FIRST ONSET AND DURATION OF TREATMENT-EMERGENT ADVERSE EVENTS IN PATIENTS WITH MAJOR DEPRESSIVE DISORDER TREATED WITH ADJUNCTIVE LUMATEPERONE 42 MG: A POOLED ANALYSIS OF 2 RANDOMIZED PLACEBO-CONTROLLED TRIALS

Background

Major depressive disorder (MDD) is a common mental illness associated with functional impairment and high rates of comorbidities. Current standard-ofcare treatments have adverse effects such as weight gain, sexual dysfunction, and metabolic disturbances that limit tolerability. Lumateperone is an atypical antipsychotic indicated for: treatment of schizophrenia in adults; treatment of depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults, as monotherapy and as adjunctive therapy with lithium or valproate; and treatment of MDD in adults as adjunct to antidepressant therapy (ADT). Two Phase 3, randomized, double-blind, placebo-controlled studies (Study 501 [NCT04985942]; Study 502 [NCT05061706]) established the efficacy and safety of lumateperone 42 mg adjunctive to ADT in patients with MDD with inadequate ADT response. A pooled analysis of these studies assessed the first onset and duration of treatment-emergent adverse events (TEAEs).

Methods

Data were pooled from Study 501 and Study 502, which enrolled males and females (18-65 years) with DSM-5–diagnosed MDD with inadequate response to 1-2 ADTs in the current depressive episode ( < 50% improvement on the Antidepressant Treatment Response Questionnaire). Eligible patients had Montgomery-Asberg Depression Rating Scale Total score ≥24, Clinical Global Impression-Severity Scale score ≥4, and Quick Inventory of Depressive Symptomatology-Self Report-16 item score ≥14. In both studies, patients were randomized 1:1 to 6-week lumateperone 42 mg + ADT or placebo + ADT. First onset and duration of TEAEs were evaluated descriptively.

Results

Of 964 patients treated (lumateperone + ADT, n=483; placebo + ADT, n=481), 91.4% completed treatment. TEAEs occurred in 68.1% and 45.1% of patients in the lumateperone 42 mg + ADT and placebo + ADT groups, respectively. The most common TEAEs (≥5% in lumateperone + ADT and twice placebo + ADT) were dizziness (lumateperone + ADT, 16.4%; placebo + ADT, 5.0%), dry mouth (12.6%; 3.3%), somnolence (10.1%; 2.1%), nausea (8.5%; 4.0%), fatigue (7.2%; 1.2%), and diarrhea (4.6%; 1.2%). Onset of TEAEs occurred at ≤1 week in 45.3% of patients, > 3 to ≤4 weeks in 4.1% of patients, and > 5 weeks in 2.1% of patients. At ≤1 week, > 3 to ≤4 weeks, and > 5 weeks, TEAE onset occurred in 11.8%, 0.7%, and 0.7% of patients for dizziness; 8.3%, 0.7%, and 0.5% for dry mouth; 8.5%, 0.2%, and 0.5% for somnolence; 6.0%, 0.2%, and 0.2% for nausea; 5.2%, 0.2%, and 0.2% for fatigue; and 2.5%, 0.2%, and 0.2% for diarrhea, respectively. The mean durations of the most common TEAEs for the lumateperone + ADT vs placebo + ADT groups were: dizziness, 9.5 vs 7.7 (median: 5.0 vs 5.0) days; dry mouth, 22.8 vs 17.3 (median: 25.0 vs 17.0) days; somnolence, 14.6 vs 14.9 (median: 9.5 vs 12.0) days; nausea, 7.2 vs 11.0 (median: 5.0 vs 6.0) days; fatigue, 20.7 vs 11.8 (median: 19.0 vs 6.5) days; and diarrhea, 7.3 vs 12.2 (median: 2.5 vs 7.0) days.

Conclusion

In this pooled analysis of 2 studies, majority of the most common TEAEs occurred early in the treatment period and resolved within approximately 1-3 weeks of onset. These data support that lumateperone is generally safe and well tolerated as an adjunctive treatment for patients with MDD with inadequate ADT response.