LB-102

Efficacy results for LB-102 are available from one trial, NOVA-1. This phase 2, randomized, double-blind, placebo-controlled, fixed-dose trial was conducted at 25 inpatient sites in the United States. It randomized 359 adults aged 18 to 55 years with an acute exacerbation of schizophrenia (mean baseline PANSS total score approximately 94) in a 3:3:3:1 ratio to placebo (108 participants) or once-daily oral LB-102 50 mg (107), 75 mg (108), or 100 mg (36) for 28 days of inpatient treatment, with no titration. Formal hypothesis testing, with a Hochberg correction, covered the primary endpoint for the 50 mg and 75 mg doses. The 100 mg arm was exploratory; no formal hypothesis was tested for it, and its data were analyzed with the same methods for descriptive purposes. The least-squares mean change in PANSS total score from baseline to week 4 was -9.3 points with placebo, -14.3 with 50 mg, -14.0 with 75 mg, and -16.1 with 100 mg. The differences from placebo were -5.0 points for 50 mg (95% CI -8.0 to -2.1; P<.001), -4.7 points for 75 mg (95% CI -7.7 to -1.7; P=.002), and -6.8 points for 100 mg (95% CI -11.1 to -2.6; P=.002). The sample size calculation had assumed a difference of 8 points. Two sets of post hoc effect sizes are reported. Hedges g, calculated from the observed change in participants who completed the trial, was 0.61 for 50 mg, 0.41 for 75 mg, and 0.83 for 100 mg. The values based on the mixed model for repeated measures were 0.50, 0.45, and 0.64. Week 4 was completed by 81.6% of participants overall: 94 (87%) with placebo, 91 (85%) with 50 mg, 85 (79%) with 75 mg, and 23 (64%) with 100 mg.

In the results that follow, figures are listed in the order placebo, 50 mg, 75 mg, and 100 mg, and P values were not controlled for multiplicity. The differences from placebo in CGI-S score were -0.33 (P<.001), -0.28 (P=.005), and -0.45 (P=.003) for the three doses, and a CGI-S score of 3 or lower at week 4 was reached by 7.4%, 23.4% (P=.001), 17.6% (P=.02), and 11.1% (P=.35) of participants. On the PANSS Positive Symptoms subscale, the differences from placebo were -1.7, -1.7, and -2.2 points (P=.005, .004, and .01). On the PANSS Negative Symptoms subscale, they were -1.1 points for 50 mg (P=.01), -0.6 for 75 mg (P=.16), and -0.7 for 100 mg (P=.26), and on the Marder Negative Symptoms factor the P values were .08, .50, and .07. In the prespecified responder analysis (a reduction of 20% or more in PANSS total score), response occurred in 18.3%, 31.9%, 32.1%, and 43.5% of participants; the comparison with placebo did not reach statistical significance for 50 mg (odds ratio 1.91; 95% CI 0.98 to 3.74; P=.06) and had P=.02 for 75 mg and for 100 mg. A post hoc analysis that rescaled item scores from a 1 to 7 range to a 0 to 6 range found response in 38.7%, 57.1%, 53.6%, and 78.3%. Cognition results are post hoc Cogstate composite scores in the 290 participants who completed week 4 with valid PANSS and Cogstate scores; the Global Cognition effect size against placebo was 0.26 for 50 mg (P=0.0476), 0.41 for 75 mg (P=0.0027), and 0.66 for 100 mg (P=0.0018). No patient-reported outcome or health-related quality of life result was found.

Any adverse event was reported in 62.0%, 72.0%, 63.0%, and 77.8% of participants, treatment-emergent adverse events in 55.6%, 69.2%, 57.4%, and 75.0%, and treatment-related events in 21.3%, 45.8%, 31.5%, and 47.2%. Serious treatment-emergent events occurred in 2 participants with placebo (psychotic disorder and 1 death) and in 1 participant in each LB-102 arm: suicidal ideation with 50 mg and dystonia with 75 mg, both deemed possibly related to treatment, and psychotic disorder with 100 mg, deemed not related. Adverse events led to withdrawal in 2 (1.9%), 2 (1.9%), 3 (2.8%), and 3 (8.3%) participants. The most frequent events were insomnia (22.2%, 25.2%, 21.3%, and 38.9%), headache (9.3%, 11.2%, 8.3%, and 5.6%), anxiety (8.3%, 9.3%, 8.3%, and 11.1%), agitation (9.3%, 10.3%, 5.6%, and 11.1%), and weight increase (3.7%, 12.1%, 7.4%, and 8.3%). The sources report extrapyramidal events at different levels of aggregation. The publication gives an extrapyramidal symptom incidence of 1.9%, 0%, 0.9%, and 2.8% and a dystonia incidence of 0.9%, 0%, 2.8%, and 2.8%. The Form 10-K and a 2026 congress presentation total dystonia, akathisia, and extrapyramidal disorder as 4 (3.7%), 1 (1.0% in the Form 10-K and 0.9% in the presentation), 6 (5.6%), and 2 (5.6%) participants. Akathisia was reported in 1, 1, 2, and 0 participants. Scores on the Simpson-Angus Scale, the Barnes Akathisia Rating Scale, and the Abnormal Involuntary Movement Scale remained stable over time.

Prolactin is reported three ways. As a laboratory finding, elevated prolactin at day 28 was present in 5.2%, 91.0%, 94.0%, and 87.5% of participants, with mean increases of 1.3, 59.9, 51.4, and 51.2 ng/mL. As adverse event terms in the publication, blood prolactin increase was recorded in 0%, 6.5%, 5.6%, and 8.3% of participants and hyperprolactinemia in 0%, 3.7%, 1.9%, and 8.3%; the Form 10-K reports hyperprolactinemia in 0, 11 (10.3%), 8 (7.4%), and 6 (16.7%) participants. Clinical adverse events related to prolactin increase (galactorrhea, breast enlargement, and erectile dysfunction) occurred in 0, 2 (1.9%), 1 (0.9%), and 2 (5.6%) participants. Mean QTc change from baseline to day 28 was 1.2, 4.9, 4.3, and 5.4 milliseconds, a change of 30 milliseconds or more occurred in 1 (0.9%), 5 (4.7%), 1 (0.9%), and 1 (2.8%) participants, and the company states that no participant met the prespecified stopping criteria. The sources differ on weight. The table of changes from baseline in the publication gives a mean weight change of 2.0, 4.3, 3.3, and 2.9 kg. The discussion of the same publication gives 2.1 kg with placebo and a range from 3.5 kg (75 mg) to 4.6 kg (50 mg), and a 2025 poster gives 2.1, 4.6, 3.5, and 3.7 kg. A weight increase of 7% or more occurred in 10.4%, 25.7%, 18.7%, and 8.8% of participants. Placebo-adjusted weight gain was reported as 2 kg in the topline results announcement and as approximately 1.6 kg in the Form 10-K.

In the phase 1 ascending-dose study (64 healthy adults, 48 of whom received LB-102), 4 cases of moderate acute dystonia occurred; 2 of them, at 100 mg twice daily, halted that cohort. QTcF rose by 20 to 46 milliseconds from pre-dose values in all participants given 200 mg once daily, prolactin reached 100 micrograms per liter or more in 11 participants, and the maximum tolerated dose was identified as 150 mg per day. The clinical study report and the NOVA-1 protocol place the single-dose dystonia case at 200 mg once daily, and the publication abstract places it at 100 mg once daily. In the PET study (16 healthy adults), striatal dopamine receptor occupancy at steady state with 50 mg once daily was within the 60% to 80% range, described as approximately 70% in the Form 10-K and as 75% in a 2021 poster, and was approximately 80% with 100 mg. NOVA-2 and NOVA-3 have reported no results. NOVA-2 is a phase 3, randomized, double-blind, placebo-controlled inpatient trial that started in March 2026. It randomizes participants 1:1:1 to LB-102 50 mg, LB-102 100 mg, or placebo for 6 weeks at approximately 25 sites in the United States, and its primary endpoint is the change in PANSS total score at week 6. Planned enrollment is 456 participants in the registry record and approximately 460 in company statements. The company expects topline results in the first half of 2027, and the registry record lists an estimated primary completion of June 2027. NOVA-3 is a 52-week, open-label safety and tolerability trial of flexible dosing from 50 mg to 100 mg in adults with stable schizophrenia. Its planned enrollment is 900 participants, who include participants completing NOVA-2 and newly enrolled participants, and its estimated primary completion is December 2028.