LB-102

LB-102 is an investigational, once-daily, oral small molecule. It is an N-methylated version of amisulpride and a selective antagonist of dopamine D2 and D3 receptors and serotonin 5-HT7 receptors. Its parent compound, amisulpride, is approved for schizophrenia in more than 50 countries outside the United States. The company states that it has no product approved for commercial sale and none for which regulatory approval to market has been sought. No nonproprietary or brand name, expedited program designation, submission date, or launch date was identified. The company expects topline results from the phase 3 NOVA-2 trial in the first half of 2027 and a pre-NDA meeting with the FDA in the second half of 2027. According to the company, the FDA noted in writing that NOVA-1 “appeared to have many of the characteristics of an adequate and well-controlled trial”, and the company plans to use NOVA-1 as one of the two adequate and well-controlled trials required for approval. The Form 10-K adds that the adequacy of NOVA-1 will be reviewed at the time of NDA submission and that an additional pivotal trial may be required. The company anticipates that the FDA will require 1,500 cumulative exposures to LB-102, including at least 300 participants with 6 months or more and at least 100 participants with 1 year or more of exposure, and it expects to enroll approximately 900 participants in the open-label NOVA-3 trial as a result.

The evidence establishes a difference from placebo on the PANSS total score after 4 weeks for the 50 mg and 75 mg doses in one trial of 359 participants at inpatient sites in the United States: -5.0 points (95% CI -8.0 to -2.1) and -4.7 points (95% CI -7.7 to -1.7), against a placebo change of -9.3 points. The 100 mg arm (-6.8 points; 95% CI -11.1 to -2.6) was exploratory, with 36 participants randomized and 23 completing week 4, and NOVA-2 studies 50 mg and 100 mg. NOVA-1 had no active comparator, lasted 4 weeks, excluded first-episode and treatment-resistant illness, and enrolled a population that was 80.8% male and 76.6% Black or African American. No efficacy or safety data beyond 4 weeks, no maintenance or relapse-prevention data, no outpatient efficacy data, and no patient-reported outcome results are available. P values for secondary endpoints were not controlled for multiplicity, the prespecified 20% responder comparison for 50 mg had P=.06, the difference on the PANSS Negative Symptoms subscale had P=.01 for 50 mg and P=.16 and P=.26 for 75 mg and 100 mg, and the cognition results are post hoc composites. The authors state that improvement in negative symptoms in a 4-week acute trial may be secondary to resolution of positive symptoms. NOVA-2 compares LB-102 with placebo for 6 weeks, and NOVA-3 is open-label.

Every comparison of LB-102 with another antipsychotic is indirect and made across trials that differ in duration, baseline severity, and placebo response. The company states that it has conducted no head-to-head clinical trial against amisulpride, and no network meta-analysis or indirect treatment comparison that includes LB-102 was identified. The NOVA-1 effect sizes were 0.61, 0.41, and 0.83 for 50 mg, 75 mg, and 100 mg as post hoc Hedges g in participants who completed the trial and 0.50, 0.45, and 0.64 as model-based values. The NOVA-1 authors place these within the range of a network meta-analysis of oral antipsychotics, from which they cite standardized mean differences of -0.73 for amisulpride, -0.56 for olanzapine, and -0.55 for risperidone; the authors of that meta-analysis note that no placebo-controlled amisulpride study was available, which makes the amisulpride evidence indirect. The company states that dopamine receptor occupancy at 50 mg of LB-102 is approximately equivalent to that at 300 to 400 mg of amisulpride. In trials of other oral agents, the placebo-subtracted difference in PANSS total score was -9.6 and -8.4 points at 5 weeks for xanomeline-trospium (placebo changes of -11.6 and -12.2 points), -5.8 and -4.2 points at 4 weeks for lumateperone 42 mg, and -6.0 to -10.4 points at 6 weeks across three cariprazine trials. A meta-analysis of three 5-week xanomeline-trospium trials gave a standardized mean difference of -0.56 (95% CI -0.72 to -0.40).

Four tolerability findings are relevant to formulary review. Elevated prolactin at day 28 was reported in 87.5% to 94.0% of LB-102 participants and 5.2% of placebo participants, with mean increases of 51.2 to 59.9 ng/mL and 1.3 ng/mL, and 5 LB-102 participants had a prolactin-related clinical adverse event within 4 weeks. In the network meta-analysis, the largest mean difference from placebo in prolactin was 48.51 ng/mL (paliperidone), the NOVA-1 authors cite hyperprolactinemia rates of 25% to 100% for amisulpride, and a 2025 review states that hyperprolactinemia “may limit its usability in the future”. A weight increase of 7% or more occurred in 25.7%, 18.7%, and 8.8% of participants receiving 50 mg, 75 mg, and 100 mg and in 10.4% receiving placebo; the authors cite weight change against placebo of -0.37 kg for xanomeline-trospium and 2.78 kg for olanzapine and state that site smoking restrictions, limited physical activity, and minimal dietary restrictions may have contributed to weight gain in NOVA-1. Mean QTc change was 4.3 to 5.4 milliseconds with LB-102 and 1.2 milliseconds with placebo, within a network meta-analysis range of -2.21 milliseconds (lurasidone) to 23.90 milliseconds (sertindole); in phase 1, QTcF rose by 20 to 46 milliseconds after a single 200 mg dose. Extrapyramidal symptom incidence was 0% to 2.8% with LB-102 and 1.9% with placebo in the publication, and 1.0% to 5.6% and 3.7% in the company total that adds dystonia and akathisia; in healthy adults, acute dystonia occurred at 150 mg to 200 mg per day and halted the 100 mg twice-daily cohort.

Current antipsychotic treatment has documented limitations. In CATIE, 1,061 of 1,432 participants (74%) discontinued the assigned antipsychotic before 18 months. Across 167 placebo-controlled trials, at least a minimal response occurred in 51% of participants receiving an antipsychotic and 30% receiving placebo. Treatment resistance developed in 22.8% of first-episode cohorts, and relapse at 1 year occurred in 27% of participants receiving maintenance antipsychotic treatment and 64% receiving placebo. Up to 60% of people with schizophrenia have prominent negative symptoms, and the company states that no therapy is approved in the United States for predominantly negative symptoms or for cognitive impairment associated with schizophrenia. NOVA-1 excluded treatment-resistant illness and provides no data on long-term discontinuation or relapse. For a formulary decision, the following remain unknown: the price, for which no announcement, economic model, or health technology assessment was identified; the labeled indication, dose, and warnings; efficacy and safety beyond 4 weeks; the results of NOVA-2 and NOVA-3; and effectiveness relative to amisulpride and to generic antipsychotics.