193. Efficacy and safety of adjunctive lumateperone 42 mg in major depressive disorder: pooled analysis of demographic and clinical subgroups from Phase 3 randomized placebo-controlled trials

Abstract

Abstract Background Major depressive disorder (MDD) presents with highly variable clinical symptoms and treatment responses. Patient characteristics can impact treatment outcomes, making it essential to evaluate efficacy across subgroups to establish consistency of treatment effects. Lumateperone is an FDA-approved antipsychotic to treat schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder. Efficacy and safety of lumateperone adjunctive to antidepressant therapy (ADT) was established in 2 Phase 3, randomized, double-blind, placebo-controlled trials (501, NCT04985942; 502, NCT05061706) in patients with major depressive disorder (MDD) with inadequate ADT response. Aims & Objectives This pooled analysis of Studies 501/502 evaluated lumateperone 42 mg + ADT in demographic and clinical subgroups of patients with MDD. Method Data were pooled from Studies 501/502 which enrolled adults with DSM-5–diagnosed MDD with inadequate response to 1-2 ADT in the current depressive episode (Montgomery-Åsberg Depression Rating Scale [MADRS] Total score ≥24, Clinical Global Impression-Severity [CGI-S] score ≥4). Patients were randomized to 6-week oral lumateperone 42 mg + ADT or placebo + ADT. MADRS Total and CGI-S scores were evaluated in the pooled population and patient subgroups by demographic and clinical characteristics. Safety was assessed. Results The pooled population comprised 950 patients (lumateperone + ADT, n=471; placebo + ADT, n=479). Lumateperone + ADT significantly improved MADRS Total score (least squares mean difference vs placebo [LSMD]=-4.7; effect size [ES]=-0.59; P<.0001) and CGI-S score (LSMD=-0.6; ES=-0.59; P<.0001) from baseline to Day 43 vs placebo + ADT. Lumateperone + ADT significantly improved MADRS Total score at Day 43 in all patient subgroups vs placebo + ADT based on age (≤40 years: LSMD=-4.5, P<.0001; >40 years: LSMD=-4.9, P<.0001), sex (male: LSMD=-4.2, P<.0001; female: LSMD=-5.0, P<.0001), region (US: LSMD=-4.7, P<.0001; non-US: LSMD=-4.6, P<.0001), disease severity (baseline MADRS Total score <32: LSMD=-4.6, P<.0001; baseline score ≥32: LSMD=-5.0, P<.0001), type of ADT (SSRI: LSMD=-4.9, P<.0001; SNRI: LSMD=-3.8, P<.001), number of ADT failures (1 failure: LSMD=-4.6, P<.0001; 2 failures: LSMD=-6.1, P<.0001), race (White: LSMD=-5.0, P<.0001; non-White: LSMD=-3.2, P<.05), ethnicity (Hispanic/Latino: LSMD=-5.1, P<.01; not Hispanic/Latino: LSMD=-4.7, P<.0001), and baseline anxious distress (Yes: LSMD=-5.9, P<.0001; No: LSMD=-4.0, P<.0001). Lumateperone + ADT significantly improved (P<.01) CGI-S score vs placebo + ADT at Day 43 in all subgroups (age, sex, race, region, ethnicity, baseline disease severity, type of ADT, number of ADT failures, baseline anxious distress). Lumateperone + ADT was generally well tolerated. Common treatment-emergent adverse events (≥5%; twice placebo + ADT) were dizziness, dry mouth, somnolence, nausea, and fatigue. No notable changes occurred in body morphology, prolactin levels, cardiometabolic parameters, or extrapyramidal symptom scales with lumateperone + ADT. Discussion & Conclusions In this pooled analysis, lumateperone 42 mg + ADT had robust efficacy vs placebo + ADT in demographic and clinical subgroups and was generally well tolerated, indicating lumateperone as an adjunctive treatment option in patients with MDD with inadequate ADT response.