Lumateperone Clinical Trial Program and Study Design in Major Depressive Disorder (MDD)

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

Watch Chapter 2 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 this video series on lumateperone, focusing on its clinical trial program and study design in major depressive disorder (MDD).
 
Lumateperone, or CAPLYTA, is an atypical antipsychotic. While the mechanism of action is unknown, its activity is thought to be mediated by antagonism at serotonin receptor 5-HT2A and partial agonist activity at central dopamine D2 receptors.

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 take a moment to walk through the clinical development program supporting lumateperone as an adjunctive treatment for MDD in adults.
 
As shown in this table, the lumateperone development program in MDD was designed to evaluate both the short-term efficacy and longer-term safety of lumateperone when added to an antidepressant. This program includes two pivotal, randomized, double-blind, placebo-controlled, 6-week trials, referred to as Studies 6 and 7 in the prescribing information (also known as Studies 501 and 502), as well as the longer-term (6-month), open-label safety extension trial (also known as Study 503), which was open to patients who completed either Study 6 or 7.

Starting with the two short-term efficacy trials, these were similarly designed, 6-week studies conducted in adult patients with MDD who had an inadequate response to their current antidepressant. In both studies, patients continued their background antidepressant and were randomized to receive either lumateperone 42 mg once daily or placebo, administered in the evening without regard to food. It is worth noting that the longer-term, open-label study was not powered for efficacy. 

As you can see on this clinical program overview, the primary endpoint in both trials was the mean change from baseline in depressive symptoms compared to placebo, as measured by the Montgomery-Åsberg Depression Rating Scale or MADRS total score at Week 6. A key secondary endpoint was the change in Clinical Global Impression Scale-Severity (CGI-S) scores at Week 6. At the same time, safety and tolerability were assessed continuously throughout the study and during a 1-week safety follow-up period. 

Looking first at the study populations for the short-term trials, they included adult patients aged 18 to 65 years who met the DSM-5 criteria for major depressive disorder and had moderate-to-severe symptom severity at baseline.
 
Importantly, all patients had an inadequate response, defined as less than 50% improvement with ≥6 weeks of one or two prior antidepressant therapies in their current depressive episode, as confirmed by the Antidepressant Treatment Response Questionnaire.

Background antidepressants included commonly prescribed SSRIs, SNRIs, and bupropion.

Demographics and baseline characteristics were generally well-balanced across treatment groups.
 
Across both studies, patients had a mean age in the mid-40s, with approximately two-thirds being female. The majority of patients were receiving SSRIs as their background antidepressant and had 1 antidepressant trial in their current episode. 
 
Baseline clinical characteristics were also comparable, with mean MADRS total scores of about 30 to 31, consistent with moderate-to-severe depression, and CGI-S scores of around 4.6 to 4.7.
 
Additionally, patients who completed Studies 6 and 7, otherwise known as Study 501 and 502, were eligible to enroll in the long-term extension, a 6-month open-label safety study. 
 
Ninety-two percent of patients who completed the double-blind, short-term trials enrolled in the 6-month, open-label safety extension study, and 85% of these individuals completed the 6-month, open-label treatment period. 
 
This study enabled evaluation of longer-term safety and tolerability, with treatment-emergent adverse events as the primary endpoint and changes in MADRS total and CGI-S scores assessed as secondary measures. These secondary measures are exploratory and should be interpreted with caution. This study was not powered or controlled to assess treatment efficacy.
 
To summarize, the lumateperone clinical development program includes two pivotal, 6-week, randomized, placebo-controlled trials and a 6-month, open-label safety extension study. Together, these studies evaluated lumateperone for both short-term efficacy and longer-term safety as an adjunctive therapy in adults with MDD.
 
In the next videos, we’ll take a closer look at the results, first exploring the efficacy findings, followed by a detailed review of the safety and tolerability profile.

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.