LB-102 Reduces Acute Schizophrenia Symptoms in Phase 2 Trial

Optimizing Benzamide Therapy for Acute Psychosis

The management of acute schizophrenia remains a significant clinical challenge, as approximately 30 percent of patients exhibit a suboptimal response to standard dopamine D2 receptor antagonists (the primary class of antipsychotics that block dopamine signaling to reduce hallucinations and delusions) [1, 2]. While current medications are essential for stabilizing acute exacerbations, clinicians must frequently balance symptom control against the risk of metabolic dysregulation and extrapyramidal side effects, such as tremors or involuntary muscle movements [3, 4]. Research into the pathophysiology of the disorder suggests that modulating dopamine and glutamate interactions at the postsynaptic density (the protein-dense region on the receiving end of a neuron that processes incoming chemical signals) is critical for addressing both positive and negative symptoms [5, 6]. Although various augmentation strategies and alternative mechanisms are under investigation, there is a persistent need for high-affinity agents that can be safely titrated during the inpatient stabilization period [7, 8, 9]. A recently completed multicenter trial now provides clinical data on a modified benzamide compound, LB-102, designed to address these therapeutic gaps [7].

Trial Design and Patient Selection

The NOVA1 trial (NCT06179108) was a US-based, multicenter, double-blind, placebo-controlled, phase 2 randomized clinical trial conducted from December 2023 to August 2024. The study evaluated the efficacy and safety of LB-102 (N-methyl amisulpride), a benzamide derivative currently under investigation for the treatment of schizophrenia. The clinical protocol was structured to manage acute symptoms within a controlled environment, beginning with an inpatient screening period of 14 days or less, followed by a 28-day inpatient treatment period and a 5-day inpatient stabilization period. To monitor safety after discharge, the researchers included an outpatient safety follow-up visit approximately 2 weeks after the treatment period ended. Eligible participants included 359 adults aged 18 to 55 years who were diagnosed with schizophrenia and required hospitalization for an acute exacerbation of psychotic symptoms. To ensure a cohort with significant symptom burden, the researchers required a baseline Positive and Negative Syndrome Scale (PANSS) total score between 80 and 120. The PANSS is a standardized medical scale used to measure the severity of schizophrenia symptoms across positive, negative, and general psychopathology domains. Furthermore, patients had to demonstrate a score of 4 or greater on at least two key items of the PANSS Positive Symptoms subscale. Clinical severity was further confirmed using the Clinical Global Impressions-Severity of Illness scale (CGI-S), a seven-point tool that allows clinicians to rate the severity of a patient's illness relative to their total clinical experience. Participants were required to have a CGI-S score of 4 or greater at both the screening and baseline assessments. The study utilized a 3:3:3:1 randomization ratio to assign participants to their respective treatment arms, resulting in 108 patients receiving a once-daily oral placebo, 107 receiving LB-102 at a 50 mg dose, 108 receiving 75 mg, and 36 receiving 100 mg. This dosing strategy allowed the investigators to evaluate the efficacy and safety of N-methyl amisulpride across a range of therapeutic levels during the acute treatment phase. The mean age of the total population was 39.1 years (standard deviation of 9.3 years), and the cohort was predominantly male, representing 80.8 percent of the participants.

Symptom Reduction and Primary End Points

The trial met its primary end point, demonstrating that LB-102 significantly reduced the severity of acute psychosis over the four-week treatment window. At the start of the 28-day treatment period, the study population exhibited a mean baseline PANSS total score of approximately 94 across all groups, indicating a high level of symptom severity. The primary end point was the change from baseline to week 4 in the PANSS total score, utilizing a Hochberg multiplicity correction (a statistical method used to adjust p-values when testing multiple dose strengths to ensure that the risk of a false positive result remains below 5 percent) for the 50 mg and 75 mg doses. Both doses demonstrated statistically significant improvements compared to placebo. Specifically, LB-102 50 mg showed a mean PANSS change of -14.3 (standard error [SE] of 1.10) compared to -9.3 (SE 1.08) for placebo (P < .001), yielding a Hedges g of 0.61. The 75 mg dose resulted in a mean PANSS change of -14.0 (SE 1.11) compared to the same placebo baseline (P = .002), with a Hedges g of 0.41. Hedges g is a measure of effect size that quantifies the standardized difference between two means; a value of 0.4 to 0.6 generally represents a moderate clinical effect. The highest dose of LB-102 100 mg also showed significance with a mean PANSS change of -16.1 (SE 1.91) and a nominal P value of .002, resulting in the largest effect size of the trial (Hedges g = 0.83). Beyond the primary metric, the researchers evaluated several secondary efficacy end points to capture a broader clinical picture, including the proportion of patients achieving a 20% or greater PANSS response, which is a common threshold for defining clinically meaningful improvement in acute trials. The analysis also incorporated PANSS Marder factor scores, a validated method of grouping the 30 PANSS items into five clinically relevant domains: positive symptoms, negative symptoms, disorganized thought, uncontrolled hostility/excitement, and anxiety/depression. This granular analysis helps clinicians understand if a drug is particularly effective for specific symptom clusters, such as social withdrawal or cognitive disorganization, rather than just global psychosis.

Safety Profile and Treatment Tolerability

The researchers evaluated the safety and tolerability of LB-102 by monitoring treatment-emergent adverse effects (TEAEs), which are any unfavorable medical occurrences that appear or worsen after the first dose of the study drug. In the placebo group, TEAEs were reported in 60 participants (56%). Among the active treatment arms, the incidence of these events varied by dose: 74 participants (69%) in the 50 mg group, 62 participants (57%) in the 75 mg group, and 27 participants (75%) in the 100 mg group experienced at least one TEAE. These data suggest that while the 75 mg dose had a side effect profile comparable to placebo in terms of overall frequency, the 50 mg and 100 mg doses were associated with higher rates of adverse events during the 28-day treatment period. Clinical management of acute schizophrenia requires a balance between symptom control and the risk of severe complications that may necessitate treatment discontinuation. In this trial, ten participants reported TEAEs leading to withdrawal from the study, including 2 in the placebo group, 2 in the 50 mg group, 3 in the 75 mg group, and 3 in the 100 mg group. Furthermore, the study recorded 5 serious TEAEs, which are defined as medical events resulting in death, life-threatening conditions, or prolonged hospitalization. These serious events occurred in 2 participants in the placebo group (including 1 death) and 1 participant in each of the LB-102 arms (50 mg, 75 mg, and 100 mg). For clinicians, these findings indicate that while LB-102 is generally tolerated and effective for acute stabilization, the risk of treatment discontinuation due to adverse effects remains a factor across all therapeutic doses, particularly at the 100 mg level where the highest percentage of TEAEs was observed.

References

1. Bartolomeis AD, Ciccarelli M, Simone GD, Mazza B, Barone A, Vellucci L. Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia. International Journal of Molecular Sciences. 2023. doi:10.3390/ijms24065945

2. Iasevoli F, Avagliano C, D’Ambrosio L, et al. Dopamine Dynamics and Neurobiology of Non-Response to Antipsychotics, Relevance for Treatment Resistant Schizophrenia: A Systematic Review and Critical Appraisal. Biomedicines. 2023. doi:10.3390/biomedicines11030895

3. Sabé M, Zhao N, Crippa A, Kaiser S. Antipsychotics for negative and positive symptoms of schizophrenia: dose-response meta-analysis of randomized controlled acute phase trials. Schizophrenia. 2021. doi:10.1038/s41537-021-00171-2

4. Bartolomeis AD, Simone GD, Prisco MD, et al. Insulin effects on core neurotransmitter pathways involved in schizophrenia neurobiology: a meta-analysis of preclinical studies. Implications for the treatment. Molecular Psychiatry. 2023. doi:10.1038/s41380-023-02065-4

5. Bartolomeis AD, Barone A, Vellucci L, et al. Linking Inflammation, Aberrant Glutamate-Dopamine Interaction, and Post-synaptic Changes: Translational Relevance for Schizophrenia and Antipsychotic Treatment: a Systematic Review. Molecular Neurobiology. 2022. doi:10.1007/s12035-022-02976-3

6. Bartolomeis AD, Vellucci L, Simone GD, Mazza B, Barone A, Ciccarelli M. Dysregulated Signaling at Postsynaptic Density: A Systematic Review and Translational Appraisal for the Pathophysiology, Clinics, and Antipsychotics’ Treatment of Schizophrenia. Cells. 2023. doi:10.3390/cells12040574

7. Eramo A, Correll CU, Walling DP, et al. Antipsychotic Efficacy and Safety of LB-102 in the Treatment of Adults With Acute Schizophrenia: A Randomized Clinical Trial.. JAMA psychiatry. 2026. doi:10.1001/jamapsychiatry.2026.0428

8. Correll CU, Solmi M, Cortese S, et al. The future of psychopharmacology: a critical appraisal of ongoing phase 2/3 trials, and of some current trends aiming to de‐risk trial programmes of novel agents. World Psychiatry. 2023. doi:10.1002/wps.21056

9. Yeh T, Correll CU, Yang F, et al. Pharmacological and nonpharmacological augmentation treatments for clozapine-resistant schizophrenia: A systematic review and network meta-analysis with normalized entropy assessment.. Asian journal of psychiatry. 2023. doi:10.1016/j.ajp.2022.103375