Lumateperone Open-Label Safety Study in Major Depressive Disorder (MDD)

Please see full Prescribing Information, including Boxed WARNINGS for CAPLYTA.

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Hi, I’m Dr Craig Chepke. I’m the medical director of Excel Psychiatric Associates in Huntersville, North Carolina, an adjunct associate professor of psychiatry with Atrium Health Psychiatry School of Residency, and I’m also the chief medical officer of Pysh Congress.

Welcome to the final video in this series on lumateperone, or CAPLYTA, as adjunctive therapy for major depressive disorder in adults. 

Before continuing, let’s review the important safety information for lumateperone.
 
INDICATIONS. CAPLYTA (lumateperone) is indicated in adults for adjunctive therapy along with antidepressants for the treatment of major depressive disorder (MDD); the treatment of depressive episodes associated with bipolar I or II disorder (bipolar depression) as monotherapy and as adjunctive therapy with lithium or valproate; and the treatment of schizophrenia.

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 increase the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening and for the 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 a history of hypersensitivity to lumateperone or any components of CAPLYTA. Reactions have included pruritus, rash, for example, allergic dermatitis, papular rash, generalized rash, and urticaria.

As a reminder, lumateperone was studied in two randomized, double-blind, placebo-controlled trials, Study 6 (also known as Study 501) and Study 7 (also known as Study 502). Across these two 6-week studies conducted in adult patients with MDD who had an inadequate response to their current antidepressant, lumateperone 42 mg was administered as adjunctive therapy. 

Both studies met their primary endpoints, showing that patients receiving lumateperone as adjunctive therapy experienced significantly greater reductions in depressive symptoms compared with placebo at Week 6, as measured by the MADRS scale.

Both studies also met their key secondary endpoints, showing that patients receiving lumateperone as adjunctive therapy experienced significantly greater reductions in overall illness severity compared with placebo at Week 6, as measured by the CGI-S scale.

The most common adverse events in the pooled short-term clinical trials (≥5% and greater than twice placebo included dizziness, dry mouth, somnolence/sedation, nausea, fatigue, and diarrhea. 

In this video, we will focus on a 6-month, open-label extension safety study that followed patients who previously participated in the two short-term pivotal trials. 

Notably, 92% of eligible patients chose to enroll, reflecting strong interest in continuing treatment. The study was designed to evaluate the longer-term safety and tolerability of lumateperone as adjunctive therapy to antidepressant medication, and 85% of those enrolled completed the full 6-month period, offering important insight into how patients responded over an extended treatment period.

The primary objective was safety and tolerability, as assessed by treatment-emergent adverse events reported in at least 5% of patients during the 6-month open-label period. The most commonly reported adverse reactions included headache at 17%, dizziness at 11%, dry mouth and nausea at 8% each, followed by somnolence at 7% and diarrhea at 6%, with nasopharyngitis reported in 5% of patients.

Generally, these events were consistent with the known safety profile of lumateperone and were primarily mild to moderate in severity.

Turning to the metabolic parameters from the long-term extension study, we can see the mean change from baseline for total cholesterol, LDL, HDL, triglycerides, and glucose in patients receiving open-label lumateperone as adjunctive therapy for 6 months.

Additionally, in patients receiving open-label lumateperone as adjunctive therapy in the long-term extension study, prolactin levels showed a minimal change from baseline of 1.1 ng/mL.

Building on that, we can also look at changes in body weight and other related measures over the same 6-month period.

Mean body weight remained largely stable. Similarly, body mass index and waist circumference showed minimal changes over time.

Efficacy was a prespecified secondary outcome of this 6-month open-label safety study. Patients entering the extension study, whether continuing lumateperone or switching from placebo, showed further decrease in MADRS total score over the 6-month treatment period. 

It’s important to mention that, as an open-label extension primarily designed to assess long-term safety and tolerability, these efficacy findings are exploratory and should be interpreted with caution.

Let’s take a look at response and remission endpoints in the short and long-term studies. A response was defined as at least a 50% reduction in MADRS total score, and remission was defined as a MADRS total score of 10 or less.

As demonstrated here, adjunctive treatment with lumateperone demonstrated higher response and remission rates compared with placebo across the short-term studies. 

In the open-label extension, response and remission rates continued to increase over time. Eighty percent of patients met criteria for response, and 65% had remission, defined as MADRS total score ≤10, after 6 months of open-label treatment.

It should be noted that Study 503 is an open-label safety extension trial designed primarily to assess long-term safety and tolerability. Efficacy outcomes are exploratory and should be interpreted with caution, as the study was not powered or controlled to assess treatment efficacy.

In summary, findings from the 6-month open-label extension study showed that the safety profile of lumateperone remained consistent with what was observed in the pivotal 6-week studies.

Across all parameters—including cholesterol, LDL, HDL, triglycerides, glucose, and weight—mean changes from baseline were small. Prolactin levels similarly showed minimal change and were comparable to placebo. 

80% of patients treated with lumateperone as adjunctive therapy demonstrated improvements in depressive symptoms at 6 months, with a ≥50% reduction in MADRS total score. 

As with all open-label extension data, these findings are exploratory and should be interpreted in the context of the study design. 

This concludes our overview of the lumateperone clinical development program in major depressive disorder, including both short-term efficacy and longer-term safety findings. 
 
Together, these studies provide a comprehensive view of lumateperone as adjunctive therapy, highlighting its efficacy and tolerability. 

WARNINGS AND 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 provided intensive symptomatic treatment and monitoring.

Tardive dyskinesia (TD) may develop in patients treated with antipsychotic drugs, including CAPLYTA. TD can develop after a relatively brief treatment period, even at low doses, or after treatment discontinuation. The TD risk appears to be highest in elderly women. The likelihood that TD will become irreversible increases with the duration of the antipsychotic drug treatment and cumulative dose. If signs and symptoms of TD appear, consider discontinuing 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. Consider discontinuing CAPLYTA if a clinically significant decline in WBC occurs in absence of other causative factors. Discontinue CAPLYTA in patients with clinically significant neutropenia or an absolute neutrophil count less than 1,000 per cubic millimeter and monitor closely until neutropenia resolves.

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 fall risk when initiating treatment and periodically during long-term treatment.

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 temperatures, 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 milligrams, or with moderate CYP3A4 inhibitors, 21 milligrams. Increased monitoring for serotonin reuptake inhibitor (SRI)-associated adverse reactions is recommended when used with SRIs, including in geriatric patients who may be at greater risk for clinically significant hyponatremia.

SPECIAL POPULATIONS. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Reduced dose for patients with moderate Child-Pugh Class B, or severe Child-Pugh Class C hepatic impairment, 21 milligrams.

ADVERSE REACTIONS. The most common adverse reactions in clinical trials (greater than or equal to 5% and greater than twice placebo with CAPLYTA versus placebo) were:

Major depressive disorder (adjunctive therapy). Dizziness, 17% versus 5%, dry mouth, 13% versus 3%, somnolence/sedation, 12% versus 2%, nausea, 9% versus 4%, fatigue, 8% versus 2%, and diarrhea, 5% versus 1%.

Bipolar depression, monotherapy, adjunctive therapy. Somnolence/sedation, 13% versus 3%, 13% versus 3%. Dizziness, 8% versus 4%, 11% versus 2%. Nausea, 8% versus 3%, 9% versus 4%, and dry mouth, 5% versus 1%, 5% versus 1%.

Schizophrenia. Somnolence/sedation 24% versus 10% and dry mouth 6% versus 2%.

CAPLYTA is available in 42 milligram, 21 milligram, and 10.5 milligram capsules.