Effects of LB-102 on cognitive performance in patients with schizophrenia: Post hoc analyses from the phase 2 randomised NOVA-1 trial

Introduction

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. Preclinical and translational studies have shown similar receptor-binding properties to amisulpride, with human studies demonstrating similar receptor occupancy between LB-102 50 mg and amisulpride 400 mg. In the phase 2 NOVA-1 clinical trial in patients with schizophrenia experiencing a psychotic relapse, LB‑102 resulted in significant improvements from baseline versus placebo at all doses tested in the Positive and Negative Syndrome Scale (PANSS) total and Positive and Negative Symptoms subscale scores after 4 weeks of treatment and was generally safe and well tolerated. With previous studies highlighting positive efficacy for amisulpride on cognitive performance in patients with schizophrenia, it was hypothesised that LB-102 would improve cognitive performance in this population.

Objectives

To evaluate the potential effects of LB-102 versus placebo on cognitive performance in the NOVA-1 clinical trial, through prespecified and post hoc analyses of the Cogstate computerised battery of cognitive tests.

Methods

NOVA-1 (NCT06179108) was a randomised, double-blind, placebo-controlled, multi-centre trial comprising a 7- to 14-day inpatient screening, 28-day inpatient treatment, up to 5-day inpatient stabilisation, and outpatient safety follow-up. Cognitive performance was defined by the Global Cognition composite score based on the Cogstate computerised battery of cognitive tests. The effect of LB-102 on cognitive performance was compared to placebo at the end of Week 4 using ANCOVA, with treatment group, pooled study site, and baseline score as covariates. Post hoc mediation analyses examined the extent to which drug-related improvements in global cognitive performance were an indirect consequence of the drug effects on total schizophrenia symptoms (PANSS total score).

Results

Altogether, 359 participants were randomised to receive placebo (n=108), LB-102 50 mg (n=107), 75 mg (n=108), or 100 mg (n=36), with LB-102 meeting the primary endpoint (least-squares mean change from baseline to Week 4 in PANSS total score of −9.3 [placebo], −14.3 [50 mg, p=0.0009], −14.0 [75 mg, p=0.0022], and −16.1 [100 mg, nominal p=0.0017]). LB-102 significantly improved Global Cognition composite score across all doses: 50 mg (p=0.0476, Cohen’s d=0.26), 75 mg (p=0.0027, d=0.41), and 100 mg (p=0.0018, d=0.66). Post hoc effect-size analyses of the individual cognitive tests suggested that the effects of LB-102 were distributed across all assessed cognitive domains. Mediation analyses indicated that the effect of LB-102 on Global Cognition composite score was independent to improvements in PANSS total score, as indirect effects were not significant (p≥0.05).

Conclusions

All LB-102 doses demonstrated an improvement in cognitive performance after 4 weeks of treatment in patients with schizophrenia experiencing a psychotic relapse. This benefit in cognitive performance appears to be a direct treatment effect of LB-102 and not mediated by its effectiveness in reducing total, positive, or negative schizophrenia symptoms. The effect of LB-102 on cognitive performance is being evaluated in ongoing and planned trials in schizophrenia, bipolar depression, and adjunctive treatment of major depressive disorder.

References

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