LB-102 in patients with bipolar I disorder experiencing a major depressive episode: Phase 2, double-blind, placebo-controlled trial design (ILLUMINATE-1)

Introduction

Bipolar I disorder is a chronic, highly recurrent mood disorder in which depressive episodes account for a disproportionate share of longitudinal morbidity, psychosocial impairment, and suicide risk. Despite multiple approved agents, therapeutic options for patients with bipolar depression remain limited by incomplete efficacy, tolerability burden, and persistent residual symptoms such as anhedonia and cognitive deficits. LB-102 is an investigational novel benzamide D₂/D₃/5-HT₇ antagonist under development as a once-daily treatment for schizophrenia and other neuropsychiatric disorders, including bipolar depression. At lower doses, the D₂/D₃/5-HT₇ receptor profile of LB-102 has mechanistic relevance to antidepressant activity, motivational symptoms, and broader neurobehavioral dysfunction in bipolar depression. The phase 2 ILLUMINATE-1 trial is designed to evaluate the efficacy and safety of LB-102 monotherapy in adults with bipolar 1 depression.

Objectives

To describe an ongoing phase 2 clinical trial to evaluate the efficacy and safety of LB-102 in adults diagnosed with bipolar I disorder experiencing a major depressive episode (ILLUMINATE-1).

Methods

ILLUMINATE-1 (NCT07494305) is an ongoing phase 2, multicentre, randomised, double-blind, placebo-controlled clinical trial with fixed-flexible dosing design being conducted at approximately 30 US sites. The trial is estimated to enrol approximately 320 adults (18–65 years) diagnosed with bipolar I disorder (defined by DSM-5) experiencing a current major depressive episode (without psychotic or mixed features and supported by the SCID-5-CT). Participant eligibility requires a Montgomery–Åsberg Depression Rating Scale-10 (MADRS-10) total score of ≥24, Clinical Global Impression Scale–Bipolar version (CGI-BP) depression severity score of ≥4, and Young Mania Rating Scale (YMRS) total score of ≤12, all at screening and baseline. Eligibility is confirmed centrally for the severity, diagnosis, and treatment history by the SAFER interview. Participants are randomised in a 1:1 ratio to receive once-daily LB-102 or matching placebo for 6 weeks of outpatient treatment. LB-102 is initiated at 25 mg for 3 weeks, with the option to escalate the dose to 50 mg in a blinded, protocol-guided manner at the start of Week 4 based on the CGI-BP improvement score. The primary endpoint is the change from baseline to Week 6 in MADRS-10 total score. Secondary efficacy endpoints include MADRS-6, CGI-BP, and dedicated scales to measure cognitive performance and anhedonia. Adverse events (AEs) will be captured and characterised by type, severity, seriousness, and relationship to treatment. All AEs will be coded using the most up-to-date version of the Medical Dictionary for Regulatory Activities (MedDRA). The incidence of treatment-emergent mania will be assessed based on the YMRS total score.

Conclusions

ILLUMINATE-1 is a well-designed phase 2 clinical trial in patients with bipolar I disorder experiencing a major depressive episode allowing investigation of two LB-102 dose levels and incorporating centralised diagnostic and symptom evaluation, prospective monitoring for treatment-emergent mania, and a prospective multidomain endpoint framework. The results of the ILLUMINATE-1 clinical trial will characterise the efficacy and safety profile of once-daily oral LB-102 for the treatment of bipolar 1 depression and inform subsequent clinical trial development.

References

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