Psychotropic agents and uses thereof

Abstract

Provided herein are methods for treating schizophrenia and / or improving cognition in a subject comprising administering to the subject a therapeutically effective amount of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein or a pharmaceutical composition thereof.

Description

PSYCHOTROPIC AGENTS AND USES THEREOFField of the Invention

[0001] The present disclosure is generally in the field of pharmaceutical compositions and methods for the treatment of neuropsychiatric and / or psychological diseases or disorders.Background

[0002] Schizophrenia is a chronic debilitating mental illness affecting about one percent of the population. The disease manifests in delusional behavior, dysfunctional thinking, agitated body movement, social withdrawal, lack of motion, energy, and motivation, and depression. Schizophrenia patients suffer a profoundly reduced quality of life, and are ten times more likely to commit suicide that the general population.

[0003] Schizophrenia is a lifelong disease for the majority of patients. The course of schizophrenia is highly variable with periods of psychosis and stabilization of varying duration and intensity. Sustained remission of both positive and negative symptoms occurs in a minority of patients even with prolonged antipsychotic therapy. Many patients, even when stable, suffer disability due to the cognitive impairments that occur despite adequate antipsychotic therapy. Compliance with long-term medication is a significant problem due to dissatisfaction with antipsychotic side effects or self-discontinuation of medication as a result of feeling better and no longer perceiving the need for continuous medication. Both of these issues contribute to relapse among schizophrenia patients (World Medical Association 2013).

[0004] Amisulpride (4-amino- / V-(((1 -ethyl-2-py rrolidi ny I) methyl)-5-(ethy Isu Ifo nyl))-2-methoxybenzamide) is an antipsychotic patented in 1981. Amisulpride binds selectively to the human dopaminergic D2 (Ki 2.8 nM) and D3 (Ki 3.2 nM) receptor subtypes without any affinity for Di, D4 and D5 receptor subtypes. Unlike classical and atypical neuroleptics, amisulpride displays low affinity for serotonin, alpha-adrenergic, histamine receptor subtypes, muscarinic receptors and sigma sites though it has also been demonstrated to bind 5-HT2B and HT?a receptors with low double digit nM Ki. This ability of amisulpride to bind 5-HT receptors is thought to result in amisulpride’s ability to treat1184896963.4symptoms of depression, improve cognition, and may explain amisulpride’s ability to treat negative symptoms of schizophrenia. Interestingly, compared to other antipsychotics, amisulpride is not noted to have any activity at the 5-HT2a receptor.

[0005] Despite the unique properties of amisulpride, the drug has low ability to cross the blood brain barrier (BBB) to interact with the receptors in the brain. In a 2014 study, passive diffusion of amisulpride across a PAMPA membrane (measured as Pe) was the lowest of 30 psychiatric drugs tested. Thus, dosing of amisulpride is two times a day and high, typically 400 to 800 mg / d (thus 1,200 mg / day is not uncommon). Such a high dose may cause adverse effects to the treated subjects.Summary of the Invention

[0006] Provided herein are uses of amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) and pharmaceutical compositions thereof. In certain embodiments, the amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein are dopamine and / or serotonin antagonists. In certain embodiments, the amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein have improved membrane (e.g., BBB) permeability compared to amisulpride. In certain embodiments, the amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) can act as central nervous system (ONS) dopamine and / or serotonin antagonists. These amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) have structures of Formula IA, Formula IB or Formula IC disclosed herein, including pharmaceutically acceptable salts thereof, stereoisomers thereof (e.g., Formula IA-S, Formula IA-R, Formula IB-S, Formula IB-R, Formula IC-S, and Formula IC-R), or deuterated analogs of structures of Formula IA, Formula IB, Formula IC, Formula IA-S, Formula IA-R, Formula IB-S, Formula IB-R, Formula IC-S, or Formula IC-R. In certain embodiments, the use of amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) and pharmaceutical compositions thereof comprises administering to a subject one, two, three, or four unit doses of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) or pharmaceutical composition disclosed herein. In certain embodiments, the use of amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) and2184896963.4pharmaceutical compositions thereof comprises administering to the subject one, two, three, or four unit doses of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) or pharmaceutical composition disclosed herein once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week. In certain embodiments, the unit dose is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, or at a dose disclosed herein. In certain embodiments, the use of amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) and pharmaceutical compositions thereof further comprises a low risk of adverse events (AEs) incurred with administration of amisulpride, other schizophrenia treatments, or antipsychotic treatments. Examples of said adverse events include, without limitation, extrapyramidal side effects (EPS, e.g., without limitation, dystonia, akathisia, and extrapyramidal disorder), sedation, and AEs related to prolactin increase (e.g., without limitation, galactorrhoea, breast enlargement, and erectile dysfunction).

[0007] In certain embodiments, the use of amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) and pharmaceutical compositions thereof is a method for delivering a dopamine and / or serotonin (e.g., 5-HT2a, 5-HT?) and / or alpha-2 adrenergic (a2) receptor antagonist to the brain of the subject comprising administering to the subject a therapeutically effective amount of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein or a pharmaceutical composition thereof, either individually or in combination with other CNS active agents; and the dopamine and / or serotonin and / or a2 receptor antagonist level in the brain being higher than administering to the subject amisulpride at a comparable dose. In certain embodiments, the method comprises administering to a subject one, two, three, or four unit doses of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) or pharmaceutical composition disclosed herein. In certain embodiments, the method comprises administering to the subject one, two, three, or four unit doses of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) or pharmaceutical composition disclosed herein once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or3184896963.4once a week. In certain embodiments, the unit dose is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, or at a dose disclosed herein. In certain embodiments, the method further comprises a low risk of adverse events (AEs) incurred with administration of amisulpride, other schizophrenia treatments, or antipsychotic treatments. Examples of said adverse events include, without limitation, EPS (e.g., without limitation, dystonia, akathisia, and extrapyramidal disorder), sedation, and AEs related to prolactin increase (e.g., without limitation, galactorrhoea, breast enlargement, and erectile dysfunction).

[0008] In certain embodiments, the use of amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) and pharmaceutical compositions thereof is a method for antagonizing dopamine and / or serotonin (e.g., 5-HT2a, 5-HT?) and / or a2 receptor in the subject comprising administering to a subject a therapeutically effective amount of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein or pharmaceutical compositions thereof, either individually or in combination with other CNS active agents. In certain embodiments, the method comprises administering to a subject one, two, three, or four unit doses of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) or pharmaceutical composition disclosed herein. In certain embodiments, the method comprises administering to the subject one, two, three, or four unit doses of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) or pharmaceutical composition disclosed herein once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week. In certain embodiments, the unit dose is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, or at a dose disclosed herein. In certain embodiments, the method further comprises a low risk of adverse events (AEs) incurred with administration of amisulpride, other schizophrenia treatments, or antipsychotic treatments. Examples of said adverse events include, without limitation, EPS (e.g., without limitation, dystonia, akathisia, and extrapyramidal disorder), sedation, and AEs4184896963.4related to prolactin increase (e.g., without limitation, galactorrhoea, breast enlargement, and erectile dysfunction).

[0009] In certain embodiments, the use of amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) and pharmaceutical compositions thereof is a method for treating one or more conditions responsive to modulation of dopamine and / or serotonin (e.g., 5-HT2a, 5-HT?) and / or a2 receptor in a subject comprising administering to a subject a therapeutically effective amount of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein or pharmaceutical compositions thereof, either individually or in combination with other CNS active agents. In certain embodiments, the method comprises administering to a subject one, two, three, or four unit doses of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) or pharmaceutical composition disclosed herein. In certain embodiments, the method comprises administering to the subject one, two, three, or four unit doses of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) or pharmaceutical composition disclosed herein once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week. In certain embodiments, the unit dose is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, or at a dose disclosed herein. In certain embodiments, the method further comprises a low risk of adverse events (AEs) incurred with administration of amisulpride, other schizophrenia treatments, or antipsychotic treatments. Examples of said adverse events include, without limitation, EPS (e.g., without limitation, dystonia, akathisia, and extrapyramidal disorder), sedation, and AEs related to prolactin increase (e.g., without limitation, galactorrhoea, breast enlargement, and erectile dysfunction).

[0010] In certain embodiments, the use of amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) and pharmaceutical compositions thereof is a method for treating one or more disorders associated with an abnormality in levels of dopamine and / or serotonin in the brain, comprising administering to a subject a therapeutically effective amount of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein or pharmaceutical compositions thereof,5184896963.4either individually or in combination with other CNS active agents. In certain embodiments, the method comprises administering to a subject one, two, three, or four unit doses of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) or pharmaceutical composition disclosed herein. In certain embodiments, the method comprises administering to the subject one, two, three, or four unit doses of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) or pharmaceutical composition disclosed herein once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week. In certain embodiments, the unit dose is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, or at a dose disclosed herein. In certain embodiments, the method further comprises a low risk of adverse events (AEs) incurred with administration of amisulpride, other schizophrenia treatments, or antipsychotic treatments. Examples of said adverse events include, without limitation, EPS (e.g., without limitation, dystonia, akathisia, and extrapyramidal disorder), sedation, and AEs related to prolactin increase (e.g., without limitation, galactorrhoea, breast enlargement, and erectile dysfunction).

[0011] Examples of the conditions responsive to modulation of dopamine and / or serotonin (e.g., 5-HT2a, 5-HT7) and / or a2 receptor and / or and the disorders associated with abnormality in levels of dopamine and / or serotonin in the brain include, e.g., without limitation, mental illnesses. Examples of the mental illnesses include, without limitation, schizophrenia, symptoms of schizophrenia, schizoaffective disorder, bipolar disorder, depression, bipolar depression I, bipolar depression II, obsessive-compulsive disorder, Alzheimer’s psychosis, oppositional defiant disorder, agitation, aggression, suicidality, hostility, personality disorders, chronic fatigue syndrome, predominantly negative symptoms of schizophrenia, Charles Bonnet Syndrome, autism, and Tourette’s disorder.

[0012] Also provided herein is a unit dose of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) or pharmaceutical composition disclosed herein, the unit dose comprises a pharmaceutical composition comprising a therapeutically effective amount of the amisulpride derivative, and the therapeutically effective amount being about 10 mg to about 250 mg, about 10 mg to about 225 mg, about 10 mg to about6184896963.4200 mg, about 10 mg to about 175 mg, about 10 mg to about 150 mg, about 10 mg to about 125 mg, about 10 mg to about 100 mg, about 10 mg to about 75 mg, about 10 mg to about 50 mg, about 10 mg to about 25 mg, about 25 mg to about 250 mg, about 25 mg to about 225 mg, about 25 mg to about 200 mg, about 25 mg to about 175 mg, about 25 mg to about 150 mg, about 25 mg to about 125 mg, about 25 mg to about 100 mg, about 25 mg to about 75 mg, about 25 mg to about 50 mg, about 50 mg to about 250 mg, about 50 mg to about 225 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 50 mg to about 150 mg, about 50 mg to about 125 mg, about 50 mg to about 100 mg, about 50 mg to about 75 mg, about 75 mg to about 250 mg, about 75 mg to about 225 mg, about 75 mg to about 200 mg, about 75 mg to about 175 mg, about 75 mg to about 150 mg, about 75 mg to about 125 mg, about 75 mg to about 100 mg, about 100 mg to about 250 mg, about 100 mg to about 225 mg, about 100 mg to about 200 mg, about 100 mg to about 175 mg, about 100 mg to about 150 mg, about 100 mg to about 125 mg, about 125 mg to about 250 mg, about 125 mg to about 225 mg, about 125 mg to about 200 mg, about 125 mg to about 175 mg, about 125 mg to about 150 mg, about 150 mg to about 250 mg, about 150 mg to about 225 mg, about 150 mg to about 200 mg, about 150 mg to about 175 mg, about 175 mg to about 250 mg, about 175 mg to about 225 mg, about 175 mg to about 200 mg, about 200 mg to about 250 mg, about 200 mg to about 225 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, or about 250 mg.

[0013] Also provided herein is a kit for use of amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) and pharmaceutical compositions thereof, as disclosed herein. In certain embodiments, the kit comprises one or more unit doses of amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) and / or pharmaceutical compositions disclosed herein. In certain embodiments, the kit further comprises instructions for the use of amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) and pharmaceutical compositions disclosed herein.7184896963.4Brief Description of the Drawings

[0014] Fig. 1A: The study schematic of a randomized, double-blinded, placebo-controlled, multicenter clinical study disclosed in Example 1.

[0015] Fig. 1 B: Participant disposition of the randomized, double-blinded, placebo-controlled, multicenter clinical study disclosed in Example 1.

[0016] Fig. 2: Positive and negative symptoms scale (PANSS) effect size across acute schizophrenia trials (clozapine, amisulpride, risperidone, paliperidone, aripiprazole, lurasidone, and cariprazine, brexpiprazole, and KarXT).

[0017] Fig. 3: Efficacy comparison of LB-102 (50 mg, 75 mg, 100 mg, 4 weeks), caplyta (42 mg dose, 4 weeks), cobenfy (5 weeks), rexulti (2 mg and 4 mg doses, 6 weeks), plotted using the total PANSS difference (PANSS A) from placebo (PBO) (±95% Cl). “Average” refers to the average of the total PANSS scores of all drugs shown in the figure. Data of caplyta, cobenfy, and rexulti were obtained from FDA labels. Cl: Confidence Interval.

[0018] Fig. 4A: QTcF interval (ms) in treatment arms of LB-102 (50 mg QD, 75 mg QD, 100 mg QD) and placebo arm, as described in Example 1. SD means standard deviation.

[0019] Fig. 4B: Mean AQTcF (ms) from baseline in treatment arms of LB-102 (50 mg QD, 75 mg QD, 100 mg QD) and placebo arm, as described in Example 1.

[0020] Fig. 5: Weight change from baseline (±SEM) in treatment arms of LB-102 (50 mg QD, 75 mg QD, 100 mg QD) and placebo arm, as described in Example 1.

[0021] Fig. 6A: Primary efficacy endpoint, table of change from baseline to week 4 in the PANSS total score, primary analysis, ITT Analysis Set. SE: Standard Error; LS: Least Squares; MMRM: Mixed Model for Repeated Measures; MAR: Missing At Random; MNAR: Missing Not At Random. Baseline was defined as the last non-missing value (either scheduled, unscheduled or repeat) before the patient receives the first dose of study drug. Missing PANSS total scores were imputed using a mixture of MAR and MNAR approaches depending on the reason for missingness. Estimates were obtained from a MMRM including treatment group, pooled study site, visit, visit by treatment interaction and baseline total PANSS score. Correlation within patients was accounted for with an unstructured matrix. Results were pooled across imputed datasets using8184896963.4Rubin’s rules. Hochberg’s step-down procedure was adopted to control type I error across the 50 and 75 mg arms.

[0022] Fig. 6B: Primary efficacy endpoint, table of change from baseline to week 4 in the PANSS total score, sensitivity analysis #1 (re-mapped ET assessments), ITT Analysis Set. ET: Early Termination. PANSS assessments occurred at an ET visit were re-mapped to the closest scheduled visit and included in the analysis. Baseline was defined as the last non-missing value (either scheduled, unscheduled or repeat) before the patient receives the first dose of study drug. Missing PANSS total scores were imputed using a mixture of MAR and MNAR approaches depending on the reason for missingness. Estimates were obtained from a MMRM including treatment group, pooled study site, visit, visit by treatment interaction and baseline total PANSS score. Correlation within patients was accounted for with an unstructured matrix. Results were pooled across imputed datasets using Rubin’s rules. Hochberg’s step-down procedure was adopted to control type I error across the 50 and 75 mg arms.

[0023] Fig. 6C: Primary efficacy endpoint, table of change from baseline to week 4 in the PANSS total score, Sensitivity Analysis #3 (Copy-Reference Imputation), ITT Analysis Set. Baseline was defined as the last non-missing value (either scheduled, unscheduled or repeat) before the patient receives the first dose of study drug. Missing PANSS total scores were imputed using a mixture of MAR and MNAR (copy-reference) approaches depending on whether they were due to drop-out for any reason or not. Estimates were obtained from a MMRM including treatment group, pooled study site, visit, visit by treatment interaction and baseline total PANSS score. Correlation within patients was accounted for with an unstructured matrix. Results were pooled across imputed datasets using Rubin’s rules.

[0024] Fig. 6D: Change from baseline in PANSS total score over time through Week 4.

[0025] Fig. 6E: Primary efficacy endpoint, change from baseline to week 4 in the PANSS total score, sensitivity analysis #2 (Tipping Point Analysis), ITT Analysis Set.

[0026] Fig. 6F: Table of change from baseline to week 4 in PANSS total score in patients with PANSS negative symptoms subscale score >24 at baseline.9184896963.4

[0027] Fig. 7A: Secondary efficacy endpoint, table of change from baseline to week 4 in the PANSS positive subscale score, ITT Analysis Set. Missing PANSS Positive Subscale scores were imputed using a mixture of MAR and MNAR approaches depending on the reason for missingness. Estimates were obtained from a MMRM including treatment group, pooled study site, visit, visit by treatment interaction and baseline PANSS Positive Subscale score. Correlation within patients was accounted for with an unstructured matrix. Results were pooled across imputed datasets using Rubin’s rules.

[0028] Fig. 7B: Secondary efficacy endpoint, table of change from baseline to week 4 in the PANSS negative subscale score, ITT Analysis Set. Missing PANSS Negative Subscale scores were imputed using a mixture of MAR and MNAR approaches depending on the reason for missingness. Estimates were obtained from a MMRM including treatment group, pooled study site, visit, visit by treatment interaction and baseline PANSS Negative Subscale score. Correlation within patients was accounted for with an unstructured matrix. Results were pooled across imputed datasets using Rubin’s rules.

[0029] Fig. 7C: LS mean PANSS changes from baseline in positive symptoms at Week 4. Left: PANSS Positive Symptoms; Right: PANSS Marder Positive Factor.

[0030] Fig. 7D: LS mean (±SE) change in PANSS positive symptoms subscale score over time through Week 4. Solid triangle: placebo (n=108), solid square: LB-102 50 mg (n=107), solid diamond: LB-102 75 mg (n=108), and solid dot: LB-102 100 mg (n=36).

[0031] Fig. 7E: LS mean (±SE) change in PANSS Marder positive symptoms factor score over time through Week 4. Solid triangle: placebo (n=108), solid square: LB-102 50 mg (n=107), solid diamond: LB-102 75 mg (n=108), and solid dot: LB-102 100 mg (n=36).

[0032] Fig. 7F: LS mean (±SE) change in PANSS negative symptoms subscale score in the total population over time through Week 4. Solid triangle: placebo (n=108), solid square: LB-102 50 mg (n=107), solid diamond: LB-102 75 mg (n=108), and solid dot: LB-102 100 mg (n=36).10184896963.4

[0033] Fig. 7G: LS mean (±SE) change in PANSS negative symptoms subscale score over time through Week 4 in participants with PANSS negative symptoms subscale score >24 at baseline. Solid triangle: placebo (n=108), solid square: LB-102 50 mg (n=107), solid diamond: LB-10275 mg (n=108), and solid dot: LB-102 100 mg (n=36).

[0034] Fig. 7H: Secondary efficacy endpoint, table of change from baseline to Week 4 in Marder Factor PANSS Scores ITT Analysis Set, wherein the Marder Factor was negative symptoms.

[0035] Fig. 7I: Secondary efficacy endpoint, table of change from baseline to Week 4 in Marder Factor PANSS Scores ITT Analysis Set, wherein the Marder Factor was positive symptoms.

[0036] Fig. 7J: Secondary efficacy endpoint, table of change from baseline to Week 4 in Marder Factor PANSS Scores ITT Analysis Set, wherein the Marder Factor was disorganized thought.

[0037] Fig. 7K: Secondary efficacy endpoint, table of change from baseline to Week 4 in Marder Factor PANSS Scores ITT Analysis Set, wherein the Marder Factor was uncontrolled hostility / excitement.

[0038] Fig. 7L: Secondary efficacy endpoint, table of change from baseline to Week 4 in Marder Factor PANSS Scores ITT Analysis Set, wherein the Marder Factor was anxiety / depression.

[0039] Fig. 7M: Change from baseline to week 4 in PANSS Marder Factor Scores. From left to right: positive symptoms, disorganized thought, uncontrolled hostility I excitement, negative symptoms, and anxiety / depression. *: p<0.05 vs. placebo; and **: p<0.01 vs. placebo.

[0040] Fig. 7N: Percentage of >20% PANSS Responders at Week 4, post hoc, floor-adjusted. From the left to right: placebo (n=108), LB-102 50 mg (n=107), LB-102 75 mg (n=108), and LB-102 100 mg (n=36).

[0041] Fig. 8A: Overall summary of treatment-emergent adverse events (TEAEs), safety analysis set. Treatment-related adverse events are those marked as either ‘Possibly Related’ or ‘Related’ by the investigator. Adverse events with missing relationship were considered as related. Percentages are based on the number of subjects in the Safety Analysis Set by treatment group and overall.11184896963.4

[0042] Fig. 8B: Treatment-emergent adverse events (TEAEs) by system organ class and preferred term, safety analysis set. Percentages were based on the number of patients in the Safety Analysis Set by treatment group and overall. Patients were counted once at the Any level and within each system organ class and preferred term reported. Adverse events were coded using MedDRA 26.1.

[0043] Fig. 9A: LS mean change from Baseline in CGI-S Score at Week 4. From the left to right: placebo (n=108), LB-102 50 mg (n=107), LB-102 75 mg (n=108), and LB-102 100 mg (n=36).

[0044] Fig. 9B: CGI-S score at baseline provided by percentage of patients in each arm, from the left to right: placebo (n=108), LB-102 50 mg (n=107), LB-102 75 mg (n=108), and LB-102 100 mg (n=36).

[0045] Fig. 9C: CGI-S score at Week 4 provided by percentage of patients in each arm, from the left to right: placebo (n=108), LB-102 50 mg (n=107), LB-102 75 mg (n=108), and LB-102 100 mg (n=36). 0 means 0 patients in the corresponding arm for the corresponding CGI-s score.

[0046] Fig. 9D: Cogstate usability and acceptability analysis.

[0047] Fig. 9E: Impact of LB-102 vs. Placebo on Cogstate Composite Scores After 4 Weeks of Treatment. Post hoc analysis. Outliners on the Groton Maze Learning Test (i.e., total errors > 150) were removed before generating composite scores. Effect size (Cohen’s d) interpretation: <0.2 = trivial, 0.2 to 0.5 = small, >0.5 to 0.8 = moderate, >0.8 to 1.1 = large, >1.1 = very large. Bold and italic indicates a clinically relevant value (effect size >=0.2) with statistical significance favoring LB-102 over placebo (p<0.05). Bold without italic indicates a clinically relevant value (effect size >0.2) not considered statistically significance (p>0.05).

[0048] Fig. 9F: The effect of LB-102 treatment (all dose level) on composites with PANSS total score as mediator. If the 95% Cl estimated from bootstrapping did not include zero, then p-value was noted as < 0.05. If the 95% Cl estimated from bootstrapping included zero, then p-value was noted as > 0.05.

[0049] Fig. 9G: The effect of LB-102 treatment by dose level on composites with PANSS total score as mediator. If the 95% Cl estimated from bootstrapping did not12184896963.4include zero, then p-value was noted as < 0.05. If the 95% Cl estimated from bootstrapping included zero, then p-value was noted as > 0.05.

[0050] Fig. 9H: The effect of LB-102 treatment (all dose level) on composites with PANSS positive subscale scores as mediator. If the 95% Cl estimated from bootstrapping did not include zero, then p-value was noted as < 0.05. If the 95% Cl estimated from bootstrapping included zero, then p-value was noted as > 0.05.

[0051] Fig. 9I: The effect of LB-102 treatment by dose level on composites with PANSS positive subscale scores as mediator. If the 95% Cl estimated from bootstrapping did not include zero, then p-value was noted as < 0.05. If the 95% Cl estimated from bootstrapping included zero, then p-value was noted as > 0.05.

[0052] Fig. 9J: The effect of LB-102 treatment (all dose level) on composites with PANSS negative subscale scores as mediator. If the 95% Cl estimated from bootstrapping did not include zero, then p-value was noted as < 0.05. If the 95% Cl estimated from bootstrapping included zero, then p-value was noted as > 0.05.

[0053] Fig. 9K: The effect of LB-102 treatment by dose level on composites with PANSS negative subscale scores as mediator. If the 95% Cl estimated from bootstrapping did not include zero, then p-value was noted as < 0.05. If the 95% Cl estimated from bootstrapping included zero, then p-value was noted as > 0.05.

[0054] Fig. 9L: Categorical change from baseline to Week 4 in CGI-S.Detailed Description of the Invention

[0055] As shown in Example 1, a randomized, double-blinded, placebo-controlled, multicenter clinical study was carried out to evaluate the antipsychotic efficacy, safety, tolerability, and PK of LB-102 at 50 mg QD, 75 mg QD, and 100 mg QD versus placebo in adult patients diagnosed with schizophrenia having an acute exacerbation of psychosis. Both 50 mg and 75 mg doses were statistically superior to placebo using Hochberg multiplicity correction (Figs. 6A-6E, and 7A-7C). The exploratory 100 mg dose also achieved statistical significance on its own. The 50 mg dose arm (n=107) led to a 5.0-point reduction in PANSS total score compared to placebo (p=0.0009). Treatment with the 75 mg dose arm (n=108) led to a 4.7-point reduction in PANSS total score compared to placebo (p=0.0022). The exploratory dose of 100 mg (n=36) demonstrated13184896963.4a 6.8-point reduction in PANSS total score compared to placebo (p=0.0017). The effect size (Hedges’ g, Table 1 D) of LB-102 at 50 mg was 0.61; the effect size g at 75 mg was 0.41 and the effect size g at 100 mg was 0.83, calculated using a methodology similar to that used by Karuna for its phase 3 trials (0.6), and as described in the Statistical Procedure herein. The effect size g of 0.83 at 100 mg was greater than the effect size of Cobenfy Rein Phase 3 and was almost double that of Caplyta (https: / / jamanetwork.com / journals / jamapsychiatry / fullarticle / 2758022). Also see PANSS effect size across acute schizophrenia trials of clozapine, amisulpride, risperidone, paliperidone, aripiprazole, lurasidone, and cariprazine (The Lancet.2019;394(10209):939-949), as well as brexpiprazole (European Neuropsychopharmacology. 2025;92;62-73). MMRM based standard effect sizes (Table 1 D) yielded directionally consistent results (Standard effect size A= 0.50 for LB-102 50 mg; A= 0.45 for LB-10275 mg; and A= 0.64 for LB-102100 mg). The treatment effect of LB-102 was observed as early as week 1 and maintained throughout the 4-week treatment period. Sensitivity analyses supported the primary findings.

[0056] LB-102 demonstrated a positive shift on the CGI-S, resulting in a significant decrease in disease severity for patients with acute schizophrenia (Figs. 9A-9C, Fig. 9L). Least-squares mean change from baseline to week 4 in CGI-S scores were: Placebo, -0.39; LB-102 50 mg, -0.72 (P=0.0008 vs placebo); LB-102 75 mg, -0.67 (P=0.0048 vs placebo); and LB-102100 mg, -0.84 (P=0.0026 vs placebo). The change from baseline to week 4 on the CGI S was associated with a statistically significant improvement in disease severity for all LB-102 doses compared to placebo. Analysis of CGI-S responders at week 4 demonstrated statistical significance for LB-102 50 mg and 75 mg compared to placebo.

[0057] Evaluation of adverse events in the clinical study show that LB-102 was generally safe and well-tolerated. Compared to the double digit rate of EPS in patients treated with amisulpride (e.g., 11% according to Australian label for Solian; and about 15% for patients with acute exacerbations of schizophrenia, see Curran 2001, Fig. 2A), LB-102 treatment showed significantly low rates of EPS (e.g., without limitation, dystonia, akathisia, and extrapyramidal disorder) in all doses (Table 3A, total EPS rate 1.0% for 50 mg dose, 5.6% for 75 mg and 100 mg doses, and 3.7% for placebo group). Other14184896963.4noticeable AEs that showed low rates in LB-102 treatment groups include, without limitation, sedation (Table 3B), gastrointestinal side effects, and AEs related to prolactin increase (e.g., without limitation, galactorrhoea, breast enlargement, and erectile dysfunction) (Table 3C). The Australian label for Solian lists amenorrhea at 4%, galactorrhea at 3%, menstrual disorder at 1%, and 1% vaginitis. Average QTcF prolongation over placebo was ~4 ms, ~3 ms, and ~4 ms at 50 mg, 75 mg, and 100 mg, respectively, on Day 28 (Figs. 4A-4B). There was no statistically significant differences between placebo and treatment arms, or among the treatment arms at different doses (Fig. 4B). Stopping criteria (increase in QTcF of 60 ms or an absolute value of > 500 ms) was never reached. The average placebo-adjusted weight gain for treated subjects was 2 kg (Fig. 5).

[0058] Provided herein are uses of amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) and pharmaceutical compositions thereof. In certain embodiments, the amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein are dopamine and / or serotonin antagonists. In certain embodiments, the amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein have improved membrane (e.g., BBB) permeability compared to amisulpride. In certain embodiments, the amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) can act as central nervous system (ONS) dopamine and / or serotonin antagonists. In certain embodiments, the amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein more selectively bind to dopamine D2 and / or D3 receptor over dopamine Di, D4 and / or Ds receptor. In certain embodiments, the amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein are capable of interacting dopamine and / or serotonin and / or a2receptors in CNS.

[0059] These amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) have structures of Formula IA, Formula IB or Formula IC disclosed herein, including pharmaceutically acceptable salts thereof, stereoisomers thereof (e.g., Formula IA-S, Formula IA-R, Formula IB-S, Formula IB-R, Formula IC-S, and Formula IC-R), or deuterated analogs of structures of Formula IA, Formula IB, Formula IC, Formula IA-S, Formula IA-R, Formula IB-S, Formula IB-R, Formula IC-S, or Formula IC-R.15184896963.4

[0060] In certain embodiments, deuterated analogs of a compound has one or more hydrogens of the compound replaced by deuterium. In certain embodiments, one or more deuteriums in the deuterated analog are present in at least 100 times the natural abundance level.

[0061] Provided herein are pharmaceutical compositions comprising one or more of the amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein and a pharmaceutically acceptable carrier. In certain embodiments, the one or more of the amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) the pharmaceutical compositions comprise are substantially enantiomerically pure, and such pharmaceutical compositions are also referred to as substantially enantiomerically pure pharmaceutical compositions. In certain embodiments, the term “substantially enantiomerically pure” means enantiomerical purity of about 50% or higher, about 60% or higher, about 70% or higher, about 80% or higher, about 90% or higher, about 95% or higher, or about 98% or higher.

[0062] Provided herein is a unit dose of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) or pharmaceutical composition disclosed herein, the unit dose comprises a pharmaceutical composition comprising a therapeutically effective amount of the amisulpride derivative, and the therapeutically effective amount being about 10 mg to about 250 mg, about 10 mg to about 225 mg, about 10 mg to about 200 mg, about 10 mg to about 175 mg, about 10 mg to about 150 mg, about 10 mg to about 125 mg, about 10 mg to about 100 mg, about 10 mg to about 75 mg, about 10 mg to about 50 mg, about 10 mg to about 25 mg, about 25 mg to about 250 mg, about 25 mg to about 225 mg, about 25 mg to about 200 mg, about 25 mg to about 175 mg, about 25 mg to about 150 mg, about 25 mg to about 125 mg, about 25 mg to about 100 mg, about 25 mg to about 75 mg, about 25 mg to about 50 mg, about 50 mg to about 250 mg, about 50 mg to about 225 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 50 mg to about 150 mg, about 50 mg to about 125 mg, about 50 mg to about 100 mg, about 50 mg to about 75 mg, about 75 mg to about 250 mg, about 75 mg to about 225 mg, about 75 mg to about 200 mg, about 75 mg to about 175 mg, about 75 mg to about 150 mg, about 75 mg to about 125 mg, about 75 mg to about 100 mg, about 100 mg to about 250 mg, about 100 mg to about 225 mg, about 100 mg to about 200 mg,16184896963.4about 100 mg to about 175 mg, about 100 mg to about 150 mg, about 100 mg to about 125 mg, about 125 mg to about 250 mg, about 125 mg to about 225 mg, about 125 mg to about 200 mg, about 125 mg to about 175 mg, about 125 mg to about 150 mg, about 150 mg to about 250 mg, about 150 mg to about 225 mg, about 150 mg to about 200 mg, about 150 mg to about 175 mg, about 175 mg to about 250 mg, about 175 mg to about 225 mg, about 175 mg to about 200 mg, about 200 mg to about 250 mg, about 200 mg to about 225 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, or about 250 mg.

[0063] In certain embodiments, the use of amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) and pharmaceutical compositions thereof is a method for delivering a dopamine and / or serotonin (e.g., 5-HT2a, 5-HT?) and / or alpha-2 adrenergic (a2) receptor antagonist to the brain of a subject comprising administering to the subject a therapeutically effective amount of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein or a pharmaceutical composition thereof; and the dopamine and / or serotonin and / or o2 receptor antagonist level in the brain being higher than administering to the subject amisulpride at a comparable dose. In certain embodiments, the method comprises administering to a subject one, two, three, or four unit doses of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) or pharmaceutical composition disclosed herein. In certain embodiments, the method comprises administering to the subject one, two, three, or four unit doses of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) or pharmaceutical composition disclosed herein once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week. In certain embodiments, the unit dose is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, or at a dose disclosed herein. In certain embodiments, the method further comprises a low risk of adverse events (AEs) incurred with administration of amisulpride, other schizophrenia17184896963.4treatments, or antipsychotic treatments. Examples of said adverse events include, without limitation, EPS (e.g., without limitation, dystonia, akathisia, and extrapyramidal disorder), sedation, and AEs related to prolactin increase (e.g., without limitation, galactorrhoea, breast enlargement, and erectile dysfunction).

[0064] In certain embodiments, the use of amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) and pharmaceutical compositions thereof is a method for antagonizing dopamine and / or serotonin (e.g., 5-HT2a, 5-HT?) and / or a2 receptor in a subject comprising administering to a subject a therapeutically effective amount of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein or pharmaceutical compositions thereof, either individually or in combination with other CNS active agents. In certain embodiments, the method comprises administering to a subject one, two, three, or four unit doses of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) or pharmaceutical composition disclosed herein. In certain embodiments, the method comprises administering to the subject one, two, three, or four unit doses of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) or pharmaceutical composition disclosed herein once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week. In certain embodiments, the unit dose is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, or at a dose disclosed herein. In certain embodiments, the method further comprises a low risk of adverse events (AEs) incurred with administration of amisulpride, other schizophrenia treatments, or antipsychotic treatments. Examples of said adverse events include, without limitation, EPS (e.g., without limitation, dystonia, akathisia, and extrapyramidal disorder), sedation, and AEs related to prolactin increase (e.g., without limitation, galactorrhoea, breast enlargement, and erectile dysfunction).

[0065] In certain embodiments, the use of amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) and pharmaceutical compositions thereof is a method for treating one or more conditions responsive to modulation of dopamine and / or serotonin (e.g., 5-HT2a, 5-HT?) and / or a2 receptor in a subject comprising administering18184896963.4to a subject a therapeutically effective amount of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein or pharmaceutical compositions thereof, either individually or in combination with other CNS active agents. In certain embodiments, the method comprises administering to a subject one, two, three, or four unit doses of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) or pharmaceutical composition disclosed herein. In certain embodiments, the method comprises administering to the subject one, two, three, or four unit doses of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) or pharmaceutical composition disclosed herein once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week. In certain embodiments, the unit dose is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, or at a dose disclosed herein. In certain embodiments, the method further comprises a low risk of adverse events (AEs) incurred with administration of amisulpride, other schizophrenia treatments, or antipsychotic treatments. Examples of said adverse events include, without limitation, EPS (e.g., without limitation, dystonia, akathisia, and extrapyramidal disorder), sedation, and AEs related to prolactin increase (e.g., without limitation, galactorrhoea, breast enlargement, and erectile dysfunction).

[0066] In certain embodiments, the use of amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) and pharmaceutical compositions thereof is a method for treating one or more disorders associated with an abnormality in levels of dopamine and / or serotonin in the brain, comprising administering to a subject a therapeutically effective amount of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein or pharmaceutical compositions thereof, either individually or in combination with other CNS active agents. In certain embodiments, the method comprises administering to a subject one, two, three, or four unit doses of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) or pharmaceutical composition disclosed herein. In certain embodiments, the method comprises administering to the subject one, two, three, or four unit doses of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) or19184896963.4pharmaceutical composition disclosed herein once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week. In certain embodiments, the unit dose is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, or at a dose disclosed herein. In certain embodiments, the method further comprises a low risk of adverse events (AEs) incurred with administration of amisulpride, other schizophrenia treatments, or antipsychotic treatments. Examples of said adverse events include, without limitation, EPS (e.g., without limitation, dystonia, akathisia, and extrapyramidal disorder), sedation, and AEs related to prolactin increase (e.g., without limitation, galactorrhoea, breast enlargement, and erectile dysfunction).

[0067] Examples of the conditions responsive to modulation of dopamine and / or serotonin (e.g., 5-HT2a, 5-HT?) and / or a2 receptor and / or and the disorders associated with abnormality in levels of dopamine and / or serotonin in the brain include, e.g., without limitation, mental illnesses. Examples of the mental illnesses include, without limitation, schizophrenia, symptoms of schizophrenia, schizoaffective disorder, bipolar disorder, bipolar depression I, bipolar depression II, depression, obsessive-compulsive disorder, Alzheimer’s psychosis, oppositional defiant disorder, agitation, aggression, suicidality, hostility, personality disorders, chronic fatigue syndrome, predominantly negative symptoms of schizophrenia, Charles Bonnet Syndrome, autism, and Tourette’s disorder.4-Amino Substituted Amisulpride derivativesN N H H O OMe Amisulpride LB-102

[0068] In certain embodiments, the amisulpride derivative is a 4-amino substituted derivative of amisulpride having a structure of Formula IA:20184896963.4Formula IAincluding pharmaceutically acceptable salts and stereoisomers thereof, and X and Z are the same or different and independently selected from the group consisting of hydrogen, alkyl (either branched or unbranched, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, and s-butyl), alkenyl (either branched or unbranched, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, and s-butyl), alkynyl (either branched or unbranched, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, and s-butyl), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl), heterocyclyl, heterocyclylalkyl, aryl (e.g., phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl), arylalkyl (e.g., -CH2C6H5, and -C2H5C6H5), heteroarylalkyl (e.g., -CH2C6H4N, and -C2H5C6H4N), and heteroaryl with one or two or three or more hetero ring atoms (such as pyridine, pyrrole, furan, thiophene, or pyrimidine), optionally the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroarylalkyl, and heteroaryl groups are further substituted with one or more substitution groups selected from the group consisting of halogens such as chlorine, bromine and fluorine, amines, hydroxy groups, carboxylic acids, nitro groups, carbonyl and other alkyl and aryl groups as defined herein; with the proviso that at least one of X and Z is not hydrogen.

[0069] In certain embodiments, the 4-amino substituted derivative of amisulpride is a stereoisomer having a structure of Formula IA-R:21184896963.4Formula IA-Rincluding pharmaceutically acceptable salts thereof, and X and Z are defined the same as above with respect to Formula IA.

[0070] In certain embodiments, the 4-amino substituted derivative of amisulpride is a stereoisomer having a structure of Formula IA-S:Formula IA-Sincluding pharmaceutically acceptable salts thereof, and X and Z are defined the same as above with respect to Formula IA.

[0071] In certain embodiments, the amisulpride derivative is a 4-amino substituted derivative of amisulpride having a structure of Formula IB:Formula IB22184896963.4including pharmaceutically acceptable salts and stereoisomers thereof, and Z is defined the same as above with respect to Formula IA with the proviso that Z is not H.

[0072] In certain embodiments, the 4-amino substituted derivative of amisulpride is a stereoisomer having a structure of Formula IB-R:Formula IB-Rincluding pharmaceutically acceptable salts thereof, and Z is defined the same as above with respect to Formula IA with the proviso that Z is not H.

[0073] In certain embodiments, the 4-amino substituted derivative of amisulpride is a stereoisomer having a structure of Formula IB-S:Formula IB-Sincluding pharmaceutically acceptable salts thereof, and Z is defined the same as above with respect to Formula IA with the proviso that Z is not H.

[0074] In certain embodiments, the amisulpride derivative has a structure of Formula IC:23184896963.4Formula ICincluding pharmaceutically acceptable salts and stereoisomers thereof, and Z is defined the same as above with respect to Formula IA with the proviso that Z is not H.

[0075] In certain embodiments, the amisulpride derivative is a stereoisomer having a structure of Formula IC-R:including pharmaceutically acceptable salts thereof, and Z is defined the same as above with respect to Formula IA with the proviso that Z is not H.

[0076] In certain embodiments, the amisulpride derivative is a stereoisomer having a structure of Formula IC-S:Formula IC-S24184896963.4including pharmaceutically acceptable salts thereof, and Z is defined the same as above with respect to Formula IA with the proviso that Z is not H.

[0077] As used herein, the singular for “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a cell” includes a plurality of cells, including mixtures thereof. Similarly, use of “a compound” for treatment of preparation of medicaments as described herein contemplates using one or more compounds of the invention for such treatment or preparation unless the context clearly dictates otherwise.

[0078] As used herein, the term “comprising” is intended to mean that the compositions and methods include the recited elements, but not excluding others. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like. “Consisting of” shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the composition of this invention. Embodiments defined by each of the transitional terms are within the scope of this invention.

[0079] The term “about” refers to a range of ± 10% of the numeral following “about.”

[0080] The term “alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation. Unless otherwise specified, the term “alkyl” refers to a group having one, two, three, four, five, six, seven, or eight carbon atoms (for example, one to six carbon atoms, or one to four carbon atoms), and which is attached to the rest of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, s-butyl, n-pentyl, and s-pentyl.

[0081] The term “alkenyl” refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched or branched chain. Unless otherwise specified, the term “alkenyl” refers to a group having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, e.g., ethenyl, 1 -propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1 -propenyl, 1-butenyl, and 2-butenyl.25184896963.4

[0082] The term “alkynyl” refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond. Unless otherwise specified, the term “alkynyl” refers to a group having in the range of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (for instance, 2 to 10, 2 to 10 carbon atoms), e.g., ethynyl, propynyl, and butnyl.

[0083] The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ring system of 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0084] The term “cycloalkylalkyl” refers to a cycloalkyl group as defined above directly bonded to an alkyl group as defined above.

[0085] The term “aryl” refers to a mono- or multi-cyclic aromatic radical having in the range of 6 up to 20 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.

[0086] The term “arylalkyl” refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH2C6H5, and -C2H5C6H5.

[0087] The term “heterocyclyl” refers to a non-aromatic 3 to 15 member ring radical which, consists of carbon atoms and at least one heteroatom selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. The heterocyclic ring radical may be a mono-, bi-, tri- or tetracyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized.

[0088] The term “heterocyclylalkyl” refers to a heterocyclyl group as defined above directly bonded to an alkyl group as defined above.

[0089] The term “heteroaryl” refers to an optionally substituted 5-14 member aromatic ring having one or more hetero ring atoms selected from the group consisting of N, O, and S as ring atoms. The heteroaryl may be a mono-, bi- or tricyclic ring system. Examples of such heteroaryl ring radicals includes, but are not limited to, oxazolyl, thiazolyl imidazolyl, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolyl, and isoquinolyl.

[0090] The term “heteroarylalkyl” refers to an heteroaryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH2C6H4N, and -C2H5C6H4N.26184896963.4

[0091] The term “subject” refers to a mammal, such as a domestic pet (for example, a dog or cat), or human. In certain embodiments, the subject is a human.

[0092] The phrase “effective amount” refers to the amount which, when administered to a subject or patient for treating a disease, is sufficient to effect such treatment for the disease.

[0093] " Treatment" or "treating" includes (1) inhibiting a disease in a subject or patient experiencing or displaying the pathology or symptomatology of the disease (e.g., arresting further development of the pathology and / or symptomatology), (2) ameliorating a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease (e.g., reversing the pathology and / or symptomatology), and / or (3) effecting any measurable decrease in a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease.

[0094] The term "pharmaceutically acceptable carrier" refers to a carrier that does not cause an allergic reaction or other untoward effect in patients to whom it is administered and are compatible with the other ingredients in the formulation. Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices. For example, solid carriers / diluents include, but are not limited to, a gum, a starch (e.g., corn starch, pregelatinized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g., microcrystalline cellulose), an acrylate (e.g., polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof. Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the therapeutic agent.

[0095] The term "salt" used herein is not limited as long as the salt is formed with a compound of the amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) and is pharmaceutically acceptable; preferred examples of salts include a hydrohalide salt (for instance, hydrochloride, hydrobromide, hydroiodide and the like), an inorganic acid salt (for instance, sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate and the like), an organic carboxylate salt (for instance, acetate salt, maleate27184896963.4salt, tartrate salt, fumarate salt, citrate salt and the like), an organic sulfonate salt (for instance, methanesulfonate salt, ethanesulfonate salt, benzenesulfonate salt, toluenesulfonate salt, camphorsulfonate salt and the like), an amino acid salt (for instance, aspartate salt, glutamate salt and the like), a quaternary ammonium salt, and the like. In addition, hydrochloride salt, sulfate salt, methanesulfonate salt, acetate salt and the like are preferred as "pharmacologically acceptable salt" of the amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein.

[0096] Isomers of the amisulpride derivatives disclosed herein (e.g., geometric isomers, optical isomers, rotamers, tautomers, and the like) can be purified using general separation means, including for example recrystallization, optical resolution such as diastereomeric salt method, enzyme fractionation method, various chromatographies (for instance, thin layer chromatography, column chromatography, glass chromatography and the like) into a single isomer.Pharmaceutical Formulations and Routes of Administration

[0097] The amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein may be administered by a variety of routes including orally and by injection (e.g. subcutaneously, intravenously, and intraperitoneally). The amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein may be formulated into a pharmaceutical composition for use in the disclosed methods. Such compositions are prepared in accordance with acceptable pharmaceutical procedures such as described in Remington’s Pharmaceutical Sciences, 17th edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Eaton, Pa. (1985), which is incorporated herein by reference.

[0098] The amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein may be administered orally in the form of a solid or liquid dosage form. In both, the amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein compound may be coated in a material to protect it from the action of acids and other natural conditions which may inactivate the compound. The amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein may be formulated as aqueous solutions, liquid dispersions, (ingestible) tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers. The oral 28184896963.4dosage forms may include excipients known in the art, such as binders, disintegrating agents, flavorants, antioxidants, and preservatives. Liquid dosage forms may include diluents such as saline or an aqueous buffer. In certain embodiments, the solid dosage is an orally dissolving tablet.

[0099] The amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein may also be administered by injection. Formulations suitable for injection may include sterile aqueous solutions (where water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The pharmaceutical composition may be sterile and be fluid to the extent that easy syringability exists. It may be stable under the conditions of manufacture and storage and be preserved against the contaminating action of microorganisms such as bacteria and fungi. The pharmaceutically acceptable carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (such as, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, and ascorbic acid. In many cases, it will be preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin. In certain embodiments, the injectable compositions are long-acting injectables (LAIs).

[0100] Sterile injectable solutions can be prepared by incorporating the therapeutic compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the therapeutic compound into a sterile carrier which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation include vacuum drying and freeze-drying which29184896963.4yields a powder of the active ingredient (i.e., the therapeutic compound) plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0101] The actual dosage amount of the compound administered to a subject may be determined by physical and physiological factors such as age, sex, body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the subject and on the route of administration. These factors may be determined by a skilled artisan. The practitioner responsible for administration will typically determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject.

[0102] In certain embodiments, the subject is administered one, two, three, or four unit doses of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) or pharmaceutical composition disclosed herein. In certain embodiments, the unit dose is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, or at a dose disclosed herein.

[0103] Single or multiple doses of the amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) are contemplated. Desired time intervals for delivery of multiple doses can be determined by one of ordinary skill in the art employing no more than routine experimentation. As an example, subjects may be administered two doses daily at approximately 12 hour intervals. In some embodiments, the amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) are administered once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week.

[0104] The amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein or pharmaceutical compositions thereof may be administered on a routine schedule. As used herein a routine schedule refers to a predetermined designated period of time. The routine schedule may encompass periods of time which are identical or which differ in length, as long as the schedule is predetermined. For instance, the routine schedule may involve administration twice a day, every day, every two days, every three days, every four days, every five days, every six days, a weekly basis, a monthly basis or any set number of days or weeks there-between. Alternatively,30184896963.4the predetermined routine schedule may involve administration on a twice daily basis for the first week, followed by a daily basis for several months. In other embodiments, the invention provides that the amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein or pharmaceutical compositions thereof agent(s) may be taken orally and that the timing of which is or is not dependent upon food intake. Thus, for example, the agent can be taken every morning and / or every evening, regardless of when the subject has eaten or will eat.

[0105] Provided herein are methods for treating schizophrenia and / or improving cognition in a subject comprising administering to the subject a therapeutically effective amount of an amisulpride derivative (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein or a pharmaceutical composition thereof.

[0106] In certain embodiments, the amisulpride derivative has a structure selected from the group consisting of Formula IA, Formula IB, and Formula IC, including pharmaceutically acceptable salts thereof, stereoisomers thereof (Formula IA-S, Formula IA-R, Formula IB-S, Formula IB-R, Formula IC-S, Formula IC-R), deuterated analogs of Formula IA, deuterated analogs of Formula IB, deuterated analogs of Formula IC, deuterated analogs of Formula IA-S, deuterated analogs of Formula IA-R, deuterated analogs of Formula IB-S, deuterated analogs of Formula IB-R, deuterated analogs of Formula IC-S, and deuterated analogs of Formula IC-R.

[0107] In certain embodiments, the amisulpride derivative is administered at an amount of 50 mg to about 100 mg once a day.

[0108] In certain embodiments, the amisulpride derivative is LB-102, and the amount administered is about 50 mg, about 75 mg, or about 100 mg

[0109] In certain embodiments, the subject is administered with the pharmaceutical composition for at least about 1 week, at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks.

[0110] In certain embodiments, the subject a baseline PANSS total score of about 80 to about 120. In certain embodiments, the subject has a baseline PANSS total score of about 93.6 to about 93.9. In certain embodiments, the subject has a baseline score of >4 (moderate or greater) for >2 of the positive scale items selected from the group consisting of delusions, conceptual disorganization, hallucinatory behavior,31184896963.4suspiciousness / persecution. In certain embodiments, wherein the subject has a CGI-S score >4. In certain embodiments, the subject has a baseline PANSS negative symptoms subscale score >24.

[0111] In certain embodiments, the LS mean reduction from baseline to week 4 in the PANSS total score is about 14.0 to about 16.1, at least about 14.0, at least about 14.3, at least about 14.5, at least about 15.0, at least about 15.5, at least about 16.0, or at least about 16.1. In certain embodiments, the LS mean reduction from baseline to week 4 in the PANSS total score, when compared to subjects not treated with LB-102, increase about 4.6 to about 6.8, at least about 4.6, at least about 4.7, at least about 4.8, at least about 4.9, at least about 5.0, at least about 5.1, at least about 5.2, at least about 5.3, at least about 5.4, at least about 5.5, at least about 5.6, at least about 5.7, at least about 5.8, at least about 5.9, at least about 6.0, at least about 6.1, at least about 6.2, at least about 6.3, at least about 6.4, at least about 6.5, at least about 6.6, at least about 6.7, or at least about 6.8.

[0112] In certain embodiments, the LS mean reduction from baseline to week 4 in the PANSS total score according to a sensitivity analysis by remapped ET assessment is about 13.5 to about 16.3, at least about 13.5, at least about 13.7, at least about 14.0, at least about 14.2, at least about 14.5, at least about 15.0, at least about 15.5, at least about 16.0, or at least about 16.3. In certain embodiments, the LS mean reduction from baseline to week 4 in the PANSS total score according to a sensitivity analysis by remapped ET assessment, when compared to subjects not treated with LB-102, increase about 4.4 to about 7.1, at least about 4.4, at least about 4.5, at least about 4.6, at least about 4.7, at least about 4.8, at least about 4.9, at least about 5.0, at least about 5.1, at least about 5.2, at least about 5.3, at least about 5.4, at least about 5.5, at least about 5.6, at least about 5.7, at least about 5.8, at least about 5.9, at least about 6.0, at least about 6.1, at least about 6.2, at least about 6.3, at least about 6.4, at least about 6.5, at least about 6.6, at least about 6.7, at least about 6.8, at least about 6.9, at least about 7.0, or at least about 7.1.

[0113] In certain embodiments, the LS mean reduction from baseline to week 4 in the PANSS total score according to a sensitivity analysis with copy- reference imputation is about 13.3 to about 15.5, at least about 13.3, at least about 13.5, at least about 14.0, at32184896963.4least about 14.2, at least about 14.5, at least about 15.0, at least about 15.4, or at least about 15.5. In certain embodiments, the LS mean reduction from baseline to week 4 in the PANSS total score according to a sensitivity analysis with copy-reference imputation, when compared to subjects not treated with LB-102, increase about 3.9 to about 6.2, at least about 3.9, at least about 4.0, at least about 4.1, at least about 4.2, at least about 4.3, at least about 4.4, at least about 4.5, at least about 4.6, at least about 4.7, at least about 4.8, at least about 4.9, at least about 5.0, at least about 5.1, at least about 5.2, at least about 5.3, at least about 5.4, at least about 5.5, at least about 5.6, at least about 5.7, at least about 5.8, at least about 5.9, at least about 6.0, at least about 6.1, or at least about 6.2.

[0114] In certain embodiments, the LS mean reduction from baseline to week 4 in the PANSS positive subscale score is about 4.5 to about 5.3, at least about 4.5, at least about 4.6, at least about 4.7, at least about 4.8, at least about 4.9, at least about 5.0, at least about 5.1, at least about 5.2, or at least about 5.3. In certain embodiments, the LS mean reduction from baseline to week 4 in the PANSS positive subscale score, when compared to subjects not treated with LB-102, increase about 1.6 to about 2.2, at least about 1.6, at least about 1.7, at least about 1.8, at least about 1.9, at least about 2.0, at least about 2.1, or at least about 2.2.

[0115] In certain embodiments, the LS mean reduction from baseline to week 1 in the PANSS negative subscale score is about 0.9 to about 1.3, at least about 0.9, at least about 1.0, at least about 1.1, at least about 1.2, or at least about 1.3. In certain embodiments, the LS mean reduction from baseline to week 1 in the PANSS negative subscale score, when compared to subjects not treated with LB-102, increase about 0.2 to about 0.7, at least about 0.2, at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, or at least about 0.7.

[0116] In certain embodiments, the LS mean reduction from baseline to week 2 in the PANSS negative subscale score is about 1.2 to about 1.9, at least about 1.2, at least about 1.3, at least about 1.4, at least about 1.5, at least about 1.6, at least about 1.7, at least about 1.8, or at least about 1.9. In certain embodiments, the LS mean reduction from baseline to week 2 in the PANSS negative subscale score, when compared to subjects not treated with LB-102, increase about 0.6 to about 1.2, at least about 0.6, at33184896963.4least about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, at least about 1.1, or at least about 1.2.

[0117] In certain embodiments, the LS mean reduction from baseline to week 3 in the PANSS negative subscale is about 1.3 to about 1.9, at least about 1.3, at least about 1.4, at least about 1.5, at least about 1.6, at least about 1.7, at least about 1.8, or at least about 1.9. In certain embodiments, the LS mean reduction from baseline to week 3 in the PANSS negative subscale score, when compared to subjects not treated with LB-102, increase about 0.1 to about 0.8, at least about 0.1, at least about 0.2, at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, at least about 0.7, or at least about 0.8.

[0118] In certain embodiments, the LS mean reduction from baseline to week 4 in the PANSS negative subscale is about 1.7 to about 2.2, at least about 1.7, at least about 1.8, at least about 1.9, at least about 2.0, at least about 2.1, or at least about 2.2. In certain embodiments, the LS mean reduction from baseline to week 4 in the PANSS negative subscale score, when compared to subjects not treated with LB-102, increase about 0.7 to about 1.1, at least about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, or at least about 1.1.

[0119] In certain embodiments, the LS mean reduction from baseline to week 1 in the Marder Factor PANSS score, the Marder Factor being positive symptoms, is about 1.4 to about 2.1, at least about 1.4, at least about 1.5, at least about 1.6, at least about 1.7, at least about 1.8, at least about 1.9, at least about 2.0, or at least about 2.1. In certain embodiments, the LS mean reduction from baseline to week 1 in the Marder Factor PANSS score, the Marder Factor being positive symptoms, when compared to subjects not treated with LB-102, increase about 0.5 to about 1.1, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, or at least about 1.1.

[0120] In certain embodiments, the LS mean reduction from baseline to week 2 in the Marder Factor PANSS score, the Marder Factor being positive symptoms, is about 2.4 to about 3.2, at least about 2.4, at least about 2.5, at least about 2.6, at least about 2.7, at least about 2.8, at least about 2.9, at least about 3.0, at least about 3.1, or at least about 3.2. In certain embodiments, the LS mean reduction from baseline to week 2 in the Marder34184896963.4Factor PANSS score, the Marder Factor being positive symptoms, when compared to subjects not treated with LB-102, increase about 0.5 to about 1.2, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, at least about 1.1, or at least about 1.2.

[0121] In certain embodiments, the LS mean reduction from baseline to week 3 in the Marder Factor PANSS score, the Marder Factor being positive symptoms, is about 3.6 to about 4.6, at least about 3.6, at least about 3.7, at least about 3.8, at least about 3.9, at least about 3.0, at least about 4.1, at least about 4.2, at least about 4.3, at least about 4.4, at least about 4.5, or at least about 4.6. In certain embodiments, the LS mean reduction from baseline to week 3 in the Marder Factor PANSS score, the Marder Factor being positive symptoms, when compared to subjects not treated with LB-102, increase about 1.7 to about 2.6, at least about 1.7, at least about 1.8, at least about 1.9, at least about 2.0, at least about 2.1, at least about 2.2, at least about 2.3, at least about 2.4, at least about 2.5, or at least about 2.6.

[0122] In certain embodiments, the LS mean reduction from baseline to week 4 in the Marder Factor PANSS score, the Marder Factor being positive symptoms, is about 4.4 to about 5.4, at least about 4.4, at least about 4.5, at least about 4.6, at least about 4.7, at least about 4.8, at least about 4.9, at least about 5.0, at least about 5.1, at least about 5.2, at least about 5.3, or at least about 5.4. In certain embodiments, the LS mean reduction from baseline to week 4 in the Marder Factor PANSS score, the Marder Factor being positive symptoms, when compared to subjects not treated with LB-102, increase about 1.8 to about 2.9, at least about 1.8, at least about 1.9, at least about 2.0, at least about 2.1, at least about 2.2, at least about 2.3, at least about 2.4, at least about 2.5, at least about 2.6, at least about 2.7, at least about 2.8, or at least about 2.9.

[0123] In certain embodiments, the LS mean reduction from baseline to week 1 in the Marder Factor PANSS score, the Marder Factor being disorganized thought, is about 1.1 to about 2.0, at least about 1.1, at least about 1.2, at least about 1.3, at least about 1.4, at least about 1.5, at least about 1.6, at least about 1.7, at least about 1.8, at least about 1.9, or at least about 2.0. In certain embodiments, the LS mean reduction from baseline to week 1 in the Marder Factor PANSS score, the Marder Factor being disorganized thought, when compared to subjects not treated with LB-102, increase about 0.2 to about35184896963.41.1, at least about 0.2, at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, or at least about 1.1.

[0124] In certain embodiments, the LS mean reduction from baseline to week 2 in the Marder Factor PANSS score, the Marder Factor being disorganized thought, is about 1.7 to about 2.4, at least about 1.7, at least about 1.8, at least about 1.9, at least about 2.0, at least about 2.1, at least about 2.2, at least about 2.3, or at least about 2.4. In certain embodiments, the LS mean reduction from baseline to week 2 in the Marder Factor PANSS score, the Marder Factor being disorganized thought, when compared to subjects not treated with LB-102, increase about 0.5 to about 1.1, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, or at least about 1.1.

[0125] In certain embodiments, the LS mean reduction from baseline to week 3 in the Marder Factor PANSS score, the Marder Factor being disorganized thought, is about 2.3 to about 3.1, at least about 2.3, at least about 2.4, at least about 2.5, at least about 2.6, at least about 2.7, at least about 2.8, at least about 2.9, at least about 3.0, or at least about 3.1. In certain embodiments, the LS mean reduction from baseline to week 3 in the Marder Factor PANSS score, the Marder Factor being disorganized thought, when compared to subjects not treated with LB-102, increase about 2.3 to about 3.1, at least about 2.3, at least about 2.4, at least about 2.5, at least about 2.6, at least about 2.7, at least about 2.8, at least about 2.9, at least about 3.0, or at least about 3.1.

[0126] In certain embodiments, the LS mean reduction from baseline to week 4 in the Marder Factor PANSS score, the Marder Factor being disorganized thought, is about 2.9 to about 3.6, at least about 2.9, at least about 3.0, at least about 3.1, at least about 3.2, at least about 3.3, at least about 3.4, at least about 3.5, or at least about 3.6. In certain embodiments, the LS mean reduction from baseline to week 4 in the Marder Factor PANSS score, the Marder Factor being disorganized thought, when compared to subjects not treated with LB-102, increase about 0.9 to about 1.7, at least about 0.9, at least about 1.0, at least about 1.1, at least about 1.2, at least about 1.3, at least about 1.4, at least about 1.5, at least about 1.6, or at least about 1.7.36184896963.4

[0127] In certain embodiments, the LS mean reduction from baseline to week 1 in the Marder Factor PANSS score, the Marder Factor being uncontrolled hostility / excitement, is about 0.7 to about 1.1, at least about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, or at least about 1.1. In certain embodiments, the LS mean reduction from baseline to week 1 in the Marder Factor PANSS score, the Marder Factor being uncontrolled hostility / excitement, when compared to subjects not treated with LB-102, increase about 0.5 to about 0.9, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, or at least about 0.9.

[0128] In certain embodiments, the LS mean reduction from baseline to week 2 in the Marder Factor PANSS score, the Marder Factor being uncontrolled hostility / excitement, is about 0.9 to about 1.3, at least about 0.9, at least about 1.0, at least about 1.1, at least about 1.2, or at least about 1.3. In certain embodiments, the LS mean reduction from baseline to week 2 in the Marder Factor PANSS score, the Marder Factor being uncontrolled hostility / excitement, when compared to subjects not treated with LB-102, increase about 0.1 to about 0.6, at least about 0.1, at least about 0.2, at least about 0.3, at least about 0.4, at least about 0.5, or at least about 0.6.

[0129] In certain embodiments, the LS mean reduction from baseline to week 3 in the Marder Factor PANSS score, the Marder Factor being uncontrolled hostility / excitement, is about 1.3 to about 1.6, at least about 1.3, at least about 1.4, at least about 1.5, or at least about 1.6. In certain embodiments, the LS mean reduction from baseline to week 3 in the Marder Factor PANSS score, the Marder Factor being uncontrolled hostility / excitement, when compared to subjects not treated with LB-102, increase about 0.7 to about 1.0, at least about 0.7, at least about 0.8, at least about 0.9, or at least about 1.0.

[0130] In certain embodiments, the LS mean reduction from baseline to week 4 in the Marder Factor PANSS score, the Marder Factor being uncontrolled hostility / excitement, is about 1.4 to about 1.9, at least about 1.4, at least about 1.5, at least about 1.6, at least about 1.7, at least about 1.8, or at least about 1.9. In certain embodiments, the LS mean reduction from baseline to week 4 in the Marder Factor PANSS score, the Marder Factor being uncontrolled hostility / excitement, when compared to subjects not treated with LB-37184896963.4102, increase about 0.8 to about 1.3, at least about 0.8, at least about 0.9, at least about 1.0, at least about 1.1, at least about 1.2, or at least about 1.3.

[0131] In certain embodiments, the LS mean reduction from baseline to week 1 in the Marder Factor PANSS score, the Marder Factor being anxiety / depression, is about 1.3 to about 2.2, at least about 1.3, at least about 1.4, at least about 1.5, at least about 1.6, at least about 1.7, at least about 1.8, at least about 1.9, at least about 2.0, at least about 2.1, or at least about 2.2. In certain embodiments, the LS mean reduction from baseline to week 1 in the Marder Factor PANSS score, the Marder Factor being anxiety / depression, when compared to subjects not treated with LB-102, increase about 0.2 to about 0.7, at least about 0.2, at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, or at least about 0.7.

[0132] In certain embodiments, the LS mean reduction from baseline to week 2 in the Marder Factor PANSS score, the Marder Factor being anxiety / depression, is about 2.3 to about 2.5, at least about 2.3, at least about 2.4, or at least about 2.5. In certain embodiments, the LS mean reduction from baseline to week 2 in the Marder Factor PANSS score, the Marder Factor being anxiety / depression, when compared to subjects not treated with LB-102, increase about 0.3 to about 0.5, at least about 0.3, at least about 0.4, or at least about 0.5.

[0133] In certain embodiments, the LS mean reduction from baseline to week 3 in the Marder Factor PANSS score, the Marder Factor being anxiety / depression, is about 2.6 to about 3.5, at least about 2.6, at least about 2.7, at least about 2.8, at least about 2.9, at least about 3.0, at least about 3.1, at least about 3.2, at least about 3.3, at least about 3.4, or at least about 3.5. In certain embodiments, the LS mean reduction from baseline to week 3 in the Marder Factor PANSS score, the Marder Factor being anxiety / depression, when compared to subjects not treated with LB-102, increase about 0.2 to about 1.2, at least about 0.2, at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, at least about 1.1, or at least about 1.2.

[0134] In certain embodiments, the LS mean reduction from baseline to week 4 in the Marder Factor PANSS score, the Marder Factor being anxiety / depression, is about 2.7 to about 3.5, at least about 2.7, at least about 2.8, at least about 2.9, at least about 3.0, at38184896963.4least about 3.1, at least about 3.2, at least about 3.3, at least about 3.4, or at least about 3.5. In certain embodiments, the LS mean reduction from baseline to week 4 in the Marder Factor PANSS score, the Marder Factor being anxiety / depression, when compared to subjects not treated with LB-102, increase about 0.2 to about 1.1, at least about 0.2, at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, or at least about 1.1.

[0135] In certain embodiments, the LS mean reduction from baseline to week 1 in the Marder Factor PANSS score, the Marder Factor being negative symptoms, is about 1.0 to about 1.2, at least about 1.0, at least about 1.1, or at least about 1.2. In certain embodiments, the LS mean reduction from baseline to week 1 in the Marder Factor PANSS score, the Marder Factor being negative symptoms, when compared to subjects not treated with LB-102, increase about 0.6 to about 0.8, at least about 0.6, at least about 0.7, or at least about 0.8.

[0136] In certain embodiments, the LS mean reduction from baseline to week 2 in the Marder Factor PANSS score, the Marder Factor being negative symptoms, is about 1.5 to about 2.1, at least about 1.6, at least about 1.7, at least about 1.8, at least about 1.9, at least about 2.0, or at least about 2.1. In certain embodiments, the LS mean reduction from baseline to week 2 in the Marder Factor PANSS score, the Marder Factor being negative symptoms, when compared to subjects not treated with LB-102, increase about 0.7 to about 1.3, at least about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, at least about 1.1, at least about 1.2, or at least about 1.3.

[0137] In certain embodiments, the LS mean reduction from baseline to week 3 in the Marder Factor PANSS score, the Marder Factor being negative symptoms, is about 1.7 to about 2.3, at least about 1.7, at least about 1.8, at least about 1.9, at least about 2.0, at least about 2.1, at least about 2.2, or at least about 2.3. In certain embodiments, the LS mean reduction from baseline to week 3 in the Marder Factor PANSS score, the Marder Factor being negative symptoms, when compared to subjects not treated with LB-102, increase about 0.5 to about 1.1, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, or at least about 1.1.39184896963.4

[0138] In certain embodiments, the LS mean reduction from baseline to week 4 in the Marder Factor PANSS score, the Marder Factor being negative symptoms, is about 1.9 to about 3.0, at least about 1.9, at least about 2.0, at least about 2.1, at least about 2.2, at least about 2.3, at least about 2.4, at least about 2.5, at least about 2.6, at least about 2.7, at least about 2.8, at least about 2.9, or at least about 3.0. In certain embodiments, the LS mean reduction from baseline to week 4 in the Marder Factor PANSS score, the Marder Factor being negative symptoms, when compared to subjects not treated with LB-102, increase about 0.3 to about 1.5, at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, at least about 1.1, at least about 1.2, at least about 1.3, at least about 1.4, or at least about 1.5.

[0139] In certain embodiments, the percentage of >20% PANSS Responders after 4 week of treatment is at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61 %, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, or at least about 80%. In certain embodiments, the percentage of >30% PANSS Responders after 4 week of treatment is at least about 30%, at least about 31 %, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, or at least about 40%. In certain embodiments, the percentage of >40% PANSS Responders after 4 week of treatment is at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, or at least about 20%, or at least about 21%.

[0140] In certain embodiments, the effect size (Hedges’ g) is about 0.40 to about 0.83, at least about 0.40, at least about 0.41, at least about 0.45, at least about 0.50, at least about 0.55, at least about 0.60, at least about 0.61, at least about 0.65, at least about 0.70, at least about 0.75, at least about 0.80, or at least about 0.83. In certain40184896963.4embodiments, the standard effect size is about 0.40 to about 0.64, at least about 0.40, at least about 0.45, at least about 0.50, at least about 0.55, at least about 0.60, or at least about 0.64.

[0141] In certain embodiments, the LS mean reduction of CGI-S score from baseline to week 4 is about 0.6 to about 0.84, at least about 0.6, at least about 0.65, at least about 0.67, at least about 0.7, at least about 0.72, at least about 0.75, at least about 0.8, or at least about 0.84. In certain embodiments, the CGI-S responder rate at week 4 is about 11 % to about 24%, at least about 11 %, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, or at least about 24%. In certain embodiments, the effect size of LB-102 treatment on global cognition after 4 weeks of treatment is about 0.26 to about 0.66, at least about 0.26, at least about 0.30, at least about 0.35, at least about 0.40, at least about 0.41, at least about 0.45, at least about 0.50, at least about 0.55, at least about 0.60, at least about 0.65, or at least about 0.66. In certain embodiments, the effect of LB-102 treatment on global cognition after 4 weeks of treatment is, as expressed using Cohen’s d when compared versus the change from baseline to week 4 with placebo, about 0.26 to about 0.66, at least about 0.26, at least about 0.30, at least about 0.35, at least about 0.40, at least about 0.41, at least about 0.45, at least about 0.50, at least about 0.55, at least about 0.60, at least about 0.65, or at least about 0.66. In certain embodiments, the indirect effect of LB-102 treatment on global cognition after 4 weeks of treatment, when compared to placebo treatment after 4 weeks, is about 0.00 to about 0.01. In certain embodiments, the indirect effect of LB-102 treatment on psychomotor function after 4 weeks of treatment, when compared to placebo treatment after 4 weeks, is about 0.00 to about 0.01. In certain embodiments, the indirect effect of LB-102 treatment on memory / executive function after 4 weeks of treatment, when compared to placebo treatment after 4 weeks, is about 0.00 to about 0.01. In certain embodiments, the impact of LB-102 on cognition is not mediated by any drug-related improvement in schizophrenia symptoms according to mediation analysis.

[0142] In certain embodiments, little to no emergence of neuromotor side effects, akathisia, tardive dyskinesia, or other involuntary motor side effects is observed. In certain41184896963.4embodiments, average QTcF prolongation over placebo is less than about 5 ms, less than about 4 ms, or less than about 3 ms. In certain embodiments, rate(s) of one or more adverse effects selected from the group consisting of EPS, sedation, and adverse effects related to prolactin increase is(are) lower than amisulpride. In certain embodiments, the rate of EPS is less than about 6%, less than about 5.6%, less than about less than about 5.5%, less than about less than about 5.0%, less than about 4.5%, less than about 4.0%, less than about 3.5%, less than about 3.0%, less than about 2.5%, less than about 2.0%, less than about 1.5%, or less than about 1.0%. In certain embodiments, the rate of sedation is less than about 3%, less than about 2.8%, less than about 2.5%, less than about 2.0%, less than about 1.5%, less than about 1.0%, or less than about 0.9%. In certain embodiments, the rate of total adverse events related to prolactin increase is less than about 6%, less than about 5.6%, less than about less than about 5.5%, less than about less than about 5.0%, less than about 4.5%, less than about 4.0%, less than about 3.5%, less than about 3.0%, less than about 2.5%, less than about 2.0%, less than about 1.9%, less than about 1.5%, or less than about 1.0%. In certain embodiments, the rate of galactorrhoea is less than about 2.0%, less than about 1.9%, less than about 1.5%, less than about 1.0%, or less than about 0.9%. In certain embodiments, the rate of breast enlargement is less than about 3.0%, less than about 2.8%, less than about 2.5%, less than about 2.0%, less than about 1.9%, less than about 1.5%, less than about 1.0%, less than about 0.5%, or less than about 0.1%. In certain embodiments, the rate of erectile dysfunction is less than about 3.0%, less than about 2.8%, less than about 2.5%, less than about 2.0%, less than about 1.9%, less than about 1.5%, less than about 1.0%, less than about 0.5%, or less than about 0.1%.

[0143] In certain embodiments, the subject has PANSS negative symptoms subscale score >24, and the LS mean reduction from baseline to week 1 in the PANSS total score is about 1.5 to about 2.0, at least about 1.5, at least about 1.6, at least about 1.7, at least about 1.8, at least about 1.9, or at least about 2.0. In certain embodiments, the subject has PANSS negative symptoms subscale score >24, and the LS mean reduction from baseline to week 1 in the PANSS total score, when compared to subjects not treated with LB-102, increase about 0.7 to about 0.9, at least about 0.7, at least about 0.8, or at least about 0.9.42184896963.4

[0144] In certain embodiments, the subject has PANSS negative symptoms subscale score >24, and the LS mean reduction from baseline to week 2 in the PANSS total score is about 2.0 to about 3.0, at least about 2.0, at least about 2.1, at least about 2.5, at least about 2.9, or at least about 3.0. In certain embodiments, the subject has PANSS negative symptoms subscale score >24, and the LS mean reduction from baseline to week 2 in the PANSS total score, when compared to subjects not treated with LB-102, increase about 1.0 to about 1.9, at least about 1.0, at least about 1.1, at least about 1.2, at least about 1.3, at least about 1.4, at least about 1.5, at least about 1.6, at least about 1.7, at least about 1.8, or at least about 1.9.

[0145] In certain embodiments, the subject has PANSS negative symptoms subscale score >24, and the LS mean reduction from baseline to week 3 in the PANSS total score is about 2.5 to about 3.3, at least about 2.5, at least about 2.6, at least about 2.7, at least about 2.8, at least about 2.9, at least about 3.0, at least about 3.1, at least about 3.2, or at least about 3.3. In certain embodiments, the subject has PANSS negative symptoms subscale score >24, and the LS mean reduction from baseline to week 3 in the PANSS total score, when compared to subjects not treated with LB-102, increase about 0.8 to about 1.4, at least about 0.8, at least about 0.9, at least about 1.0, at least about 1.1, at least about 1.2, at least about 1.3, or at least about 1.4.

[0146] In certain embodiments, the subject has PANSS negative symptoms subscale score >24, and the LS mean reduction from baseline to week 4 in the PANSS total score is about 2.5 to about 3.5, at least about 2.5, at least about 2.6, at least about 2.7, at least about 2.8, at least about 2.9, at least about 3.0, at least about 3.1, at least about 3.2, at least about 3.3, at least about 3.4, or at least about 3.5. In certain embodiments, the subject has PANSS negative symptoms subscale score >24, and the LS mean reduction from baseline to week 4 in the PANSS total score, when compared to subjects not treated with LB-102, increase about 1.0 to about 1.8, at least about 1.0, at least about 1.1, at least about 1.2, at least about 1.3, at least about 1.4, at least about 1.5, at least about 1.6, at least about 1.7, or at least about 1.8.

[0147] In certain embodiments, the subject has PANSS negative symptoms subscale score >24, and the LS mean reduction from baseline to week 4 in the PANSS Negative43184896963.4Symptoms subscale score is about 2.6 to about 3.4, at least about 2.6, at least about 2.7, at least about 2.8, at least about 2.9, at least about 3.0, at least about 3.1, at least about 3.2, at least about 3.3, or at least about 3.4. In certain embodiments, the subject has PANSS negative symptoms subscale score >24, and the LS mean reduction from baseline to week 4 in the PANSS Negative Symptoms subscale score, when compared to subjects not treated with LB-102, increase about 1.0 to about 1.7, at least about 1.0, at least about 1.1, at least about 1.2, at least about 1.3, at least about 1.4, at least about 1.5, at least about 1.6, or at least about 1.7.

[0148] In certain embodiments, the subject has PANSS negative symptoms subscale score >24, the effect size is about 0.34 to about 0.67, at least about 0.3, at least about 0.34, at least about 0.4, at least about 0.45, at least about 0.50, at least about 0.55, at least 0.60, at least 0.65, or at least 0.67.

[0149] In certain embodiments, the subject has negative symptoms at baseline, the mean change in negative symptom scores at week 4 is about 2.6 to about 3.4, at least about 2.6, at least about 2.7, at least about 2.8, at least about 2.9, at least about 3.0, at least about 3.1, at least about 3.2, at least about 3.3, or at least about 3.4. In certain embodiments, the subject has negative symptoms at baseline, the mean change in negative symptom scores at week 4, when compared to subjects not treated with LB-102, is about 1.0 to about 1.8, at least about 1.0, at least about 1.1, at least about 1.2, at least about 1.3, at least about 1.4, at least about 1.5, at least about 1.6, at least about 1.7, or at least about 1.8.

[0150] In certain embodiments, the subject has negative symptoms at baseline, the effect size is about 0.34 to about 0.67, at least about 0.34, at least about 0.35, at least about 0.40, at least about 0.45, at least about 0.50, at least about 0.55, at least about 0.60, at least about 0.65, or at least about 0.67.Kits

[0151] Also provided herein is a kit for use of amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) and pharmaceutical compositions thereof, as disclosed herein. In certain embodiments, the kit comprises one or more unit doses of44184896963.4amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) and / or pharmaceutical compositions disclosed herein.

[0152] In certain embodiments, the kit further comprises instructions for the use of amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) and pharmaceutical compositions disclosed herein.Combination therapy

[0153] In addition to being used as a monotherapy, the amisulpride derivatives (e.g., without limitation, LB-102, LB-103, and LB-104) disclosed herein or pharmaceutical compositions thereof may also find use in combination therapies. Effective combination therapy may be achieved with a single pharmaceutical composition or pharmacological formulation that includes both agents, or with two distinct pharmaceutical compositions or pharmacological formulations, administered at the same time, wherein one composition includes a compound of this invention, and the other includes the second agent(s). Alternatively, the therapy may precede or follow the other agent treatment by intervals ranging from minutes to months.

[0154] The additional agent or agents may be selected from any agent or agents useful for treating a psychological disorder, for example any agent or agent and / or a2s useful for treating an imbalance of dopamine, serotonin, histamine, or glutamate. In one embodiment, the additional agent or agent is useful in improving psychological function, e.g., an antipsychotic, such as quetiapine, geodon, zyprexa, latuda, olanzapine, risperidone, iloperidone, ziprasidone, clozapine, haloperidol, chlorpromazine, citrlopram, escitalopram, paroxetine, fluoxetine, fluvoxamine, sertraline, desvenlafaxine, duloxetine, milnacipran, venlafaxine, vilazodone, lumateperone, aripirazole, brexpiprazole, vraylar, xanomeline / trospium, and combinations thereof.

[0155] Having described the invention with reference to the embodiments and illustrative examples, those in the art may appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous 45184896963.4publications. Further, all references cited above and in the examples below are hereby incorporated by reference in their entirety, as if fully set forth herein.ExamplesExample 1: Phase 2 clinical study of LB-102

[0156] A randomized, double-blinded, placebo-controlled, multicenter clinical study was carried out to evaluate the antipsychotic efficacy, safety, tolerability, and PK of LB-102 at 50 mg QD, 75 mg QD, and 100 mg QD versus placebo in adult patients diagnosed with schizophrenia having an acute exacerbation of psychosis.

[0157] Of 622 individuals screened, 263 (42.3%) were excluded (Fig. 1 B, ‘initially, 270 participants did not pass screening; however, after re-screening 13 participants, 7 were found to be eligible and were randomized). The primary reasons for screen failure included not meeting randomization criteria (n=229, 87.1%) and study withdrawal (n=27, 10.3%). 359 patients were randomized to receive 1 of 4 study treatments in a 3:3:3:1 ratio: placebo QD, LB-10250 mg QD, LB-10275 mg QD, or LB-102 100 mg QD, for 28 days, with all randomized patients receiving >1 treatment dose and providing >1 postbaseline assessment and no protocol exceptions. The baseline demographics are summarized in Table 1A below. Mean baseline PANSS total scores (Fig. 6A) ranged from 93.6-93.9 (placebo, 93.8; LB-102 50mg, 93.9; 75mg, 93.6; 100mg, 93.9). The completion rate after 4 weeks of treatment was 81.6% across all arms, with 72.7% completing the end-of-study visit. The most common reasons for early termination were participant withdrawal (n=56, 57.1%), lost to follow-up (n=26, 26.5%), and AEs (n=10, 10.2%).

[0158] See Section I for additional patient disposition information (Table 4A), patient information in various analysis sets (Table 4B), and demographics of safety analysis set (Table 4C). 171 participants (47.6% of the total population) had a PANSS negative symptoms subscale score >24 at baseline. Demographics and clinical characteristics were similar across treatment arms (Table 1 B) and consistent with the total population.Table 1A: Baseline demographicsPlacebo 50 mg 75 mg 100 mg Overall (n=108) (n=107) (n=108) (n=36) (N=359) Age at informed consent, mean (SD) 39.1 (9.1) 39.0 (9.6) 39.2 (9.2) 39.1 (9.2) 39.1 (9.3)Sex, n (%) Male 85 (79%) 87 (81%) 90 (83%) 28 (78%) 290 (81%)46184896963.4Female 23 (21%) 20 (19%) 18 (17%) 8 (22%) 69 (19%) Ethnicity, n Latino 17 (16%) 12 (11%) 8 (7%) 6 (17%) 43 (12%) (%)White 24 (22%) 17 (16%) 18 (17%) 9 (25%) 68 (19%) Black 80 (74%) 83 (77%) 275 (77%) Race, n (%) 87 (81%) 25 (69%)Asian 1 (1%) 0 2 (2%) 0 3 (1%) Native American 0 0 2 (2%) 0 2 (1%) Weight at baseline (kg), mean (SD) 85.6 84.0 88.4 85.9 86.0(17.2) (19.5) (18.5) (18.0) (18.4) BMI at baseline (kg / m2), mean (SD) 28.2 (5.2) 27.4 (6.0) 28.8 (5.6) 28.0 (6.0) 28.1 (5.6) Baseline PANSS total score, mean - (SD) 93.8 (8.2) 93.9 (7.5) 93.6 (7.8) 93.9 (9.0)Years since diagnosis, mean (range) 16.4 15.2 16.2 13.5 15.8(2-41) _ (2-38) (2-39) (2-36) (2-41) _Table 1B: Demographics and Baseline Characteristics of Participants With _ PANSS Negative Symptoms Subscale Score >24 at Baseline _LB-102 50 LB-102 75 LB-102 100Parameter Statistic mg mg mg Placebo Overall (N=55) (N=42) (N=17) (N=57) (N=171) n 55 42 17 57 171 Age at Informed Consent Mean (SD) 38.7 (9.74) 40.5 (9.83) 37.5 (8.66) 37.9 (8.36) 38.7 (9.20) (years) Median 40.0 41.5 38.0 38.0 39.0Min, Max 20, 54 20, 54 19, 54 19, 54 19, 54 Gender n 55 42 17 57 171 Male n (%) 44 (80.0) 33 (78.6) 13 (76.5) 45 (78.9) 135 (78.9) Female n (%) 11 (20.0) 9 (21.4) 4 (23.5) 12 (21.1) 36 (21.1) Fertility Status n 11 9 4 12 36 Childbearing Potential n (%) 8 (72.7) 9 (100.0) 4 (100.0) 5 (41.7) 26 (72.2) Post-Menopausal n (%) 2 (18.2) 0 0 1 (8.3) 3 (8.3) Surgically Sterile n (%) 1 (9.1) 0 0 6 (50.0) 7 (19.4) Ethnicity n 55 42 17 57 171 Hispanic or Latino n (%) 5 (9.1) 4 (9.5) 3 (17.6) 11 (19.3) 23 (13.5) Not Hispanic or Latino n (%) 50 (90.9) 38 (90.5) 14 (82.4) 46 (80.7) 148 (86.5) Race n 55 42 17 57 171 White n (%) 6 (10.9) 6 (14.3) 4 (23.5) 12 (21.1) 28 (16.4) Black or African n (%) 47 (85.5) 30 (71.4) 12 (70.6) 42 (73.7) 131 (76.6) AmericanAsian n (%) 0 2 (4.8) 0 0 2 (1.2) American Indian or n (%) 0 1 (2.4) 0 0 1 (0.6) Alaska NativeNative Hawaiian or Other n (%) 0 0 0 0 0 Pacific IslanderOther n (%) 1 (1.8) 2 (4.8) 0 3 (5.3) 6 (3.5) Multiple n (%) 1 (1.8) 1 (2.4) 1 (5.9) 0 3 (1.8) Height at Screening (cm) n 55 42 17 57 171Mean (SD) 174.8 174.0 (8.66) 177.8 (7.90) 173.9 (8.11) 174.6 (9.09)(10.60)Median 175.0 174.5 178.0 174.0 175.0 Min, Max 153, 198 152, 185 161, 195 154, 189 152, 198Weight at Screening (kg) n 55 42 17 57 17147184896963.4Mean (SD) 85.69 84.98 85.08 87.01 85.90(21.500) (17.513) (16.777) (17.544) (18.692) Median 84.10 78.75 84.40 84.40 84.10 Min, Max 49.4, 149.7 61.7, 124.7 58.9, 113.5 53.1, 136.1 49.4, 149.7 BMI (kg / m2) n 55 42 17 57 171Mean (SD) 27.98 28.06 27.05 28.75 28.16(6.155) (5.346) (5.796) (5.435) (5.663) Median 28.20 26.70 25.10 27.90 26.70 Min, Max 18.0, 40.0 18.8, 39.9 19.4, 37.9 18.9, 39.5 18.0, 40.0 Waist Circumference n 55 42 17 57 171 (cm) Mean (SD) 95.72 95.10 92.33 96.16 95.38(16.805) (15.434) (14.822) (15.140) (15.638) Median 94.00 94.85 90.00 92.00 92.00Min, Max 66.0, 146.0 70.0, 138.0 70.0, 124.0 75.0, 130.0 66.0, 146.0Table 1C: Ongoing Psychiatric & Neurological Medical History at screening, n(%)Placebo 50 mg 75 mg 100 mg Overall (n=108) (n=107) (n=108) (n=36) (N=359) Psychiatric disorders 108 (100%) 107 (100%) 108 (100%) 36 (100%) 359 (100%) Schizophrenia 108 (100%) 107 (100%) 108 (100%) 36 (100%) 359 (100%) Insomnia 79 (73.1%) 83 (77.6%) 75 (69.4%) 29 (80.6%) 266 (74.1%) Anxiety 59 (54.6%) 68 (63.6%) 63 (58.3%) 21 (58.3%) 211 (58.8%) Depression 36 (33.3%) 43 (40.2%) 34 (31.5%) 5 (13.9%) 118 (32.9%) Agitation 32 (29.6%) 41 (38.3%) 26 (24.1%) 9 (25.0%) 108 (30.1%) Nervous system disorders 48 (44.4%) 53 (49.5%) 46 (42.6%) 18 (50.0%) 165 (46.0%)Headache 41 (38.0%) 49 (45.8%) 37 (34.3%) 17 (47.2%) 144 (40.1%)

[0159] The study was conducted in 19 study centers.

[0160] Study participation included a 14-day inpatient screening phase (up to a 14-day extension of the screening phase was allowed, if necessary with the approval of the Medical Monitor), an inpatient Study Treatment Period with 4 weeks of daily study treatment, an inpatient Stabilization Period of up to 5 days (during which patients were stabilized on standard antipsychotic medication), and an outpatient Final Safety Followup of approximately 2 weeks after the end of the Treatment Period.

[0161] Patients were evaluated at Baseline and periodically thereafter using the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions-Severity of Illness scale (CGI-S), Angus Scale (SAS), Barnes Akathisia Rating Scale (BARS), Involuntary Movement Scale (AIMS), Columbia-Suicide Severity Rating Scale (C-SSRS), 12-lead electrocardiograms (ECG), vital signs, clinical laboratory values, body weight / waist circumference, total cholesterol, triglycerides, high-density lipoprotein (HDL)48184896963.4and low-density lipoprotein (LDL), and reported / observed Adverse Events (AEs). In addition, blood samples were collected for pharmacokinetic (PK) analysis.

[0162] The study is summarized graphically in Fig. 1 A. The participant disposition is provided in Fig. 1 B.

[0163] Both 50 mg and 75 mg doses were statistically superior to placebo using Hochberg multiplicity correction. The exploratory 100 mg dose also achieved statistical significance on its own. See the primary and secondary efficacy data provided in Section II of this example. Examples of primary efficacy endpoint data include changes from baseline to week 4 in the PANSS total score (Fig. 6A, and Fig. 6D), a sensitivity analysis of same by remapped ET assessments (Fig. 6B), a sensitivity analysis of same using a tipping-point approach (Fig. 6E), and another sensitivity analysis of same with copyreference imputation (Fig. 6C). Changes from baseline to week 4 in PANSS total score in patients with PANSS negative symptoms subscale score >24 at baseline are summarized in Fig. 6F.

[0164] Examples of secondary efficacy endpoint data include changes from baseline to week 4 in the PANSS positive subscale score (Figs. 7A, 7C and 7D), and PANSS negative subscale score (Figs. 7B and 7F), as well as, without limitation, changes in CGI-S, PANSS Marder factor scores, >20% PANSS responder rate (non-floor adjusted) and CGI-S responder rate (i.e., proportion of participants with a score of 1 [“normal”], 2 [“borderline ill”], or 3 [“mildly ill”]) at week 4 (Figs. 9J-9L). Fig. 7G shows change in PANSS negative symptoms subscale score over time through Week 4 in participants with PANSS negative symptoms subscale score >24 at baseline.

[0165] LB-102 demonstrated a positive shift on the CGI-S, resulting in a significant decrease in disease severity for patients with acute schizophrenia (Figs. 9A-9C, Fig. 9L). Least-squares mean change from baseline to week 4 in CGI-S scores were: Placebo, -0.39; LB-102 50 mg, -0.72 (P=0.0008 vs placebo); LB-102 75 mg, -0.67 (P=0.0048 vs placebo); and LB-102100 mg, -0.84 (P=0.0026 vs placebo). The change from baseline to week 4 on the CGI S was associated with a statistically significant improvement in disease severity for all LB-102 doses compared to placebo. Analysis of CGI-S responders at week 4 demonstrated statistical significance for LB-102 50 mg and 75 mg compared to placebo.49184896963.4

[0166] Exploratory endpoints included evaluating cognition via Cogstate. Post hoc analysis of effect size and floor-adjusted >20%, >30%, or >40% PANSS total score responder rates (after rescaling PANSS item scores from 1-7 to 0-6) was conducted (Table 1 E).

[0167] The effect size (Hedges’ g) of LB-102 at 50 mg was 0.61; the effect size at 75 mg was 0.41 and the effect size at 100 mg was 0.83, calculated using a methodology similar to that used by Karuna for its phase 3 trials (0.6). The effect size of 0.83 at 100 mg was greater than the effect size of Cobenfy in Phase 3 and was almost double that of Caplyta. MMRM based standard effect sizes yielded directionally consistent results (Standard effect size A= 0.50 for LB-10250 mg; A= 0.45 for LB-10275 mg; and A= 0.64 for LB-102 100 mg). See Table 1 D below for effect size calculations.Table 1D. Effect Size CalculationsLB-102 LB-102 LB-102 Placebo Statistic 50m g 75mg 100mgPANSS Total Score Effect Size - Change from Baseline to Week 4 (Observed means)~N 91 84 23 93Hedges’ g 0.61 0.41 0.8395% CI 0.91, 0.32 0.72, 0.12 1.32, 0.37PANSS Total Score Effect Size - Change from Baseline to Week 4 (mITT Population, MMRM) N 104 103 34 100 Standard Effect Size, A 0.50 0.45 0.6495% CI 0.79, 0.21 0.74, 0.16 1.06, 0.22

[0168] The LS mean changes from baseline to week 4 in PANSS total score were -9.3 (placebo), -14.3 (50 mg, p=0.0009 vs placebo; effect size=0.61), -14.0 (75 mg, p=0.0022; effect size=0.41), and -16.1 (100 mg, nominal p=0.0017; effect size=0.83). The treatment effect of LB-102 (all doses) on PANSS Total Score was observed as early as day 8 and maintained throughout the 4-week study period. A similar dose-related treatment effect was observed for LB-102 (all doses) on the PANSS Positive subscale and PANSS Marder Positive Factor score. Mean changes from baseline to week 4 in CGI-S total score were -0.39 (placebo), -0.72 (50 mg, p=0.0008 vs. placebo), -0.67 (75 mg, p=0.0048), and -0.84 (100 mg, p=0.0026). The effect on PANSS Negative subscale score at week 4 was -1.1 (placebo), -2.2 (50mg, D -1.08; p=0.0116 vs placebo), -1.750184896963.4(75mg, D -0.61; p=0.1633), and -1.8 (100mg, D -0.7; p=0.2632). In patients with negative symptoms at baseline, the mean change in negative symptom scores at week 4 was -1.6 (placebo), -3.4 (50mg, D -1.74, p=0.0045 vs placebo; effect size=0.67), -2.6 (75mg, D -1.00, p=0.1501; effect size=0.34), and -3.3 (100mg, D -1.70, p=0.0658; effect size=0.60). Across all analyses, the treatment effect on negative symptoms was seen as early as week 1, which continued through week 4. The least-squares mean changes from baseline to week 4 in PANSS Negative Symptoms subscale score in participants with PANSS negative symptoms subscale score >24 at baseline (Figure 7G) were: Placebo, -1.6; LB-10250 mg, -3.4 (A -1.70, p=0.0045 vs placebo; effect size=0.67); LB-102 75 mg, -2.6 (A -1.00, p=0.1501 vs placebo, effect size=0.34); LB-102 100 mg, -3.3 (A -1.70, p=0.0658 vs placebo, effect size=0.60)

[0169] LB-102 demonstrated greater improvements than placebo across all five PANSS Marder factor scores, which was statistically significant for three of the factor scores (Positive Symptoms, Disorganized Thought, and Uncontrolled Hostility / Excitement). There was a lack of statistical significance for Negative Symptoms and Anxiety / Depression, which may reflect a non-enriched patient population. The LSM changes at week 4 of the PANSS Marder Positive Symptoms factor score were -2.5 (placebo), -4.4 (50 mg, p=0.0020), -4.4 (75 mg, p=0.0020), and -5.4 (100 mg, p=0.0020), also see Figs. 7E, 7I, and 7M. A non-significant treatment effect was observed for each LB-102 dose versus placebo on the PANSS Marder Negative Symptoms factor score at week 4 (LSM change from baseline: placebo, -1.6; 50 mg, -2.5, p=0.0774; 75 mg, -1.9, p=0.4958; 100 mg, -3.0, p=0.0669, see also Fig. 7H) and PANSS Marder Anxiety / Depression factor score (LSM change: placebo, -2.4; 50 mg, -2.7, p=0.5437; 75 mg, -3.2, p=0.0926; 100 mg, -3.5, p=0.1296, see also Fig. 7L). All LB-102 doses were associated with significantly greater improvements from baseline to week 4 on the PANSS Marder Disorganized Thought factor score (LSM change: placebo, -2.0; 50 mg, -3.6, p=0.0002; 75 mg, -2.9, p=0.0301; 100 mg, -3.3, p=0.0447, see also Fig. 7J) and PANSS Marder Uncontrolled Hostility / Excitement factor score (LSM change: placebo, -0.7; 50 mg, -1.5, p=0.0203; 75 mg, -1.5, p=0.0248; 100 mg, -1.9, p=0.0290, see also Fig.7K). All LB-102 doses showed greater Day 28 improvements than placebo on most individual PANSS items, especially positive PANSS symptoms (hallucinatory behavior,51184896963.4delusions, suspiciousness / persecution, unusual thought content) and key general PANSS items (tension, anxiety, preoccupation, poor attention). Smaller, more variable effects were reported on negative PANSS items.

[0170] In a priori analysis of >20% PANSS total score responder rate at week 4 (non-floor adjusted), all LB-102 doses demonstrated a statistically significant difference from placebo. Post hoc (floor-adjusted) analysis demonstrated a higher proportion of responders for each LB-102 dose compared to placebo for the >20% and >30% PANSS total score responders, as well as >40% PANSS total score responders for LB-10250mg and 75 mg compared to placebo (Table 1 E).Table 1E. Summary of Efficacy Endpoints (Modified Intent-to-T eat Analysis Set)LB-10250 mg LB-10275 mg LB-102100 mg Placebo Endpoint / Stat i st ic (N=107) (N=108) (N=36) (N=108) LP.r'.! P.?.ry..?.p.s*P9inl[PANSS total score - Change from baseline to week 4N _ 91 84 23 93 Baseline, mean (SD) _ 93.9 (7.53) 93.6 (7.79) 93.9 (9.01) 93.8 (8.17) Baseline, median (min,92 (82, 115) 92 (81, 116) 92 (82, 114) 93 (80, 118) max)77.6 (12.25) 79.5 (13.49) 77.2 (8.91) 83.4 (12.24) change (SE) -14.3 (1.10) -14.0 (1.11) -16.1 (1.91) -9.3 (1.08) LS mean -5.0 (1.51) -4-7 (1.53) -6.8 (2.17)95% Cl -8.0, -2.1 _ -7.7, -1.7 _ -11.1, -2.6p-valuea<.001 '.002.002I Secondary endpoints[^GPS^core^Change7rom^sejjneJo^reek£ ’ N _ _ _ 91 83 23 94 Baseline, mean (SD)..4.8 (0.57) '.4.9. (0,53) '...4:8.(0.61) '...4.8 (0.57) j Day 28, mean (SD) 3.9 (0.77) 4.1 (0.85) 4.0 (0.60) 4.3 (0.74)-0.72 (0.08) -0.67 (0.08) -0.84 (0.14) -0.39 (0.07) LS mean difference (SE) -0.33 (0.10) -0.28 (0.10) -0.45 (0.15) 95% cP " ^■^'TLl'6""'<.001.005.003 i Responders,bn (%) 25(23.4) 19(17.6) 4(11.1) 8(7.4)14.9, 31.9 10.0, 25.2 0.0, 22.8 2.0, 12.8 I Difference vs placebo 16.0 10.2 3.7 f 95% Cl ’ ' " ' "6.5, 25.4 1.5, 18.9 -7.7, 15.? i p-value.001.02.35 [PANSS PositiveSyrnptomssubsca I N 91 84 23 93 _ [ Bas^ 25.2 (2.92) 25.5 (2.88) 25.0 (3.46) 25.1 (3.61)2^6 ^33)'52184896963.4| LS mean change (SE) -4.8 (0.43) -4.9 (0.43) -5.3 (0.76) -3.1 (0.41) | j LS mean | difference ^(^ -1.7 (0.59) -1.7 (0.59) -2.2 (0.86)n ^5%JCTZ zz z zz zz zi -2.8, -0.5 -2.9, -0.6 -3.8, -0.5; p-value.005 '.004- ' ".01 'I PANSS Marder PY91P1: O91Stact9r sc9r94i N 91 84 23 93 Baseline, mean (SD) 30.2 (3.85).29.6.(3.74) Day 28, mean (SD) 24.8 (4.90) " 26.1 (628)" " 24.4 (5.55) 26.6 (4?86)" JrP P9a999 (PP) -4.4 (0.43) -4.4 (0.44) -5,4 (0.82) -2.5 (0.42) LS mean | difference (^ -1 -9 (0.60) -1.9 (0.60);2.8 (0.91)95%ci _ -3.0, -0.7 " -3.1, -0.7 ';4.6, -1.1p-value.002.002.002subscale score - Change from baseline to week 491 84 23 93 Baseline, mean (SD) 23.4 (3.35)' 22.8 (3.20)' 23:4 (3.60) 23.3 (3.50) j Day 28, mean (SD) 21.1 (3.70) 20.8 (3.95) 21.4 (4.10) 21.9 (4.08) LS mean change (SE):2.2 (0.31) -1,7 (0.32) T1,8 (O-55) -1.1 (0.31) LS mean difference (SE) 71-1(0-4;3) -0.6 (0.44) 70 7(0 63)95% Cl;1 9,;0.2 -1 -5, 0.3 -1.9, 0.5p-value.01.16.26PANSS Marder Negative Symptoms factor score - Change from baseline to week 4~N 91 84 23 93 Baseline, mean (SD) > 22.9 (3.88) > 22.3 (3.53) > 23.4 (4.54) > > 23.2 (3.89) Pay.?8!.9igaP.(PP) 20.4 (4.06) L ''20.3X4"37)" ' ’ 20.7 ’(5.08)’’ Z ZZZZZzZ Z LS 91999999999 (PP) -2.5 (O.37) -1.9 (0.37) -3,0 (0.70) -1.6 (0.36) -0.9 (0.50) -0.4 (0.51) -1.4 (0.78) _95%d _ ' -1.9, 0.1 " -1.4, 0.7 " -3.0, 0.1p-value,.08.50.07PANSS Marder Disorganized Thought factor score - Change from baseline to week 491 84 23 93 Baseline, mean (Sp) 21.6 (3.40) ZZZ2ff-97ZZ Z"2l'j'(325)""" P9y P8’ 91999 (PP)17.8 (3.7'l )’’ 18.1 f3-98) 18:5 (2.87) 19.2 (395) LS mean change (SE) -3.6 (0.31):2.9 (0.31) -3,3 (0.58) -2.0 (0.30) LS mean difference (SE) -1,6 (0.42) -0.9 (0.4-3) ~1 -3 (0.65)95%CI -2.5, -0.8 -1.8, -0.1 -2.6, 0.0P-vajug <.001 0.03PANSS Marder Uncontrolled Hostility / Excitement factor score - Change from baseline to week 491 84 23 93 Baseline, mean (SD) 9,2 (2.81) 8.9 (2.83) 9,2 (3.43) 8,8 (2.66) Day 28,.91999 (PP) ZZZZZ ZlIzllZ ZZZZZ 8 oZZZ7Z LS mean change (SE) -1,5 (0.26) -1,5 (0.27) -1,9 (0.50) -0.7 (0.26) LS mean difference (SE);0,8 (0-36) I0 8!0 37);1.2 (0.56)95% Cl -1.6, -0.1 -1.5, -0.1:2.3, -0.1p-value 0.02 0.02 0.03PANSS Marder Anxiety / Depression factor score - Change from baseline to week 4^~N | 91 | 84 | 23 | 9353184896963.4| Baseline, mean (SD) _ 10.7 (3.27) 10.9 (3.16) 10.6 (3.22) 10.8 (3.33) |7.4 (3.24) 7.7 (3.43) 6.9 (3.01)[ iS rn^ -2.7 (0.32) -3.2 (0.32) -3.5 (0.60) ZZiZSiziLZ] i LS mean difference (SE) -0.3 (0.43)' -0.7 (0.44) ' -1.0 (0.67) ' ziiizSizz] -1.1, 0.6 -1,6, 0,1 -2.3, 0.3[ p-value 0.54 0.09 0.13Responder rate:: S20% PANSS total score reduction at week 4 (a priori, not toor adjusted) | Responders,0n (%) 29 (31.9) 27 (32.1) 10 (43.5) 17 (18.3)22.29, 41,44 22.16, 42.13 23.22, 63.74 10.42, 26.13 = Odds rat jo _ _ 1.91 2.27 2.87(QR) 0,98, 3.74 " 1,16, 4.41 " 1,17, 7.05 ’p-value.06.02.02Responder rate: >20% PANSS total score reduction at week 4 {post hoc, floor-adjusted)52 (57.1)...45 (53.6) > 18 (78.3) 36..(.38. Z).. „ 95% Cl 46.98, 67.3 j 42.91, 64.24 61.40, 95.12 ' 28.81, 48.61“ " 1 Odds ratio 1.92 1.95 4.7595% Cl OR 1,08, 3.40 1.10, 3.46 1,83, 12,34p-value.03.02.01psstotai sGQ rerec, LJ9t'c>r,?t week 4floor-adjusted)I n (%) 29 (31.9) 26 (31.0) 9 (39.1) 15 (16.1) IZ^^PiZZZZZ 22.29, 41.44 21,07, 40.84 19,19, 59.08 8.65, 23.60 L Odds ratio 2.20 2.47 2.90i'''Z5ZZ(9R).""1J°l-37 1.24,1.92 1,1.5, 7.331 p-valuej Responder rate:>40% PANSS total score reduction at week 4 {post hoc, floor-adjusted) j n (%) 19 (20.9).1.4 (16.7).. 3 (13.0) 6 (6.5) 95% Cl 12.53, 29.23 8.70, 24.64 0,00, 26.81 1.46, 11.441 Odds ratio 3.38 3.08 1.7395% Cl OR 1,32, 8.64 1,17, 8.05 0,42, 7,10.01.02.45aResults from the analysis of the primary endpoint for 50 mg and 75 mg were adjusted for multiplicity using a standard Hochberg procedure.bA CGI-S responder was defined as a participant with a CGI-S rating of 3 (mildly ill), 2 (borderline mentally ill), or 1 (normal, not at all ill). Most CGI-S responders at week 4 were rated mildly ill; there were 4 participants rated borderline mentally ill (LB-102 50mg, n=2 / 91 [2.2%]; LB-102 75mg, n=1 / 83 [1.2%]; LB-102 100mg, n=0 / 23; and placebo, n=1 / 94 [1.1%]) and none rated normal, not at all ill.CA >20% PANSS responder was defined as a participant with >20% improvement (reduction) from baseline in PANSS total score, derived from the standard item rating scale (item score range: 1-7, total score range: 30-210).CGI-S, Clinical Global Impressions-Severity of Illness; Cl, confidence interval; LS, leastsquares; OR, odds ratio.Table 1 F: Summary of Primary Efficacy Sensitivity Analyses Intent to Treat PopulationLB-102 50mg LB-102 75mg LB-102 100mg PlaceboStatistic (N=107) _ (N=108) _ (N=36) _ (N=108)54184896963.4PANSS Total Score - Change from Baseline to Week 4N 91 84 23 93 Baseline, mean (SD) 93.9 (7.53) 93.6 (7.79) 93.9 (9.01) 93.8 (8.17) Day 28, mean (SD) 77.6 (12.25) 79.5 (13.49) 77.2 (8.91) 83.4 (12:24) Mean change (SD) _ 1,6.1 (1 1.56) 3-9 (10.97) -17.6 (8.92) -9.6 (9.82) LS mean difference (SE);5.0 (1.5) -4.7 (1.5) -6.8 (2.2)-7-97, -2.05;7-67, -1.68;2;55p-value<.001.002.002Sensitivity Analysis I (Re-Mapped Early Termination Assessment)LB-102 50 mg LB-102 75 mg LB-102 100 mg Placebo Statistic (N=107) (N=108) (N=36) (N=108) PANSS Total Score - Change from Baseline to Week 4N 91 84 23 93 Baseline, mean (SD) 93^88~(7529)7 93;55 (7.791) ^92 (9X)j2^~Day 28, mean (SD) 77.57 (12.24-9)?8.14.8.. Q..8.'.4.8.?..7. L2.2...(8.808. L 83:35 (12.238) LS mean i change (SD):14.2Q (1.080) -13.69 (1.085) -16.30 (1.864) -9.23 (1.066) " LS mean difference (SE);4.98 (1.491) -4.4-7 (1.514-) -7.08 (2.118)795%^;790, -2.05;7-44, -1.50;11:23, -2.92p-value <.001 TXKF 76oiSensitivity Analysis II (Tipping Point Analysis)PANSS Total Score - from Baseline to Week 4Placebo LB-10250 mg LB-10275 mg LB-102 Shift StatisticShift (N=107) _ (N=108) _ 2 2 LS mean difference (SE);4-98 (j:513) " ' -4.48 ("<530) "95% ^;7.95, -2.02 -7.48, -1.48 p-value.001.003 Significant (Hochberg) Yes Yes4 2 LS mean difference (SE) -4-72 (1.521) -4.05 (1.537)95% cr ^;7.70, -1.74 -7.07, -1.04 p-value 0.002 _ 0.008 Significant (Hochberg) Yes4 LS mean difference (SE);4;96 0.522)^^9LZZZZZZZZZZZZZ -7.94, -1.97p-value.001 _.005 _ Significant (Hochberg) Yes Yes6 2 LS mean difference (SE) -4-45 (1.533) ^627^549) -7.46^-1.45 -6.66, -0.59 p-value.004 _.02 _ Significant (Hochberg) Yes Yes4 LS mean difference (SE) -3.86 (1.551) -7-70, -1.68;6.90, -0.82 " p-value.002 _.01 _Significant (Hochberg) Yes Yes55184896963.46 LS mean difference (SE);4.93 (1.537) -4.09 (1.553)~7-94, -1.92 -7.14, -1.05 p-value.001 _.008 _ Significant (Hochberg) Yes Yes 8 2 LS mean difference (SE) -3 19 (1.567)95% ci;7;23, q.15 -6.27, -0.12 p-value.007 _ 0.04 Significant (Hochberg) Yes Yes 4 LS mean difference (SE) -4.43 (1.552)95%CT2 -7.47, -1.38 -6.50, -0.36 p-value.004 _.03 _ Significant (Hochberg) Yes Yes 6 LS mean difference (SE) -4.6611:5:55) -^677^5711)95%^CT3^;7.71, -1.62 -6.74, -0.59 p-value.003 _.02 Significant (Hochberg) Yes Yes 8 LS mean difference (SE);4-90 (1 -559) )3.90 (1.575)95%^^ ~7-96, -1.85;6.99, -0.81 p-value.002.01 Significant (Hochberg) Yes Yes 10 2 LS mean difference (SE);2.77 (1.589)95% CI -7.01, -0.84 -5.88, 0.35 p-value.01.08 Significant (Hochberg) Yes No4 LS mean difference (SE);4.16 (1.575) -3.00 1.59095%^^;7.25, -1.07 -6.12, 0.12 p-value.008 _.06 Significant (Hochberg) Yes No6 LS mean difference (SE) -4.40 (1.578) -3.24 (1.593)95% Cl _ -7.49, -1.31 -6.36, -0.11 p-value.005.04 Significant (Hochberg) Yes Yes 8 LS mean difference (SE) -4.64 (1.582);3.47 (1 -597)95%;7.74, -1.54;6.6Q:;0.34 p-value.003.03 Significant (Hochberg) Yes.. Yes _ 10 LS mean difference (SE) ™4^7lT^7)™"^ "-^nTeo^95% Cl _ -7.99. -1.76 -6.85, -0.57 p-value.002 _.02Significant (Hochberg) Yes Yes Sensitivity Analysis III Reference Imputation)Statistic LB-10250 mg LB-10275 mg LB-102100 mg Placebo56184896963.4|.<N=107) | (N=108) ] (N=36) [(N=108) | PANSS Total Score - Change from Baseline to Week 4 i LS mean (SE) -14.22 (1.083) -13.35 (1.097) -15.40 (1.950)95%CI _ -1550, -11.20;19.23, -11.58LS mean difference (SE);4-80 (1.497) ■~3.?3.(..1...^.9.)..-5:98 (2.189)95% Cl J7-74, -1.87 -6.85, -1.01;1O:27, -1.69 s p-value.001.008.006Significant (Hochberg) Yes Yes. j Missing PANSS total scores were imputed using a mixture of MAR and MNAR (copyreference) approaches depending on whether they were due to drop-out for any reason or not.

[0171] An exploratory post hoc analysis was conducted to evaluate LB-102’s impact on cognitive performance. This study pre-specified assessment of the impact of LB-102 on cognition, analyzing the global cognitive score from the Cogstate schizophrenia battery, a well-validated digital cognitive assessment of attention, working memory, verbal memory and executive function. The Cogstate schizophrenia battery included tests of attention (Detection and Identification tests), working memory (One Back Test), verbal memory (International Shopping List Test) and executive function (Groton Maze Learning Test). It was administered at Baseline and after 4 weeks by trained and credentialed raters. Global cognition was defined by the equally weighted average of standardized change from baseline scores on these five Cogstate tests. The effect of LB-102 on global cognition was compared to placebo at the end of Week 4 using ANCOVA, treating treatment group, pooled study site and baseline cognitive score as covariates. The magnitude of differences between treatment groups was expressed using Cohen’s d (d). Sensitivity analyses were conducted on the endpoints from the individual cognition tests. Post-hoc mediation analyses were conducted to examine the extent to which drug-related improvement in general cognition was an indirect consequence of the drug effects on total schizophrenia symptoms (PANSS total score). Sensitivity analyses re-examined these relationships with LB-102 dose added as a covariate, and with PANSS positive and negative subscale scores considered separately.

[0172] Analysis of global cognition demonstrated a significant treatment effect size for LB-102 after 4 weeks compared to placebo (LB-102 50 mg, effect size = 0.26, p = 0.0476; 75 mg, effect size = 0.41, p = 0.0027; 100mg, effect size = 0.66, p = 0.0018). Such results exceeded the predefined clinical relevance threshold of 0.2 and achieved57184896963.4statistical significance vs. placebo. Cognitive deficits, such as impairments in memory, attention, executive function, and social cognition, are common in patients with schizophrenia, persist even when psychotic symptoms are controlled, and remain a core driver of functional disability (CLIRESZ. Published April 1, 2020. Accessed August 15, 2025. https: / / curesz.org / 2020 / 04 / 01 / coqnitive-deficits-in-schizophrenia / ). Current antipsychotic treatments largely fail to address this domain. Most antipsychotics, while effective for positive symptoms, show little to no benefit for cognitive dysfunction, with only modest, or inconsistent, improvements observed for a small number of atypical agents, and overall cognitive symptoms remain unmet in treatment strategies. See, e.g., CURESZ at https: / / curesz.orq / 2020 / 04 / 01 / coqnitive-deficits-in-schizophrenia / ; Citrome L. J Clin Psychiatry. 2014;75 Suppl 1:21 -6; Guilera G, et al. Eur J Psychiatry. 2009;23(2):77-89; and Haddad C, et al. BMC Psychiatry. 2023;23(1):61. A usability and acceptability assessment of the dataset was performed prior to conducting the post hoc Cogstate analyses (Table in Fig. 9D). There were 18 test completion failures from a total of 3243 tests administered, indicating a usability rate of 99.4%. There were 76 test performance failures from a total of 2578 tests administered for which a test performance check was computed, providing an acceptability rate of 97.1%. As a result of the usability and acceptability analysis, the total trial population was deemed appropriate for further analysis.

[0173] Acceptability and usability of the Cogstate was very high across all timepoints, with data loss during performance less than 1% across all tests. ANOVA indicated that in the total trial population, when compared versus the change from baseline to week 4 with placebo, LB-102 significantly improved global cognition across all doses (Fig. 9F): LB-10250 mg (p=0.0476, d=0.26), 75 mg (p=0.0027, d=0.41 ) and 100 mg (p=0.0018, d=0.66). Post-hoc exploration of effect size for any treatment differences on the individual tests indicated that the benefits of LB-102 occurred across all aspects of tested cognition. The mediation analysis indicated that the impact of LB-102 on cognition was not mediated by any drug-related improvement in schizophrenia symptoms (p > 0.05, indirect effect). Sensitivity analyses highlighted that this result did not change when a) LB-102 dose (Figs. 9G, 9I, and 9K) or b) effects on PANSS positive (Fig. 9H) or negative (Fig. 9J) symptoms were included in the model.58184896963.4

[0174] Analysis of the Cogstate Brief Battery global composite score demonstrated a significant dose-related treatment effect for LB-102 compared to placebo after 4 weeks of treatment (Table in Fig. 9E). Clinical improvements with LB-102 treatment on the Attention (Psychomotor Function) and Memory (Executive Function) composite scores were also observed after 4 weeks of treatment (Table in Fig. 9E).

[0175] LB-102 demonstrated a moderate to large improvement in global cognition in patients with acute schizophrenia (Fig. 9F). This benefit in cognition appears to be a direct treatment effect of LB-102 and was not mediated by its effectiveness in reducing total, positive or negative schizophrenia symptoms. The independence of the effects of LB-102 on global cognition and schizophrenia symptoms supports the hypothesis of a direct procognitive mechanism, potentially attributable to 5-HT7 antagonism. These findings highlight LB-102 as a candidate for addressing the major unmet need of cognitive impairment in schizophrenia, warranting further investigation in longer-term and dedicated cognitive trials.

[0176] LB-102 (50 mg, 75 mg, 100 mg, 4 weeks) was also not statistically different from other successful schizophrenia drugs at their approved dose, e.g., Caplyta (42 mg dose, 4 weeks), Cobenfy (5 weeks), and Rexulti (2 mg and 4 mg doses, 6 weeks) (Fig.3). “Average” was calculated by average of the total PANSS scores of all drugs shown in the figure.

[0177] Evaluation of adverse events in the clinical study show that LB-102 was generally safe and well-tolerated. TEAEs were reported in 56% (placebo, n = 60, 157 events), 69% (50mg, n = 74, 204 events), 57% (75mg, n=62, 139 events), and 75% (100mg, n=27, 60 events) of participants. Ten participants reported TEAEs leading to withdrawal (placebo, n=2; 50mg, n=2; 75mg, n=3; 100mg, n=3) and 5 reported serious TEAEs (placebo, n=2 [including 1 death]; each LB-102 arm, n=1). One death was reported in the placebo group. Most TEAEs were mild or moderate. Severe TEAEs were reported in 5 participants (1.4%), including dystonia (75mg, n=1 ), psychotic disorder (100mg, n=1), schizophrenia (placebo, n=2), and death (placebo, n=1 ).

[0178] Adverse events that occurred in a treatment arm at a rate that was greater than or equal to 5% is summarized in Table 2 below. TEAEs were generally balanced across treatment arms, except insomnia (more frequent with 75mg) and weight increase.59184896963.4Treatment-related TEAEs occurred in 123 participants (34.3%; 212 events), with the most common being insomnia, weight increase, headache, and blood prolactin increased (Table 2).

[0179] Elevated prolactin levels at Day 28 were reported across all treatment arms (placebo, 5.2%, +1,3ng / ml; 50mg, 92.2%, +59.1 ng / ml; 75mg, 94.2%, +50.3ng / ml; 100mg, 87.5%, +51.3ng / ml;). Clinical AEs related to prolactin increase were reported in 5 participants, including galactorrhea (50mg, n=2; 75mg, n=1 ), breast enlargement (1 OOmg, n=1 ), and erectile dysfunction (100mg, n=1). (Table 3C).

[0180] Average QTcF prolongation over placebo was ~4 ms, ~3 ms, and ~4 ms at 50 mg, 75 mg, and 100 mg, respectively, on Day 28 (Figs. 4A-4B). Change from baseline to week 4 in SAS, AIMS, and BARS demonstrated no difference between treatment arms. There was no statistically significant differences between placebo and treatment arms, or among the treatment arms at different doses (Fig. 4B). Little to no emergence of neuromotor side effects (e.g., EPS), akathisia, tardive dyskinesia, or other involuntary motor side effects was observed. Stopping criteria (increase in QTcF of 60 ms or an absolute value of > 500 ms) was never reached (Fig. 8A).

[0181] Although there was a trend to greater weight gain in all treatment arms and placebo group, such trend has not shown clear statistical significance (Fig. 5). Weight increase was the only TEAE to occur in >5% of the total population at a rate at least twice that observed with placebo, but was not dose-dependent (placebo, n=4 [3.7%; 2.1kg]; 50mg, n=13 [12.1%; mean increase: 4.6kg]; 75mg, n= 8 [7.4%; 3.5kg]; 100mg, n=3 [8.3%; 3.7kg]) A >7% weight increase at the last observation was reported by 58 participants (placebo, n=11 [10.2%; +6.9kg]; 50mg, n=25 [24.4%; +7.9kg]; 75mg, n=19 [17.6%; +7.3kg]; 100mg, n=3 [8.3%; +7.8kg]) (Table 2).

[0182] TEAEs leading to trial drug discontinuation occurred in 10 participants (Table 2). The only TEAE leading to trial discontinuation occurring in more than one participant was “worsening schizophrenia” (placebo, n=2; LB-102 50mg, n=1). Other discontinuation-related TEAEs included psychotic disorder, suicidal ideation, alanine aminotransferase increase, lipase increase, toothache, COVID-19, and dystonia. EPS incidence was low across all groups (placebo, n=2 [1.9%]; LB-10250mg [0%]; 75mg, n=1 [0.9%]; 100mg, n=1 [2.8%]), as was dystonia (placebo, n=1 [0.9%]; LB-10250mg, [0%];60184896963.475mg, n=3 [2.8%]; 100mg, n=1 [2.8%]). There were no clinically meaningful changes in blood pressure, pulse rate, or body temperature from baseline to day 28, and no notable shifts observed in QTcF values (Table 2C). One TEAE of hypertension was reported in one participant in the placebo group, which was assessed as non-serious and unrelated to the trial medication.

[0183] See Tables 14.3.1.1 and 14.3.1.2 (Figs. 8A-B) for additional information on adverse events incurred in the clinical trial.Table 2A: AEs that occurred in a treatment arm at a rate that is greater than or equal to 5%LB-10250 mg LB-10275 mg LB-102100 mg Placebo (N=107) (N=108) (N=36) (N=108) Insomnia 27 (25.2%) 23 (21.3%) 14 (38.9%) 24 (22.2%) Headache 12 (11.2%) 9 (8.3%) 2 (5.6%) 10 (9.3%) Anxiety 10 (9.3%) 9 (8.3%) 4 (11.1%) 9 (8.3%) Agitation 11 (10.3%) 6 (5.6%) 4 (11.1%) 10 (9.3%) Weight increased 13 (12.1%) 8 (7.4%) 3 (8.3%) 4 (3.7%) Blood prolactin increased 7 (6.5%) 6 (5.6%) 3 (8.3%) 0 Blood creatine phosphokinase 4 (3.7%) 1 (0.9%) 2 (5.6%) 2 (2.8%) increasedHyperprolactinaemia 4 (3.7%) 2 (1.9%) 3 (8.3%) 0 Alanine aminotransferase 3 (2.8%) 1 (0.9%) 2 (5.6%) 1 (0.9%) increasedSomnolence 1 (0.9%) 4 (3.7%) 2 (5.6%) 0Constipation 4 (3.7%) 1 (0.9%) 2 (5.6%) 0Table 2B: Treatment-related TEAEs occurring in >5% of participants, No. (%) LB-102 LB-102 LB-102 Overall Placebo50 mg 75 mg 100 mg (N=359)(N=108)(N=107) (N=108) (N=36)Insomnia 11 (10.3) 6 (5.6) 3 (8.3) 5 (4.6) 25 (7.0) Weight (increase) 11 (10.3) 6 (5.6) 3 (8.3) 2 (1.9) 22 (6.1) Headache 9 (8.4) 6 (5.6) 1 (2-8) 5 (4.6) 21 (5.8) Blood prolactin (increase) 7 (6.5) 6 (5.6) 3 (8.3) 0 16 (4.5) Somnolence 1 (0-9) 4 (3.7) 2 (5.6) 0 7 (1.9) Alanine aminotransferase 3 (2.8) 1 (0.9) 2 (5.6) 0 6 (1.7)(increase)Agitation 2 (1.9) 0 2 (5.6) 2 (1.9) 6 (1.7)Table 2C: Mean change from baseline to day 28 in selected safety parametersLB-10250 mg LB-10275 mg LB-102100 mg Placebo Overall61184896963.4(N=107) (N=108) (N=36) (N=108) (N=359) Weight (kg) +4.6 +3.5 +3.6 +2.1 - Weight increase >7%, No. (%) 25 (23%) 19 (18%) 3 (8%) 11 (10%) - Weight increase >7% (kg) +7.9 +7.3 +7.8 +6.9 - Prolactin (ng / ml) +59.1 +50.3 +51.3 +1.3 - Fasting glucose (mg / dl) +2.3 +2.0 +4.1 +0.7 - Total cholesterol (mg / dl) +6.2 +2.0 +6.5 +0.9 - QTc (msec) +4.9 +4.3 +5.4 + 1.7 - Mean change >30 msec, n (%) 5 (4.7) 1 (0.9) 1 (2.8) 1 (0.9) - Mean change >60 msec, n (%) 0 0 0 0 -Mean change >500 msec, n (%) 0 0 0 0 -

[0184] The rates of EPS (Table 3A), sedation (Table 3B), and AEs related to prolactin increase (Table 3C) were lower than amisulpride and some other available schizophrenia treatments. Elevated prolactin levels at Day 28 compared to baseline were reported across all treatment arms (placebo, 5.2%, +1.3 ng / ml; 50 mg, 92.2%, +59.1 ng / ml; 75 mg, 94.2%, +50.3ng / ml; 100 mg, 87.5%, +51.3 ng / ml). Clinical adverse events related to prolactin increase were reported in 5 participants (Table 3C).Table 3A: Rates of EPS in LB-102 treatments and other schizophrenia treatments, number of subjects (% of treatment group)AEs Dystonia Akathisia Extrapyramidal disorder Total EPSLB-10250 mg (N=107) 0 1 (0.9%) 0 1 (1.0%)LB-10275 mg (N=108) 3 (2.8%) 2 (1.9%) 1 (0.9%) 6 (5.6%)LB-102100 mg (N=36) 1 (2.8%) 0 1 (2.8%) 2 (5.6%)Placebo (N=108) 1 (0.9%) 1 (0.9%) 2 (1.9%) 4 (3.7%)Table 3B: Rates of sedation in LB-102 treatments, number of subjects (% of treatment group)AE LB-10250 mg LB-10275 mg LB-102100 mg Placebo (N=107) (N=108) (N=36) (N=108)Sedation 0 3 (2.8%) 1 (2.8%) 1 (0.9%) Table 3C: Rates of AEs related to prolactin increase in LB-102 treatments, number of subjects (% of treatment group)AEs LB-10250 mg LB-10275 mg LB-102 100 mg Placebo (N=107) (N=108) (N=36) (N=108) Galactorrhoea 2 (1.9%) 1 (0.9%) 0 0 Breast enlargement 0 0 1 (2.8%) 0 Erectile dysfunction 0 0 1 (2.8%) 0 Total AEs related to 2 (1.9%) 1 (0.9%) 2 (5.6%) 0prolactin62184896963.4

[0185] Clinical efficacy with LB-10250mg was demonstrated by a-14.3-point mean reduction from baseline to week 4 in PANSS total score versus placebo, corresponding to an effect size Hedges’ g=0.61 with LB 102100 mg achieving g=0.83 (exploratory). The magnitude of effect falls within the range reported for established oral antipsychotics in multi episode acute schizophrenia in a large network meta analysis of 402 trials (e.g., amisulpride (standardized mean difference, SMD=-0.73; credible interval, 95% Crl -0.89 to -0.58) olanzapine (-0.56; -0.62 to -0.50), and risperidone (- 0.55; -0.62 to -0.48): cross trial and cross method differences and the exploratory status of 100 mg warrant cautious interpretation.6 The 4 week PANSS reductions observed with LB 102 after 4 weeks of treatment are consistent with early trajectories reported for amisulpride over 3-6 weeks in the pragmatic BeSt InTro trial, acknowledging design and population differences.

[0186] Antipsychotics remain the benchmark for patients with acute schizophrenia, yet clinical utility is often curtailed by adverse effects, including extrapyramidal reactions, weight gain, and sedation, which promote non-adherence and relapse. LB-102 demonstrated a reduced endocrine and metabolic burden usually observed with strong D2 receptor antagonists. Elevated prolactin was reported in 6.5% of the LB-102 50mg group compared with historical non-controlled ranges of 25-100% for amisulpride. Weight gain with LB-102 ranged from 3.5kg (75mg) to 4.6kg (50mg) compared to 2.1kg with placebo, between weight-neutral KarXT (-0.37 kg [95% Cl: -1.19, 0.46] vs. placebo) and olanzapine (2.78kg [2.44, 3.13 vs. placebo]). EPS, QTc prolongation, and hepatic enzyme changes with LB-102 remained similar to placebo. Overall, LB-102 was generally well-tolerated.

[0187] This study was conducted over 4 weeks and was not designed to evaluate the long-term durability of treatment. The inpatient setting minimized risks related to nonadherence, illicit substance use, and unauthorized concomitant medications. Sitelevel smoking restrictions and limited opportunity for physical activity, combined with minimal dietary or food restrictions, may have contributed to weight gain, limiting the ability to fully assess the metabolic profile of LB-102 under real-world outpatient conditions. While LB-102 demonstrated a statistically significant improvement in PANSS total score versus placebo, the 9-point reduction observed with placebo may reflect inpatient stabilization or design-related factors (e.g., number of treatment arms and site63184896963.4participation). TEAEs were reported in adherence to MedDRA 26.1, with common baseline comorbidities, such as insomnia, anxiety, headache, depression, and agitation, among the most frequently reported TEAEs, suggesting a portion of the observed TEAEs may represent the re-emergence, exacerbation, or fluctuation of preexisting symptoms rather than new, drug-related effects (e.g. insomnia affected 74% of participants at baseline with -25% of participants reporting insomnia as a TEAE; anxiety and agitation showed a similar pattern).

[0188] In this phase 2 trial of participants with schizophrenia experiencing acute psychosis, 4-week treatment with once-daily LB-102, a novel D2 / D3 / 5-HT7 receptor antagonist, produced statistically significant symptomatic improvement than placebo across all tested doses, as measured by the change in PANSS total score at week 4. Benefits were directionally consistent on the CGI-S, PANSS Positive and Negative Symptoms subscale scores, and PANSS Marder factor scores, underscoring broad symptomatic efficacy. LB-102 was generally safe and well tolerated, with minimal weight gain over the trial. While prolactin-related TEAEs were observed in a small percentage of participants, the incidence of EPS was very low. The phase 2 results demonstrate a manageable metabolic profile for LB-102, with a narrowing of the longstanding trade-off between potency and tolerability traditionally seen with antipsychotics. These findings suggest LB-102 offers clinically meaningful antipsychotic efficacy with a generally favorable short-term safety profile, supporting longer and larger trials to confirm its durability and metabolic effects in broader patient populations.I. Study population

[0189] Patients must have met all inclusion criteria and had none of the exclusion criteria at Baseline to be enrolled in the study. No deviations was permitted from the inclusion or exclusion criteria.

[0190] To ensure the inclusion of appropriate patients, the information collected during the screening phase that pertained to the diagnosis of schizophrenia, evaluation of the level of disease severity and exacerbation, and the distinction between symptoms of exacerbated schizophrenia and comorbid conditions were recorded (e.g., using an audio recording device). In addition, the Mini International Neuropsychiatric Interview version 7.0.2 (MINI 7.0.2), Placebo-Control Reminder Script (PCRS) and Structured64184896963.4Clinical Interview for the Positive and Negative Syndrome Scale (SCI-PANSS) were audio recorded. The information and recorded interviews were submitted for review by an experienced independent central reviewer to confirm that the patient was appropriate for inclusion in the study. In addition, at Baseline and final endpoint, SCI-PANSS were evaluated by a local rater with central supervision via independent, central review. In addition, SCI-PANSS was audio recorded at all applicable visits when they were administered; however, the patient withdrawal or refusal of consent for recording did not preclude participation in the study.A) Inclusion Criteria

[0191] Patients were eligible for inclusion in the study if they met all of the following criteria:1. Patient, who was able to provide written informed consent (as required by Institutional Review Board [IRB]) prior to the initiation of any protocol-required procedures. Ability, in the opinion of the Principal Investigator (PI), to understand the nature of the trial and follow protocol requirements, including the prescribed dosage regimens, tablet ingestion, and discontinuation of prohibited concomitant medication, and to be reliably rated on assessment scales.2. Must be willing to be hospitalized for the duration of the inpatient period of the study, and willing to comply with instructions from the Investigator and study staff.3. Had stable living environment when not in a hospital, as demonstrated by the ability to provide contact information for themselves or family / friend(s) / caregiver(s).4. Male and female patients 18 to 55 years of age inclusive at the time of informed consent with a diagnosis of schizophrenia as defined by DSM-5 criteria and confirmed by the MINI 7.0.2 for Schizophrenia and Psychotic Disorders Studies.5. Body mass index (BMI) must be >18 and <40 kg / m2.6. Patient who was:• experiencing an acute exacerbation of psychotic symptoms, with onset <6 weeks before Screening AND the patient required hospitalization for this acute exacerbation of psychotic symptoms.OR65184896963.4• if already an inpatient at Screening, had been hospitalized for onset <2 weeks for the current exacerbation.7. Patients who were experiencing an acute exacerbation of psychotic symptoms and marked deterioration of usual function as demonstrated by meeting ALL of the following criteria at the Screening and Baseline visits:• Total PANSS score between 80 and 120, inclusive, and• Score of >4 (moderate or greater) for >2 of the following Positive Scale (P) items: Item 1 (P1; delusions), Item 2 (P2; conceptual disorganization), Item 3 (P3; hallucinatory behavior), Item 6 (P6; suspiciousness / persecution), and • CGI-S score >4 (moderately to severely ill).8. Had received previous antipsychotic treatment (dose and duration as per the label) and who showed a previous good response to such antipsychotic treatment (other than clozapine) in the last 12 months, according to the Investigator’s opinion.9. Had history of relapse and / or exacerbation of symptoms when they were not receiving antipsychotic treatment, according to the Investigator’s opinion.10. Patients willing to discontinue all prohibited psychotropic medications prior to Screening, if determined to be clinically appropriate by the Investigator, and not for the sole purpose of inclusion in the trial.B) Exclusion criteria

[0192] Patients were excluded from the study if they met any of the following criteria:

[0193] Sex and Reproductive Status1. Sexually active females of childbearing potential and male patients who were not practicing 2 different methods of birth control with their partner during the trial and for 30 days after the last dose of trial medication or who would not remain abstinent during the trial and for 30 days after the last dose. If employing birth control, each couple must use 2 of the following precautions: oral contraceptives, patch contraceptives, injection contraceptives, implantable hormonal contraceptives, male condom with intravaginal spermicide, diaphragm or cervical cap with spermicide, vaginal contraceptive ring, intrauterine device or system, surgical sterilization (hysterectomy, bilateral oophorectomy, and / or bilateral66184896963.4salpingectomy), tubal ligation / occlusion, vasectomized partner, or sexual abstinence, if this was the patient’s current practice. Contraceptive requirements did not apply to patients who are in same sex relationship, who were medically or surgically sterilized (e.g., bilateral tubal ligation, bilateral oophorectomy, hysterectomy); or practiced sexual abstinence during this study.2. Females who were breastfeeding or who had a positive pregnancy test result prior to receiving trial medication.

[0194] Target Disease3. Patients who presented with a first episode of schizophrenia based on the clinical judgment of the Investigator and patients with diagnosed schizophrenia equal to or less than a year.4. Improvement of >20% in total PANSS score between the Screening and Baseline assessments.5. History of treatment resistance to schizophrenia medications defined as failure to respond to 2 adequate courses of pharmacotherapy (dose and duration as per the label) or required clozapine within the last 12 months.6. Current DSM-5 Axis I diagnosis other than schizophrenia including, but not limited to, schizoaffective disorder, major depressive disorder, bipolar disorder, post-traumatic stress disorder, anxiety disorders, delirium, dementia, amnestic or other cognitive disorders, as determined by the MINI 7.0.2. Also, patients with borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial personality disorder, as determined by the MINI 7.0.2 and Mini International Neuropsychiatric Interview with Borderline Personality Disorder Module version 7.0.2 (MINI-Plus BPD 7.0.2).7. Risk for suicidal behavior during the study as determined by the Investigator’s clinical assessment and Columbia-Suicide Severity Rating Scale (C-SSRS) as confirmed by the following: answers “Yes” on items 4 or 5 (C-SSRS - Ideation) with the most recent episode occurring within the 6 months before Screening, or answers “Yes” to any of the 5 items (C-SSRS - Suicidal Behavior) with an episode occurring within the 12 months before Screening. This assessment was repeated67184896963.4at Baseline Visit (at baseline “Since Last Visit” version of the CSSR-S scale should be used). Non-suicidal self-injurious behavior was not exclusionary.8. Risk of violent or destructive behavior based on the Investigator’s opinion and homicidal ideation based on responses to SCI- PANSS interview questions or statements made by the patient at any other times during the Screening or Baseline visits.9. Patients with clinically significant tardive dyskinesia determined by a score of >3 on Item 8 of the Abnormal Involuntary Movement Scale (AIMS) at Screening. 10. Patients with a score of >3 on the Barnes Akathisia Rating Scale (BARS) global clinical assessment of akathisia at Screening.

[0195] Medical History and Concurrent Diseases11. Patients who met DSM-5 criteria for substance abuse or dependence within the past 1 year, including alcohol and benzodiazepines, but excluding caffeine and nicotine. Previous occasional use of alcohol or cannabis was allowed as long as the level of use did not meet DSM-5 criteria for any moderate or severe substance use disorder within the 12 months prior to Screening, and the use of alcohol or cannabis was not considered to be the precipitating factor of the current psychotic episode in the opinion of the Investigator; subjects were required to abstain from alcohol and cannabis use during the trial.12. Patients with hypothyroidism or hyperthyroidism (unless the condition had been stabilized with medications for at least the past 90 days) and / or clinically significant abnormal thyroid function (abnormal thyroid-stimulating hormone [TSH] levels followed by free T3 and T4 levels), as assessed by the Investigator, in discussion with the study Medical Monitor.13. History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or oncologic disease or any other condition that, in the opinion of the Investigator, would jeopardize the safety of the subject or the validity of the study results. Positive result at Screening for hepatitis B surface antigen (HbsAg), hepatitis C virus, or human immunodeficiency virus- (HIV)-1 or -2. Patients with chronic hepatitis B or hepatitis C may be included after discussion with the Medical68184896963.4Monitor provided that their condition was stable and values for liver function test met the specified criteria of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2 x upper limit of normal (ULN). The Medical Monitor was contacted in any instance where the Investigator was uncertain regarding the stability of a patient’s medical condition(s) and the potential impact of the condition(s) on trial participation.14. Patients with insulin-dependent diabetes mellitus (i.e., any patient using insulin) were excluded. Patients with non-insulin-dependent diabetes mellitus may be eligible for the trial if their condition was stable as determined by satisfying ALL of the following criteria:• Glycosylated hemoglobin (HbA1c) <7.0%, and• Screening glucose must have been <125 mg / dLor <6.94 mmol / L (fasting) or <200 mg / dL or <11.1 mmol / L (non-fasting). If the non-fasting Screening glucose was >200 mg / dL or >11.1 mmol / L, patients must have been retested in a fasted state and the retest value must have been <125 mg / dL or <6.94 mmol / L, and• Patient had been maintained on a stable regimen of oral antidiabetic medication(s) for at least 28 days prior to Screening or diabetes had been well controlled by diet for at least 28 days prior to Screening, and• Patient had no hospitalizations within the 12 months prior to Screening due to diabetes or complications related to diabetes, and• Patient’s diabetes should not be newly diagnosed during Screening for the trial.15. Patients with uncontrolled hypertension (diastolic blood pressure [DBP] >95 mmHg or systolic blood pressure [SBP] >145 mmHg in any position) or symptomatic hypotension, or orthostatic hypotension defined as a decrease of >20 mmHg in SBP and / or a decrease of >10 mmHg in DBP after at least 3 minutes standing compared with the previous supine blood pressure, OR development of symptoms. NOTE: Blood pressure measurements may be repeated once to ensure reproducibility of the exclusionary result(s) before excluding a patient based on the criteria noted above.69184896963.416. Patients with known ischemic heart disease or any history of myocardial infarction, congestive heart failure (whether controlled or uncontrolled), angioplasty, stenting, or coronary artery bypass surgery.17. Patients with epilepsy or a history of seizures (with the exception of febrile seizure).

[0196] Physical and Laboratory Results18. Patients with a positive urine drug screen or a positive blood alcohol test. Detectable levels of marijuana, barbiturates, benzodiazepines or opiates in the drug screen were not exclusionary if, in the Investigator’s documented opinion, the patient did not meet DSM-5 criteria for substance abuse or dependence, in the Investigator’s documented opinion, the positive test did not signal a clinical condition that would impact the safety of the patient or interpretation of the trial results, and approval was granted by the Medical Monitor prior to treatment.19. Patients with a history of alcohol use disorder, substance use disorder (by DSM-5 criteria) within 12 months of Screening or a positive screen for drugs of abuse at Screening (unless consistent with current prescription for medical condition).20. The following laboratory test results are exclusionary:• Platelets <75,000 / pL or <75x109 / L• Hemoglobin <9 g / dL or <90 g / L• Neutrophils, absolute <1000 / pL or <1 x109 / L• AST >2 x ULN• ALT >2 x ULN• Creatine phosphokinase >3 x ULN, unless discussed with and approved by the Medical Monitor• Creatinine >2 mg / dL or >176.8 pmol / L• Estimated creatinine clearance of <45 mL / min, calculated using the Cockcroft-Gault equation, at Screening• HbA1c >7.0%70184896963.4• Abnormal free T4 (during Screening), unless discussed with and approved by the Medical Monitor (Note: Free T4 would be measured only if the result for TSH was abnormal).21. Clinically significant abnormal finding on the triplicate set of electrocardiograms (ECGs) or evidence of any of the following cardiac conduction abnormalities at Screening (mean values will be used for the following criteria):• Heart rate <40 beats per minute (bpm) and >110 bpm (based on the ECG reading). NOTE: The Medical Monitor should be contacted in any instance where the Investigator was uncertain regarding the stability of a patient’s medical condition(s) and the potential impact of the condition(s) on trial participation• Interval between Q and T wave corrected for heart rate using Fridericia’s formula (QTcF) interval >450 msec for males and females• PR interval >200 msec• Intraventricular conduction delay with QRS duration >120 msec• Evidence of second- or third-degree atrioventricular block• Electrocardiographic evidence of complete left bundle branch block (LBBB), complete right bundle branch block (RBBB), or incomplete LBBB

[0197] Prohibited Therapies or Medications22. Patients who were currently taking oral antipsychotic medications, monoamine oxidase inhibitors (MAOIs), anticonvulsants (e.g., lamotrigine, Depakote), tricyclic antidepressants (e.g., imipramine, desipramine), selective serotonin reuptake inhibitors, and any other antidepressants or any other psychoactive medications (except lorazepam, zolpidem, zaleplon, eszopiclone, or similar benzodiazepines, diphenhydramine, benztropine, and propranolol). Patients taking prohibited psychotropic medications may be eligible for inclusion in the study if it was clinically appropriate to discontinue the medication before the Baseline Visit (in the opinion of the Investigator). The prohibited psychotropic agent must be discontinued and washed out at least 5 half-lives prior to Baseline. Subjects taking a depot antipsychotic could not have received a dose of medication for at least 1 and a half71184896963.4injection cycles before Baseline. The medications should not be discontinued solely to make the patient eligible for enrollment in the study.23. Patients who received electroconvulsive therapy within 90 days of Screening.24. Patients who received Transcranial Magnetic Stimulation (TMS) within 90 days of Screening.

[0198] Allergies and Adverse Drug Reactions25. Patients with a history of neuroleptic malignant syndrome.26. Patients with a history of allergic response (defined as hypersensitivity reactions such as flushing, rash, wheezing, abdominal cramps, hypotension, seizure, etc., not intolerance) to more than 1 class of medications.

[0199] OthersStatis LB-102 LB-102 LB-102 Placeb Parameter tic 50 mg 75 mg 100 mg 0 Overall Randomized Patients n 107 108 36 108 359 Patients Receiving Study n (%) 107 108 36 108 359 Treatment [a] (100.0) (100.0) (100.0) (100.0) (100.0) Not Treated Patients [a] n (%) 0 0 0 0 0 Completed Study [a] n (%) 76 80 22 83 261(71.0) (74.1) (61.1) (76.9) (72.7) Did Not Complete Study [a] n (%) 31 28 14 25 98(29.0) (25.9) (38.9) (23.1) (27.3) Reason for Non-Completionof Study [b]Lost to Follow-Up n (%) 12 4 (14.3) 1 (7.1) 9 (36.0) 26(38.7) (26.5) Protocol Deviation n (%) 0 1 (3.6) 0 1 (4.0) 2 (2.0) Adverse Event n (%) 2 (6.5) 3 (10.7) 3 (21.4) 2 (8.0) 10(10.2) Study Terminated by n (%) 0 0 0 0 0 SponsorPhysician Decision n (%) 1 (3.2) 1 (3.6) 0 0 2 (2.0) Withdrawal by Subject n (%) 16 19 10 11 56(51.6) (67.9) (71.4) (44.0) (57.1) Non-Compliance with Study n (%) 0 0 0 0 0DrugDeath n (%) 0 0 0 1 (4.0) 1 (1.0)72184896963.4Lack of Efficacy n (%) 0 0 0 1 (4.0) 1 (1.0)Other n (%) 0 0 0 0 027. Prisoners or patients who were compulsorily detained (involuntarily hospitalized) for treatment of either a psychiatric or physical illness or had been in the last 6 months prior to the Screening Visit must not be enrolled into this study.28. Patients who had participated in another clinical study in which they received an experimental or investigational drug agent within 3 months of Screening.

[0200] The patient disposition of the intent-to-treat (ITT) analysis set is provided in Table 4A.Table 4A: Patient Disposition, ITT Analysis SetLB-102 LB-102 LB-102Parameter Statistic 50 mg 75 mg 100 mg Placebo Overall Randomized Patients n 107 108 36 108 359 Patients Receiving Study Treatment n (%) 107 108 36 108 359 (a) (100.0) (100.0) (100.0) (100.0) (100.0) Not Treated Patients (a) n (%) 0 0 0 0 0 Completed Study [a] n (%) 76 (71.0) 80 (74.1) 22 (61.1) 83 (76.9) 261 (72.7) Did Not Complete Study [a] n (%) 31 (29.0) 28 (25.9) 14 (38.9) 25 (23.1) 98 (27.3) Reason for Non-Completion ofStudy (b)Lost to Follow-Up n (%) 12 (38.7) 4 (14.3) 1 (7.1) 9 (36.0) 26 (26.5) Protocol Deviation n (%) 0 1 (3.6) 0 1 (4.0) 2 (2.0) Adverse Event n (%) 2 (6.5) 3 (10.7) 3 (21.4) 2 (8.0) 10 (10.2) Study Terminated by Sponsor n (%) 0 0 0 0 0 Physician Decision n (%) 1 (3.2) 1 (3.6) 0 0 2 (2.0) Withdrawal by Subject n (%) 16 (51.6) 19 (67.9) 10 (71.4) 11 (44.0) 56 (57.1) Non-Compliance with Study n (%) 0 0 0 0 0 DrugDeath n (%) 0 0 0 1 (4.0) 1 (1.0) Lack of Efficacy n (%) 0 0 0 1 (4.0) 1 (1.0) Other n (%) 0 0 0 0 0[a] Percentages are based on the number of patients in the ITT Analysis Set by treatment and overall.[b] Percentages are based on the number of patients who did not complete the study. C) Analysis populations

[0201] The following analysis populations were provided:• Intent-to-treat (ITT) Analysis Set: all randomized patients, irrespective of whether they received the drug or not.73184896963.4• Modified Intent-to-treat (mITT) Analysis Set: all randomized patients with at least 1 dose of study drug or placebo and provided at least one post-baseline efficacy assessment. This was the main analysis population for efficacy analysis purposes and patients were analyzed based on the treatment they were randomized to. • Safety Analysis Set: all randomized patients who received study drug. Analyses based on this population used the actual treatment received rather than the randomized one.• Pharmacokinetic Analysis Set: the first 60 randomized patients regardless of cohort

[0202] The respective numbers (%>) of patients included in the ITT analysis set, modified intent-to-treat (mITT) analysis set, safety analysis set, and pharmacokinetic analysis set are provided in Table 4B. Percentages are based on the number of patients in the ITT Analysis Set by treatment and overall.Table 4B: Number (%) of patients included in various analysis sets, based on the ITT analysis setNumber (%) of Patients IncludedAnalysis Set LB-10250 mg LB-10275 mg LB-102100 mg Placebo Overall ITT Analysis Set 107 108 36 108 359 mITT Analysis Set 107 (100.0) 108 (100.0) 36 (100.0) 108 (100.0) 359 (100.0) Safety Analysis Set 107 (100.0) 108 (100.0) 36 (100.0) 108 (100.0) 359 (100.0)Pharmacokinetic Analysis Set 19 ( 17.8) 22 ( 20.4) 5 ( 13.9) 21 ( 19.4) 67 ( 18.7)

[0203] The demographics of safety analysis is provided in Table 40. Percentages are based on the number of patients in the Safety Analysis Set with non-missing data by treatment group and overall.Table 4C: Demographics of safety analysis setLB-10250 LB-10275 LB-102100 Placebo Overall Parameter Statistic mg (N=107) mg (N=108) mg (N=36) (N=108) (N=359) n 107 108 36 108 359 Mean 39.0 (9.64) 39.2 (9.17) 39.1 (9.19) 39.1 (9.11) 39.1 (9.26) (SD)Median 39.0 38.0 38.0 39.0 39.0 Age at Informed Min, 19, 55 20, 55 19, 55 19, 55 19, 55 Consent (years) MaxGender n 107 108 36 108 359 Male n (%) 87 (81.3) 90 (83.3) 28 (77.8) 85 (78.7) 290 (80.8)Female n (%) _ 20 (18.7) 18 (16.7) 8 (22.2) 23 (21.3) 69 (19.2)74184896963.4LB-10250 LB-10275 LB-102100 Placebo Overall Parameter Statistic mg (N=107) mg (N=108) mg (N=36) (N=108) (N=359) Fertility Status n 20 18 8 23 69 Childbearing n (%) 14 (70.0) 15 (83.3) 5 (62.5) 12 (52.2) 46 (66.7) PotentialPost-Menopausal n (%) 3 (15.0) 1 (5.6) 1 (12.5) 3 (13.0) 8 (11.6) Surgically Sterile n (%) 3 (15.0) 2 (11.1) 2 (25.0) 8 (34.8) 15 (21.7) Ethnicity n 107 108 36 108 359 Hispanic or Latino n (%) 12 (11.2) 8 (7.4) 6 (16.7) 17 (15.7) 43 (12.0) Not Hispanic or n (%) 95 (88.8) 100 (92.6) 30 (83.3) 91 (84.3) 316 (88.0) LatinoRace n 107 108 36 108 359 White n (%) 17 (15.9) 18 (16.7) 9 (25.0) 24 (22.2) 68 (18.9) Black or African n (%) 87 (81.3) 83 (76.9) 25 (69.4) 80 (74.1) 275 (76.6) AmericanAsian n (%) 0 2 (1.9) 0 1 (0.9) 3 (0.8) American Indian or n (%) 0 2 (1.9) 0 0 2 (0.6) Alaska NativeNative Hawaiian or n (%) 0 0 0 0 0 Other Pacific IslanderOther n (%) 1 (0.9) 2 (1.9) 1 (2.8) 3 (2.8) 7 (1.9) Multiple n (%) 2 (1.9) 1 (0.9) 1 (2.8) 0 4 (1.1) Height at Screening n 107 108 36 108 359 (cm) Mean 175.1 (9.66) 175.2 (8.53) 175.3 (8.03) 174.3 174.9(SD) (8.89) (8.92) Median 176.0 175.0 174.5 174.0 175.0 Min, 152, 198 152, 196 157, 195 154, 201 152, 201 MaxWeight at Screening n 107 108 36 108 359 (kg) Mean 84.03 88.37 85.87 85.56 85.98(SD) (19.523) (18.486) (17.980) (17.178) (18.377) Median 79.70 84.80 84.55 82.10 82.30 Min, 49.4, 149.7 53.5, 147.1 50.5, 125.2 53.1, 136.1 49.4, Max 149.7 BMI (kg / m2) n 107 108 36 108 359Mean 27.41 28.78 28.01 28.15 28.10 (SD) (5.975) (5.604) (5.984) (5.220) (5.647) Median 26.30 28.20 26.65 27.20 26.90 Min, 18.0, 40.0 18.8, 41.1 18.0, 38.9 18.9, 40.0 18.0, 41.1 MaxWaist Circumference n 107 108 36 108 359 (cm) Mean 93.21 97.27 93.02 94.51 94.81(SD) (15.729) (15.006) (14.531) (14.345) (15.021) Median 90.00 95.00 91.15 92.50 93.00 Min, 66.0, 146.0 70.0, 138.0 63.5, 124.0 71.0, 130.0 63.5,Max 146.0 SD: Standard Deviation; BMI: Body Mass Index.75184896963.4II. Study

[0204] 395 patients were randomized to receive 1 of 4 study treatments in a ratio of about 3:3:3:1: placebo, LB-10250 mg QD, LB-102 75 mg QD, or LB-102 100 mg QD for 28 days (Table 1 A).

[0205] LB-102 and placebo were administered as visually matched tablets for the treatment of adult patients with an acute exacerbation of schizophrenia. LB-102 tablets were 50 mg in strength. The placebo tablets matched the 50-mg tablets in appearance. Tablet-splitting procedures are outlined in the Pharmacy Manual that describes how patients were dosed. The API of the LB-102 tablets were made by Procos in Italy. The placebo and LB-102 tablets were made by Quotient in UK. The following tablets were administered based on randomization:Table 5A: Tablet administered to treatment arms and placebo armDose Number of active tablets Number of placebo tablets Total number of tablets per dose Placebo 0 2.5 2.550 mg 1 1.5 2.575 mg 1.5 1 2.5100 mg 2 0.5 2.5A) Formulation and Preparation

[0206] See below a summary of material requirements (Table 5B).Table 5B: Material informationMaterial / trade name Functional Manufacturer / Unit (%) Qty for Qty for requirement Supplier compositi Tee. CTM on (mg) Transfer Batch (kg)1Batch (kg)1N-Methyl API Procos 50.0000 57.14 0.9000 3.6000 Intra- Amisulpride (LB- granular 102)3Lactose Diluent / filler Meggie / Fisher 25.0000 28.57 0.4500 1.8000 MonohydrateNF (Spherolac100)Sodium Starch Disintegrant JRS 1.7500 2.00 0.0315 0.1260 Glycolate (typeA) NF (Explotab)Methyl cellulose Binder DuPont / Colorcon 2.5000 2.86 0.0450 0.1800 NF(METHOCELA4C Premium)Diluent / filler Duppont / IMCD 2.562576184896963.4Extra- Microcrystalline 2.93 0.04613 0.1845 granular Cellulose NF(Avicel PH 102)Sodium Starch Disintegrant JRS 4.3750Glycolate (type 5.00 0.0788 0.3150 A) NF(Explotab)Magnesium Lubricant Faci 1.3125 1.50 0.0236 0.0945 stearate NFTotal 87.50 100.00 1.5750 6.30001Specific requirement for Sponsor supplied materials were detailed in the project Technical Agreement. All start materials had appropriate controls as defined in SOP QAS013.3N-Methyl Amisulpride (LB-102) was replaced with Microcrystalline cellulose in case of placebo tablets.

[0207] Study drugs was packaged and labeled by PCI in Illinois in accordance with applicable regulatory requirements.

[0208] Study drug was stored at secure and locked location at temperature ranges between 20°C - 25°C (68°F - 77°F) with acceptable excursions to 15°C - 30°C (59°F and 86°F) allowed.

[0209] Verbal and written instructions for proper storage, handling, and administration of the study drug were given to the patient and included instructions to contact the study site immediately if they experience problems with the study drug and / or administration.

[0210] Site storage conditions were monitored by the site personnel and reviewed by the monitor during site visits. Deviations from the storage requirements was documented and reported to the Sponsor.

[0211] Complete instructions for proper study drug storage and handling were provided in the Pharmacy Manual.

[0212] All study drugs were supplied by the Sponsor and shipped to sites by PCI. No study drug would be shipped to a site until authorization was given by the Sponsor or its representative. The study drug was shipped under ambient conditions.B) Treatment assignment

[0213] Patients were randomized in a 3:3:3:1 ratio to either placebo, LB-10250 mg QD, LB-10275 mg QD, or LB-102 100 mg QD (Table 1A). An unblinded biostatistician, contracted with Worldwide Clinical T rials (Worldwide), was responsible for generating and77184896963.4implementing the randomization scheme that determined treatment assignment. Randomization occurred through an integrated response technology (IRT) system. The IRT system generated the randomization number and the randomization number was captured by and integrated into the electronic data capture (EDC) system. The patient identification was a 6-digit number (i.e., the 1 -digit country number, followed by a 2-digit site number followed by a hyphen and a 3-digit consecutive number).

[0214] This study was conducted under double-blind conditions such that neither the patient nor the Investigator or study staff members working directly with patients knew the identity of each patient’s treatment.

[0215] Each site assigned a dedicated unblinded pharmacist and / or applicable unblinded study team member for the preparation of LB-102 or placebo. The knowledge of the patients assigned treatment was only available to assigned unblinded pharmacist / unblinded study staff member. The unblinded pharmacist / unblinded staff team member ensured the treatment assignment was not shared with any study staff having direct patient contact and that no other unblinding occurred.

[0216] Clinical sites followed site specific procedures / processes to ensure the blind was maintained.

[0217] Treatment assignment for an individual patient was restricted. In an emergency situation the Investigator may unblind the patient via the IRT when knowledge of the treatment assignment was urgently needed for the clinical management or welfare of the patient.

[0218] Study drug unblinding was restricted to the designated unblinded pharmacist / unblinded study team member and the Worldwide clinical pharmacovigilance team, and was provided electronically from the IRT.C) Prior and Concomitant Medications

[0219] All prescription, nonprescription medications (e.g., over-the-counter [OTC]) drugs and herbal supplements) and non-medical treatments starting from 30 calendar days before Screening until end of the study were recorded in source documents and the eCRF. For each medication, documentation listed the trade or generic name, the total daily dose including units (or the dose, units, and scheduled and actual frequency of78184896963.4administration if the medication was not taken daily), the route of administration, and the reason for use.

[0220] Changes, additions, or discontinuations to medications were assessed and recorded in the eCRF during each study visit. All as-needed prescriptions were converted to reflect actual dose taken per day.

[0221] Starting on the first day of the screening phase, after written informed consent for the study were provided, all antipsychotic or other psychotropic medications were stopped with clinically appropriate titration down as per the Investigator’s clinical judgment. Patients were instructed not to take any medication(s) during the conduct of the study unless approved by the Investigator. Any patient unable to be safely discontinued from current antipsychotic therapy or other psychotropic medications were not eligible for the study. Any treatment other than the study treatment given were considered a concomitant medication and were documented in the eCRF. Any patient requiring emergency treatment with prescription or nonprescription medication during the screening phase through the EoS Visit were approved by the Investigator. If the Investigator determined that the patient required medication during the study, the Medical Monitor were contacted within 24 hours.

[0222] Psychotropic medications were prohibited except for lorazepam as needed for agitation, restlessness, irritability, or hostility; zolpidem, zaleplon, or eszopiclone for insomnia; diphenhydramine or benztropine for EPS; and propranolol for akathisia.

[0223] Within the daily limits shown in Table 5C below, lorazepam, benztropine, and propranolol were allowed on as needed basis; every administration was considered and approved by the Investigator prior to administration.

[0224] The AEs associated with the need for lorazepam, benztropine, or propranolol were recorded on the Adverse Events in the eCRF. The amount and timing for each lorazepam, benztropine, or propranolol administration were recorded for each patient.Table 5C: Permitted concomitant medicationsMedication Study Period Dose Permitted Timing Restriction Lorazepam Screening phase Maximum of 6 Not within 12 hours priorthrough Day 7 mg / day to PANSS79184896963.4Day 8 though Day Maximum of 414 mg / dayDay 15 through Maximum of 2Day 28 mg / day On no morethan4 days / WeekBenztropine Screening phase Maximum 4 mg / day Not within 12 hours prior Through Day 28 to SAS, BARS, or AIMS Propranolol Screening phase Maximum of 40Through Day 28 mg / daySleep Medication Day 1 and Day 28 No restrictions3Not within 8 hours prior zolpidem, zaleplon, or to Cogstate test eszopiclone forinsomniaaAllow nighttime use only (pm); exclude regular use; exclude daytime use; exclude use within 12 hours of a study visit Abbreviations: AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale; mg = milligram; PANSS = Positive and Negative Syndrome Scale; SAS = Simpson-Angus Scale

[0225] During the End of Stabilization period, the use of lorazepam, benztropine, and propranolol was not restricted. Smoking was allowed, under supervision

[0226] A select list of CYP2D6 inhibitors (Celecoxib, Methadone, Chloroquine, Moclobemide, Chlorpheniramine, Paroxetine, Clemastine, Pyrilamine, Clomipramine, Quinidine, Fluoxetine, Terbinafine, Halofantrine, Tripelennamine, and Hydroxyzine), CYP3A4 inhibitors (Fluvoxamine, Amprenavir, Indinavir, Aprepitant, Itraconazole, Chloramphenicol, Ketoconazole, Cimetidine, Nefazodone, Clarithromycin, Nelfinavir, Clotrimazole (if used orally), Quinupristin / Dalfopristin, Delavirdine, Ritonavir, Diltiazem, Saquinavir, Erythromycin, Troleandomycin, Fluconazole, and Verapamil) and CYP3A4 inducers (Carbamazepine, Phenytoin, Dexamethasone, Primidone, Efavirenz, Rifampin, Nevirapine, St. John’s Wort, Oxcarbazepine, Troglitazone, and Phenobarbital) were prohibited within 14 days or randomization and for the duration of the trial. CYP is abbreviation of cytochrome P450.D) Acceptable Contraceptive Methods

[0227] For females of childbearing potential who participated in the study, the following methods of contraception, if used properly and used for the duration of the study and for 30 days after the last dose of study medication, were generally considered reliable; however, if employing birth control, each couple must have used 2 of the80184896963.4following precautions: oral contraceptives, patch contraceptives, injection contraceptives, implantable hormonal contraceptives, male condom with intravaginal spermicide, diaphragm or cervical cap with spermicide, vaginal contraceptive ring, intrauterine device or system, surgical sterilization (hysterectomy, bilateral oophorectomy, and / or bilateral salpingectomy), tubal ligation / occlusion, vasectomized partner, or sexual abstinence, if this was the patient’s current practice. Contraceptive requirements did not apply to patients who were in same sex relationship, who were medically or surgically sterilized (e.g., bilateral tubal ligation, bilateral oophorectomy, hysterectomy); or practiced sexual abstinence during this study.

[0228] These methods of contraception also applied to female partners of male patients. The Investigator and each patient determined the appropriate method of contraception for the patient during participation in the study. This was documented at the Screening Visit in the patient’s source documentation / medical record.E) Study conduct

[0229] Study participation included a 14-day inpatient screening phase (up to a 14-day extension of the screening phase was allowed, if necessary with the approval of the Medical Monitor), an inpatient Study Treatment Period with 4 weeks of daily study treatment, an inpatient Stabilization Period of up to 5 days (days 29 to 33, during which patients were stabilized on standard antipsychotic medication), and an outpatient Final Safety Follow-up of approximately 2 weeks after the end of the Treatment Period (Visit 8, Day 42 ± 2 days). The study is summarized graphically in Fig. 1 A. Table 5D provides a schedule of assessments in the protocol for the study.Table 5D: Schedule of AssessmentsEvent Screening Baseline Study T reatment Period End of End Phase Stabilization of Period Study Visit Up to 14 Day 1 Days Day Days Day Days Day Days Day 33cDay days32-7 8 ± 9-14 15 16- 21 22- 28 42± 21 ± 1 20 ± 1 27 orETVisit Number 1 2 NAb3 NAb4 NAb5 NAb6 7 8 Entrance / ScreeningCriteriaInformed Consent3X81184896963.4Admission to Inpatient XUnit3Inclusion / Exclusion X XCriteria Review3Screening XAdjudication Form(s)and Recordings'1Medical History® XMINI-PIUS BPD 7.0.2 XPrior Medication XWashout’Hepatitis / HIV XUrine Drug and Blood X9Alcohol Screen^Randomization XEfficacy(PCRS) SCI-PANSS xhxhX X X xhand CGI-SCogstate Test X’ Xi XiSafetyPrior and Concomitant X X X X X X X X X X X X MedicationPhysical Exami X X X X X X X AIMS X xkxkxkxkxkSAS X xkxkxkxkxkBARS X xkxkxkxC-SSRS X1XmrXkxXkmXn mXrnXrn xmBMI and Waist X X X X X X Circumference"Urine Pregnancy Test0X X X XClinical Laboratories X(for Screening andexclusionarypurposesjpHematology, Serum X X X X X XChemistry includingProlactin, Urinalysis'1TSHrX XPT, aPTT, and INR X X XACTH and Cortisol X XResting 12-lead ECGSX X X X X XVital Signs’ X X X X X XAdverse Events0X X X X X X X X X X X X OtherStudy Drug Dosing X X X X X X X X X82184896963.4PK Sample CollectionvX X XRestart Standard XAntipsychotic*a. Screening began when the IGF was signed and took place between Day -14 and Day -1; up to a 14-day extension of the screening phase was allowed, if necessary with the approval of the Medical Monitor; screening procedures should be initiated with a sufficient amount of time allotted in order to obtain central laboratory results and ECG results from the central reader prior to randomization. Review of inclusion / exclusion criteria at Baseline was based on assessments performed during Screening. Hospitalization began with the signing of the ICF for patients who were not already hospitalized at the initial Screening Visit.b. Each patient received the QD administration of study treatment. No other assessments were scheduled; however, AEs observed or reported, and concomitant medications were recorded. In case of an AE, an unscheduled visit might be conducted at the discretion of the PI.c. Stabilization Period was up to 5 days.d. The Screening assessments to be audio recorded included the MINI 7.0.2, PCRS and SCI-PANSS and were submitted to an independent central reviewer for review and eligibility confirmation.e. Included full psychiatric history, DSM-5 diagnosis of schizophrenia, and MINI 7.0.2. f. Washout of prohibited medications began after signing the ICF and after diagnosis of Schizophrenia was confirmed by MINI. The recommended duration of the washout period was 5 x the duration of the known half-life of the drug. Prohibited and restricted medications were selected CYP2D6 inhibitors, selected CYP3A4 inhibitors, and selected CYP3A4 inducers provided supra.g. Urine drug screen (full panel including opioids) and a blood alcohol test were required at the designated times, but either or both could be conducted at any time during the trial at the discretion of the Investigator.h. At Screening, Baseline, and final endpoint, SCI-PANSS and CGI-S were evaluated by a local site rater with central supervision via independent, central review. SCI-PANSS was audio recorded at any visit where they were administered. SCI-PANSS assessment were preceded by the PCRS. Patients with improvement of >20% in total PANSS score between the Screening and Baseline assessments were excluded from study participation. SCI-PANSS was administered first on visits before any other scales, when SCI-PANSS and CGI-S were being administered with the exception of Screening where MINI-Plus BPD 7.0.2 was administered first. The Placebo-Control Reminder Script© Hassman and Cohen, 2019, Version 5.0 educated clinical trial subjects of key causes of the placebo and nocebo effects, level setting of the subject’s study expectations, reminding subjects what a placebo was and how that related to their reporting of symptoms and potential side effects, and explaining how interactions with research site staff differred from their experience with clinical providers. The PCRS informed subjects that they were to be honest about their symptoms and that the site staff had no expectations of symptom improvement or worsening and would not be disappointed by the subject’s responses, and asked subjects to explain in their own words PCRS content to ensure comprehension. The PANSS Rater read the PCRS before administering the PANSS at each study visit.83184896963.4i. During Screening, patients underwent a practice assessment of the Cogstate test. On Day 1 and Day 28, the actual Cogstate testing was performed. Note: Cogstate Battery test could not be done within 8 hours of receiving a benzodiazepine or sleep medication.j. To include height at the Screening Visit only. A full physical examination was conducted at the Screening Visit and at EoT Visit. At each other study visit, patients were assessed for continued dosing and any possible physical symptoms and a targeted physical examination was performed, if indicated.k. On Days 1, 8, 15, 21, and 28, the SAS, BARS, and AIMS assessments were to be conducted 3 to 6 hours after the administration of study treatment with the exception of ET Visit.l. If the administration of C-SSRS at Screening highlighted the risk of suicide not previously known, in the opinion of the Investigator, the patient should be excluded from the trial. At this visit the “Baseline / Screening” version of the C-SSRS scale was used.m. At all other study visits the “Since Last Visit” version of the C-SSRS scale should be used.n. BMI; derived programmatically from body weight and height measurements.o. All positive urine pregnancy test results were confirmed by a serum test. Patients with positive urine and serum pregnancy test results at Screening must not be enrolled. Patients with positive urine and serum pregnancy test results during the trial must discontinue treatment and be withdrawn from the trial. Pregnancy tests could be performed at any point during the trial if pregnancy was suspected.p. Clinical laboratory samples at Screening for exclusionary purposes were to be taken after a fast of at least 8 hours. Vital signs and ECG were completed before any blood samples were collected. Clinical laboratory test results drawn within ± 24 hours of the scheduled timepoint may be used. Clinical laboratory tests included the following:• Hematology Screening assessments (excluded test result) will include measurement of hemoglobin (<9 g / dL or <90 g / L), platelets (<75,000 / pL or <75x109 / L), neutrophils (absolute <1000 / pL or <1 x109 / L).• Clinical chemistry tests for exclusionary purposes are for ALT (>2 x ULN), AST (>2 x ULN), creatinine (>2 mg / dL or >176.8 pmol / L), CPK (>3 x ULN, unless discussed with the Medical Monitor), HbA1c (>7.0%), TSH. Important note: Free T4 was measured only if the result for TSH was abnormal.• Creatinine clearance was calculated at Screening using the Cockcroft-Gault equation; estimated creatinine clearance of <45 mL / min was exclusionary. q. Clinical laboratory samples are to be taken after a fast of at least 8 hours. Vital signs and ECG should be completed before any blood samples are collected. Clinical laboratory test results drawn within ± 24 hours of the scheduled timepoint may be used. Routine clinical laboratory tests to be monitored throughout the study will include the following:• Hematology will include measurement of hematocrit, RBC, reticulocytes, and WBC with differential.• Clinical chemistry will include measurement of albumin, ALT, ALP, amylase, AST, bicarbonate, bilirubin-total, blood urea nitrogen, calcium, creatine kinase, creatinine, gamma-glutamyl transpeptidase, globulin, glucose, lactate84184896963.4dehydrogenase, lipase, magnesium, phosphate, potassium, prolactin, sodium, total protein, total cholesterol, triglycerides, HDL, LDL and uric acid.• Urinalysis: pH of freshly voided specimen, specific gravity, protein, glucose, ketones, blood, and microscopic examination of the sediment.r. Important note: Free T4 was measured only if the result for TSH was abnormal. s. Standard 12-lead ECGs (in triplicate) were performed after the patient had been supine and at rest for >5 minutes. The captured ECGs must be separated by at least 1 minute. A central ECG service will be utilized to review all ECGs in order to standardize interpretations for the safety analysis. In addition, ECG results will be evaluated at the investigational site to monitor safety during the trial. Any Screening ECG with abnormal result(s) considered to be clinically significant should be repeated to confirm the finding(s) before excluding the patient from the trial. Patients will be randomized based on Screening ECG results from the central reader and Baseline ECG results from the trial site. If the Baseline ECG results from the central reader, when available, indicate a QTcF >450 msec at Baseline, the Investigator must contact the Medical Monitor to discuss the patient’s continued participation in the trial. ECGs scheduled for the same visit as blood samples were completed before blood was drawn.t. Vital signs included body temperature, SBP, DBP, and heart rate. Blood pressure and heart rate were measured in the following order: supine, sitting and standing after the patient had been in each position for at least 3 minutes. Vital signs scheduled for the same visit as blood sample had to be completed before blood was drawn.u. The recording of AEs was to start immediately after the IGF was signed and up to 14 days after the end of EoT.v. PK analyses included the first 60 randomized patients regardless of cohort. PK blood samples were collected on Day 1, 8, and 21 during the following timepoints after the morning dose: 15 minutes, 30 minutes, 1, 2, 3, 4, 8, and 24 hours. On Day 1 only, a pre-dose PK blood sample was collected. Samples were collected after ECGs and vital signs. The total volume of blood to be collected during the Screening, treatment, and End of Stabilization period was 161 ml_. Approximately 21 mL of blood was collected during the Screening Visit, 130 mL was collected during the 28-day Treatment Period, and 10 mL was collected during the End of Stabilization period. w. On Day 29 patients were to be started on standard antipsychotic medication as prescribed by the Investigator.Abbreviations: ACTH = adrenocorticotropic hormone; AE = adverse event; AIMS = Abnormal Involuntary Movement Scale; ALP = alkaline phosphatase; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; BARS = Barnes Akathisia Rating Scale; BMI = body mass index; CGI-S = Clinical Global Impressions-Severity of Illness scale; CPK = creatine phosphokinase; C-SSRS = Columbia-Suicide Severity Rating Scale; DBP = diastolic blood pressure; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; ECG = electrocardiogram; EoT = end of treatment; ET = early termination; HDL = high-density lipoprotein, HIV = human immunodeficiency virus; ICF = informed consent form; INR = international normalized ratio; LDL = low-density lipoprotein; MINI 7.0.2 = Mini International Neuropsychiatric Interview version 7.0.2; MINI-Plus BPD 7.0.2 = Mini International Neuropsychiatric Interview with Borderline Personality Disorder Module85184896963.4version 7.0.2; NA = not applicable; PANSS = Positive and Negative Syndrome Scale; PCRS = Placebo-Control Reminder Script; PK = pharmacokinetic; PT = prothrombin time; QD = once daily; QTcF = interval between Q and T wave corrected for heart rate using Fridericia’s formula; RBC = red blood cells; SAS = Simpson-Angus Scale; SBP = systolic blood pressure; SCI-PANSS= Structured Clinical Interview for the Positive and Negative Syndrome Scale; TSH = thyroid-stimulating hormone; ULN = upper limit of normal; WBC = white blood cells.

[0230] Patients were evaluated at Baseline and periodically thereafter using the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions-Severity of Illness scale (CGI-S), Angus Scale (SAS), Barnes Akathisia Rating Scale (BARS), Involuntary Movement Scale (AIMS), Columbia-Suicide Severity Rating Scale (C-SSRS), 12-lead electrocardiograms (ECG), vital signs, clinical laboratory values, body weight / waist circumference, total cholesterol, triglycerides, high-density lipoprotein (HDL) and low-density lipoprotein (LDL), and reported / observed Adverse Events (AEs). In addition, blood samples were collected for pharmacokinetic (PK) analysis.F) Efficacy assessments

[0231] The primary endpoint was the change from Baseline to Week 4 in the PANSS total score, compared to placebo.

[0232] The secondary efficacy endpoints were as follows:• Change from Baseline to Week 4 in the CGI-S score• Change from Baseline to Week 4 in PANSS positive subscale score• Change from Baseline to Week 4 in PANSS negative subscale score• Change from Baseline to Week 4 in PANSS Marder Factor scores• Response rate, defined as: Reduction of >20% from Baseline in PANSS total score at Week 4.

[0233] The exploratory endpoint was effect of LB-102 on Cogstate test score.i) Mini International Neuropsychiatric Interview Version 7.0.2 and Mini International Neuropsychiatric Interview With Borderline Personality Disorder Module Version 7.0.2.

[0234] The MINI 7.0.2 was a brief structured interview for the major Axis I psychiatric disorders in the DSM-5 and the International Statistical Classification of Diseases and Related Health Problems, Version 10. Seventeen diagnostic modules consisting of screening and a series of secondary questions were answered with “yes” or86184896963.4“no” responses. If the patient answered “yes” to a screening question, the interviewer proceeded to questions in the module. If the patient answered “no” to a screening question, the interviewer would move forward accordingly to the subsequent module, following instructions in the structured interview. The Mini International Neuropsychiatric Interview-Plus version 7.0.2 (MINI-Plus 7.0.2) contained additional modules beyond what was included in the MINI 7.0.2. For this study, the MINI-Plus 7.0.2 module for Borderline Personality Disorder was used.

[0235] The MINI 7.0.2 was intended to meet the need for a short but accurate structured psychiatric interview for multicenter clinical trials and had an administration time of approximately 20-30 minutes. At Screening, the patients were assessed for Schizophrenia as well as the lack of exclusionary psychiatric diagnoses by the MINI 7.0.2 and the MINI-Plus BPD 7.0.2.ii) Positive and Negative Syndrome Scale

[0236] The PANSS consisted of 3 subscales containing a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicating the absence of symptoms and a score of 7 indicating extremely severe symptoms. The symptom constructs for each subscale were as follows:1. Positive subscale (7 positive symptom constructs: delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness / persecution, and hostility)2. Negative subscale (7 negative symptom constructs: blunted affect, emotional withdrawal, poor rapport, passive / apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking) 3. General psychopathology subscale (16 symptom constructs: somatic concern, anxiety, guilt feelings, tension, mannerisms and posturing, depression, motor retardation, uncooperativeness, unusual thought content, disorientation, poor attention, lack of judgment and insight, disturbance of volition, poor impulse control, preoccupation, and active social avoidance).

[0237] The PANSS were administered using the clinician rated semi-structured interview via the SCI-PANSS. Instructions for administering this instrument were provided87184896963.4to the site. PANSS was administered first on visits when PANSS and CGI-S were being administered.:iii) Placebo-Control Reminder Script (PCRS)

[0238] The PCRS® Hassman and Cohen, 2019, Version 5.0 educated clinical trial subjects of key causes of the placebo and nocebo effects, level setting of the subject’s study expectations, reminding subjects what a placebo was and how that related to their reporting of symptoms and potential side effects, and explaining how interactions with research site staff differred from their experience with clinical providers. The PCRS informed subjects that they were to be honest about their symptoms and that the site staff had no expectations of symptom improvement or worsening and would not be disappointed by the subject’s responses and asked subjects to explain in their own words PCRS content to ensure comprehension. The PANSS Rater read the PCRS before administering the PANSS at each study visit.iv) Clinical Global Impressions-Severity of Illness Scale (CGI-S)

[0239] The severity of illness for each patient were rated using the CGI-S. To perform this assessment, the rater or Investigator answered the following question: “Considering your total clinical experience with this particular population, how mentally ill is the patient at this time?” Response choices include: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill patients.v) Cogstate Computerized Battery of Tests

[0240] The Cogstate Computerized Schizophrenia Battery of Tests was a measure of cognitive ability in subject with Schizophrenia in both the acute and chronic stages and would take approximately 22 to 35 minutes to complete. Patients had 1 practice session during the Screening Visit and completed the actual test on Day 1 (Baseline) and Day 28 (Visit 6) ET Visit). For each Cogstate test, the construct validity for cognitive impairment in Schizophrenia and sensitivity to change in cognition in such patients were demonstrated in scientific literature. Patients performed the test on a provided laptop and then it was uploaded via a web-based portal.88184896963.4G) Safety assessments

[0241] Tolerability was assessed by reported and observed AEs. Frequency and severity of AEs were summarized. Routine safety assessments were performed throughout the study, with a final assessment performed when a patient completed the study on Day 42 / Visit 7 or patient discontinues.

[0242] Safety was assessed by the following:•AE reporting•Physical examination•Vital signs•Bodyweight, BMI; derived programmatically from body weight and height measurements), and waist circumference•Clinical laboratory tests (hematology, serum chemistry [including prolactin], urinalysis, and pregnancy tests); prothrombin time (PT), activated partial thromboplastintime (aPTT), international normalized ratio (INR), HbA1c, cortisol, adrenocorticotropichormone (ACTH), TSHandtotal cholesterol, triglycerides, high- density lipoprotein (HDL) and low-density lipoprotein (LDL)•12-leadECGs•Assessments of extrapyramidal side effects (EPS): the Simpson-Angus Scale (SAS), the AIMS, the BARS•Columbia-Suicide Severity Rating Scale (C-SSRS)i) Physical Examination and Height

[0243] When required, a full physical examination included examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, heart, lungs, abdomen, lymph nodes, extremities, and nervous system. An AE form must be completed for all changes identified as clinically noteworthy. Height without shoes would be recorded in inches. At other time points as noted in the Schedule of Assessments (SoA), a brief or targeted exam that was focused on any changes since the previous exam might be conducted.ii) Vital Signs and Body Weight

[0244] Vital signs included body temperature, SBP, DBP, and heart rate. Blood pressure and heart rate were measured in the following order: supine, sitting and standing89184896963.4after the patient had been in each position for at least 3 minutes. Vital signs scheduled for the same visit as blood sample were completed before blood was drawn.

[0245] Body weight without shoes were recorded in pounds.

[0246] An AE form was completed for all changes identified as clinically noteworthy.iii) Electrocardiogram

[0247] Standard 12-lead ECGs (in triplicate) were performed after the patient was supine and at rest for >5 minutes. The captured ECGs were separated by at least 1 minute. A central ECG service was utilized to review all ECGs in order to standardize interpretations for the safety analysis. In addition, ECG results were evaluated at the investigational site to monitor safety during the trial. Any Screening ECG with abnormal result(s) considered to be clinically significant was repeated to confirm the finding(s) before excluding the patient from the trial. Patients were randomized based on Screening ECG results from the central reader and Baseline ECG results from the trial site. If the Baseline ECG results from the central reader, when available, indicated a Qcff>450 msec at Baseline, the Investigator must contact the Medical Monitor to discuss the patient’s continued participation in the trial. ECGs scheduled for the same visit as blood samples were completed before blood was drawn.iv) Clinical Laboratory Tests

[0248] The following clinical laboratory tests (samples were taken after an overnight fast of at least 8 hours) were performed as indicated in the SoA:• Hematology: hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell (WBC) count (with differential), and platelet count• Coagulation: PT, aPTT, and INR• Chemistry: albumin, albumin / globulin ratio, ALT, alkaline phosphatase, AST, bilirubin-direct, bilirubin-indirect, bilirubin-total, blood urea nitrogen, blood urea nitrogen / creatinine ratio, calcium, chloride, creatine kinase, creatinine, gammaglutamyl transpeptidase, globulin, glucose, HbA1c, lactate dehydrogenase, phosphate, potassium, prolactin, sodium, total cholesterol, triglycerides, HDL, LDL, and uric acid90184896963.4• Urinalysis: pH of freshly voided specimen, specific gravity, protein, glucose, ketones, blood, and microscopic examination of the sediment• Pregnancy tests: urine or serum pregnancy tests, only required for female patients of childbearing potential (e.g., not postmenopausal or surgically sterile [hysterectomy, bilateral oophorectomy, and / or bilateral salpingectomy])• Other: urine drug screen / blood alcohol test and TSH• ACTH and cortisol

[0249] Laboratory samples were analyzed by a central laboratory to ensure consistent interpretation of results. Additional details on the processing and shipment of specimens were provided in the Laboratory Manual. In the event of an unexplained clinically noteworthy abnormal laboratory test value, the test was repeated immediately and followed up until it had returned to the normal range and / or an adequate explanation of the abnormality was found.H) Adverse Events

[0250] All AEs occurring after the patient signed the IGF and up to 14 days after the end of the Treatment Period were recorded.i) Definitions and criteria of adverse events reporting (AEs)a) Adverse Events

[0251] Per International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) E2A,2 an AE is “any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether considered related to the medicinal product.”

[0252] Medical interventions such as surgeries, diagnostic procedures, and therapeutic procedures were not AEs, but the action taken to treat the medical condition. They should be recorded as treatment(s) of the AEs.91184896963.4b) Serious Adverse Events (SAE)

[0253] An SAE or a serious adverse drug reaction (ADR) was any untoward event that at any dose met any of the following criteria:• Death• Life-threatening• Inpatient hospitalization or prolongation of existing hospitalization• Persistent or significant disability / incapacity• Congenital anomaly / birth defect in the offspring of a patient who received study drug• Other: important medical events that might not result in death, be life-threatening, or require hospitalization, might be considered an SAE when, based upon appropriate medical judgment, they might jeopardize the patient and might require medical or surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such events were:o Intensive treatment in an emergency room or at home for allergic bronchospasmo Blood dyscrasias or convulsions that did not result in inpatient hospitalizationo Development of drug dependency or drug abuse

[0254] For deaths, the underlying or immediate cause of death should always be reported as an SAE.

[0255] An AE was life-threatening if the patient was at immediate risk of death from the event; it did not refer to an event that hypothetically might have caused death if it were more serious. For example, drug-induced hepatitis that resolved without evidence of hepatic failure would not be considered life-threatening even though drug-induced hepatitis could be fatal.

[0256] All AEs requiring hospitalization should be considered SAEs. Hospitalization for elective surgery or routine clinical procedures that were not the result of AEs (e.g., elective surgery for a pre-existing condition that has not worsened) need not be considered AEs or SAEs. If anything untoward was reported during the procedure,92184896963.4that occurrence must be reported as an AE, either “serious” or “nonserious” according to the criteria outlined above.

[0257] An AE was incapacitating or disabling if the experience resulted in a substantial and / or permanent disruption of the patient’s ability to carry out normal life functions.

[0258] Any serious, untoward event that occurred subsequent to the reporting period that the Investigator assessed as related to study drug should also be reported and managed as an SAE.c) Unexpected Adverse Drug Reactions

[0259] An unexpected ADR was a reaction for which the nature or severity was not consistent with the applicable product information (Investigator’s Brochure [IB]). Until product information was amended, expedited reporting was required for additional occurrences of the reaction. Reports that added significant information on specificity or severity of a known, already documented SAE constituted unexpected events. For example, an event more specific or more severe than described in the IB would be considered “unexpected.” Specific examples would be (a) acute renal failure as a labeled ADR with a subsequent new report of interstitial nephritis, and (b) hepatitis with a first report of fulminant hepatitis.d) Clinical Laboratory Changes

[0260] Any abnormality in a laboratory value that was new in onset or which had worsened in severity or frequency from the Baseline condition and met 1 of the following criteria was recorded on the AE pages of the eCRF:• Required therapeutic intervention or diagnostic tests• Lead to discontinuation of study drug• Had accompanying or inducing symptoms or signs• Was judged by the Investigator as clinically significant

[0261] Combined elevations of aminotransferases and bilirubin, either serious or nonserious, and whether or not causally related, meeting the criteria of a potential Hy’s Law case (total bilirubin level >2 x ULN with simultaneously ALT or AST >3 x ULN) were always reported to the Sponsor as soon as possible, with the Investigator’s assessment of seriousness, causality, and a detailed narrative.93184896963.4e) Assessment of Severity

[0262] Each AE was classified according to the following criteria:Mild: The AE did not interfere in a significant manner with the patient’s normal level of functioning.Moderate: The AE produced some impairment of functioning, but was not hazardous to the patient’s health.Severe: The AE produced significant impairment of functioning or incapacitation and was a definite hazard to the patient’s health.

[0263] Severity versus Seriousness: Severity was used to describe the intensity of a specific event while the event itself might be of relatively minor medical significance (such as severe headache). Severity was not the same as “seriousness,” which was based on patient / event outcome at the time of the event.

[0264] When changes in the severity of an AE occurred more frequently than once a day, the maximum severity for the experience was noted. If the severity category changed over several days, those changes were recorded as separate AEs (with distinct onset dates).f) Assessment of Relationship

[0265] Each AE was assessed as to its relationship to the study drug, based on the following criteria. Although the attribution by the Investigator was collected for reported events, for analytic purposes a temporal association with the use of the study drug was assumed sufficient for at least plausible association.Not related: No causal relationship existed between the study drug and the AE, but an obvious alternative cause existed, e.g., the patient’s underlying medical condition or concomitant therapy.Possibly related: A connection with the administration of the study drug appeared unlikely, but could not be ruled out with certainty. An AE may be considered possibly related if or when it met 2 of the following criteria: (1 ) it followed a reasonable temporal sequence from administration of the study drug; (2) it could not readily have been produced by the patient’s clinical state, environmental or toxic factors, or other modes of therapy administered to the patient; or (3) it followed a known pattern of response to the study drug.94184896963.4Related: There was a reasonable / plausible possibility that the AE might have been caused by the study drug.

[0266] When assessing the relationship to the study drug, the following criteria were considered:• Positive rechallenge• Positive dechallenge (resolution upon stopping the suspect study drug, in absence of other intervention or treatment)• Known class effect• Biological plausibility• Lack of alternative explanation (e.g., a concomitant drug or disease)g) Action Taken Regarding Study Drug

[0267] The action taken regarding the study drug as a result of an AE was selected from 1 of the categories listed below and recorded in the eCRF:• Dose Not Changed: No change in study drug dose was made.• Drug Interrupted: The study drug was temporarily stopped.• Drug Withdrawn: The study drug was permanently stopped.• Not Applicable: Patient died, study treatment had been completed prior to reaction / event, or reaction / event occurred prior to the start of treatment.• Unknown.h) Other Action Taken for Event

[0268] Other action(s) taken as a result of the AE were selected from 1 of the categories listed below and recorded in the eCRF:• None (i.e., no treatment was required)• Therapy(ies) required (i.e., prescription and / or OTC medication was required to treat the AE)• Hospitalization or prolongation of hospitalization required (i.e., hospitalization was required or prolonged because of the AE, whether medication was required) • Other95184896963.4i) Adverse Event Outcome

[0269] The outcome of the AE was selected from 1 of the categories listed below and recorded in the eCRF:• Recovered / Resolved (i.e., the patient fully recovered from the AE with no residual effect observed)• Recovering / Resolving (i.e., the AE improved but had not fully resolved)• Not Recovered / Not Resolved (i.e., the AE was still present and observable) • Recovered / Resolved with Sequelae (i.e., the residual effects of the AE were still present and observable, including sequelae / residual effects)• Fatal (i.e., “fatal” should be used when death was a direct outcome of the AE) • Unknowni) Simpson-Angus Scale (SAS)

[0270] The SAS was a measure of EPS and consists of a list of 10 symptoms of Parkinsonism (gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, leg pendulousness, head dropping, glabella tap, tremor, and salivation). Each item was rated on a 5-point scale, with a score of 0 representing absence of symptoms, and a score of 4 representing a severe condition. The SAS total score was the sum of the scores for all 10 items. Anticholinergics, propranolol, benzodiazepines, and non-benzodiazepine sleep aids were not permitted within 12 hours of scale administration. Investigators were encouraged to delay scale administration until 12 hours have elapsed, if at all possible. However, if delaying administration of the scale was not feasible, the SAS was administered and the use of the medication documented, including a notation of the drug name, dose, and time of administration in the eCRF.ii) Barnes Akathisia Rating Scale (BARS)

[0271] The BARS consists of 4 items related to akathisia: objective observation of akathisia by the Investigator, subjective feelings of restlessness by the patient, subjective distress due to akathisia, and global clinical assessment of akathisia. The first 3 items will be rated on a 4-point scale, with a score of zero representing absence of symptoms and a score of 3 representing a severe condition. The global clinical evaluation will be made on a 6-point scale, with 0 representing absence of symptoms and a score of 5 representing severe akathisia. To complete this scale, patients were observed while they 96184896963.4were seated and then standing for a minimum of 2 minutes in each position. Symptoms observed in other situations (e.g., while engaged in neutral conversation or engaged in activity on the ward) may also be rated. Subjective phenomena were elicited by direct questioning. Anticholinergics, propranolol, benzodiazepines, and non-benzodiazepine sleep aids were not permitted within 12 hours of scale administration. Investigators were encouraged to delay scale administration until 12 hours have elapsed, if at all possible. However, if delaying administration of the scale was not feasible, the BARS were administered and the use of the medication documented, including a notation of the drug name, dose, and time of administration in the eCRF.

[0272] The BARS global score was defined as the global clinical assessment of akathisia.iii) Abnormal Involuntary Movement Scale (AIMS)

[0273] The AIMS assessment consists of 10 items describing symptoms of dyskinesia. Facial and oral movements (items 1 through 4), extremity movements (items 5 and 6), and trunk movements (item 7) will be observed unobtrusively while the patient was at rest (e.g., in the waiting room), and the Investigator also made global judgments on the patient’s dyskinesias (items 8 through 10). Each item was rated on a 5-point scale, with a score of 0 representing absence of symptoms (for item 10, no awareness), and a score of 4 indicating a severe condition (for item 10, awareness, severe distress). For this scale, the patient was sitting on a hard, firm chair. In addition, the AIMS included 2 yes / no questions that address the patient’s dental status. The AIMS movement rating score was defined as the sum of items 1 through 7 (i.e., items 1 through 4, facial and oral movements; items 5 and 6, extremity movements; and item 7, trunk movements). Anticholinergics, propranolol, benzodiazepines, and non-benzodiazepine sleep aids were not permitted within 12 hours of scale administration. Investigators were encouraged to delay scale administration until 12 hours had elapsed, if at all possible. However, if delaying administration of the scale was not feasible, the AIMS was still administered and the use of the medication documented, including a notation of the drug name, dose, and time of administration in the eCRF.iv) Columbia-Suicide Severity Rating Scale (C-SSRS)

[0274] Suicidality was monitored during the trial using the C-SSRS.97184896963.4

[0275] The C-SSRS was developed by researchers at Columbia University as a tool to help systematically assess suicidal ideation and behavior during participation in a clinical trial of centrally acting drugs. The C-SSRS was composed of 5 questions addressing suicidal ideation, with sub-questions assessing the severity of ideation as well as 5 suicidal behavior categories (Completed Suicide, Actual Attempt, Interrupted Attempt, Aborted Attempt, and Preparatory Acts or Behavior). The tool was administered via interview with the patient (by a trained operator / interviewer). All attempts were made to use the same interviewer for the same patient throughout the study.

[0276] This study used the “Baseline / Screening” and “Since Last Visit” versions of the scale. The “Baseline / Screening” version, which assessed the lifetime experience of the patient with suicide events and suicidal ideation and the occurrence of suicide events and / or ideation within a specified time period prior to entry into the trial, was completed for all patients at the Screening Visit to determine eligibility (prior to the first dose). Risk for suicidal behavior during the study as determined by the Investigator’s clinical assessment and C-SSRS was confirmed by the following: answers “Yes” on items 4 or 5 (C-SSRS - Ideation) with the most recent episode occurring within the 6 months before Screening, or answers “Yes” to any of the 5 items (C-SSRS - Suicidal Behavior) with an episode occurring within the 12 months before Screening. This assessment was repeated at Baseline Visit (using the Since Last Visit” C-SSRS). The “Since Last Visit” C-SSRS form was completed at all post-Screening visits.I) Pharmacokinetic assessments

[0277] PK analyses included the first 60 patients randomized in the study regardless of cohort. PK blood samples were collected on Day 1, 8, and 21 at the following timepoints after the morning dose: 15 minutes, 30 minutes, 1, 2, 3, 4, 8, and 24 hours. On Day 1 only, a pre-dose PK blood sample was collected.

[0278] The following windows for PK collection are allowed• Pre-dose PK can be drawn up to 60 minutes prior to first dose.• ± 5 minutes window on the 15 minutes, 30 minutes, 1, 2, 3, 4, 8 hours, PK collection times.• ±15 minutes window on 24-hour PK collection time.Note: The 24-hour PK must be drawn prior to next applicable dose.98184896963.4

[0279] Plasma concentrations of LB-102 and metabolites (including amisulpride) were measured during the study and PK parameters derived using noncompartmental or compartmental methods as appropriate. The following PK parameters (as appropriate) were calculated: area under the concentration-time curve from time zero to time (AUC0-t), area under the concentration-time curve from time of dosing up to 24 hours (AUC0-24), area under the concentration-time curve from time zero to infinity (AUC0-inf), area under the concentration-time curve extrapolated from time t to infinity as a percentage of the total AUC (AUC%extrap), oral clearance (CL / F), maximum concentration (Cmax), time to reach Cmax (Tmax), terminal elimination rate constant (Az), and apparent terminal half-life (t1 / 2).

[0280] No value for Az, AUC0-inf, CL / F, or t’ / 2was reported for cases that did not exhibit a terminal log-linear phase in the concentration versus time profile.

[0281] No PK parameters was calculated for patients with detectable concentrations for 2 or fewer time points.

[0282] Individual and mean plasma concentration-time curves (both linear and log-linear) were included in the final report.

[0283] PK parameters of LB-102 and metabolites were summarized by cohort using descriptive statistics (sample size, arithmetic means, geometric means, standard deviation [SD], % coefficient of variation [CV], minimum, median, and maximum). Figures will be created to display mean and individual patient LB-102 and amisulpride concentration-time curves in plasma on both a linear and logarithmic scale. Dose proportionality will be assessed using linear regression, or another acceptable approach.J) Statistical Procedure

[0284] 395 patients were randomized in a ratio of about 3:3:3:1 placebo: LB-102 50 mg QD: LB-102 75 mg QD: LB-102 100 mg QD (Table 1). This ensured at least 85% power at a 2-sided 5% significance level to detect a treatment difference on the primary endpoint of 8 between either LB-102 50 mg or 75 mg and placebo QD, assuming a common standard deviation (SD) of 18, an overall drop-out rate of 25% and a Hochberg procedure to adjust for multiplicity. The sample size was estimated via Monte Carlo simulations using 10,000 simulated trials. In the event of any discrepancies between the procedure described in this section J) and the rest of this Example 1, the procedure specified in this section J) applied.99184896963.4i) Analysis of efficacy

[0285] A formal and detailed statistical data analysis plan was prepared before database lock. The primary endpoint was the change from Baseline to Week 4 on the PANSS total score. Formal statistical testing for comparison of the LB-102 50 mg and 75 mg treatment groups to placebo was performed for the primary endpoint only, using appropriate procedures for multiplicity adjustment. In addition, descriptive statistics for safety, efficacy, and PK variables were provided for all treatment groups. Shift tables for safety parameters were prepared for appropriate categorical variables and change from Baseline and effect sizes were calculated for efficacy measures.

[0286] The primary efficacy analysis was performed using a Mixed Model for Repeated Measures (MMRM) using the modified Intent- to-Treat population as analysis set. The model included treatment, site, visit, and treatment by visit interaction as categorical covariates and Baseline PANSS as continuous covariate. Within-patient correlation was accounted for using an unstructured correlation. A similar model was considered for continuous secondary endpoints. The response rate endpoint was analyzed using a logistic regression model with treatment as categorical covariate and Baseline PANSS total score as continuous covariate.ii) Estimand

[0287] For the definition of the main study estimand, the following intercurrent events (ICEs) were deemed as relevant:a) Taking a prohibited medication prior to Week 4b) Starting an emergency treatment prior to Week 4

[0288] The primary estimand for all the above events followed the treatment-policy strategy, to estimate the difference in means (population-level summary) between any active dose of LB-102 and placebo (treatment) in adult patients with acute schizophrenia as defined by the inclusion / exclusion criteria (population) for change from Baseline to Week 4 in the PANSS total score (variable) regardless of the occurrence of the above-mentioned ICEs.iii) Primary Efficacy Endpoint

[0289] The primary endpoint was the change from Baseline to Week 4 in the PANSS total score. The null and alternative hypothesis for each dose level are as follows:100184896963.4Ho: the difference in the change from Baseline to Week 4 in the PANSS total score between LB-102 active treatment and placebo was equal to 0;Hi: the difference in the change from Baseline to Week 4 in the PANSS total score between LB-102 active treatment and placebo was different from 0.

[0290] All efficacy endpoints were analyzed for the mITT Analysis Set.a) Principal Analysis

[0291] In line with the estimand definition, all data collected after the occurrence of an ICE were included in the primary efficacy analysis. As a primary analysis, all missing data due to study discontinuation for lack of efficacy or drug-related AEs were imputed assuming a Missing Not At Random (MNAR) mechanism and assuming that after withdrawal the subjects revert to the distribution of the worst PANSS score values observed up to time of discontinuation, whereas missing data due to discontinuation for any other reason, were imputed under a Missing At Random (MAR) assumption using a Multiple Imputation (Ml) approach.

[0292] The primary efficacy endpoint (change from Baseline to Week 4 on the PANSS total score) was analyzed using a Mixed Model for Repeated Measures (MMRM) approach, including site, visit, treatment, and their interaction as categorical covariates and Baseline PANSS as continuous covariates. Within-patient correlation across repeated measures was accounted for by using an unstructured correlation, or the best fit structure should an unstructured matrix cause convergence issues. The differences between active treatment groups and placebo at Week 4 were estimated alongside confidence intervals (Cis) and Rvalues. The model was fit separately for each imputed dataset and results pooled using Rubin’s rules to derive one treatment effect estimate.

[0293] A post hoc calculation of Hedges’ g effect size (bias corrected standardized mean differences) was conducted on the population of participants who competed the trial, using the absolute value of the difference in the observed mean change in PANSS total score from baseline to week 4 between each individual LB-102 treatment arm and placebo, divided by the pooled standard deviation. An additional post hoc analysis of model standardized effect size was conducted in the mITT population using MMRM analysis, based on the methodology of Borenstein (Borenstein M. Effect Sizes for Continuous Data. In: Cooper H, Hedges LV, Valentine JC, eds. The handbook of research101184896963.4synthesis and meta-analysis, second edition. Russell Sage Foundation; 2019.). See Borenstein M. Effect Sizes for Continuous Data. In: Cooper H, Hedges LV, Valentine JC, eds. The handbook of research synthesis and meta-analysis, second edition. Russell Sage Foundation; 2019.

[0294] This analysis was performed for the mITT as well. Should the mITT and ITT differ substantially (e.g., by at least 10%) the primary analysis would be performed for the ITT and the mITT only be regarded as supportive information.

[0295] A strategy for pooling sites enrolling a limited number of patients was specified in a statistical analysis plan (SAP) as provided in section (ll)(J)(x) of this example prior to unblinding, and the derived ‘pooled study site’ variable used in all relevant statistical analyses.b) Sensitivity Analysis

[0296] As a sensitivity analysis, missing data that was imputed under a MAR mechanism in the primary analysis were imputed under a MNAR mechanism using a tipping-point approach to check robustness of the main analysis results. Details of the Ml model for this and the main analysis as well as further sensitivity analyses were provided in the SAP.

[0297] The analysis model was the same as for the primary analysis, with results obtained on each imputed dataset that were pooled to provide a single measure of treatment effectiveness (alongside 95% Cl and Rvalues).c) Exploratory Analysis

[0298] Further exploratory assessments were performed to investigate heterogeneity of treatment effects across investigational sites, by summarizing the primary endpoint separately by study site.d) Subgroup Analysis

[0299] Subgroups of interest were defined based on BMI and severity of disease at Baseline (as measured by the PANSS total score). The primary and secondary endpoints were descriptively analyzed within the relevant subgroup strata.102184896963.4iv) Secondary Efficacy Endpoint(s)

[0300] All continuous secondary efficacy variables were analyzed using similar approaches to what was described for the primary endpoint, using the appropriate Baseline measurement instead of the Baseline PANSS score, without any data imputation.

[0301] The secondary efficacy endpoints to analyze in this way are the following:• Change from Baseline to Week 4 in CGI-S score• Change from Baseline to Week 4 in PANSS positive subscale score• Change from Baseline to Week 4 in PANSS negative subscale score• Change from Baseline to Week 4 in PANSS Marder factor scores

[0302] The MMRM model for the above endpoints allowed to estimate the least square (LS) means and their difference between each active dose and placebo alongside their 95% Cl and P values, which was only displayed for informative / descriptive purposes (i.e., no multiplicity correction will be implemented).

[0303] An additional exploratory endpoint was clinical response, defined as a reduction of >20% from Baseline in PANSS total score at Week 4. This was analyzed consistently with a “composite strategy” estimand, where a patient was considered a responder if the criteria for clinical response were met and none of the ICEs mentioned above had occurred. For the purposes of this endpoint, only study discontinuations related to the treatment (e.g., lack of efficacy, AE related to the underlying condition such as worsening, etc.) were considered as relevant ICEs and thus contributed to a nonresponder status if occurring.

[0304] This endpoint was analyzed using a logistic regression model including treatment and Baseline PANSS score as covariates to estimate the odds ratio of response of any active dose vs placebo.Exploratory Efficacy Endpoint

[0305] The Cogstate Computerized Battery of Tests scores were analyzed using an Analysis of Covariance (ANCOVA) model including site and treatment as categorical covariates and Baseline Cogstate score as continuous covariate. No imputations was performed for missing data and similar quantities to compare treatments as for the103184896963.4primary analysis model (LS means and their differences across arms) would be presented.v) Multiplicity

[0306] Results from the analysis of the primary endpoint were adjusted for multiplicity using a standard Hochberg procedure. This approach involved ranking the P values from the smallest (P(i)) to the largest (P(2)) and comparing the larger P value against 0.05 and if this hypothesis was rejected then even the other one was rejected, otherwise the smaller Rvalues was tested against 0.025.vi) Analysis of Safety

[0307] All safety analyses were performed using the Safety Analysis Set: Safety variables examined in this study included AEs, physical examinations, vital signs, body weight, BMI (derived programmatically from body weight and height measurements), waist circumference, clinical laboratory tests (hematology, serum chemistry [including prolactin]), urinalysis, pregnancy tests, PT, aPTT, INR, HbA1c, cortisol, ACTH, TSH, total cholesterol, triglycerides, HDL, and LDL, ECGs, and an evaluation of extrapyramidal symptoms using the SAS, AIMS, and BARS. The C-SSRS was used to assess and classify reported suicidal behavior.a) Extent of Exposure

[0308] Extent of exposure was summarized by treatment as number of drug administrations received and the overall duration of the exposure (from first to last dose) in days.b) Adverse Events

[0309] AEs were characterized by type, severity, seriousness, and relationship to treatment. AEs were coded by preferred term and system organ class (SOO) using Medical Dictionary for Regulatory Activities (MedDRA) Version 23.0.

[0310] The incidence of TEAEs (number and percent of patients reporting the AE at least once during the study), SAEs, AEs related to study treatment, SAEs related to treatment, and AEs leading to study discontinuation were summarized by treatment.104184896963.4

[0311] A TEAE was defined as any AE that had an onset on or after the dose of study drug, or any pre-existing condition that has worsened on or after the first dose of study drug.

[0312] Any AE commencing after the last dose of study drug plus 14 calendar days was be considered treatment-emergent.

[0313] The incidence of TEAEs and treatment-related AEs were also summarized by maximum severity and strongest relationship to study drug by MedDRA primary SOC and preferred term. The summary included the total number and percentage of patients reporting a particular event as well as the total number of events. In counting the number of events reported, a continuous event, i.e., reported more than once and which did not cease, was counted only once; noncontinuous AEs reported several times by the same patient were counted as multiple events.

[0314] Relative risks for the occurrence of any AE (i.e., at least 1 AE) during the course of the study as well as for each SOC / preferred term were calculated for each LB-102 dose vs placebo alongside 95% Cl and P values. For such analysis, a Poisson regression model with a log-link and a robust error variance was considered, using the binary indicator for the presence of a given SOC / preferred term (or any AE) as response and treatment as the only covariate whose betas would be exponentiated to return the associated relative risk.c) Electrocardiogram

[0315] A list of patients with abnormal 12-lead ECG parameters were presented. Baseline and change from Baseline in ECG parameters (heart rate, cardiac rhythm, PR interval, QRS interval, QT interval, and QTc interval) were summarized at each postBaseline time point.d) Vital Signs

[0316] Summary statistics for absolute vital sign value and the changes from Baseline were presented by treatment group for each visit.e) Physical Examination

[0317] Physical examination data were listed only.105184896963.4f) Clinical Laboratory Tests

[0318] Mean changes from Baseline at each post-Baseline time point for each laboratory variable were presented. In addition, each reading was classified as below, within, or above normal range, based on ranges supplied by the laboratory used. Shift tables for the Baseline and follow-up measurements would be presented.g) Other Variables Related to Safety

[0319] Other safety variables included the SAS, the BARS, the AIMS, and the C-SSRS.

[0320] These scales were summarized by treatment group and visit including, where appropriate, change from Baseline measures.vii) Pharmacokinetics

[0321] Data from patients who participated in the study were included in the PK analysis. Patients with missing sample concentrations were included in the PK analyses, provided their PK parameters could be adequately characterized based upon the remaining data.

[0322] Deviation from procedures described in this protocol that impacted the quality of data required to meet the objectives of the study was documented and might result in the exclusion of PK data from the analyses for a particular patient. This included any deviations or events that would invalidate the evaluation of the PK. Examples of deviations and events that could result in the exclusion of PK data from the analyses included emesis after dosing (within the predetermined time), sample processing, or assay errors that led to inaccurate bioanalytical results. Other deviations or events that did not disqualify data from analyses might require minor adjustments to calculations. If these occur, data analyses were adjusted and documented accordingly such that conclusions were not biased. An example of such an event included, but was not limited to, minor deviations between the actual and scheduled time of sample collection.viii) Other PK analyses may be performed as appropriate.

[0323] Plasma concentrations of LB-102 and metabolites (including amisulpride) were measured during the study and PK parameters derived using noncompartmental or compartmental methods as appropriate. The following PK parameters (as appropriate) were calculated: AUCo-t, AUCo-24, AUC0-inf, AUC° / oextrap, CL / F, Cmax, Tmax, Az, and t1 / 2.106184896963.4

[0324] No value for Az, AUC0-inf, CL / F, or t1 / 2was reported for cases that did not exhibit a terminal log-linear phase in the concentration versus time profile.

[0325] No PK parameters were calculated for patients with no detectable concentrations for 2 or fewer time points.

[0326] Individual and mean plasma concentration-time curves (both linear and log-linear) were included in the final report.

[0327] PK parameters of LB-102 and metabolites were summarized by cohort using descriptive statistics (sample size, arithmetic means, geometric means, SD, % CV, minimum, median, and maximum). Dose proportionality was assessed using linear regression, or another acceptable approach.ix) Interim Analysis

[0328] No interim analysis was performed for this study.x) Statistical Analysis Plan (SAP)1. Introduction

[0329] This SAP details the planned statistical analyses for LB Pharmaceuticals Inc., protocol LB-102-003 study titled “A Randomized, Double-blinded, Placebo-controlled, Multicenter Study to Evaluate the Antipsychotic Efficacy and Safety of LB-102 in the Treatment of Adult Patients with Acute Schizophrenia.” This SAP (section x) was applicable in the event of any discrepancy between this SAP with the rest of Example 1.

[0330] The analyses were based on the contents of the amended version (Version 3.0) of the protocol.

[0331] This was a Phase 2 randomized, double-blinded, placebo-controlled, fixed dose, multicenter clinical study, designed to evaluate the efficacy, safety, tolerability, and pharmacokinetics (PK) of LB-10250 mg QD, LB-10275 mg QD, and LB-102 100 mg QD versus placebo in patients diagnosed with schizophrenia having an acute exacerbation of psychosis. The study included a 14-day inpatient screening phase, an inpatient Study Treatment Period with 4 weeks of daily study treatment, an inpatient Stabilization Period of up to 5 days (during which patients will be stabilized on standard antipsychotic medication), and an outpatient Final Safety Follow-up of approximately 2 weeks after the end of the Treatment Period.107184896963.42. Study objectives, Endpoints, and estimands2.1 Objective2.1.1 Primary Objective

[0332] The primary objective of this study was to determine whether LB-102 ( / V-methyl amisulpride) administered orally to patients with acutely exacerbated schizophrenia demonstrated antipsychotic efficacy, as determined by a change from Baseline on the Positive and Negative Syndrome Scale (PANSS) total score, compared to placebo.2.1.2 Secondary Objectives

[0333] Secondary objectives of this study were:• To evaluate the safety and tolerability of LB-102 in patients with acutely exacerbated schizophrenia.• To assess the effect of LB-102 on the severity of illness in patients with acutely exacerbated schizophrenia, as determined by a change from Baseline in the Clinical Global Impressions-Severity of Illness scale (CGI-S) score.• To assess the effect of LB-102 on PANSS subscale and Marder Factor scores in patients with acutely exacerbated schizophrenia.2.1.3 Exploratory Objectives

[0334] To explore the effect of LB-102 on Cogstate test score2.2 Endpoints2.2.1 Primary Endpoint

[0335] The primary endpoint of this study was:• Change from Baseline to Week 4 in the PANSS total score, compared to placebo 2.2.2 Secondary Efficacy Endpoints

[0336] The secondary endpoints of this study were:• Change from Baseline to Week 4 in the CGI-S score• Change from Baseline to Week 4 in PANSS positive subscale score• Change from Baseline to Week 4 in PANSS negative subscale score• Change from Baseline to Week 4 in PANSS Marder Factor scores• Response rate, defined as reduction of >20% from Baseline in PANSS total score at Week 4.108184896963.42.2.3 Exploratory Endpoint

[0337] Effect of LB-102 on Cogstate test score2.2.4 Safety Endpoints

[0338] Safety was assessed by the following:• AE reporting• Physical examination• Vital signs• Body weight, body mass index (BMI; derived programmatically from body weight and height measurements), and waist circumference• Clinical laboratory tests (hematology, serum chemistry [including prolactin], urinalysis, and pregnancy tests); prothrombin time (PT), activated partial thromboplastin time (aPTT), international normalized ratio (INR), glycosylated hemoglobin (HbA1c), cortisol, adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH) and total cholesterol, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL)• 12-lead ECGs• Assessments of EPS: the Simpson-Angus Scale (SAS), the Abnormal Involuntary Movement Scale (AIMS), the Barnes Akathisia Rating Scale (BARS)• Columbia-Suicide Severity Rating Scale (C-SSRS)2.3 Estimands

[0339] The primary study estimand is described in Table 6A below.Table 6A. Primary Study Estimand: PANSS Total Score at Week 4 Objective: To determine whether LB-102 ( / V-methyl amisulpride) administered to patients with acutely exacerbated schizophrenia demonstrates antipsychotic efficacy as determined by a change from Baseline on the PANSS total score, compared to placeboEstimand: Treatment effect of LB-102 vs Placebo regardless of intercurrent events (treatment-policy) Treatment: LB-102 (50 mg or 75 mg) and matching PlaceboESTIMAND ANALYSISTarget population Analysis setAdult patients with acute schizophrenia as intent-to-freat (ITT) analysis set, defined as all identified by the study eligibility criteria randomized patients.Should the ITT and modified ITT (mITT) analysis sets overlap substantially (i.e. 95% of patients in the former were also in the latter), the mITT was considered as the reference analysis set for allestimand-related analyses.109184896963.4[Variable _ I Outcome measure ] i PANSS Total Score at Week 4 | Change from Baseline to Week 4 in the PANSS total[score _i Handling of intercurrent events [ Handling of missing data 1 • Taking a prohibited medication prior to [ All missing data due to study discontinuation for lack Week 4 of efficacy or drug-related adverse events (AEs) I • Starting an emergency treatment prior to were imputed assuming a Missing Not at Random I Week 4 (MNAR) mechanism and assuming that afterI All of these intercurrent events (ICEs) will be withdrawal the patients reverted to the distribution of t handled via a treatment-policy strategy, i.e. data the worst PANSS score values observed up to time § collected after their occurrence will be included of discontinuation, whereas missing data due to i in the statistical analysis of the endpoint. discontinuation for any other reason, would be imputed under a Missing at Random (MAR) assumption using a Multiple Imputation (Ml) approach. § i As a sensitivity analysis, missing data that was imputed under a MAR mechanism in the primary analysis was imputed under a MNAR mechanism I using a tipping-point approach to check robustness of the main analysis results. Another sensitivity analysis adopted a reference-based imputation to I further explore the impact of the MNAR assumption for missing data on the primary analysis results.Another sensitivity analysis used assessments from re-mapped early termination visits (see Section 5.2.4 for details) in the analysis, adopting the same strategy for missing data as described for theJ.. PrLrT1.a-ry.an^|y.si.s:Population-level summary measure LAnaiysjs.approach j i Mean difference between patients treated LB- The difference between treatment arms of the Least i 102 (50 mg or 75 mg) and those treated with I Squares (LS) means of change from Baseline to 4 I matching Placebo in the change from Baseline weeks post-baseline in the PANSS total score was I to 4 weeks post-baseline in the PANSS total estimated from a Mixed Model for Repeated i score. Measures (MMRM), including treatment, visit,treatment-by-visit interaction, study site and Baseline PANSS total score. The model was fit across all s imputed datasets and results pooled using Rubin’s rules to obtain one single treatment effect estimate and its 95% confidence interval (Cl).For the sensitivity analysis, the same model (MMRM) and analytical approach (pooling across imputations) were adopted and one treatment effect■■L.e.stimate P,^

[0340] In addition to the above, a secondary estimand for the secondary endpoint related to response rate (i.e. a reduction of >20% from Baseline in PANSS total score at Week 4) was also defined and presented in Table 6B.Table 6B. Secondary Study Estimand: Response Rate (PANSS-based) at Week 4 I Objective: To determine whether N-methyl amisuipride (LB-102) administered to patients with acuteiy I exacerbated schizophrenia demonstrates antipsychotic efficacy, as determined by a change from110184896963.4Estimand: Treatment effect of LB-102 vs Placebo assuming intercurrent events classify as nonrespondersTreatment: LB-102 (50 mg or 75 mgj and matching PlaceboESTIMAND ANALYSISTarget population Analysis setAdult patients with acute schizophrenia as Intent-to-Treat (ITT) analysis set, defined as all identified by the study eligibility criteria randomized patients.Should the ITT and mITT analysis sets overlap substantially (i.e. 95% of patients in the former were also in the latter), the mITT was considered as the reference analysis set for all estimand-related analyses.Variable Outcome measurePANSS Total Score at Week 4 Response rate, defined as a >20% decrease from baseline to Week 4 in the PANSS total score Handling of intercurrent events Handling of missing dataTaking a prohibited medication prior to Week 4 Missing data at Week 4 because of discontinuation Starting an emergency treatment prior to Week due to ‘Lack of Efficacy’ or a drug-related AE was 4 imputed as non-responders. For all other missing All of these intercurrent events (ICEs) were data, the PANSS total score imputed for the primary handled via a composite strategy, i.e. patients analysis of the primary endpoint was dichotomized were considered as non-responders as responders or not.As a sensitivity analysis, all missing data was imputed as non-responders.Population-level summary measure Analysis approachDifference between patients treated with LB-102 This endpoint was analyzed using a logistic(50 or 75 mg QD) and those treated with regression model including treatment and Baseline matching placebo in the PANSS response rate PANSS score as covariates to estimate the odds at Week 4 post-baseline. ratio (OR) of response of LB-102 (50 or 75 mg QD) vs placebo. The model was fit separately to all imputed datasets and results pooled across imputations to obtain one single treatment effect estimate alongside 95% Cl.The same model was also fit for the sensitivityanalysis and a single OR (alongside its 95% Cl).3. Sample size

[0341] Approximately 350 patients were randomized in a 3:3:3:1 ratio to placebo, LB-10250 mg QD, LB-10275 mg QD, or LB-102 100 mg QD, respectively, with 105 patients randomized to each of the first 3 arms and 35 to the last one (LB-102 100 mg). This ensured at least 85% power at a 2-sided 5% significance level to detect a treatment difference on the primary endpoint of 8 between either LB-10250 mg or 75 mg and placebo QD, assuming a common SD of 18, an overall drop-out rate of 25% and a Hochberg procedure to adjust for multiplicity. The sample size was estimated via Monte Carlo simulations using 10,000 simulated trials.111184896963.44. Randomization

[0342] Patients were randomized in a 3:3:3:1 ratio to placebo, LB-10250 mg QD, LB-10275 mg QD, or LB-102 100 mg QD. An unblinded biostatistician, contracted with Worldwide Clinical Trials (Worldwide), was responsible for generating and implementing the randomization scheme that would determine treatment assignment. Randomization occurred through an integrated response technology (IRT) system. The IRT system generated the randomization number and the randomization number was captured by and integrated into the electronic data capture (EDC) system. The patient identification was a 6-digit number (i.e., the 1 -digit country number, followed by a 2-digit site number followed by a 3-digit consecutive number). Before the study was initiated, the log-in information and directions for the IRT were provided to each site.5. Planned Analyses

[0343] The Statistical Analysis Plan (SAP) and Table, Figure, Listing (TFL) Shells (and any amendments) were approved prior to database lock (DBL). If post DBL, additional statistical analyses or changes to the statistical analysis were required, then those were documented in a Post DBL SAP Addendum.5.1 Analysis Sets5.1.1 Screened Set

[0344] The Screened Set included all patients screened.5.1.2 lntent-to-treat (ITT) Analysis Set

[0345] The ITT Analysis Set included all randomized patients, irrespective of whether they received the drug or not. This was the main analysis population for efficacy analysis purposes and patients were analyzed based on the treatment they were randomized to.5.1.3 Modified lntent-to-treat (mITT) Analysis Set

[0346] The mITT Analysis Set included all randomized patients with at least 1 dose of study drug. This was a secondary analysis set for the analysis of the primary endpoint, however, if the ITT and the mITT substantially overlapped (i.e. at least 95% of ITT patients were also in the mITT), the latter was used as primary efficacy analysis set for all efficacy endpoints.112184896963.45.1.4 Safety Analysis Set

[0347] The Safety Analysis Set included all patients who received any study drug. Analyses based on this population used the actual treatment received rather than the randomized one.5.1.5 Pharmacokinetic (PK) Analysis Set

[0348] The PK Analysis Set included all patients who provide plasma concentration samples.5.2 Derived Data

[0349] This section describes the derivations required for statistical analysis. Unless otherwise stated, variables derived in the source data was not re-calculated.5.2.1 Race

[0350] Where more than one race category was selected for a patient, these race categories were combined into a single category labelled “Multiple Race” in the summary tables. The listings reflected the original selected categories.5.2.2 Baseline

[0351] Baseline was defined as the last non-missing value (either scheduled, unscheduled, or repeat) before the patient received the first dose of study drug.5.2.3 Change from Baseline

[0352] Change from Baseline for any variable at a given visit was calculated by subtracting the Baseline value of that variable from the value of the variable at the given visit, e.g. for the Week 4 timepoint:Change from Baseline to Week 4 = Week 4 value - Baseline value

[0353] Percent change from Baseline was calculated as follows for all variables:Percent change from Baseline to Week 4 = ((Week 4 value - Baseline value) / Baseline value) x 1005.2.4 Early Terminations Assessments

[0354] Early termination assessments were mapped to closest scheduled visit using the analysis windows described in Table 6C. If the planned visit that an early termination assessment was mapped to had occurred and data was collected, then the early termination assessment would not be included in the statistical analyses or summaries of any endpoint but would only be included in the listing, otherwise if the113184896963.4planned visit had not occurred or it had occurred but not all applicable assessments were completed, then assessments from the early termination visit mapped to that visit would be used in the statistical analyses and summaries.fable 6C. Analysis WindowsVisit Window Start Dav Window End DayDay 8 Day 2 Day 11Day 15 Day 12 Day 18Day 21 Day 19 Day 24Day 28 Day 25 Day 30

[0355] For sensitivity analyses of the primary endpoint purposes, if an early termination assessment occurred that was mapped to a window where a planned visit was collected and where the PANSS score was correctly completed, the PANSS score collected at the early termination assessment was used to replace the primary endpoint value at the planned visit.5.2.5 Duration I Study Day / Time

[0356] Study day was calculated as the number of days from first dose of study drug.• date of event - date of first dose of study drug + 1, for events on or after first dose• date of event - date of first dose of study drug, for events before first dose 5.2.6 Conventions for Missing and Partial Dates

[0357] Missing and partial start and stop date were imputed for analysis purposes as follows.Partial or missing stop date was imputed as follows:• If the stop date was completely missing and the event had resolved, or the patient had stopped taking the concomitant medication, the stop date was imputed as the date of the patient’s last clinic visit in the study.• If only the year was known, the stop date was imputed as “31 -Dec” of that year or as the date of the patient’s last clinic visit in the study if in the same year.• If the month and year were known, the stop date was imputed as the last day of that month unless the stop date corresponds to the same month as the patient’s114184896963.4last clinic visit in which case the date of patient’s last clinic visit in the study will be used instead.Missing start date was imputed as follows:• If the stop date occurred on or after the start of study drug or the event I concomitant medication was ongoing, the start date was imputed as the date of the first application of study drug.• If the stop date occurred before the start of study drug, the start date of the event I concomitant medication was imputed as the patient’s screening date or the stop date of the event / concomitant medication whichever the earlier.Partial start date (year present, but month and day missing)• If the stop date occurred on or after the start of study drug or the event I concomitant medication was ongoing, and the year was the same as the year of first dosing the start date was imputed as the date of application of study drug. If the year was different from the year of first dosing, “01 -Jan” was used.• If the stop date occurred before the start of study drug, the start date of the event I concomitant medication was imputed as the “01 -Jan” of the same year Partial start date (month and year present, but day missing)• If the stop date occurred on or after the start of study drug or the event I concomitant medication was ongoing, the start date was imputed as the first day of the same month and year unless this partial start date was in same month as the first application of study drug in which case the date of first application of study drug was used.• If the stop date occurred before the start of study drug, the start date was imputed as the first day of the month and year of the partial start date.

[0358] All dates presented in the individual patient listings were as recorded on the Electronic Case Report Form (eCRF).5.2.7 Exposure to Study Drug

[0359] Exposure to study drug was calculated as follows:date of last dosing minus the first day of dosing + 1115184896963.4

[0360] The exposure calculation did not take into account breaks in therapy. In addition to the above, the number of doses received was also derived, to account for any break in therapy.5.2.8 Treatment Compliance

[0361] Treatment compliance was derived as the ratio between the planned number of doses (i.e. 28 for patients completing the inpatient treatment period or the number of days from the first dose to the early termination date for patients not completing the inpatient treatment period, one for each planned day of the inpatient treatment period) and the actual number of doses received, as follows:Actual Received Doses% Compliance = 100 xTotal Planned Doses

[0362] Compliance was also categorized as follows:• <70% (poorly compliant)• 70% to 90% (moderately compliant)• 90% to 100% (fully compliant)5.2.9 Inexact Values

[0363] In the case where a variable was recorded as “> x”, “> x”, “< x” or “< x”, a value of x was taken for analysis purposes. The inexact value, inclusive of the symbol, was reported in the listings.5.2.10 Electrocardiogram (ECG) Data

[0364] For ECG data recorded on continuous scales, triplicate values recorded at a time point were averaged and rounded to the integer for summarization purposes. For the overall interpretation, the most severe (worst case) of the replicate readings was taken (separately for the central reader and the investigator assessment).5.2.11 Vital Signs

[0365] For blood pressure (both systolic and diastolic) and pulse rate, the orthostatic changes was calculated as standing minus sitting readings.

[0366] A patient was defined to have orthostatic hypotension if either or both of the below criteria were met:• a decrease of > 20 mm Hg in systolic blood pressure in measurements from supine to standing116184896963.4• a decrease of > 10 mm Hg in diastolic pressure in measurements from supine to standing

[0367] Temperatures reported in Fahrenheit was converted to Celsius for reporting using the following formula: Celsius = (Fahrenheit - 32) / 1.8

[0368] Weights reported in pounds were converted to kilograms using the following formula: Kilograms = pounds* 0.453592

[0369] Heights and waist circumferences reported in inches were converted to centimeters using the following formula: Centimeters = inches*2.545.2.12 Positive and Negative Symptoms Scale (PANSS)

[0370] The PANSS was a questionnaire consisting of 30 items, divided in 3 subscales (negative symptoms, positive symptoms, and general psychopathology), where each item (representing a symptom construct) was rated with a value ranging from 1 to 7. The total score was obtained by summing the scores for each item / symptom, and similarly the sub-scale scores were obtained by summing the scores of the individual items included in each of them.

[0371] In addition to this, PANSS Marder factor scores were defined as a further combination of the items, using the mapping described in Table 6D. The scores for each factor were obtained by summing up the scores of each individual item listed in the table below for the respective factor.Table 6D PANSS Marder Factors MappingFactor Name ItemsNegative Symptoms Blunted affectEmotional withdrawalPoor rapportPassive social withdrawalLack of spontaneityMotor retardationActive social avoidancePositive Symptoms DelusionsHallucinatory behaviorGrandiositySuspiciousnessStereotyped thinkingSomatic concernUnusual thought contentLack of judgement and insightDisorganized Thought Conceptual disorganizationDifficulty in abstract thinkingMannerism and posturing117184896963.4Poor attentionDisturbance of volitionPreoccupationDisorientationUncontrolled Hostility / Excitement ExcitementHostilityUncooperativenessPoor impulse controlAnxiety / Depression AnxietyGuiltTensionDepression5.2.13 Columbia-Suicide Severity Rating Scale (C-SSRS)

[0372] The following outcomes (Table 6E) were C-SSRS categories and had binary responses (yes I no). The categories were re-ordered from the actual scale to facilitate the definition of composite endpoints.Table 6E: C-SSRS categoriesCategory 1 Wish to be DeadCategory 2 Non-specific Active Suicidal ThoughtsCategory 3 Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act Category 4 Active Suicidal Ideation with Some Intent to Act, without Specific Plan Category 5 Active Suicidal Ideation with Specific Plan and IntentCategory 6 Preparatory Acts or BehaviorCategory 7 Aborted AttemptCategory 8 Interrupted AttemptCategory 9 Actual Attempt (non-fatal)Category 10 Completed Suicide

[0373] Suicidal Ideation since baseline - A “yes” answer at any time during double blind treatment to any one of the 5 suicidal ideation questions (categories 1-5) on the C-SSRS.

[0374] Suicidal Behavior since baseline - A “yes” answer at any time during double blind treatment to any one of the 5 suicidal behavior questions (categories 6-10) on the C-SSRS.

[0375] There was no imputation of missing data for C-SSRS.5.2.14 Clinical Global Impression - Severity (CGI-S)

[0376] The CGI-S assessed the physician / investigator’s assessment of the severity of the patient’s illness, using a 7-point rating scale ranging from 1 (= normal, not at all ill) to 7 (= among the most extremely ill patients).118184896963.4

[0377] Patients were classified as a responder on the CGI-S if they provided a score of either 1 (= normal, not at all ill), 2 (= borderline mentally ill) or 3 (=mildly ill).5.2.15 Simpson-Angus Scale (SAS)

[0378] The SAS was a measure of extrapyramidal side effects (EPS) and consisted of a list of 10 symptoms of Parkinsonism (gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, leg pendulousness, head dropping, glabella tap, tremor, and salivation). Each item was rated on a 5-point scale, with a score of 0 representing absence of symptoms, and a score of 4 representing a severe condition. The SAS total score is the sum of the scores for all 10 items.5.2.16 Abnormal Involuntary Movement Scale (AIMS)

[0379] The AIMS assessment consisted of 10 items describing symptoms of dyskinesia. Each item was rated on a 5-point scale, with a score of 0 representing absence of symptoms (for item 10, no awareness), and a score of 4 indicating a severe condition (for item 10, awareness, severe distress). The AIMS movement rating score was defined as the sum of items 1 through 7 (i.e., items 1 through 4, facial and oral movements; items 5 and 6, extremity movements; and item 7, trunk movements).5.2.17 Unscheduled Visits

[0380] Only values collected at scheduled assessments values were tabulated, unless otherwise stated. All repeat / unscheduled assessments were included in all listings in the relevant appendices to the Clinical Study Report (CSR).5.2.18 Pooled Study Site

[0381] Sites enrolling fewer than 10 patients was pooled such that the smallest pooled site became the size of the smallest standalone site but not larger than approximately three times the size of the smallest standalone site. The choice of which sites to pool was done preliminarily once 75% of all patients were randomized and was confirmed at the end of the recruitment period and was based on geographical considerations. The exact pooling strategy was agreed upon prior to unblinding and database lock and detailed in the CSR.5.3 Conventions

[0382] All data listings, summaries, figures, and statistical analyses were generated using SAS® version 9.4 or higher.119184896963.4

[0383] Listings were sorted in the following order: treatment group, patient, visit, and parameter, unless otherwise stated. All data were listed, and patients who were not randomized (i.e. screen failures) were displayed after the randomized treatment groups in relevant listings.

[0384] Continuous variables were summarized by the number of non-missing observations, mean, median, standard deviation (SD), and minimum and maximum. Summaries of PK concentrations also included geometric means and coefficient of variations (CV), the former being derived as exp(jiZn)and the latter as Jexp(afn) - 1where p[nand a2lnwere, respectively, the mean and variance calculated on the natural log-transformed concentrations.

[0385] Categorical variables were summarized by presenting the frequency and percent. Percentages were based either on the number of patients in the column header or on the number of patients in the respective analysis set with available data, as specified in the table footnotes. For each variable, all categories were shown. Zero frequencies (but not the percent) within a category will be presented.

[0386] Means, medians, and percentiles were displayed to one more decimal place than the data, dispersion statistics (e.g., standard deviation) had two more decimal places, and the minimum and maximum were displayed to the same number of decimal places as reported in the raw data. Percentages were displayed with one decimal place.

[0387] P-values were quoted to 4 decimal places consistent with SAS PVALUE w.d format set to PVALUE6.4. P-values < 0.0001 were presented as p<0.0001.5.4 Patient Disposition

[0388] Patient disposition were summarized as follows:• The number of patients who were screened and who failed screening were tabulated for the Screened Set alongside the reason for screen failure.• The number of patients randomized, and who were in each analysis set were summarized separately for each study site by treatment group and overall.120184896963.4• The number of study and treatment discontinuations and the reasons for discontinuation were tabulated by treatment group and overall for all randomized patients.• The number of patients present at each scheduled visit was summarized by treatment group for the Safety Analysis Set.

[0389] All patient disposition data were listed.5.5 Protocol Deviations (PD)

[0390] PDs were summarized by classification (minor, major) and reason.5.6 Baseline Comparability

[0391] The comparability of treatment groups with respect to patient demographics and baseline characteristics were assessed in a descriptive manner.

[0392] Standard continuous or categorical variable summaries were presented for the Safety Analysis Set by actual treatment group for the following variables:• Demographicso Age at Informed Consent (years),o Gender, n (%) ('Male', 'Female'),o Fertility status for women, n (%) (a) ('Childbearing Potential', 'Postmenopausal', 'Surgically Sterile'),o Ethnicity, n (%) ('Hispanic or Latino', 'Not Hispanic or Latino'), o Race, n (%) ('American Indian or Alaska Native', 'Asian', 'Black or African American', 'Native Hawaiian or Other Pacific Islander', 'White', 'Multiple Race’, ‘Unknown’, ‘Not Reported’).• Other baseline characteristicso Weight (kg),o Height (cm),o Body Mass Index (kg / m2),o Waist Circumference (cm).

[0393] The MINI 7.0.2 questionnaire with the Borderline Personality Disorder (BPD) module was only listed.121184896963.45.1 Medical History

[0394] Separate tabulations of previous and ongoing conditions at screening were presented by actual treatment group and overall for the Safety Analysis Set.Conditions were presented by Medical Dictionary of Regulated Activities (MedDRA) primary system organ class and preferred term, using version 26.1 or higher for coding.

[0395] All medical history information was also listed.5.8 Prior and Concomitant Medications

[0396] Prior medications were defined as all medications that were stopped in the 30 days before ICF sign-off, whereas concomitant medications were defined as medications taken on or after such date.

[0397] Separate tabulations were produced for prior and concomitant medications presented by actual treatment group and overall for the Safety Analysis Set. Concomitant medications were coded using the WHO dictionary (version B3 Global Mar-2023 or later) and summarized using Anatomic Therapeutic Chemical (ATC) Level 2.

[0398] Prior medication washout information was also listed separately.5.9 Exposure to Study Drug

[0399] Extent of exposure were summarized descriptively by actual treatment group for the Safety Analysis Set, including the following parameters:• Length of exposure (days)• Number of doses received• Number of doses missed5.10 Treatment Compliance

[0400] Treatment compliance was summarized descriptively by treatment groups for the Safety Analysis Set. In addition, the categories of compliance defined in Section 5.2.8 were also summarized with counts and percentages.5.11 Efficacy Analyses

[0401] Statistical tests were performed using a two-tailed 5% overall significance level, unless otherwise stated. For the primary analysis of the primary endpoint, a multiplicity strategy was in place to ensure that the familywise error rate (FWER) was controlled at this level across the doses tested (see Section 5.11.7 for details).122184896963.4

[0402] All comparisons between treatments were reported with 95% confidence intervals for the difference.5.11.1 Primary Endpoint

[0403] The primary endpoint was the change from Baseline to Week 4 in the PANSS total score. The null hypothesis associated with this endpoint was that the decrease from Baseline to Week 4 in either the LB-10250 mg or 75 mg arms were equal or smaller than what observed in the Placebo arm, and the alternative being that the decrease in the active arm was larger than in the Placebo arm. This set of hypotheses can be formalized as follows:LB-10250 mg arm:Hoi: LB-10250 mg — PIaceboHl 1: LB-10250 mg < PIaceboLB-10275 mg arm:H02: PLB-102 75 mg — PPIaceboH12: PLB-102 75 mg < PPIacebo

[0404] No formal hypothesis was tested for the LB-102100 mg arm, but data were included in any analysis model for all the primary and secondary efficacy endpoints and Cis and p-values provided for descriptive purposes.

[0405] Methods to control type I error rate at the nominal 5% level are described in Section 5.11.7.5.11.2 Primary Efficacy Analysis

[0406] In line with the primary study estimand, prior to performing the statistical modelling missing data due to a discontinuation related to either lack of efficacy or drug-related AEs was imputed assuming a MNAR mechanism whereas missing data due to discontinuation for any other reason or non-monotone missing data was imputed under a MAR mechanism.

[0407] The MAR imputation used a fully conditional specification approach with a predictive mean matching (PMM) method, where a missing value was imputed using a value randomly selected from a set of k (= 5) observed values that were the closest to the predicted value for the missing data point. This imputation was performed using the following SAS code:123184896963.4proc mi data = <input-dataset> nimpute = 100 seed = 99 out = imputeOl minimum = 30 maximum = 210 round = 1;by trtOlp;var baseline week_1 week_2 week_3 week_4;fcs nbiter = 1000 regpmm( baseline);fcs nbiter = 1000 regpmm(week_1 = baseline);fcs nbiter = 1000 regpmm(week_2 = baseline week_1);fcs nbiter = 1000 regpmm(week_3 = baseline week_1 week_2);fcs nbiter = 1000 regpmm(week_4 = baseline week_1 week_3);run;

[0408] Missing values for patients dropping out from the study because of lack of efficacy or drug-related AEs were imputed iteratively assuming that after withdrawal the patients followed the distribution of the worst values observed up to the study visit at which they withdraw. A schematic illustration of the process was as follows:a) All patients with non-missing Week 1 PANSS score values (including both those with an actual observed Week 1 value and those who had this value imputed as part of the MAR imputation step described above) had a variable (WORST1) calculated which was the maximum PANSS score values observed between baseline and Week 1, whereas those with a missing Week 1 value had a missing value for WORST1 as wellb) The imputation step used WORST1 as the variable to be imputed and baseline and Week 1 values as predictors using the PMM method described above for the MAR imputation step. Patients with a missing Week 1 value thus had their Week 1 value imputed by the WORST1 value predicted by the imputation procedure.c) A similar approach was thus followed for Week 2, i.e. creating a WORST2 variable, imputing it using a PMM approach and using this imputed value as the Week 2 value for patients with a missing assessment at that visit.d) This approach was then repeated for Week 3 and 4, until at last all values missing because of lack of efficacy or drug-related AEs had been imputed / replaced.

[0409] The below sample SAS code implemented the above steps, with the input dataset of the first DATA STEP being the output dataset of the PROC Ml step above124184896963.4and including the patient ID and the MAR-imputed PANSS data in wide format, one column for timepoint, i.e. baseline, Week 1, 2, 3 and 4:* Create W0RST1 variable;data stepl;set analysis02;if not missing(week_1) then worstl = max(baseline, week_1);run;* Impute W0RST1 for patients with missing Week 1 data;proc mi data = stepl nimpute = 1 seed = 99 out = step2a minimum = 30 maximum = 210;by -imputation;var baseline worstl;fcs nbiter = 1000 regpmm(worst1 = baseline);run;* Set Week 1 = WORST1 for missing data and create W0RST2 variable;data step2b;set step2a;week_1 = ifn(missing(week_1 ), worstl, week_1 );if not missing(week_2) then worst2 = max(baseline, week_1, week_2);run;* Impute WORST2 for patients with missing Week 2 data;proc mi data = step2b nimpute = 1 seed = 99 out = step3a minimum = 30 maximum = 210;by -imputation;var baseline week_1 worst2;fcs nbiter = 1000 regpmm(worst2 = baseline week_1);run;* Set Week 2 = WORST2 for missing data and create WORSTS variable;data step3b;set step3a;week_2 = ifn(missing(week_2), worst2, week_2);if not missing(week_3) then worsts = max(baseline, week_1, week_2, week_3); run;* Impute W0RST3 for patients with missing Week 3 data;125184896963.4proc mi data = step3b nimpute = 1 seed = 99 out = step4a minimum = 30 maximum = 210;var baseline week_1 week_2 worst3;fcs nbiter = 1000 regpmm(worst3 = baseline week_1 week_2);run;* Set Week 3 = W0RST3 for missing data and create W0RST4 variable;data step4b;set step4a;week_3 = ifn(missing(week_3), worsts, week_3);if not missing(week_4) then worst4 = max(baseline, week_1, week_2, week_3, week_4);run;* Impute W0RST4 for patients with missing Week 4 data;proc mi data = step4b nimpute = 1 seed = 99 out = step5a minimum = 30 maximum = 210;var baseline week_1 week_2 week_3 worst4;fcs nbiter = 1000 regpmm(worst4 = baseline week_1 week_2 week_3);run;* Set Week 4 = W0RST4 for missing data;data step5b;set step5a;week_4 = ifn(missing(week_4), worst4, week_4);run;

[0410] Upon completion of the above imputation steps, the change from baseline in the PANSS score was derived and used in the statistical modelling. To such aim, a MMRM was fit for each imputed dataset, including pooled study site, visit, treatment and treatment by visit interaction as categorical effects and Baseline PANSS total score as continuous covariate and the change from Baseline in the PANSS total score at 1, 2, 3 and 4 weeks after baseline as response. Correlation between repeated observations within a patient was accounted for via an unstructured correlation matrix, however, should this structure lead to convergence issues, the following decreasingly complex alternative structures were fit in turn until the model converges: Toeplitz, first-order autoregressive, and compound symmetry. The assessment of model convergence was done prior to unblinding. The LS means for change from Baseline to all post-Baseline timepoints in the PANSS total score and their differences between the active treatment126184896963.4arms (50 and 75 mg) and placebo were estimated for each imputed dataset. Model assumptions were examined graphically for a random selection of 10% imputations (i.e.10) via inspection of conditional residuals scatterplots (residuals vs predicted values), quantile-quantile plots and histograms. Should any substantial violation be observed, non-parametric analyses (e.g. Wilcoxon rank-sum test) were adopted, and this decision was documented based on blinded data prior to database lock. This model was fit using the example SAS code below:ods output estimates = est LSMeans = Ism diffs = diff;proc mixed data = <input-dataset> plots (only) = studentpanel(marginal); by _imputation_;class subjid trtOlpn avisitn siteid;model chg = trtOlpn siteid avisitn trtO1pn*avisitn base / ddfm = kr;repeated avisitn I type = un subject = subjid;Ismeans trtO1 pn*avisitn I diff cl;run;

[0411] The model estimates (LS means and their differences between treatment arms) were pooled using Rubin’s combination rules to incorporate the between-imputation with the within-imputation variability and to obtain one single point and interval treatment effect estimate for each active arm using the PROC MIANALYZE procedure. The below sample SAS code implemented the pooling across imputations:proc mianalyze data = <input-dataset>;by trtOlpn avisitn;modeleffects estim;stderr sem;ods output parameterestimates = parmest;run;where estim and sem were the point and variability estimates from the MMRM analysis for each imputed dataset for each relevant parameter. In the above code, the BY statement ensured that the pooling was done across imputations within each level of TRT01 PN and AVISITN (these variable names might change depending on the actual variable used in the analysis). LS means and their differences between the active arms and Placebo alongside 95% Cis and p-values for the differences were thus reported after the above pooling had been done, inclusive of the results of the multiplicity adjustment procedure described in Section 5.11.7. The estimated LS means over time was graphically displayed alongside their 95% Cl in a line plot. A descriptive summary of PANSS total scores and their changes from baseline was also presented.127184896963.4

[0412] This analysis (inclusive of the graphical representation) was performed for the ITT analysis set and repeated also for the mITT Analysis Set, however if the two analysis sets overlapped substantially (i.e. if at least 95% of the patients in the ITT were also included in the mITT) the primary analysis was performed for the mITT and the ITT only was regarded as supportive information.

[0413] All PANSS score data, inclusive of individual items responses as well as subscale scores, were also be listed.5.11.3 Sensitivity Analysis5.11.3.1 Sensitivity Analysis #1: Re-mapped Early Termination Assessments

[0414] The primary analysis was repeated but including PANSS values obtained during early termination assessments in the analysis, i.e. by re-mapping them to the analysis windows described in Section 5.2.4 in place of PANSS collected at the planned visit mapped to the same analysis window. Similar displays and quantities to the primary analysis were provided.5.11.3.2 Sensitivity Analysis #2: Tipping-Point Analysis

[0415] As an additional sensitivity analysis, all missing PANSS total score values that were imputed using a MAR approach as described in Section 5.11.2 were imputed under a MNAR mechanism using a tipping-point approach, i.e. by adding a treatmentspecific constant shift (e.g., ±2 to ±10 points) to the MAR-imputed values in order to assess how severe a MAR violation needed to be for the results to change, i.e. for the results of the primary analysis to no longer be deemed as statistically significant (that is, for neither of the 50 or 75 mg arms to meet the thresholds described in Section 5.11.7). The following set of shifts values were initially considered: 2, 4, 6, 8 and 10, with the potential combinations across arms described in Table 6F below. This analysis was conditioned on initial statistical significance and aimed to test the robustness of conclusions against deviations from the MAR assumption.Table 6F. Shift combinations for tipping point analysisLB-102 Arms Shift2 4 6 8 10 Placebo 2 X X X X XArm Shift 4 X X X X128184896963.46 X X X8 X X10 X

[0416] The lower triangle was investigated because it would be associated with scenarios where the penalties were larger for the Placebo arm, thus unlikely to reveal any negative change in study results.

[0417] The same MMRM as considered for the primary analysis was then fit for each multiply imputed dataset by shift pair, and results pooled to obtain, for every set of shift values, one treatment effect for each active arm. This analysis was only performed if at least one active arm’s primary analysis result was deemed as statistically significant under the multiple testing strategy defined in Section 5.11.7. The first combination of shifts where significance could not be concluded for any active arm (using the same multiplicity approach as for the primary analysis) was identified as the tipping-point, and its plausibility evaluated. For this purpose, the shifts combinations was ordered columnwise, e.g. assuming that a combination of placebo / active shifts of 8-8 is more ‘plausible’ then a 2-10. If no tipping-point was identified using the above combinations, extra shifts were evaluated by shifting the values for LB-102 arms by a value of 12 and then, within this, exploring shifts from 2 to 12 for Placebo, and so on until a shift was identified or all MAR imputed data imputed to maximum PANSS total score possible (= 210).

[0418] For each of the above pairs, the treatment effects and associated p-values for both arms were presented, alongside results of the multiplicity adjustment procedure described in Section 5.11.7.5.11.3.3 Sensitivity Analysis #3: Reference-based Imputation

[0419] For this sensitivity analysis, all missing data due to drop-out was imputed using a pattern-mixture model, whereby data were imputed only using data from patients with no missing data from the Placebo (reference) arm, i.e. assuming that all patients randomized to an active arm had had a profile on the primary endpoint similar to that of patients randomized to Placebo. To achieve this, first non-monotone missing data on the PANSS was imputed under a MAR mechanism using a Markov-Chain Monte Carlo (MCMC) approach, using the below sample SAS code:129184896963.4proc mi data = <input-dataset> nimpute = 100 seed = 99 out = <output-dataset> minimum = 30 maximum = 210;by trtOlpn;var base d8 d15 d21 d28;memo chain = multiple impute = monotone initial = em prior = Jeffreys;run;

[0420] Where the variables included in the VAR statement represented the PANSS total score at the relevant timepoints throughout the study, the IMPUTE = MONOTONE option means that missing data points were imputed to achieve a monotone missing data pattern, and the PRIOR = JEFFREYS option specified a non-informative prior for the imputation process, so that the posterior distribution used for the imputation was largely affected by the observed data themselves. These imputed datasets were then imputed using the copy-reference method via the below SAS code:proc mi data = <input-dataset> nimpute = 1 seed = 99 out = <output-dataset> minimum = 30 maximum = 210;by _imputation_;class trtOlp;var baseline d8 d15 d21 d28;fcs nbiter = 1000 regpmm(baseline d8 d15 d21 d28);mnar model(baseline d8 d15 d21 d28 / modelobs = (trtOlp = 'Placebo'));run;

[0421] The BY statement ensured that the above MNAR imputation was performed separately for each MAR-imputed dataset as generated by the previous imputation step. The same MMRM was then fit to all imputed datasets and results pooled across imputations, using the SAS code described in Section 5.11.2 for both the analysis and the pooling, and thus reporting similar quantities from the model.5.11.4 Exploratory Analysis5.11.4.1 Subgroup analysis

[0422] The primary analysis model (MMRM) described in Section 5.11.2 was used for the purposes of subgroups analyses, with no prior imputation for missing data. For each subgroup variable stratum the model was fit and estimates of LS means and their differences over time were provided, alongside 95% Cis as well as, for differences, p-values (only for descriptive purposes). The following subgroups were explored:• BMI at Baseline: < 25 kg / m225 to 30 kg / m2, > 30 kg / m2• Baseline PANSS (disease severity): <95, > 95130184896963.4

[0423] The results for these subgroups analysis were also displayed in a forest plot (Week 4 only).5.11.4.2 Site Effect

[0424] Descriptive summaries of observed and change from baseline values for the PANSS total score were provided by study site (regardless of pooling), but no statistical analysis was performed.5.11.5 Secondary Endpoints

[0425] All secondary endpoints were analyzed on the ITT analysis set. As described in Section 5.11.2, should the ITT and mITT analysis sets overlap substantially, secondary endpoints were only analyzed on the mITT analysis set.5.11.5.1 Change from Baseline to Week 4 in the CGI-S score

[0426] The change from Baseline in the CGI-S score was analyzed using a similar MMRM as the one for the primary endpoint, replacing baseline CGI-S as covariate in the model. Similar quantities (LS means and their differences, with 95% Cis and p-values) were presented. Descriptive summaries of observed and change from Baseline values were presented for all treatment arms.

[0427] CGI-S response, defined as a CGI-S score < 3, was also analyzed separately for each time-point, categorizing any patient with missing data as a nonresponder. The number of patients meeting this definition was summarized descriptively on the mITT analysis set with counts and percentages, including approximate Wald-type 95% Cl (with a continuity correction). The difference between treatment arms in the above defined responder rate was analyzed by reporting the estimated difference in proportions alongside its 95% Wald-type 95% Cl with a continuity correction as well as the F-value derived from Fisher’s exact test (using a Monte Carlo approximation to deal with the large sample size). Example SAS code is provided below:ods output RiskDiff Col2 = diff FishersExact = fisher;proc freq data = <input-dataset>;by atptn;tables trtO1 pn*avalc / riskdiff (column = 2 cl = (wald(correct))) chisq;exact fisher I me seed = 123;run;

[0428] For the derivation of the exact p-value, it was assumed that the 2x2 table for each visit had the following form (Table 6G).131184896963.4Table 6G: Table for derivation of the p-value for each visit Treatment Non-Response ResponseLB-102 a bPlacebo c d

[0429] Under the above structure, Fisher’s test as implemented in PROC FREQ was defined based on the value a in the first row / column and the associated one-sided p-values support different alternative hypotheses (the null being that of independence between row and columns):• Left-sided p-value: supported the alternative that the probability of a patient treated with LB-102 of being a non-responder is smaller than what would be expected under the independence null;• Right-sided p-value: supported the alternative that the probability of a patient treated with LB-102 of being a non-responder is larger than what would be expected under the independence null.

[0430] Since the hypothesis we were interested in (without being bound by any theory) was that patients treated with LB-102 were more likely to be responders than non-responder, a small left-sided p-value supported this hypothesis and as such this was the p-value that was reported in the table. All CGI-S data was also listed.5.11.5.2 Change from Baseline to Week 4 in PANSS positive subscale score

[0431] This endpoint was analyzed as described in Section 5.11.5.1, both with respect to the modelling strategy (inclusive of the imputation step and with appropriate changes to the baseline measurement to use as a covariate) and the descriptive summary approach.

[0432] All PANSS subscale scores were listed alongside the total score.5.11.5.3 Change from Baseline to Week 4 in PANSS negative subscale score

[0433] This endpoint was analyzed as described in Section 5.11.5.1, both in terms of model to fit and quantities to report.132184896963.45.11.5.4 Change from Baseline to Week 4 in PANSS Marder Factor scores

[0434] This endpoint was analyzed as described in Section 5.11.5.1, both in terms of model to fit and quantities to report (but with no imputation step), separately for each factor score described in Section 5.2.12.5.11.5.5 Response rate, defined as a reduction of >20% from Baseline in PANSS total score at Week 4

[0435] As described in Table 6B, prior to analysis the PANSS score data imputed under a MAR mechanism was dichotomized as being a responder or non-responder, and then missing data due to discontinuation because of lack of efficacy or drug-related AE as well as any data collected after any relevant ICE (start of emergency of prohibited treatment prior to Week 4) was imputed as non-responders. The resulting dataset was analyzed using a logistic regression using the response status at Week 4 as a response and baseline PANSS score, and treatment as covariates, using the below sample SAS code:ods output Diffs = <outut-dataset>;proc logistic data = <input-dataset> descending;by _imputation_;class trtO1 p (ref = 'Placebo');model response = trtO1 p baseline / link = logit;Ismeans trtO1 p / diff ilink om oddsratio;run;

[0436] From the above, the log odds ratio alongside its standard error was estimated and then pooled across imputed datasets to return one single estimate, which was exponentiated (alongside its 95% Cl) to obtain an OR for each treatment arm. The proportion of responders at day 28 was also descriptively summarized (based purely on observed data), with an approximate 95% Cl reported, derived using the following sample SAS code:ods output RiskDiffCol2 = <output-dataset>;proc freq data = <input-dataset>;table trtO1 p*response / riskdiff (column = 2);run;

[0437] This endpoint was also analyzed by imputing all missing data as non-responders and fitting the same logistic regression as above, from which the OR for each arm was estimated.133184896963.4

[0438] Response status was listed in the general PANSS listing.5.11.6 Exploratory Endpoints

[0439] All exploratory endpoints were analyzed on the ITT analysis set. As described in Section 5.11.2, should the ITT and mITT analysis sets overlap substantially, secondary endpoints were only analyzed on the mITT analysis set.5.11.6.1 Effect of LB-102 on Cogstate test scores

[0440] Summaries for the actual and change from Baseline values for each of the Cogstate test scores (International Shopping List Test, Detection Test, Identification Test, One Back Test and Modified Groton Maze Learning Test) were provided by treatment group. International Shopping List Test (ISLT) measures verbal list learning. Detection Test (DET) measures simple reaction time. Identification Test (IDN) measures choice reaction time. One Back Test (ONB) measures working memory. Groton Maze Learning Test (GMLT) measures executive function.

[0441] Changes from baseline in the individual tests were prespecified exploratory endpoints, with the following composite scores generated post hoc in the total trial population: Cogstate Brief Battery global composite score (aggregates performance on the DET, IDN, ISLT, GMLT, ONB [speed]), attention (Psychomotor Function) composite score (aggregates performance on the DET and IDN), and memory (Executive Function) composite score (aggregates performance on the ISLT and GMLT). Based on previously published literature, the threshold for clinical relevance of the treatment effect size was pre-determined as 0.2 (Cohen, J. (1988). Statistical power analysis for the behavioral sciences (2nd ed.). Hillsdale, NJ: Lawrence Erlbaum Associates).

[0442] In addition, an analysis of covariance (ANCOVA) model was also fit including pooled study site and treatment as categorical covariates and baseline Cogstate test score as continuous covariate and change from baseline to day 28 in the Cogstate test score as the response. LS means and their differences alongside 95% Cis and p-values for the comparison of active arms vs placebo were reported. The following sample SAS code was used:ods output estimates = est LSMeans = Ism diffs = diff;proc mixed data = <input-dataset> plots (only) = studentpanel(marginal); by test;134184896963.4class trtO1 pn siteid;model chg = trtO1 pn siteid base / ddfm = kr;Ismeans trtO1 pn I diff cl;run;

[0443] All Cogstate test score results were also listed.5.11.7 Multiplicity

[0444] Results from the analysis of the primary endpoint across the 50 and 75 mg doses were adjusted for multiplicity using a standard Hochberg procedure. This approach involved ranking the P values from the smallest (P(i)) to the largest (P(2)) and then comparing P(2) against 0.05 and if this hypothesis was rejected then reject also the one associated with P(i>, otherwise P(i)was further tested at a local 0.025 two-sided level, and if the test was significant at this level than the null hypothesis associated with it was rejected, whereas the one associated with P(2)was retained.5.12 Pharmacokinetic Analyses

[0445] Blood samples for determination of plasma concentrations of drug were collected on Day 1, 8 and 21 at the following time-points: pre-dose (only at Day 1 ), 15 minutes, 30 minutes, 1, 2, 3, 4, 8, and 24 hours post dose. Concentration-time data were tabulated by nominal (planned) time, analyte, and treatment using descriptive statistics. For presentation of the individual data and summary statistics, concentrations below the limit of quantitation (BLQ) were set to half the lower limit of quantitation (LLOQ).

[0446] Individual patient and mean plasma concentration-time data was presented graphically on linear and semi-logarithmic scales. Mean data was plotted using nominal sample times, and individual data was plotted using actual times.

[0447] The following PK parameters were also summarized by analyte and treatment using descriptive statistics: area under the concentration-time curve from time zero to time (AUC0-t), area under the concentration-time curve from time of dosing up to 24 hours (AUC0-24), area under the concentration-time curve from time zero to infinity (AUCo-inf), area under the concentration-time curve from time 0 to the last available sampling time (AUCiast), area under the concentration-time curve extrapolated from time t to infinity as a percentage of the total AUC (AUC%extraP), oral clearance (CL / F),135184896963.4maximum concentration (Cmax), time to reach Cmax (Tmax), terminal elimination rate constant (Az), and apparent terminal half-life (t1 / 2).

[0448] Dose proportionality was assessed by using a power model separately for the Cmax and AUCiast separately for each applicable visit. In this model the log-transformed PK parameter of interest was considered as the response variable and the log-transformed dose (i.e. 50, 75 and 100 mg) was the only model covariate. The model was fit using the following sample SAS code:ods output parameterestimates = parms;proc mixed data = <input-dataset> plots = none;by visit;model logaval = logdose I ddfm = kr;run;

[0449] From the above model the slope estimate |3 was derived alongside its 90% confidence interval, and dose proportionality was met if the confidence intervals lied entirely within this range:M0 / Jto 1 +In (r) In (r)

[0450] Where r was the ratio between the largest and the smallest dose (= 100 / 50 = 2) and 0£and &Hwere defined as 0.8 and 1.25 (similar to standard bioequivalence margins). As such the dose-proportionality range for the slope parameter was 0.678 to 1.322.5.13 Safety Analyses

[0451] The safety analyses were presented by treatment received for the Safety Analysis Set.5.13.1 Adverse Events

[0452] Treatment-emergent adverse events (TEAEs) were reported according to protocol as any AE that had an onset on or after the dose of study drug or any preexisting condition that was worsened on or after the first dose of study drug through 14 days following last dose of study drug. The following TEAE flag was applied to distinguish AEs from TEAEs:• Any AE that had a start date and time on or after the first dose of study drug and before last dose of study drug + 14 days136184896963.4

[0453] A treatment-related AE was defined as an AE as being possibly related or related to the study drug. If an AE had missing relationship it was assumed to be related to the study drug for analysis purposes.

[0454] Maximum severity was assumed for an AE with missing severity.

[0455] The following tables were prepared for AEs incidence and / or number of events were reported as appropriate:• Overall summary of AEs:o TEAEso Treatment-related TEAEso Treatment-emergent serious adverse events (TESAEs)o Treatment-related TESAEso TEAEs by severityo TEAEs leading to study discontinuationo Deaths• TEAEs by system organ class and preferred term• Treatment related TEAEs by system organ class and preferred term• TESAEs by system organ class and preferred term• TEAEs by system organ class, preferred term and maximum severity• TEAEs by system organ class, preferred term and strongest relationship• TEAEs leading to study discontinuation by system organ class and preferred term• Listing of Serious AEs.• Listing of Deaths.

[0456] Adverse event incidence was counted only once per system organ class and once per preferred term. The number and percent of patients experiencing events were reported. Outputs reported at maximum severity or strongest relationship showed the highest severity / relationship reported by a patient per system organ class and preferred term.

[0457] In addition to the above summary tables, relative risks for the occurrence of any AE (i.e., at least 1 AE) during the course of the study as well as for each system organ class / preferred term were estimated for each LB-102 dose vs placebo via a log-137184896963.4binomial regression model. For such analysis, the binary indicator for the presence of a given system organ class / preferred term (or any AE) was used as response and the treatment group was the only covariate, whose estimated regression coefficient was exponentiated to return the associated relative risk, alongside their 95% Cl and p-values. To such aim, as an example, the following sample SAS code was used:ods output estimates = rr;proc genmod data = <input-dataset> descending;by aedecod aeterm;class subjid trtOlan;model ae_binary = trtOlan I dist = binomial link = log;estimate 'RR LB-10250 mg vs. Placebo' trtO1 pn 1 00 -1 / exp alpha = 0.05; estimate 'RR LB-10275 mg vs. Placebo' trtO1 pn 01 0 -1 / exp alpha = 0.05; estimate 'RR LB-102 100 mg vs. Placebo' trtO1 pn 001 -1 / exp alpha = 0.05; run;

[0458] The above code assumed that the TRT01 PN variable was ordered such that placebo was the last arm (i.e. TRTOI PN = 4) and the others were sorted in ascending order, lowest to highest, and that AEDECOD and AETERM were the system organ class and preferred term variables, respectively.

[0459] All AEs were listed.5.13.2 Laboratory Data

[0460] Descriptive statistics of the observed values and change from baseline (continuous data) was presented by treatment group and visit for each hematology, urinalysis, chemistry, coagulation, and hormone (ACTH, TSH, cortisol) parameter. Each measurement (continuous data) was classed as below, within, or above normal range, based on ranges supplied by the laboratory used. Shift tables in relation to the normal range from baseline to each follow-up visit were presented.

[0461] A summary of the number of abnormal parameter values was also prepared. All laboratory data was listed, with a separate listing only including abnormal (i.e. out of range) values.5.13.3 Vital Signs

[0462] Descriptive statistics for observed values and changes from baseline in the following vital signs were presented by treatment group and visit:• Systolic blood pressure (mmHg)• Diastolic blood pressure (mmHg)138184896963.4• Pulse rate (bpm)• Body temperature (degrees Celsius)• Body weight (kg)

[0463] In addition, a separate table presenting BMI and waist circumference was also provided. A listing was provided including all measurements.

[0464] For blood pressure and pulse rate, the orthostatic changes were calculated as standing minus sitting readings. At each visit, the number of patients meeting the criteria for orthostatic hypotension as described in Section 5.2.11 was summarized. Orthostatic changes were listed separately, including a flag to identify cases of hypotension.5.13.4 Electrocardiogram Data

[0465] Descriptive statistics for observed values and changes from baseline in the following ECG variables was tabulated at each follow-up:• Heart rate (bpm...

Claims

CLAIMS1. A method for treating schizophrenia and / or improving cognition in a subject, the method comprising administering to the subject a therapeutically effective amount of an amisulpride derivative or a pharmaceutical composition thereof.

2. The method of claim 1, wherein the amisulpride derivative has a structure selected from the group consisting of Formula IA, Formula IB, and Formula IC, including pharmaceutically acceptable salts thereof, stereoisomers thereof (Formula IA-S, Formula IA-R, Formula IB-S, Formula IB-R, Formula IC-S, Formula IC-R), deuterated analogs of Formula IA, deuterated analogs of Formula IB, deuterated analogs of Formula IC, deuterated analogs of Formula IA-S, deuterated analogs of Formula IA-R, deuterated analogs of Formula IB-S, deuterated analogs of Formula IB-R, deuterated analogs of Formula IC-S, and deuterated analogs of Formula IC-R.

3. The method of claim 1 or claim 2, wherein the amisulpride derivative is LB-102, LB-103 or LB-104.

4. The method of any one of the preceding claims, wherein the amisulpride derivative is administered at an amount of 50 mg to about 100 mg once a day.

5. The method of any one of the preceding claims, wherein the amisulpride derivative is LB-102, and the amount administered is about 50 mg, about 75 mg, or about 100 mg.

6. The method of any one of the preceding claims, wherein the subject is administered with the pharmaceutical composition for at least about 1 week, at least about 2 weeks, at least about 3 weeks, or at least about 4 weeks.

7. The method of any one of the preceding claims, wherein the subject has a baseline PANSS total score of about 80 to about 120.

8. The method of any one of the preceding claims, the subject has a baseline PANSS total score of about 93.6 to about 93.9.152184896963.

49. The method of any one of the preceding claims, wherein the subject has a baseline score of >4 (moderate or greater) for >2 of the positive scale items selected from the group consisting of delusions, conceptual disorganization, hallucinatory behavior, suspiciousness / persecution.

10. The method of any one of the preceding claims, wherein the subject has a CGI-S score >4.

11. The method of any one of the preceding claims, wherein the subject has a baseline PANSS negative symptoms subscale score >24.

12. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 4 in the PANSS total score is about 14.0 to about 16.1, at least about 14.0, at least about 14.3, at least about 14.5, at least about 15.0, at least about 15.5, at least about 16.0, or at least about 16.1; and / orthe LS mean reduction from baseline to week 4 in the PANSS total score, when compared to subjects not treated with LB-102, increase about 4.6 to about 6.8, at least about 4.6, at least about 4.7, at least about 4.8, at least about 4.9, at least about 5.0, at least about 5.1, at least about 5.2, at least about 5.3, at least about 5.4, at least about 5.5, at least about 5.6, at least about 5.7, at least about 5.8, at least about 5.9, at least about 6.0, at least about 6.1, at least about 6.2, at least about 6.3, at least about 6.4, at least about 6.5, at least about 6.6, at least about 6.7, or at least about 6.8.

13. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 4 in the PANSS total score according to a sensitivity analysis by remapped ET assessment is about 13.5 to about 16.3, at least about 13.5, at least about 13.7, at least about 14.0, at least about 14.2, at least about 14.5, at least about 15.0, at least about 15.5, at least about 16.0, or at least about 16.3; and / orthe LS mean reduction from baseline to week 4 in the PANSS total score according to a sensitivity analysis by remapped ET assessment, when compared153184896963.4to subjects not treated with LB-102, increase about 4.4 to about 7.1, at least about 4.4, at least about 4.5, at least about 4.6, at least about 4.7, at least about 4.8, at least about 4.9, at least about 5.0, at least about 5.1, at least about 5.2, at least about 5.3, at least about 5.4, at least about 5.5, at least about 5.6, at least about 5.7, at least about 5.8, at least about 5.9, at least about 6.0, at least about 6.1, at least about 6.2, at least about 6.3, at least about 6.4, at least about 6.5, at least about 6.6, at least about 6.7, at least about 6.8, at least about 6.9, at least about 7.0, or at least about 7.1.

14. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 4 in the PANSS total score according to a sensitivity analysis with copy-reference imputation is about 13.3 to about 15.5, at least about 13.3, at least about 13.5, at least about 14.0, at least about 14.2, at least about 14.5, at least about 15.0, at least about 15.4, or at least about 15.5; and / orthe LS mean reduction from baseline to week 4 in the PANSS total score according to a sensitivity analysis with copy-reference imputation, when compared to subjects not treated with LB-102, increase about 3.9 to about 6.2, at least about 3.9, at least about 4.0, at least about 4.1, at least about 4.2, at least about 4.3, at least about 4.4, at least about 4.5, at least about 4.6, at least about 4.7, at least about 4.8, at least about 4.9, at least about 5.0, at least about 5.1, at least about 5.2, at least about 5.3, at least about 5.4, at least about 5.5, at least about 5.6, at least about 5.7, at least about 5.8, at least about 5.9, at least about 6.0, at least about 6.1, or at least about 6.2.

15. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 4 in the PANSS positive subscale score is about 4.5 to about 5.3, at least about 4.5, at least about 4.6, at least about 4.7, at least about 4.8, at least about 4.9, at least about 5.0, at least about 5.1, at least about 5.2, or at least about 5.3; and / orthe LS mean reduction from baseline to week 4 in the PANSS positive subscale score, when compared to subjects not treated with LB-102, increase about 1.6 to154184896963.4about 2.2, at least about 1.6, at least about 1.7, at least about 1.8, at least about 1.9, at least about 2.0, at least about 2.1, or at least about 2.2.

16. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 1 in the PANSS negative subscale score is about 0.9 to about 1.3, at least about 0.9, at least about 1.0, at least about 1.1, at least about 1.2, or at least about 1.3; and / orthe LS mean reduction from baseline to week 1 in the PANSS negative subscale score, when compared to subjects not treated with LB-102, increase about 0.2 to about 0.7, at least about 0.2, at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, or at least about 0.7.

17. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 2 in the PANSS negative subscale score is about 1.2 to about 1.9, at least about 1.2, at least about 1.3, at least about 1.4, at least about 1.5, at least about 1.6, at least about 1.7, at least about 1.8, or at least about 1.9; and / orthe LS mean reduction from baseline to week 2 in the PANSS negative subscale score, when compared to subjects not treated with LB-102, increase about 0.6 to about 1.2, at least about 0.6, at least about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, at least about 1.1, or at least about 1.2.

18. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 3 in the PANSS negative subscale is about 1.3 to about 1.9, at least about 1.3, at least about 1.4, at least about 1.5, at least about 1.6, at least about 1.7, at least about 1.8, or at least about 1.9: and / orthe LS mean reduction from baseline to week 3 in the PANSS negative subscale score, when compared to subjects not treated with LB-102, increase about 0.1 to about 0.8, at least about 0.1, at least about 0.2, at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, at least about 0.7, or at least about 0.8.155184896963.

419. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 4 in the PANSS negative subscale is about 1.7 to about 2.2, at least about 1.7, at least about 1.8, at least about 1.9, at least about 2.0, at least about 2.1, or at least about 2.2; and / orthe LS mean reduction from baseline to week 4 in the PANSS negative subscale score, when compared to subjects not treated with LB-102, increase about 0.7 to about 1.1, at least about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, or at least about 1.1.

20. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 1 in the Marder Factor PANSS score, the Marder Factor being positive symptoms, is about 1.4 to about 2.1, at least about 1.4, at least about 1.5, at least about 1.6, at least about 1.7, at least about 1.8, at least about 1.9, at least about 2.0, or at least about 2.1; and / or the LS mean reduction from baseline to week 1 in the Marder Factor PANSS score, the Marder Factor being positive symptoms, when compared to subjects not treated with LB-102, increase about 0.5 to about 1.1, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, or at least about 1.1.

21. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 2 in the Marder Factor PANSS score, the Marder Factor being positive symptoms, is about 2.4 to about 3.2, at least about 2.4, at least about 2.5, at least about 2.6, at least about 2.7, at least about 2.8, at least about 2.9, at least about 3.0, at least about 3.1, or at least about 3.2; and / orthe LS mean reduction from baseline to week 2 in the Marder Factor PANSS score, the Marder Factor being positive symptoms, when compared to subjects not treated with LB-102, increase about 0.5 to about 1.2, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, at least about 1.1, or at least about 1.2.156184896963.

422. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 3 in the Marder Factor PANSS score, the Marder Factor being positive symptoms, is about 3.6 to about 4.6, at least about 3.6, at least about 3.7, at least about 3.8, at least about 3.9, at least about 3.0, at least about 4.1, at least about 4.2, at least about 4.3, at least about 4.4, at least about 4.5, or at least about 4.6; and / orthe LS mean reduction from baseline to week 3 in the Marder Factor PANSS score, the Marder Factor being positive symptoms, when compared to subjects not treated with LB-102, increase about 1.7 to about 2.6, at least about 1.7, at least about 1.8, at least about 1.9, at least about 2.0, at least about 2.1, at least about 2.2, at least about 2.3, at least about 2.4, at least about 2.5, or at least about 2.6.

23. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 4 in the Marder Factor PANSS score, the Marder Factor being positive symptoms, is about 4.4 to about 5.4, at least about 4.4, at least about 4.5, at least about 4.6, at least about 4.7, at least about 4.8, at least about 4.9, at least about 5.0, at least about 5.1, at least about 5.2, at least about 5.3, or at least about 5.4; and / orthe LS mean reduction from baseline to week 4 in the Marder Factor PANSS score, the Marder Factor being positive symptoms, when compared to subjects not treated with LB-102, increase about 1.8 to about 2.9, at least about 1.8, at least about 1.9, at least about 2.0, at least about 2.1, at least about 2.2, at least about 2.3, at least about 2.4, at least about 2.5, at least about 2.6, at least about 2.7, at least about 2.8, or at least about 2.9.

24. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 1 in the Marder Factor PANSS score, the Marder Factor being disorganized thought, is about 1.1 to about 2.0, at least about 1.1, at least about 1.2, at least about 1.3, at least about 1.4, at least about 1.5, at least about 1.6, at least about 1.7, at least about 1.8, at least about 1.9, or at least about 2.0; and / or157184896963.4the LS mean reduction from baseline to week 1 in the Marder Factor PANSS score, the Marder Factor being disorganized thought, when compared to subjects not treated with LB-102, increase about 0.2 to about 1.1, at least about 0.2, at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, or at least about 1.1.

25. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 2 in the Marder Factor PANSS score, the Marder Factor being disorganized thought, is about 1.7 to about 2.4, at least about 1.7, at least about 1.8, at least about 1.9, at least about 2.0, at least about 2.1, at least about 2.2, at least about 2.3, or at least about 2.4; and / or the LS mean reduction from baseline to week 2 in the Marder Factor PANSS score, the Marder Factor being disorganized thought, when compared to subjects not treated with LB-102, increase about 0.5 to about 1.1, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, or at least about 1.1.

26. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 3 in the Marder Factor PANSS score, the Marder Factor being disorganized thought, is about 2.3 to about 3.1, at least about 2.3, at least about 2.4, at least about 2.5, at least about 2.6, at least about 2.7, at least about 2.8, at least about 2.9, at least about 3.0, or at least about 3.1; and / orthe LS mean reduction from baseline to week 3 in the Marder Factor PANSS score, the Marder Factor being disorganized thought, when compared to subjects not treated with LB-102, increase about 2.3 to about 3.1, at least about 2.3, at least about 2.4, at least about 2.5, at least about 2.6, at least about 2.7, at least about 2.8, at least about 2.9, at least about 3.0, or at least about 3.1.

27. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 4 in the Marder Factor PANSS158184896963.4score, the Marder Factor being disorganized thought, is about 2.9 to about 3.6, at least about 2.9, at least about 3.0, at least about 3.1, at least about 3.2, at least about 3.3, at least about 3.4, at least about 3.5, or at least about 3.6; and / or the LS mean reduction from baseline to week 4 in the Marder Factor PANSS score, the Marder Factor being disorganized thought, when compared to subjects not treated with LB-102, increase about 0.9 to about 1.7, at least about 0.9, at least about 1.0, at least about 1.1, at least about 1.2, at least about 1.3, at least about 1.4, at least about 1.5, at least about 1.6, or at least about 1.7.

28. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 1 in the Marder Factor PANSS score, the Marder Factor being uncontrolled hostility / excitement, is about 0.7 to about 1.1, at least about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, or at least about 1.1; and / orthe LS mean reduction from baseline to week 1 in the Marder Factor PANSS score, the Marder Factor being uncontrolled hostility / excitement, when compared to subjects not treated with LB-102, increase about 0.5 to about 0.9, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, or at least about 0.9.

29. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 2 in the Marder Factor PANSS score, the Marder Factor being uncontrolled hostility / excitement, is about 0.9 to about 1.3, at least about 0.9, at least about 1.0, at least about 1.1, at least about 1.2, or at least about 1.3; and / orthe LS mean reduction from baseline to week 2 in the Marder Factor PANSS score, the Marder Factor being uncontrolled hostility / excitement, when compared to subjects not treated with LB-102, increase about 0.1 to about 0.6, at least about 0.1, at least about 0.2, at least about 0.3, at least about 0.4, at least about 0.5, or at least about 0.6.159184896963.

430. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 3 in the Marder Factor PANSS score, the Marder Factor being uncontrolled hostility / excitement, is about 1.3 to about 1.6, at least about 1.3, at least about 1.4, at least about 1.5, or at least about 1.6; and / orthe LS mean reduction from baseline to week 3 in the Marder Factor PANSS score, the Marder Factor being uncontrolled hostility / excitement, when compared to subjects not treated with LB-102, increase about 0.7 to about 1.0, at least about 0.7, at least about 0.8, at least about 0.9, or at least about 1.0.

31. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 4 in the Marder Factor PANSS score, the Marder Factor being uncontrolled hostility / excitement, is about 1.4 to about 1.9, at least about 1.4, at least about 1.5, at least about 1.6, at least about 1.7, at least about 1.8, or at least about 1.9; and / orthe LS mean reduction from baseline to week 4 in the Marder Factor PANSS score, the Marder Factor being uncontrolled hostility / excitement, when compared to subjects not treated with LB-102, increase about 0.8 to about 1.3, at least about 0.8, at least about 0.9, at least about 1.0, at least about 1.1, at least about 1.2, or at least about 1.3.

32. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 1 in the Marder Factor PANSS score, the Marder Factor being anxiety / depression, is about 1.3 to about 2.2, at least about 1.3, at least about 1.4, at least about 1.5, at least about 1.6, at least about 1.7, at least about 1.8, at least about 1.9, at least about 2.0, at least about 2.1, or at least about 2.2; and / orthe LS mean reduction from baseline to week 1 in the Marder Factor PANSS score, the Marder Factor being anxiety / depression, when compared to subjects not treated with LB-102, increase about 0.2 to about 0.7, at least about 0.2, at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, or at least about 0.7.160184896963.

433. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 2 in the Marder Factor PANSS score, the Marder Factor being anxiety / depression, is about 2.3 to about 2.5, at least about 2.3, at least about 2.4, or at least about 2.5; and / orthe LS mean reduction from baseline to week 2 in the Marder Factor PANSS score, the Marder Factor being anxiety / depression, when compared to subjects not treated with LB-102, increase about 0.3 to about 0.5, at least about 0.3, at least about 0.4, or at least about 0.5.

34. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 3 in the Marder Factor PANSS score, the Marder Factor being anxiety / depression, is about 2.6 to about 3.5, at least about 2.6, at least about 2.7, at least about 2.8, at least about 2.9, at least about 3.0, at least about 3.1, at least about 3.2, at least about 3.3, at least about 3.4, or at least about 3.5; and / orthe LS mean reduction from baseline to week 3 in the Marder Factor PANSS score, the Marder Factor being anxiety / depression, when compared to subjects not treated with LB-102, increase about 0.2 to about 1.2, at least about 0.2, at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, at least about 1.1, or at least about 1.2.

35. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 4 in the Marder Factor PANSS score, the Marder Factor being anxiety / depression, is about 2.7 to about 3.5, at least about 2.7, at least about 2.8, at least about 2.9, at least about 3.0, at least about 3.1, at least about 3.2, at least about 3.3, at least about 3.4, or at least about 3.5; and / orthe LS mean reduction from baseline to week 4 in the Marder Factor PANSS score, the Marder Factor being anxiety / depression, when compared to subjects not treated with LB-102, increase about 0.2 to about 1.1, at least about 0.2, at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, at least161184896963.4about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, or at least about 1.1.

36. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 1 in the Marder Factor PANSS score, the Marder Factor being negative symptoms, is about 1.0 to about 1.2, at least about 1.0, at least about 1.1, or at least about 1.2; and / orthe LS mean reduction from baseline to week 1 in the Marder Factor PANSS score, the Marder Factor being negative symptoms, when compared to subjects not treated with LB-102, increase about 0.6 to about 0.8, at least about 0.6, at least about 0.7, or at least about 0.8.

37. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 2 in the Marder Factor PANSS score, the Marder Factor being negative symptoms, is about 1.5 to about 2.1, at least about 1.6, at least about 1.7, at least about 1.8, at least about 1.9, at least about 2.0, or at least about 2.1; and / orthe LS mean reduction from baseline to week 2 in the Marder Factor PANSS score, the Marder Factor being negative symptoms, when compared to subjects not treated with LB-102, increase about 0.7 to about 1.3, at least about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, at least about 1.1, at least about 1.2, or at least about 1.3.

38. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 3 in the Marder Factor PANSS score, the Marder Factor being negative symptoms, is about 1.7 to about 2.3, at least about 1.7, at least about 1.8, at least about 1.9, at least about 2.0, at least about 2.1, at least about 2.2, or at least about 2.3; and / orthe LS mean reduction from baseline to week 3 in the Marder Factor PANSS score, the Marder Factor being negative symptoms, when compared to subjects not treated with LB-102, increase about 0.5 to about 1.1, at least about 0.5, at162184896963.4least about 0.6, at least about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, or at least about 1.1.

39. The method of any one of the preceding claims, wherein:the LS mean reduction from baseline to week 4 in the Marder Factor PANSS score, the Marder Factor being negative symptoms, is about 1.9 to about 3.0, at least about 1.9, at least about 2.0, at least about 2.1, at least about 2.2, at least about 2.3, at least about 2.4, at least about 2.5, at least about 2.6, at least about 2.7, at least about 2.8, at least about 2.9, or at least about 3.0; and / orthe LS mean reduction from baseline to week 4 in the Marder Factor PANSS score, the Marder Factor being negative symptoms, when compared to subjects not treated with LB-102, increase about 0.3 to about 1.5, at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, at least about 1.1, at least about 1.2, at least about 1.3, at least about 1.4, or at least about 1.5.

40. The method of any one of the preceding claims, wherein the percentage of >20% PANSS Responders after 4 week of treatment is at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71 %, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, or at least about 80%.

41. The method of any one of the preceding claims, wherein the percentage of >30% PANSS Responders after 4 week of treatment is at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, or at least about 40%.163184896963.

442. The method of any one of the preceding claims, wherein the percentage of >40% PANSS Responders after 4 week of treatment is at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, or at least about 20%, or at least about 21%.

43. The method of any one of the preceding claims, wherein the effect size (Hedges’ g) is about 0.40 to about 0.83, at least about 0.40, at least about 0.41, at least about 0.45, at least about 0.50, at least about 0.55, at least about 0.60, at least about 0.61, at least about 0.65, at least about 0.70, at least about 0.75, at least about 0.80, or at least about 0.83.

44. The method of any one of the preceding claims, wherein the standard effect size is about 0.40 to about 0.64, at least about 0.40, at least about 0.45, at least about 0.50, at least about 0.55, at least about 0.60, or at least about 0.64.

45. The method of any one of the preceding claims, wherein the LS mean reduction of CGI-S score from baseline to week 4 is about 0.6 to about 0.84, at least about 0.6, at least about 0.65, at least about 0.67, at least about 0.7, at least about 0.72, at least about 0.75, at least about 0.8, or at least about 0.84.

46. The method of any one of the preceding claims, wherein the CGI-S responder rate at week 4 is about 11 % to about 24%, at least about 11 %, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, or at least about 24%.

47. The method of any one of the preceding claims, wherein the effect size of LB-102 treatment on global cognition after 4 weeks of treatment is about 0.26 to about 0.66, at least about 0.26, at least about 0.30, at least about 0.35, at least about 0.40, at least about 0.41, at least about 0.45, at least about 0.50, at least about 0.55, at least about 0.60, at least about 0.65, or at least about 0.66.

48. The method of any one of the preceding claims, wherein the effect of LB-102 treatment on global cognition after 4 weeks of treatment is, as expressed using Cohen’s 164184896963.4d when compared versus the change from baseline to week 4 with placebo, about 0.26 to about 0.66, at least about 0.26, at least about 0.30, at least about 0.35, at least about 0.40, at least about 0.41, at least about 0.45, at least about 0.50, at least about 0.55, at least about 0.60, at least about 0.65, or at least about 0.66.

49. The method of any one of the preceding claims, wherein the indirect effect of LB-102 treatment on global cognition after 4 weeks of treatment, when compared to placebo treatment after 4 weeks, is about 0.00 to about 0.01.

50. The method of any one of the preceding claims, wherein the indirect effect of LB-102 treatment on psychomotor function after 4 weeks of treatment, when compared to placebo treatment after 4 weeks, is about 0.00 to about 0.01.

51. The method of any one of the preceding claims, wherein the indirect effect of LB-102 treatment on memory / executive function after 4 weeks of treatment, when compared to placebo treatment after 4 weeks, is about 0.00 to about 0.01.

52. The method of any one of the preceding claims, wherein the impact of LB-102 on cognition is not mediated by any drug-related improvement in schizophrenia symptoms according to mediation analysis.

53. The method of any one of the preceding claims, wherein little to no emergence of neuromotor side effects, akathisia, tardive dyskinesia, or other involuntary motor side effects is observed.

54. The method of any one of the preceding claims, wherein average QTcF prolongation over placebo is less than about 5 ms, less than about 4 ms, or less than about 3 ms.

55. The method of any one of the preceding claims, wherein rate(s) of one or more adverse effects selected from the group consisting of EPS, sedation, and adverse effects related to prolactin increase is(are) lower than amisulpride.

56. The method of any one of the preceding claims, wherein the rate of EPS is less than about 6%, less than about 5.6%, less than about less than about 5.5%, less than 165184896963.4about less than about 5.0%, less than about 4.5%, less than about 4.0%, less than about 3.5%, less than about 3.0%, less than about 2.5%, less than about 2.0%, less than about 1.5%, or less than about 1.0%.

57. The method of any one of the preceding claims, wherein the rate of sedation is less than about 3%, less than about 2.8%, less than about 2.5%, less than about 2.0%, less than about 1.5%, less than about 1.0%, or less than about 0.9%.

58. The method of any one of the preceding claims, wherein the rate of total adverse events related to prolactin increase is less than about 6%, less than about 5.6%, less than about less than about 5.5%, less than about less than about 5.0%, less than about 4.5%, less than about 4.0%, less than about 3.5%, less than about 3.0%, less than about 2.5%, less than about 2.0%, less than about 1.9%, less than about 1.5%, or less than about 1.0%.

59. The method of any one of the preceding claims, wherein the rate of galactorrhoea is less than about 2.0%, less than about 1.9%, less than about 1.5%, less than about 1.0%, or less than about 0.9%.

60. The method of any one of the preceding claims, wherein the rate of breast enlargement is less than about 3.0%, less than about 2.8%, less than about 2.5%, less than about 2.0%, less than about 1.9%, less than about 1.5%, less than about 1.0%, less than about 0.5%, or less than about 0.1%.

61. The method of any one of the preceding claims, wherein the rate of erectile dysfunction is less than about 3.0%, less than about 2.8%, less than about 2.5%, less than about 2.0%, less than about 1.9%, less than about 1.5%, less than about 1.0%, less than about 0.5%, or less than about 0.1%.

62. The method of any one of claims 1 -61, wherein the subject has PANSS negative symptoms subscale score >24, and:the LS mean reduction from baseline to week 1 in the PANSS total score is about 1.5 to about 2.0, at least about 1.5, at least about 1.6, at least about 1.7, at least about 1.8, at least about 1.9, or at least about 2.0; and / or166184896963.4the LS mean reduction from baseline to week 1 in the PANSS total score, when compared to subjects not treated with LB-102, increase about 0.7 to about 0.9, at least about 0.7, at least about 0.8, or at least about 0.9.

63. The method of any one of claims 1 -61, wherein the subject has PANSS negative symptoms subscale score >24, and:the LS mean reduction from baseline to week 2 in the PANSS total score is about 2.0 to about 3.0, at least about 2.0, at least about 2.1, at least about 2.5, at least about 2.9, or at least about 3.0; and / orthe LS mean reduction from baseline to week 2 in the PANSS total score, when compared to subjects not treated with LB-102, increase about 1.0 to about 1.9, at least about 1.0, at least about 1.1, at least about 1.2, at least about 1.3, at least about 1.4, at least about 1.5, at least about 1.6, at least about 1.7, at least about 1.8, or at least about 1.9.

64. The method of any one of claims 1 -61, wherein the subject has PANSS negative symptoms subscale score >24, and:the LS mean reduction from baseline to week 3 in the PANSS total score is about 2.5 to about 3.3, at least about 2.5, at least about 2.6, at least about 2.7, at least about 2.8, at least about 2.9, at least about 3.0, at least about 3.1, at least about 3.2, or at least about 3.3; and / orthe LS mean reduction from baseline to week 3 in the PANSS total score, when compared to subjects not treated with LB-102, increase about 0.8 to about 1.4, at least about 0.8, at least about 0.9, at least about 1.0, at least about 1.1, at least about 1.2, at least about 1.3, or at least about 1.4.

65. The method of any one of claims 1 -61, wherein the subject has PANSS negative symptoms subscale score >24, and:the LS mean reduction from baseline to week 4 in the PANSS total score is about 2.5 to about 3.5, at least about 2.5, at least about 2.6, at least about 2.7, at least about 2.8, at least about 2.9, at least about 3.0, at least about 3.1, at least about 3.2, at least about 3.3, at least about 3.4, or at least about 3.5; and / or167184896963.4the LS mean reduction from baseline to week 4 in the PANSS total score, when compared to subjects not treated with LB-102, increase about 1.0 to about 1.8, at least about 1.0, at least about 1.1, at least about 1.2, at least about 1.3, at least about 1.4, at least about 1.5, at least about 1.6, at least about 1.7, or at least about 1.8.

66. The method of any one of claims 1 -61, wherein the subject has PANSS negative symptoms subscale score >24, and:the LS mean reduction from baseline to week 4 in the PANSS Negative Symptoms subscale score is about 2.6 to about 3.4, at least about 2.6, at least about 2.7, at least about 2.8, at least about 2.9, at least about 3.0, at least about 3.1, at least about 3.2, at least about 3.3, or at least about 3.4; and / orthe LS mean reduction from baseline to week 4 in the PANSS Negative Symptoms subscale score, when compared to subjects not treated with LB-102, increase about 1.0 to about 1.7, at least about 1.0, at least about 1.1, at least about 1.2, at least about 1.3, at least about 1.4, at least about 1.5, at least about 1.6, or at least about 1.7.

67. The method of any one of claims 1 -61, wherein the subject has PANSS negative symptoms subscale score >24, the effect size is about 0.34 to about 0.67, at least about 0.3, at least about 0.34, at least about 0.4, at least about 0.45, at least about 0.50, at least about 0.55, at least 0.60, at least 0.65, or at least 0.67.

68. The method of any one of claims 1 -61, wherein the subject has negative symptoms at baseline, and:the mean change in negative symptom scores at week 4 is about 2.6 to about 3.4, at least about 2.6, at least about 2.7, at least about 2.8, at least about 2.9, at least about 3.0, at least about 3.1, at least about 3.2, at least about 3.3, or at least about 3.4; and / orthe mean change in negative symptom scores at week 4, when compared to subjects not treated with LB-102, is about 1.0 to about 1.8, at least about 1.0, at168184896963.4least about 1.1, at least about 1.2, at least about 1.3, at least about 1.4, at least about 1.5, at least about 1.6, at least about 1.7, or at least about 1.8.

69. The method of any one of claims 1 -61, wherein the subject has negative symptoms at baseline, the effect size is about 0.34 to about 0.67, at least about 0.34, at least about 0.35, at least about 0.40, at least about 0.45, at least about 0.50, at least about 0.55, at least about 0.60, at least about 0.65, or at least about 0.67.169184896963.4

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