Lumateperone Efficacy and Safety Outcomes From Pivotal Trials in Major Depressive Disorder (MDD)

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

Watch Chapter 3 here.

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 Pysch Congress.

Welcome to the next video in this series on lumateperone, or CAPLYTA, for adjunctive treatment of MDD in adults.

In this segment, we’ll focus on the key outcomes from the short-term pivotal trials to better understand the efficacy and safety of lumateperone as an adjunctive therapy for MDD 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.

Let’s start with the primary efficacy endpoint, which was the change from baseline in the MADRS total score at Week 6. 

As shown in these graphs, in both studies, lumateperone as adjunctive therapy demonstrated significantly greater reductions in depressive symptoms compared with placebo, with separation between treatment groups emerging as early as Week 1 and continuing through Week 6. 

In Study 6 or 501, as shown on the left, the least-squares (or LS) mean difference from placebo at Week 6 was −4.9, with a P-value of <0.0001 and an effect size of −0.61. 

In Study 7 or 502, as shown on the right, the LS mean difference was −4.5, which was also statistically significant, with an effect size of −0.56. 

From a clinical perspective, the effect sizes observed across both studies are noteworthy. A difference of at least 2 points on the MADRS compared to placebo is widely recognized as clinically meaningful, and lumateperone demonstrated LS mean differences of 4.9 and 4.5 points.

In addition to improvements in depressive symptoms, lumateperone also demonstrated significant benefits for its key secondary efficacy outcome on overall illness severity, as measured by the CGI-S scale. 
 
As shown here, patients receiving lumateperone as adjunctive therapy in both studies experienced significantly greater reductions in CGI-S scores compared with placebo. 

At Week 6, the LS mean difference from placebo was −0.7 in Study 6 or 501 (as shown on the left) and −0.5 in Study 7 or 502 (as shown on the right). Both results had a P-value of less than 0.0001. 

Importantly, the effect sizes, approximately −0.67 in Study 6 (501) and −0.51 in Study 7 (502), further support a clinically meaningful improvement in overall illness severity.

As an additional efficacy objective, both studies evaluated the Quick Inventory of Depressive Symptomatology-Self-Report 16-item scale (QIDS-SR-16), which is a patient's self-reported measure of depressive symptomatology. 

As shown here in Study 6 or 501, lumateperone showed an LS mean change of -8.0, compared with -5.6 for placebo, a difference of 2.4 points. Study 7 showed a similar result, with a change of -7.9 versus -5.7, a difference of 2.2 points.

In Study 7, sexual functioning was also evaluated as a prespecified secondary endpoint. 

As shown here, patients receiving lumateperone as an adjunct to an antidepressant demonstrated an increase from baseline in Changes in Sexual Functioning Questionnaire, 14-item version (CSFQ-14) total scores compared with placebo, with a mean change of 4.8 versus 2.1 at Week 6.

Now, let’s dive into the safety data from the key clinical trials. Shown here are the most common adverse reactions observed in the pooled, short-term 6-week pivotal trials.

The most common adverse events reported were dizziness at 17%, dry mouth at 13%, somnolence and sedation at 12%, nausea at 9%, fatigue at 8%, and diarrhea at 5%. 

Most treatment-emergent adverse events were considered to be mild to moderate in severity, and no single treatment-emergent adverse event led to discontinuation in more than 2% of patients. 

Extrapyramidal symptom (EPS)-related adverse events were low with adjunctive lumateperone, including akathisia and restlessness. 

Importantly, there were no notable changes from baseline in clinician-rated and objective measures of movement disorders, including the Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale, and Simpson-Angus Scale.

On average, patients experienced minimal changes in body weight and metabolic parameters that were comparable to placebo at 6 weeks. 

Across the 6-week double-blind studies, lumateperone 42 mg as adjunctive therapy to antidepressants demonstrated statistically significant and clinically meaningful efficacy compared with placebo. 
 
These improvements were observed across two clinician-rated measures, including the change in MADRS total score and CGI-S score. 

In terms of safety, the most common adverse events—occurring in at least 5% of patients and at rates more than twice those of placebo—including dizziness, dry mouth, somnolence or sedation, nausea, fatigue, and diarrhea. 

Stay tuned, because in the next video, we’ll explore results from the 6-month, open-label extension study, highlighting longer-term safety, tolerability, and outcomes over time with lumateperone. 

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.