Efficacy and Safety of Adjunctive Lumateperone 42 mg in Major Depressive Disorder: A Pooled Analysis of Demographic and Clinical Subgroups from 2 Phase 3 Randomized Placebo-Controlled Trials
W. R. Earley, S. Durgam, C. Chen, R. Migliore, J. Riise, S. G. Kornstein, R. S. McIntyre, M. FavaIntroduction
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.
Objectives
This pooled analysis of Studies 501/502 evaluated lumateperone 42mg+ADT in demographic and clinical subgroups of patients with MDD.
Methods
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 42mg+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 ( P < .05) MADRS Total score at Day 43 in all patient subgroups vs placebo+ADT based on age (≤40 years: LSMD=‒4.5; >40 years: LSMD=‒4.9), sex (male: LSMD=‒4.2; female: LSMD=‒5.0), region (US: LSMD=‒4.7; non-US: LSMD=‒4.6), disease severity (baseline MADRS Total score <32: LSMD=‒4.6; baseline score ≥32: LSMD=‒5.0), type of ADT (SSRI: LSMD=‒4.9; SNRI: LSMD=‒3.8), number of ADT failures (1 failure: LSMD=‒4.5; 2 failures: LSMD=‒6.3), race (White: LSMD=‒5.0; non-White: LSMD=‒3.2), and baseline anxious distress (Yes: LSMD=-5.9; No: LSMD=-4.0). Lumateperone+ADT significantly improved ( P <.01) CGI-S score vs placebo+ADT at Day 43 in all subgroups (age, sex, race, region, baseline disease severity, type of ADT, number of ADT failures, baseline anxious distress).
Lumateperone+ADT was generally well tolerated. Common treatment-emergent AEs (≥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.
Conclusions
In this pooled analysis, lumateperone 42mg+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.
Disclosure of Interest
W. Earley Employee of: Intra-Cellular Therapies, a Johnson & Johnson Company, S. Durgam Employee of: Intra-Cellular Therapies, a Johnson & Johnson Company, C. Chen Employee of: Intra-Cellular Therapies, a Johnson & Johnson Company, R. Migliore Employee of: Intra-Cellular Therapies, a Johnson & Johnson Company, J. Riise Employee of: Johnson & Johnson, S. Kornstein Grant / Research support from: National Institutes of Health and the National Science Foundation, Consultant of: Lilly, Sage Therapeutics, Reunion Neuroscience, Relmada, AbbVie, Gerbera, and Arrivo Bioventures, R. McIntyre Grant / Research support from: CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute, Speakers bureau of: Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Neurawell, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris Pharma, Sanofi, Eisai, Intra-Cellular Therapies, NewBridge Pharmaceuticals, Viatris, AbbVie, and Atai Life Sciences, M. Fava Shareholder of: Compellis; Neuromity; Psy Therapeutics; Revival Therapeutics; Sensorium Therapeutics, Grant / Research support from: AbbVie; Acadia Pharmaceuticals; Aditum Bio Management Company, LLC; Allergan, Alkermes, Inc.; Altimate Health Corporation; Alto Neuroscience, Inc.; Ancora Bio, Inc.; Angelini S.p.A; Aptinyx; Arbor Pharmaceuticals LLC; Avanir Pharmaceuticals Inc.; Axsome; Benckiser Pharmaceuticals, Inc.; BioClinica, Inc.; Biogen; BioHaven; BioShin Limited; Cambridge Science Corporation; Centrexion Therapeutics Corporation; Cerecor; Cybin IRL Limited; Damona Pharmaceuticals; EmbarkNeuro; Eliem Therapeutics LTD; Gate Neurosciences, Inc.; GenOmind, LLC; Gentelon, LLC; Gerbera Therapeutics, Inc.; Happify; Johnson & Johnson; Lundbeck Inc.; Marinus Pharmaceuticals; Medpace, Inc.; Methylation Sciences, Inc.; Millennium Pharmaceutics, Inc.; Minerva Neurosciences; Neuralstem; Neurocrine Biosciences, Inc.; NeuroRX Inc.; Novaremed; Novartis; Otsuka; Pfizer; Premiere Research International; Praxis Precision Medicines; Protagenic Therapeutics, Inc.; Relmada Therapeutics Inc.; Reckitt; Shenox Pharmaceuticals; Stanley Medical Research Institute (SMRI); Taisho; Takeda; University of Michigan; Vistagen; WinSanTor, Inc.; Xenon Pharmaceuticals, Inc.; National Institute of Drug Abuse (NIDA); National Institutes of Health (NIH); National Institute of Mental Health (NIMH); and PCORI, Consultant of: Massachusetts General Hospital, except for Revival Therapeutics and Sensorium Therapeutics