Transcript

Most important attributes of CAPLYTA for bipolar depression

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What are the most important attributes of CAPLYTA for bipolar depression?
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Please see Important Safety Information, Including Boxed Warnings regarding increased mortality in elderly patients with dementia-related psychosis at the end of this video.
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Intra-Cellular Therapies, Inc. is sponsoring this video presentation. The speakers are presenting on behalf of the company and have received compensation for these services. The speakers are presenting information that is consistent with FDA guidelines.
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Please see Important Safety Information, including Boxed Warnings, and full Prescribing Information via the link adjacent to this video player.

(Dr. Heather Luing)
Today we are here to talk about the most important attributes of CAPLYTA for bipolar depression. I am Dr. Heather Luing, medical director of the mental health unit at Flagler Hospital in St Augustine, Florida, and as a provider who has clinical experience with CAPLYTA, I am excited to share my insights. But I'll first turn it over to my esteemed colleague, Dr. Rakesh Jain, to kick us off by sharing his thoughts on this important topic.
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Heather Luing, MD
Medical Director
Florida Center for TMS
Medical Director, Mental Health Unit
Flagler Hospital
St Augustine, Florida

(Dr. Rakesh Jain)
Well, thank you very much, Dr. Luing. I am Dr. Rakesh Jain, clinical professor, department of psychiatry at Texas Tech University School of Medicine in Midland, Texas, and I too, am excited to share my clinical insights and experience.
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Rakesh Jain, MD, MPH
Clinical Professor, Department of Psychiatry
Texas Tech University School of Medicine
Midland, Texas
Private Practice
Austin, Texas

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(Dr. Rakesh Jain)
What resonates with me about CAPLYTA is the totality of the clinical evidence. It's right there in the indication: CAPLYTA is indicated for depressive episodes associated with bipolar I and bipolar II disorder—or bipolar depression—in adults as both monotherapy and as adjunctive therapy with lithium or valproate. Look at the breadth— indications in both bipolar I and II depression. But also consider the depth—it can be used as monotherapy or as adjunctive therapy.

Like other antipsychotic drugs, CAPLYTA has a Boxed Warning that elderly patients with dementia-related psychosis are at an increased risk of death. CAPLYTA is not approved for these patients. There is also a Boxed Warning regarding the increased risk of suicidal thoughts and behaviors in pediatric and young adults in short-term studies. Patients must be closely monitored for clinical worsening and for emergence of suicidal thoughts and behaviors when treated with antipsychotics.

The indication of CAPLYTA represents another important treatment option to address the burden associated with depressive episodes in bipolar I and II disorder. We know that approximately 90% of patients with bipolar disorder have reported severe impairment due to a depressive episode. And let's not overlook the fact that bipolar II depression is associated with a particularly high symptom burden; these patients typically experience a higher frequency of depressive episodes that last longer, with 81% of their time ill due to depressive episodes versus 70% for patients with bipolar I. Dr. Luing, what do you think?
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(Dr. Heather Luing)
You bring up a really excellent point regarding the burden of the depressive episodes.
Managing bipolar depression has always been challenging, especially those with bipolar II, because there have historically been limited treatment options. Not to mention, there's also challenges seen with regard to diagnosis, since many patients with bipolar I and II depression are misdiagnosed, most often with unipolar depression.

When I think about CAPLYTA, one of the aspects I'd like to point out is the symptom improvement, as you noted, which was observed across bipolar I and II. And I've seen efficacy results in practice that are similar to those demonstrated in the clinical trials. Let's consider the data on depressive symptoms across the monotherapy and adjunctive therapy trials. In the monotherapy trial, the impact of CAPLYTA on depressive symptoms was evaluated based on the least squares, or LS, mean change in the Montgomery-Åsberg Depression Rating Scale, or MADRS, total score from baseline to week 6; this was the primary efficacy endpoint. The LS mean change from baseline in the MADRS total score was minus 16.7 and minus 12.1 with CAPLYTA 42 mg and placebo, respectively. Overall, there was a 54% improvement from baseline to week 6 with CAPLYTA.

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(Dr. Rakesh Jain)
Absolutely, and to add onto that, what makes the data even more interesting is that, with CAPLYTA, there was also improvement observed across all individual MADRS item scores in monotherapy at week 6. But of course, these are exploratory endpoints, so such results would require cautious interpretation. And similar results to the monotherapy results you just mentioned, were also observed when CAPLYTA was added to lithium or valproate. The LS mean change in MADRS total score from baseline was minus 16.9 vs minus 14.5 with placebo plus lithium or valproate.

Overall, there was a 52% improvement from baseline to week 6 with CAPLYTA when added to lithium or valproate. Thinking about CAPLYTA, I also have to point out the safety profile. It is reassuring that CAPLYTA had a consistent safety and tolerability profile across clinical trials. The most common adverse reactions in both the monotherapy and adjunctive trials were somnolence or sedation, dizziness, nausea, and dry mouth. And it is important to note that in the monotherapy and adjunctive therapy trials, there was no single adverse reaction leading to discontinuation that occurred at a rate of greater than 2% in patients treated with CAPLYTA.

(Dr. Heather Luing)
That's another great point. The safety profile of CAPLYTA is certainly one important consideration for patients. And why is that? Well, bipolar depression is not an illness we treat for a few weeks or a few months; this is something we're gonna be treating patients long-term. Because of that, any side effect burden that patients may encounter over that time is a cause for concern. Therefore, being able to share with my patients the safety data for CAPLYTA, including its effect on weight, metabolic parameters, and EPS and akathisia, is important. For example, it resonates with some of my patients that the effects of CAPLYTA on weight were similar to placebo and importantly, that 99% of participants receiving CAPLYTA did not experience clinically significant weight gain, which was defined as greater than or equal to 7% increase in body weight. In addition, the EPS and akathisia profile of CAPLYTA in the bipolar depression trials was similar to placebo.

I do want to remind everyone that antipsychotic drugs have been reported to cause hyperglycemia, diabetes, dyslipidemia, and weight gain. Therefore, it is important for us, as clinicians, to measure our patients' weight and assess fasting plasma glucose and lipids when initiating CAPLYTA and monitor periodically during long-term treatment. Antipsychotic drugs have also been reported to cause tardive dyskinesia, or TD, a syndrome of potentially irreversible, dyskinetic, and involuntary movements, which may increase as the duration of treatment and total cumulative dose increases. The syndrome can develop after a relatively brief treatment period, even at low doses, or after treatment discontinuation. Given these considerations, CAPLYTA should be prescribed in a manner most likely to reduce the risk of TD and if needed, discontinue CAPLYTA if clinically appropriate.
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(Dr. Rakesh Jain)
One thing that's really important to me is how a treatment performs over the long term. Which is why I want to mention that we have 6-month data with CAPLYTA from an open-label safety study. It highlights the favorable weight, metabolic, and prolactin profile in patients with bipolar depression.

For example, the effect of CAPLYTA on body weight was evaluated, with a mean change in body weight of -0.02 pounds at 6 months. In addition, the mean change from baseline in glucose, insulin, hemoglobin A1c, prolactin, and lipid parameters were also evaluated at 6 months.

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(Dr. Heather Luing)
Those are great points. Since diabetes, obesity, and metabolic syndrome are common comorbid conditions in patients with bipolar disorder, it is important we consider this data in our evaluation and monitor patients periodically during long-term treatment.

I want to switch gears now to another aspect of the CAPLYTA profile—the pharmacology. While the mechanism of action of CAPLYTA is unknown, the efficacy of CAPLYTA can be mediated through a combination of antagonist activity with a high binding affinity at central serotonin 5-HT2A receptors and postsynaptic antagonist activity with a moderate binding affinity at central dopamine D2 receptors. In fact, CAPLYTA's affinity for 5-HT2A is approximately 60 times higher than for D2. The moderate binding affinity of CAPLYTA to the D1 receptor may result in indirect activation of glutamatergic AMPA and NMDA receptors. Lastly, CAPLYTA has a low binding affinity for off-target receptors, such as muscarinic and histaminergic receptors.

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(Dr. Rakesh Jain)
Thank you, Dr. Luing, for those insights on the pharmacologic profile of CAPLYTA. As we close out our discussion, I want to highlight one final aspect of CAPLYTA that is important to me, as a provider, and to my patients; the dosing and administration. Really understanding the dosing regimen can be helpful when it comes to initiating patients on CAPLYTA. The therapeutic dose of CAPLYTA is 42 mg once daily with no titration required. CAPLYTA 42 mg can be administered at any time of the day, with or without food.

For patients with moderate or severe hepatic impairment and those taking certain CYP3A4 inhibitors, dosage strengths of 21 mg and 10.5 mg are available for dose adjustment. That being said, I want to reiterate that for the vast majority of patients, the therapeutic dose of CAPLYTA is 42 mg once daily with no titration required.

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(Dr. Heather Luing)
Dr. Jain, great conversation. I'd say we're in agreement about the key attributes of CAPLYTA. I've seen firsthand the efficacy and safety of CAPLYTA in some of my patients with bipolar depression. Particularly, the favorable weight, metabolic, and EPS and akathisia profiles. These characteristics are why CAPLYTA is an essential part of my treatment plan when I'm considering options for my patients with bipolar depression.

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(Dr. Rakesh Jain)
I have to agree with you. Based on the combination of clinical data and clinical experience in both bipolar I and bipolar II depression, this totality of the clinical evidence is why CAPLYTA is an important treatment option for patients with bipolar depression. Thank you for joining us. Please stay tuned for additional important safety information.

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CAPLYTA is indicated in adults for the treatment of schizophrenia and depressive episodes associated with bipolar I or II disorder (bipolar depression), as monotherapy and as adjunctive therapy with lithium or valproate.

Important Safety Information
Boxed Warnings:

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. CAPLYTA is not approved for the treatment of patients with dementia-related psychosis.
Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adults in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. The safety and effectiveness of CAPLYTA have not been established in pediatric patients.

Contraindications: CAPLYTA is contraindicated in patients with known hypersensitivity to lumateperone or any components of CAPLYTA. Reactions have included pruritus, rash (e.g., allergic dermatitis, papular rash, and generalized rash), and urticaria.
Warnings & Precautions: Antipsychotic drugs have been reported to cause:

Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis, including stroke and transient ischemic attack. See Boxed Warning above.
Neuroleptic Malignant Syndrome, which is a potentially fatal reaction. Signs and symptoms include hyperpyrexia, muscle rigidity, delirium, autonomic instability, elevated creatinine phosphokinase, myoglobinuria (and/or rhabdomyolysis), and acute renal failure. Manage with immediate discontinuation of CAPLYTA and provide intensive symptomatic treatment and monitoring.
Tardive Dyskinesia (TD), a syndrome of potentially irreversible, dyskinetic, and involuntary movements which may increase as the duration of treatment and total cumulative dose increases. The syndrome can develop after a relatively brief treatment period, even at low doses, or after treatment discontinuation. Given these considerations, CAPLYTA should be prescribed in a manner most likely to reduce the risk of TD. Discontinue CAPLYTA if clinically appropriate.
Metabolic Changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma or death, has been reported in patients treated with antipsychotics. Measure weight and assess fasting plasma glucose and lipids when initiating CAPLYTA and monitor periodically during long-term treatment.
Leukopenia, Neutropenia, and Agranulocytosis (including fatal cases). Perform complete blood counts in patients with pre-existing low white blood cell count (WBC) or history of leukopenia or neutropenia. Discontinue CAPLYTA if clinically significant decline in WBC occurs in absence of other causative factors.
Orthostatic Hypotension and Syncope. Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease. Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension.
Falls. CAPLYTA may cause somnolence, postural hypotension, and motor and/or sensory instability, which may lead to falls and, consequently, fractures and other injuries. Assess patients for risk when using CAPLYTA.
Seizures. Use CAPLYTA cautiously in patients with a history of seizures or with conditions that lower seizure threshold.
Potential for Cognitive and Motor Impairment. Advise patients to use caution when operating machinery or motor vehicles until they know how CAPLYTA affects them.
Body Temperature Dysregulation. Use CAPLYTA with caution in patients who may experience conditions that may increase core body temperature such as strenuous exercise, extreme heat, dehydration, or concomitant anticholinergics.
Dysphagia. Use CAPLYTA with caution in patients at risk for aspiration.

Drug Interactions: Avoid concomitant use with CYP3A4 inducers. Reduce dose for concomitant use with strong CYP3A4 inhibitors (10.5 mg) or moderate CYP3A4 inhibitors (21 mg).
Special Populations: Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Breastfeeding is not recommended. Reduce dose for patients with moderate or severe hepatic impairment (21 mg).
Adverse Reactions: The most common adverse reactions in clinical trials with CAPLYTA vs placebo were:

Schizophrenia: somnolence/sedation (24% vs 10%) and dry mouth (6% vs 2%).
Bipolar Depression (Monotherapy, Adjunctive therapy): somnolence/sedation (13% vs 3%, 13% vs 3%), dizziness (8% vs 4%, 11% vs 2%), nausea (8% vs 3%, 9% vs 4%), and dry mouth (5% vs 1%, 5% vs 1%).

Please see full Prescribing Information, including Boxed Warnings, via the link adjacent to this video player.