610. LONG-TERM ADJUNCTIVE LUMATEPERONE TREATMENT IN MAJOR DEPRESSIVE DISORDER: RESULTS FROM A SIX-MONTH OPEN-LABEL EXTENSION STUDY

Abstract Background Current treatments for major depressive disorder (MDD) are limited by side effects including weight gain and metabolic disturbances. Approximately 50% of patients with MDD have inadequate response to antidepressant therapy (ADT) leading to reduced adherence, functioning, and quality of life. Lumateperone is an FDA-approved, atypical antipsychotic to treat schizophrenia and depressive episodes associated with bipolar I or II disorder. The efficacy and safety of lumateperone 42mg adjunctive to ADT in patients with MDD with inadequate ADT response was recently demonstrated in 2 Phase 3 trials (Study 501 NCT04985942; Study 502 NCT05061706). Aims & Objectives This Phase 3 open-label extension trial, Study 503 (NCT05061719), investigated the long-term safety of adjunctive lumateperone 42mg in patients who completed Study 501 or 502. Method Study 501 and 502 enrolled patients (18-65 years) meeting DSM-5 criteria for MDD with inadequate response to 1-2 adequate courses of ADT in the current depressive episode and Montgomery-Asberg Depression Rating Scale (MADRS) Total score ≥24 and Clinical Global Impression Scale-Severity (CGI-S) score ≥4. Patients who safely completed the 6-week double-blind treatment period could enroll in Study 503 to receive 26-week, open-label, oral, once-daily lumateperone 42mg adjunctive to continued ADT. The primary endpoint was safety and tolerability of lumateperone 42mg, measured by adverse events (AEs), extrapyramidal symptoms (EPS), suicidality, and changes in laboratory parameters, vital signs, and electrocardiogram (ECG) measures. The secondary endpoint was improvement/maintenance of depressive symptoms, measured by MADRS and CGI-S Total scores change from Study 501 or 502 baseline to Week 26 of open-label treatment. Results Of 809 patients enrolled and treated, 684 (84.5%) completed the treatment period. Treatment-emergent AEs (TEAEs) occurred in 548 patients (67.7%), with 292 (36.1%) experiencing a drug-related TEAE. Treatment discontinuation due to an AE occurred in 7.4% of patients. TEAEs reported in ≥5% of patients were headache (16.6%), dizziness (10.6%), dry mouth (8.0%), nausea (7.7%), somnolence (7.2%), diarrhea (6.2%), and nasopharyngitis (5.2%). Most TEAEs (98.9%) reported were mild to moderate in severity. The rates of EPS-related TEAEs based on broad standard Medical Dictionary for Regulatory Activities query were low (3.8%) with no mean increase in EPS scales. Mean changes from baseline to end of treatment were minimal and not clinically meaningful for body morphology (weight, body mass index, waist circumference), cardiometabolic laboratory values, prolactin levels, blood pressure, and ECG measures. No patients reported emergence of serious suicidal ideation or suicidal behavior during the study. Symptoms of depression improved as measured by mean change from baseline to Week 26 in MADRS Total score (−22.9; P<.0001) and CGI-S Total score (−2.7; P<.0001). Discussion & Conclusions Lumateperone 42mg adjunctive to ADT was safe and effective during 26-week treatment in patients with MDD and inadequate ADT response.