The investigational benzamide antipsychotic N-methyl amisulpride (LB-102), a modified version of amisulpride, significantly reduced symptoms in adults hospitalized with acute schizophrenia in the phase 2 NOVA-1 study, with a generally favorable safety profile.

Amisulpride — a second-generation antipsychotic approved in over 50 countries outside the US — has been shown to be effective for acute and chronic schizophrenia, particularly for reducing psychotic and negative symptoms and improving global functioning.

However, its clinical use is constrained by poor penetration of the blood-brain barrier, necessitating twice-daily dosing at higher levels, as well as side effects such as elevated prolactin levels and cardiac risks.

“LB-102 is an N-methylated amisulpride derivative designed to preserve amisulpride-like D2/D3 and 5-HT7 pharmacology, while improving brain penetration, enabling once-daily dosing at much lower systemic exposure and related side effects than amisulpride,” study investigator Christoph U. Correll, MD, professor of psychiatry at the Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York, told Medscape Medical News.

In NOVA-1, once-daily oral LB-102 met the primary endpoint in adults with acute schizophrenia, with significantly greater improvements in Positive and Negative Syndrome Scale (PANSS) total scores over 4 weeks compared with placebo, with improvements seen as early as the first week of treatment.

LB-102 demonstrated “statistically significant benefit vs placebo at all doses studied, including rapid onset of effect at week 1 and sustained benefit through the endpoint of the trial,” Anna Eramo, MD, chief medical officer, LB Pharmaceuticals, New York City, which is developing LB-102, told Medscape Medical News.

She said LB-102 has a “potentially class-leading safety profile with low rates of extrapyramidal symptoms (including akathisia), minimal sedation, and few GI [gastrointestinal] side effects.”

The results of the NOVA-1 study were published online on April 22 in JAMA Psychiatry.

Primary and Secondary Endpoints Met

The trial enrolled 359 adults (mean age, 39 years; 81% male) with schizophrenia who were hospitalized for an acute exacerbation of psychotic symptoms. They were randomly assigned to placebo or to LB-102 at doses of 50 mg, 75 mg, or 100 mg for 4 weeks. The mean baseline PANSS total score was roughly 94 across groups.

The trial met the primary endpoint: LB-102 50 mg and 75 mg were statistically superior to placebo in change from baseline to week 4 in PANSS total score. On average, PANSS scores dropped by about 14 points in the 50-mg and 75-mg groups, compared with a roughly 9-point reduction in the placebo group.

Correll said the “smaller and exploratory” 100-mg group also showed “nominally significant improvement with an even larger effect size than the two lower doses.”

LB-102 also led to significant improvement across multiple secondary efficacy endpoints, including the Clinical Global Impressions-Severity of Illness scale, the PANSS subscale scores, and PANSS Marder factor scores. “Across doses, LB-102 improved positive symptoms, global severity, disorganized thought, and hostility/excitement,” Correll told Medscape Medical News.

The drug was generally well tolerated, although treatment-emergent adverse events (TEAEs) were common — occurring in 56% of patients on placebo and 69%, 57%, and 75% of patients on 50-mg, 75-mg, and 100-mg LB-102, respectively. TEAEs leading to discontinuation were low and similar across groups.

The most common TEAEs included insomnia, headache, anxiety, agitation, and weight gain. The mean weight increase from baseline to 28 days in the LB-102 groups ranged from 2.9 to 4.3 kg (6.39-9.48 lb), compared with 2.0 kg (4.4 lb) with placebo. Prolactin elevations were noted but were low in frequency and severity.

“Extrapyramidal symptoms were low, and QTc [corrected QT interval] changes — a potential problem with the much less brain-penetrant amisulpride — were not clinically notable. That is important because it may narrow the usual trade-off between antipsychotic potency and tolerability,” said Correll.

He noted, however, that NOVA-1 was a short, 4-week phase 2 inpatient study without an active comparator.

“The real and full clinical value will depend on phase 3 data, longer-term metabolic/endocrine outcomes, relapse prevention, functioning, adherence, and head-to-head comparisons,” he noted.

Phase 3 Trial Recruiting

Eramo said a phase 3 US trial began recruiting last month, with top-line results expected in the second half of 2027.

“We believe LB-102 has the potential to be the first benzamide antipsychotic drug approved for neuropsychiatric disorders in the United States,” she said.

Roger McIntyre, MD, professor of psychiatry and pharmacology at the University of Toronto in Toronto, Ontario, Canada, noted that the parent compound, amisulpride, has long been viewed by clinicians around the world as particularly effective for “difficult-to-treat symptoms not only in people with psychotic disorders but also in people who live with mood disorders.”

This reputation is supported not only by research but also by his own clinical experience treating patients with amisulpride outside the US, said McIntyre, who wasn’t involved in the study.

“LB-102 has been modified to improve bioavailability, allowing for lower doses and better tolerability and the safety. It’s a promising new asset that seems to have replicated efficacy across psychotic, negative, and depressive symptoms,” he added.

The NOVA-1 trial was sponsored and funded by LB Pharmaceuticals Inc., including medical writing support for the development of the manuscript. Disclosures for the study authors are available in the original study publication. McIntyre has reported receiving speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, and other pharmaceutical companies.