Lumateperone safe, effective for depressive symptoms among patients with bipolar disorders

Lumateperone appeared to significantly improve depressive symptoms among patients with a bipolar 1- or 2-associated major depressive episode, according to data presented at the American Society of Clinical Psychopharmacology Annual Meeting.

“Depressive episodes associated with bipolar disorder are difficult to treat,” Suresh Durgam, MD, senior vice president of late stage clinical development and medical affairs at Intra-Cellular Therapies Inc, told Healio Psychiatry. “There are few approved treatments for major depressive episodes in bipolar disorder, with only one approved for bipolar 2 disorder. Given the heterogeneity of the disease, not all medications are effective for every patient and response can vary over time. Treatment can also be complicated by side effects, including cardiometabolic disturbances and extrapyramidal symptoms. Therefore, there is an urgent need for new medications for the treatment of depressive episodes of bipolar 1 and 2 disorders.”

Prior trials showed similar efficacy of lumateperone (Caplyta, Intra-Cellular Therapies Inc.) and risperidone, with a similar safety profile to placebo among patients with schizophrenia. Past results also showed patients with schizophrenia with moderate-to-severe depression symptoms at baseline exhibited significant improvement in depression symptoms compared with placebo.

In the current phase 3 randomized, double-blind, parallel group, placebo-controlled study, Durgam and colleagues aimed to determine the efficacy and safety of lumateperone monotherapy across 6 weeks among patients with bipolar 1 or 2 disorder who experienced a major depressive episode. They randomly assigned patients 1:1 to lumateperone dosed at 42 mg or placebo administered once daily. The primary endpoint was change from baseline to 43 days in Montgomery-Åsberg Depression Rating Scale (MADRS) total score, and the key secondary endpoint was change from baseline to 43 days in Clinical Global Impression Scale-Bipolar Version-Severity (CGI-BP-S) total score.

The investigators analyzed endpoints using a mixed-effects model for repeated measures in the intent-to-treat population and in subgroups stratified by bipolar 1 or 2 disorder diagnosis. They used logistic regression analysis to analyze response and remission rates at 43 days. In safety assessments, they included descriptive statistics for evaluation of treatment-emergent adverse events, extrapyramidal symptoms, suicidal ideation and behavior, mania, physical examinations and changes in laboratory parameters and vital signs.

The study included 381 randomly assigned patients, of whom 377 received treatment and 333 completed treatment, with withdrawal of consent and adverse events the most common reasons for study discontinuation. The groups had similar characteristics, and mean MADRS total score at baseline indicated that patients had moderate-to-severe depressive symptoms.

Results showed the study met the primary efficacy objective, with lumateperone exhibiting a statistically significant improvement on the MADRS total score compared with placebo at 43 days (P < .0001). MADRS total score improved significantly among the intent-to-treat population as early as 8 days, and these improvements continued throughout treatment. The investigators noted a statistically significant greater MADRS total score improvement for lumateperone compared with placebo among patients with both bipolar 1 (P < .0001) and bipolar 2 (P < .001) disorders. The study also met the key secondary efficacy objective, with lumateperone treatment associated with significantly greater improvement in overall disease severity according to CGI-BP-S total score. Durgam and colleagues observed a statistically significant greater CGI-BP-S total score improvement with lumateperone compared with placebo among patients with both bipolar 1 (P < .001) and bipolar 2 (P < .01) disorders.

Both bipolar disorder groups, as well as the intent-to-treat population, exhibited significantly greater improvement with lumateperone compared with placebo according to CGI-BP-S depression score. In the overall intent-to-treat population, MADRS response rate was significantly greater among lumateperone-treated patients than patients assigned placebo. Further, lumateperone treatment was linked to significantly higher MADRS remission rates relative to placebo among the intent-to-treat population.

Durgam and colleagues noted that overall rates of treatment-emergent adverse events for lumateperone were similar to placebo. Those that occurred more frequently in the lumateperone vs. placebo group included headache (17.6% vs. 10.1%), somnolence (8.5% vs. 1.1%) and nausea (6.4% vs. 2.1%). The majority of treatment-emergent adverse events had mild-to-moderate severity. One serious adverse event of mania occurred in the lumateperone group; however, no deaths occurred during the study.

For both lumateperone-treated patients and those who received placebo, weight and body morphology remained stable. Neither group exhibited notable changes in metabolic parameters, and prolactin did not increase with lumateperone treatment. The only extrapyramidal-related treatment-emergent adverse event was one case of dyskinesia among the lumateperone group. Mean changes from baseline for Barnes Akathisia Rating scale, Abnormal Involuntary Movement Scale and Simpson-Angus Scale scores were similar for the lumateperone and placebo groups. The researchers observed suicidal ideation, as assessed by the Columbia-Suicide Severity Rating Scale, among 5.3% of lumateperone-treated patients and 10.1% of patients assigned placebo. They observed no clinically meaningful changes in liver function tests, electrocardiogram or vital signs.

“The clinical profile of lumateperone shows promise as a potential new treatment option for major depressive episodes associated with bipolar 1 or bipolar 2 disorder,” Durgam said. “These efficacy and safety results are very encouraging.”