerability of CAPLYTA, let's first review the clinical trial designs. Both were 4-week, randomized, double-blind, placebo-controlled, multicenter US trials in adult patients with schizophrenia.

In Study 1, patients were randomized to receive either CAPLYTA 42 mg, placebo, or risperidone 4 mg, once daily in the morning with food. It's 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 42 mg versus placebo.

The primary endpoint across both studies was the change from baseline to Day 28 on the Positive and Negative Syndrome Scale, or PANSS, total score.

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, with mean baseline PANSS total scores of 88.1 and 90.1, respectively, in Study 1 and Study 2.

Here we can see the efficacy results demonstrated in Study 1.

Based on the primary endpoint data from Study 1, CAPLYTA resulted in a 78% greater reduction in PANSS total score at Day 28 compared with placebo, as well as a 5.8- point reduction over placebo.

And when we look at the results of Study 2, we can see that CAPLYTA resulted in a 41% greater reduction in PANSS total score at Day 28 compared with placebo, including a 4.2-point reduction over placebo.

In addition, the PANSS total score for CAPLYTA was seen to separate from placebo as early as 8 days, which was the first time point measured in this study. 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.

Now, let's transition to the safety profile of CAPLYTA. 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.

Starting with the short-term safety data, the 2 most common adverse reactions that separated CAPLYTA from placebo were somnolence/sedation and dry mouth, at 24% and 6%, respectively. The 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. In addition, tardive dyskinesia, which may increase as the duration of treatment and cumulative dose increases, can develop after brief treatment periods or after discontinuation.

In addition to demonstrating safety, I also want to point out that there was no single adverse reaction leading to discontinuation that occurred at a rate of >2% in patients treated with CAPLYTA.

We will continue our discussion of the safety data from the short-term trials and here, we can see the incidence of extrapyramidal symptoms, or EPS, with CAPLYTA versus placebo. In these studies, the incidence of EPS, including akathisia, was similar for CAPLYTA and placebo, at 6.7% vs 6.3%, respectively.

The impact of CAPLYTA on EPS was assessed using various rating scales including the Simpson Angus Scale, which evaluates EPS, the Barnes Scale, which evaluates akathisia, and the AIMS, which evaluates abnormal, involuntary movements. The mean changes from baseline for patients on CAPLYTA vs placebo, respectively, on these scales were 0.1 vs 0 for the Simpson Angus Scale, negative 0.1 vs 0 on the Barnes Scale, and 0.1 vs 0 on the AIMS.

Regarding the incidence of akathisia alone, 2% of patients in the CAPLYTA 42-mg arm reported events compared with 2.9% of patients in the placebo arm.

Now, it is important to remember there is a class warning and precaution in the prescribing information for all antipsychotics, including CAPLYTA, regarding tardive dyskinesia. Antipsychotic drugs have been reported to cause tardive dyskinesia. The risk of tardive dyskinesia may increase as the duration of treatment and cumulative dose increases; however, it can develop after brief treatment periods or after discontinuation. Therefore, we need to screen and monitor for this when prescribing CAPLYTA.

When it comes to atypical antipsychotics, we know that clinicians and patients alike are interested in the impact of these drugs on weight. So how do patients tend to think about the impact on their weight? They will often contextualize this impact by saying “my pants do not fit me anymore," thus making weight an important factor for our patients and one that should be addressed in practice.

In the short-term placebo-controlled trials with CAPLYTA, mean changes in weight from baseline to the end of the study were similar in patients treated with CAPLYTA and placebo.

In the short-term placebo-controlled trials, the average increases in weight were 3.5 lb with CAPLYTA 42 mg, and 2.9 lb with placebo. But what about the proportion of patients who experienced a significant increase in weight? This was defined as greater or equal to 7% from baseline to the end of the study and across the short- term trials. Based on this threshold, a similar proportion of patients treated with CAPLYTA and placebo experienced significant weight gain.

It's important to remember that there is a warning in the prescribing information for all atypical antipsychotics, including CAPLYTA, about weight gain, so it's recommended to monitor weight at baseline and frequently thereafter.

As we continue to review data from the short-term trials, we can see here that CAPLYTA also had a favorable impact on metabolic parameters. Specifically, the mean change in fasting glucose, total cholesterol, and triglycerides was similar between CAPLYTA and placebo. The figures here show these mean changes from baseline, including a 0.7 mg/dL increase in fasting glucose, a 3-point reduction in total cholesterol, and a 1.7-point reduction in triglycerides with CAPLYTA.

Remember, there is a warning in the prescribing information of all atypical antipsychotic medications, including CAPLYTA, regarding the risk of hyperglycemia and diabetes, and the potential impact on metabolic parameters, including glucose and lipids, so it's important to monitor these parameters in all patients taking antipsychotic treatment.

Furthermore, patients on CAPLYTA 42 mg had a mean change in prolactin levels of -1.3 ng/mL compared with -0.2 ng/mL for patients on placebo.

Let's now transition to the data supporting the long-term use of CAPLYTA over the course of 1 year. This study enrolled 603 stable outpatients with schizophrenia on antipsychotic treatment in an uncontrolled, open-label outpatient study, with the primary objective of evaluating the long-term safety of CAPLYTA. Patients received CAPLYTA 42 mg with no dose titration, and in this case, they were dosed once daily in the evening for up to one year, whereas in the short-term, placebo-controlled trials, patients were dosed in the morning in an inpatient setting.

This graph depicts the mean changes in key metabolic and endocrine parameters from baseline in this one-year, open-label safety study. The study concluded that CAPLYTA had a favorable metabolic and endocrine profile with long-term use.

Something that's also relevant to look at is the shifts in metabolic parameters. This table shows the proportion of patients who had shifts from baseline in key metabolic parameters at Day 300, first from normal to low, those that started normal and remained normal, and from normal to high.

The majority of patients were in the middle column, meaning they started normal and stayed normal. This means that most patients had no shift, either high or low, in their glucose, insulin, hemoglobin A1C, or cholesterol.

Again, we know there is a warning in the prescribing information for all atypical antipsychotics regarding metabolic disturbances, including changes in glucose, lipids, and weight. So, it's essential to monitor these parameters periodically during treatment with CAPLYTA.

Earlier we discussed how the mean weight change was similar for CAPLYTA and placebo in the short-term clinical trials. Now, let's look at the weight change data from the long-term study.

In this one-year, open-label safety study, patients treated with CAPLYTA showed mean decreases in body weight of 4.4 lb at Day 175, and 7 lb at Day 350. At one year, 24% of patients had a clinically significant weight decrease, defined as a ≥7% decrease in body weight, and 8% of patients experienced a clinically significant weight increase, defined as a ≥7% increase in body weight.

Once again, we should remember that there is a warning in the prescribing information for all atypical antipsychotics about weight gain, so it's recommended to monitor weight at baseline and frequently thereafter.

In summary, CAPLYTA 42 mg once daily demonstrated improvements in schizophrenia symptoms across 2 double-blind, placebo-controlled clinical trials based on the reduction in PANSS total score compared with placebo. The most common adverse events with CAPLYTA were somnolence/sedation and dry mouth. CAPLYTA also demonstrated a favorable impact on weight, metabolic, and endocrine parameters over the short and long term.

Remember, there is a warning in the prescribing information of all atypical antipsychotic medications, including CAPLYTA, regarding the risk of hyperglycemia and diabetes, and the potential impact on metabolic parameters, including glucose and lipids, so it's important to monitor these parameters in all patients taking antipsychotic treatment.

Overall, this significant symptom improvement and demonstrated safety support the proven and effective clinical profile of titration-free, once-daily CAPLYTA for adults with schizophrenia.

Please listen to the following Important Safety Information.