Antipsychotic Efficacy and Safety of LB-102 in the Treatment of Adults With Acute Schizophrenia: A Randomized Clinical Trial.

Importance: LB-102 (N-methyl amisulpride) is a novel benzamide under investigation for the treatment of schizophrenia. Objective: To evaluate the efficacy and safety of LB-102 in acute schizophrenia. Design, Setting, and Participants: This US-based, multicenter, double-blind, placebo-controlled, phase 2 randomized clinical trial (NOVA1) conducted from December 2023 to August 2024 comprised an inpatient screening period (≤14 days), 28-day inpatient treatment period, 5-day inpatient stabilization period, and outpatient safety follow-up visit approximately 2 weeks after the treatment period end. Eligible participants were adults (aged 18-55 years) with schizophrenia who required hospitalization or continued hospitalization for an acute exacerbation of psychotic symptoms and had a Positive and Negative Syndrome Scale (PANSS) total score of 80 to 120, PANSS Positive Symptoms subscale item score of 4 or greater on 2 or more key items, and a Clinical Global Impressions-Severity of Illness scale (CGI-S) score of 4 or greater at screening and baseline. Interventions: Participants were randomized (3:3:3:1) to oral once-daily placebo, LB-102 50 mg, 75 mg, or 100 mg. Main outcomes and Measures: The primary end point was change from baseline to week 4 in PANSS total score (Hochberg multiplicity correction for LB-102 50 mg and 75 mg vs placebo). Secondary efficacy end points included changes from baseline to week 4 in CGI-S score, CGI-S response, PANSS subscale scores, PANSS Marder factor scores, and 20% or greater PANSS response. Safety and tolerability end points included treatment-emergent adverse effects (TEAEs). Results: A total of 359 participants (mean [SD] age, 39.1 [9.3] years; 290 male [80.8%]; mean baseline PANSS total score = approximately 94 across groups) were randomized and included in the safety and intention-to-treat populations (placebo, n = 108; 50 mg, n = 107; 75 mg, n = 108; 100 mg, n = 36). The trial met the primary end point: LB-102 50 mg and 75 mg, were statistically superior to placebo in change from baseline to week 4 in PANSS total score (mean [SE], placebo, -9.3 [1.08]; 50 mg, -14.3 [1.10], P < .001; Hedges g = 0.61; 75 mg, -14.0 [1.11], P = .002; Hedges g = 0.41); LB-102 100 mg, also showed significance (mean [SE], -16.1 [1.91]; nominal P = .002; Hedges g = 0.83). TEAEs were reported in 60 participants (56%) in the placebo group, 74 (69%) in the group receiving 50 mg, 62 (57%) in the group receiving 75 mg, and 27 (75%) in the group receiving 100 mg. Ten participants reported TEAEs leading to withdrawal (placebo, n = 2; 50 mg, n = 2; 75 mg, n = 3; 100 mg, n = 3) with 5 serious TEAEs (placebo, n = 2 [including 1 death]; each LB-102 arm, n = 1). Conclusions and Relevance: This randomized clinical trial provided rigorous evidence demonstrating the efficacy and safety of LB-102 for the treatment of adults with acute schizophrenia. Trial Registration: ClinicalTrials.gov Identifier: NCT06179108.