EFFICACY OF LUMATEPERONE 42 MG FOR THE TREATMENT OF MAJOR DEPRESSIVE DISORDER: ANALYSIS OF DEMOGRAPHIC AND CLINICAL SUBGROUPS IN A PHASE 3 RANDOMIZED PLACEBO-CONTROLLED TRIAL

Background

Lumateperone is an FDA-approved antipsychotic to treat schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder, and adjunct to antidepressant therapy (ADT) for major depressive disorder (MDD). Efficacy and safety of lumateperone 42 mg + ADT was demonstrated in a Phase 3, randomized, double-blind, placebocontrolled study (Study 501 [NCT04985942]) in patients with MDD with inadequate ADT response. To investigate consistency of treatment effect, this analysis of Study 501 evaluated the efficacy of lumateperone 42 mg + ADT in demographic and clinical subgroups of patients with MDD with inadequate ADT response.

Methods

Adults (18-65 years) had DSM-5 criteria for MDD with inadequate response to 1-2 courses of ADT in the current depressive episode, and Montgomery-Asberg Depression Rating Scale (MADRS) Total score ≥24, Clinical Global Impression-Severity (CGI-S) score ≥4, and Quick Inventory of Depressive Symptomatology-Self Report-16 item (QIDS-SR-16) score ≥14. Patients were randomized 1:1 to 6-week, oral lumateperone 42 mg or placebo adjunctive to ADT. Efficacy was evaluated in the overall population and in patient subgroups by demographic and baseline disease characteristics, using a mixed-effects model for repeated measures or analysis of covariance.

Results

The modified intent-to-treat (mITT) population comprised 481 patients (lumateperone + ADT, n=239; placebo + ADT, n=242). At Day 43, lumateperone + ADT significantly improved MADRS Total score (least squares mean difference vs placebo [LSMD], −4.9; effect size [ES], −0.61; P < .0001), CGI-S score (LSMD, −0.7; ES, −0.67; P < .0001), and QIDS-SR-16 Total score (LSMD, −2.4; P < .0001) vs placebo + ADT. Improvements in MADRS Total score were significant from baseline to Day 43 in demographic subgroups with lumateperone + ADT vs placebo + ADT: younger (≤40y: LSMD, −4.6; ES, −0.57; P < .001), older ( > 40y: LSMD, −5.1; ES, −0.64; P < .0001), male (LSMD, −4.3; ES, −0.54; P < .001), female (LSMD, −5.2; ES, −0.65; P < .0001), White (LSMD, −5.5; ES, −0.69; P < .0001), non-White (LSMD, −3.1; ES, −0.39; P < .05), Hispanic/Latino (LSMD, −9.8; ES, −1.23; P < .01), not Hispanic/Latino (LSMD, −4.5; ES, −0.57; P < .0001), US (LSMD, −5.7; ES, −0.71; P < .0001), and non-US (LSMD, −4.3; ES, −0.54; P < .0001). Lumateperone + ADT significantly improved MADRS Total score from baseline to Day 43 irrespective of baseline disease severity (MADRS Total score < 32: LSMD, −4.5; ES, −0.56; P < .0001; MADRS Total score ≥32: LSMD, −5.7; ES, −0.71; P < .0001), type of ADT (SSRI: LSMD, −5.3; ES, −0.66; P < .0001; SNRI/other: LSMD, −4.0; ES, −0.51; P < .01), number of ADT failures in the current episode (1 failure: LSMD, −4.5; ES, −0.56; P < .0001; 2 failures: LSMD, −7.5; ES, −0.94; P < .001), and presence of anxious distress (yes: LSMD, −6.8; ES, −0.85; P < .0001; no: LSMD, −3.5; ES, −0.44; P < .001). Significant improvements (P < .05) in CGI-S score occurred with lumateperone + ADT vs placebo + ADT from baseline to Day 43 in all patient subgroups. Lumateperone + ADT significantly improved (P < .05) QIDS-SR-16 Total score at Day 43 vs placebo + ADT in all patient subgroups, except for race (White, P < .0001; non-White, P=.5011).

Conclusion

Lumateperone 42 mg adjunctive to ADT demonstrated robust efficacy over placebo adjunctive to ADT in subgroups of patients with MDD based on demographic and clinical features. These results indicate lumateperone as a promising adjunctive treatment option for patients with MDD with inadequate ADT response.