Novel Antipsychotic Shows Promise in Acute Schizophrenia

The investigational benzamide antipsychotic N-methyl amisulpride (LB-102) led to significant symptom improvement among hospitalized adults with acute schizophrenia, a randomized trial showed.

In this phase II study, the mean change from baseline to week 4 in the Positive and Negative Syndrome Scale (PANSS) total score was -14.3 points in those who received the 50-mg dose of LB-102, -14 points in those who received the 75-mg dose, and -16.1 points in those who received the 100-mg dose compared with a change of -9.3 points in the placebo group (P≤0.002 for all).

“The magnitude of effect falls within the range reported for established oral antipsychotics in multi-episode acute schizophrenia in a large network meta-analysis … although methodological differences warrant cautious interpretation,” wrote Anna Eramo, MD, of developer LB Pharmaceuticals in New York City, and colleagues in JAMA Psychiatry.

“The reduction in PANSS total score observed with LB-102 after 4 weeks of treatment is consistent with early trajectories reported for [LB-102’s predecessor] amisulpride over 3 to 6 weeks in the pragmatic Best Intro trial,” they added. That trial showed that amisulpride was more efficacious than aripiprazole (Abilify) or olanzapine (Zyprexa) for improving schizophrenia symptoms.

Introduced in the 1980s, amisulpride has since been approved in over 50 countries but was never submitted for FDA approval. LB-102 — a selective antagonist of dopamine (D₂), D₃, and 5-HT₇ receptors — is similar to amisulpride, but has some key differences.

For one, it’s only dosed once per day, as opposed to twice-daily dosing with amisulpride, due to its greater ability to permeate the blood-brain barrier. In addition, adverse events are more likely with amisulpride due to its strong D₂ receptor antagonism. Meanwhile, rates of extrapyramidal symptoms, QTc prolongation, and hepatic enzyme changes with LB-102 were comparable to placebo. No clinically meaningful changes in blood pressure, pulse rate, or body temperature were reported in this study.

Elevated prolactin was reported for 6.5% to 8.3% of the LB-102 treatment arms, while data on amisulpride have showed hyperprolactinemia rates of 25% to 100%.

“Traditional first- and second-generation antipsychotics are central for managing positive symptoms in patients with schizophrenia; however, they exert only modest effects on negative and cognitive symptoms, constraining overall functional recovery and broader long-term outcomes, and are often associated with cardiometabolic, endocrine, and neuromotor adverse effects,” Eramo and colleagues wrote.

“These tolerability issues can include extrapyramidal symptoms driven by strong D₂ receptor antagonism, sedation related to off-target histaminergic and/or α1-adrenergic activity, and gastrointestinal effects linked to anticholinergic/muscarinic burden (e.g., constipation, dry mouth), which may contribute to poor adherence and treatment discontinuation,” they pointed out.

These downsides leave a large unmet need for new pharmacotherapies for patients with schizophrenia, Eramo told MedPage Today.

The double-blind NOVA trial was conducted across 25 U.S. inpatient sites from December 2023 to August 2024. The trial included a 14-day screening period, a 28-day inpatient treatment period, an inpatient stabilization period, and a final outpatient safety follow-up 2 weeks after treatment.

Adults with schizophrenia who required hospitalization for a current acute exacerbation of psychotic symptoms were recruited. All were free from antipsychotic treatment for at least 2 weeks before baseline.

A total of 359 participants were randomized 3:3:3:1 to oral once-daily placebo or to LB-102 doses of 50 mg, 75 mg, or 100 mg. Average age was 39.1, 80.8% were men, 76.6% were Black, and mean PANSS total score at baseline was 94.

Treatment with LB-102 led to significant improvements in several secondary outcomes, including the Clinical Global Impressions-Severity of Illness scale, the PANSS Positive Symptoms subscale score, and the PANSS Marder Positive Symptoms factor score.

The drug was generally well tolerated. Treatment-emergent adverse events (TEAEs), including insomnia, headache, anxiety, agitation, and weight increase, occurred in 69% of patients on 50 mg, 57% on 75 mg, 75% on 100 mg, and 56% on placebo. Weight gain ranged from 7.7 lb to 10.1 lb in the LB-102 groups compared with a gain of 4.6 lb with placebo.

TEAEs leading to early withdrawal occurred in 10 participants across all groups. Most events were mild or moderate. One death occurred in the placebo arm.

Because of the 4-week trial duration, long-term treatment durability wasn’t evaluated. Also, the inpatient study design minimized risks related to nonadherence, illicit substance use, and unauthorized concomitant medications.

A phase III study is underway, testing 50-mg and 100-mg doses against placebo, with results expected in the second half of 2027. LB-102 is also being tested for bipolar I disorder and as an adjunct for major depressive disorder.