METABOLIC PROFILE OF ADJUNCTIVE LUMATEPERONE 42 MG IN MAJOR DEPRESSIVE DISORDER: A POOLED ANALYSIS OF 2 RANDOMIZED, PLACEBO-CONTROLLED TRIALS

Background

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 major depressive disorder (MDD) in adults as adjunct to antidepressant therapy (ADT). Two Phase 3, randomized, double-blind, placebo-controlled studies (501 [NCT04985942]; 502 [NCT05061706]) demonstrated efficacy and safety of lumateperone 42mg+ADT in patients with MDD with inadequate ADT response. A pooled analysis of these studies evaluated the metabolic profile associated with adjunctive lumateperone 42mg.

Methods

Data were pooled for Studies 501/502, which enrolled adults (18-65y) meeting DSM5 criteria for MDD with inadequate response to 1-2 ADTs in the current depressive episode. Patients with Montgomery-Asberg Depression Rating Scale Total score ≥24, Clinical Global Impression-Severity score ≥4, and Quick Inventory of Depressive Symptomatology-Self Report16 item score ≥14 were randomized to 6-week lumateperone 42mg+ADT or placebo+ADT. Assessments included changes in weight, body mass index (BMI), waist circumference, cardiometabolic laboratory parameters (cholesterol [total, high-density lipoprotein, low-density lipoprotein], triglycerides, glucose, insulin), and prolactin levels. Subgroups were analyzed by baseline BMI category (normal weight: ≥18.5 to < 25kg/m2; overweight: ≥25 to < 30kg/m2; obese: ≥30kg/m2).

Results

The safety population comprised 964 patients (lumateperone+ADT, n=483; placebo+ADT, n=481). Changes from baseline to end of treatment (EOT) were minimal with lumateperone+ADT vs placebo+ADT for weight (−0.1kg vs +0.0kg), BMI (−0.0kg/m2 vs +0.0kg/m2), and waist circumference (−0.2cm vs −0.3cm). Potentially clinically significant (PCS) weight increase (≥7% from baseline) was rare during treatment (lumateperone+ADT, 0.4%; placebo+ADT, 1.3%). There were no clinically meaningful changes in cardiometabolic parameters or prolactin levels. At baseline, proportions of patients across BMI categories were similar: normal weight (lumateperone+ADT, 32.3% vs placebo+ADT, 34.3%), overweight (38.5% vs 31.8%), and obese (29.2% vs 33.9%). Changes at EOT were minimal across BMI subgroups and treatment groups for weight (−0.3kg to +0.3kg), BMI (−0.1kg/m2 to +0.1kg/m2), and waist circumference (−0.6cm to +0.1cm). PCS weight increase was rare with lumateperone+ADT vs placebo+ADT (normal weight: 0.7% vs 1.2%; overweight: 0.6% vs 0%; obese: 0% vs 2.5%). Changes in cardiometabolic parameters and prolactin levels at EOT were not clinically relevant across BMI subgroups and treatment groups. Most patients remained in their BMI category by EOT (normal weight: lumateperone+ADT, 91.0% vs placebo+ADT, 95.2%; overweight: 89.8% vs 86.9%; obese: 91.5% vs 94.5%).

Conclusion

Lumateperone+ADT had a favorable safety profile with minimal changes in metabolic parameters across BMI subgroups, indicating that lumateperone may be a welltolerated adjunctive treatment for patients with MDD with inadequate ADT response.