Lumateperone 42 mg in major depressive disorder: demographic and clinical subgroups efficacy analysis in a phase 3 randomized placebo-controlled trial

Background

In patients with major depressive disorder (MDD), it is important to assess treatment efficacy by patient characteristics and establish consistency of treatment effect, as certain attributes can impact treatment outcomes.

Lumateperone is an FDA-approved antipsychotic for the treatment of schizophrenia, depressive episodes associated with bipolar depression, and as adjunctive therapy for MDD. 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 antidepressant therapy (ADT) response. Lumateperone 42 mg+ADT met the primary and key secondary endpoints, with significant improvement vs placebo+ADT at Day 43 in Montgomery-Asberg Depression Rating Scale (MADRS) Total score and Clinical Global Impression-Severity (CGI-S) score, respectively, and was generally safe and well tolerated. 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 MADRS Total score ≥24, 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 or analysis of covariance. Demographic subgroups included age (≤40 or >40 years), sex, race (White or non-White), ethnicity (Hispanic/Latino or not Hispanic/Latino), and region (US or non-US). Baseline disease characteristics included disease severity, type of ADT, number of ADT failures in the current episode, number of lifetime ADT failures, and presence/absence of DSM-5–defined anxious distress.

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.

Conclusions

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.

References

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