Amisulpride is a benzamide-based antipsychotic that is not approved in the US but is approved in more than 50 countries outside the US and is consistently ranked as among the most efficacious agents for acute and chronic schizophrenia. Although low-dose amisulpride shows clinically meaningful reductions in symptoms of schizophrenia, its clinical efficacy is limited by its low blood-brain barrier permeability. LB-102 (N-methyl amisulpride) is a novel benzamide antipsychotic designed to improve blood-brain barrier penetration and dopamine D2/D3 receptor occupancy at lower systemic exposures than amisulpride, potentially improving efficacy and tolerability. This phase 2 trial evaluated the efficacy, safety, and tolerability of LB-102 in adults with acute schizophrenia.

NOVA1 was a multicenter, randomized, double-blind, placebo-controlled phase 2 trial conducted across 25 inpatient sites in the United States between December 2023 and August 2024. Adults aged 18–55 years with acute exacerbations of schizophrenia requiring hospitalization were eligible. Participants were randomized in a 3:3:3:1 ratio to receive once-daily oral placebo or LB-102 at 50 mg, 75 mg, or 100 mg for 4 weeks.

The primary endpoint was change from baseline to week 4 in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcomes included changes in Clinical Global Impressions–Severity (CGI-S), PANSS subscales and Marder factor scores, and responder analyses. Safety assessments included treatment-emergent adverse events (TEAEs), laboratory values, prolactin levels, metabolic measures, electrocardiograms, and extrapyramidal symptom scales.

A total of 359 participants were randomized (mean age 39.1 years; 80.8% male), with baseline PANSS total scores of approximately 94 across groups. The study met its primary endpoint, where change from baseline to week 4 in PANSS total scores showed statistical superiority with LB-102 at both 50 and 75 mg (placebo: -9.3; 50 mg: -14.3, P < .001; 75 mg: -14.0, P = .002). LB-102 100 mg also showed significant improvement (-16.1; nominal P = .002). The effect of LB-102 on PANSS total score was observed as early as week 1 and maintained throughout the 4-week treatment period. Secondary analyses showed significant improvements across CGI-S scores, PANSS positive symptom scores, and several PANSS Marder factor domains, including disorganized thought and hostility/excitement. LB-102 also demonstrated favorable responder rates relative to placebo.

LB-102 was generally well tolerated. TEAEs were mostly mild or moderate, with insomnia, headache, anxiety, agitation, and weight gain being the most common. Additionally, prolactin elevations occurred more frequently with LB-102 than with placebo. Medication-Induced movement disorders, QTc prolongation, and movement-disorder ratings remained low compared to placebo. Serious adverse events were uncommon, with one death occurring in the placebo group.

In this phase 2 randomized clinical trial, LB-102 demonstrated significant antipsychotic efficacy in adults with acute schizophrenia, with improvements observed across multiple symptom domains and early onset of effect. LB-102 was generally safe and well-tolerated, with relatively low rates of medication-induced movement disorders and manageable metabolic and prolactin-related effects. These findings support continued phase 3 development of LB-102 as a potentially effective and better-tolerated antipsychotic treatment.

Reference:
Eramo A, Correll CU et al. JAMA Psychiatry 2026;Epub ahead of print. Abstract