LUMATEPERONE 42 MG IN MAJOR DEPRESSIVE DISORDER: DEMOGRAPHIC AND CLINICAL SUBGROUPS EFFICACY ANALYSIS IN A PHASE 3 RANDOMIZED PLACEBO-CONTROLLED TRIAL

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). The Phase 3, randomized, double-blind, placebo-controlled Study 502 (NCT05061706) demonstrated the efficacy and safety of lumateperone 42mg+ADT in patients with MDD with inadequate ADT response. To assess consistency of treatment effect with adjunctive lumateperone, this analysis evaluated the efficacy of lumateperone 42mg+ADT in demographic and clinical subgroups of patients in Study 502.

Methods

Eligible patients (18-65 years) met DSM-5 criteria for MDD with inadequate response to 1-2 ADT courses and had Montgomery-Åsberg Depression Rating Scale (MADRS) Total score ≥24, Clinical Global Impression-Severity (CGI-S) score ≥4, and Quick Inventory of Depressive Symptomatology-Self Report-16 item (QIDS-SR-16) score ≥14. Patients were randomized 1:1 to 6-week oral lumateperone 42mg or placebo adjunctive to ADT. Efficacy was assessed in the overall population and in patient subgroups by demographic and baseline disease characteristics, using a mixed-effects model for repeated measures.

Results

The modified intent-to-treat (mITT) population comprised 469 patients (lumateperone+ADT, n=232; placebo+ADT, n=237). At Day 43 vs placebo+ADT, lumateperone+ADT significantly improved MADRS Total score (least squares mean difference [LSMD]=−4.5; P < .0001), CGI-S score (LSMD=−0.5; P < .0001), and QIDS-SR-16 Total score (ITT population: LSMD=−2.2; P < .0001). Lumateperone+ADT significantly improved MADRS Total score from baseline to Day 43 in demographic subgroups vs placebo+ADT: age (≤40y: LSMD=−4.3; P < .01; > 40y: LSMD=−4.6; P < .0001), sex (male: LSMD=−4.0; P < .01; female: LSMD=−4.8; P < .0001), region (US: LSMD,−3.5; P < .05; non-US: LSMD=−4.8; P < .0001). Treatment effect did not reach statistical significance for race (White: LSMD=−4.5; P < .0001; non-White: LSMD=−0.7; P=.8717) and ethnicity (Hispanic/Latino: LSMD=−2.9; P=.1468; not Hispanic/Latino: LSMD=−4.8; P < .0001) subgroups. MADRS Total score significantly improved from baseline to Day 43 with lumateperone+ADT irrespective of baseline disease severity (MADRS score < 32: LSMD=−4.6; P < .0001; MADRS score ≥32: LSMD=−4.4; P < .001), type of ADT (SSRI: LSMD=−4.3; P < .0001; SNRI and other: LSMD=−4.6; P < .001), number of ADT failures in the current episode (1 ADT failure: LSMD=−4.4; P < .0001; 2 ADT failures: LSMD=−5.1; P < .05), and presence of anxious distress (yes: LSMD=−4.7; P < .001; no: LSMD=−4.4; P < .0001). Lumateperone+ADT significantly improved (P < .05) CGI-S and QIDS-SR-16 Total scores from baseline to Day 43 vs placebo+ADT across most subgroups.

Conclusion

Lumateperone+ADT demonstrated robust efficacy vs placebo+ADT in subgroups of patients with MDD, supporting the drug as a promising adjunctive treatment option for patients with MDD with inadequate ADT response.