Objective stated in the publication

“To evaluate the efficacy and safety of LB-102 in acute schizophrenia.” (opens the source at this quote in a new tab)

Primary, secondary, and exploratory objectives in the protocol

“To determine whether LB-102 administered to patients with acutely exacerbated schizophrenia demonstrates antipsychotic efficacy, as determined by a change from Baseline on the PANSS total score, compared to placebo.” (opens the source at this quote in a new tab)
“To evaluate the safety and tolerability of LB-102 in patients with acutely exacerbated schizophrenia.” (opens the source at this quote in a new tab)
“To assess the effect of LB-102 on PANSS subscale and Marder Factor scores in patients with acutely exacerbated schizophrenia.” (opens the source at this quote in a new tab)
“To explore the effect of LB-102 on Cogstate test score” (opens the source at this quote in a new tab)

Registered study purpose

“This is a Phase 2, randomized, double-blind, placebo-controlled, multi-center inpatient study to evaluate the efficacy and safety of LB-102 in adult patients diagnosed with acutely exacerbated schizophrenia.” (opens the source at this quote in a new tab)
“The secondary objectives of the study are to evaluate improvement in CGI-S, safety and tolerability, and pharmacokinetics.” (opens the source at this quote in a new tab)

Study dates in the registry

Milestone	Registry record
Study start (actual)	“2023-11-29”
Primary completion (actual)	“2024-12-04”
Study completion (actual)	“2024-12-04”
First posted	“2023-12-21”
Results first posted	“2025-10-22”

Sites and conduct period reported in the publication

“conducted at 25 inpatient sites in the US between December 2023 and August 2024” (opens the source at this quote in a new tab)

Registered locations

“This study has 25 locations” (opens the source at this quote in a new tab)

Study centers and contract research organization in the protocol

“This study will be conducted in up to 25 study centers, with up to 25 Investigators, located in the US. Worldwide Clinical Trials, a contract research organization, will oversee operational aspects of this study on behalf of LB Pharmaceuticals Inc, the Sponsor of the study.” (opens the source at this quote in a new tab)

Topline results announcement date

“The topline results from the trial were announced in January 2025.” (opens the source at this quote in a new tab)

Phase 2 randomized, double-blind, placebo-controlled, fixed-dose design

“This Phase 2 randomized, double-blinded, placebo-controlled, fixed dose, multicenter clinical study is designed to evaluate the efficacy, safety, tolerability, and PK of LB-102 50 mg QD, LB-102 75 mg QD, and LB-102 100 mg QD versus placebo in patients diagnosed with schizophrenia having an acute exacerbation of psychosis.” (opens the source at this quote in a new tab)

Study periods

“Trial participation lasted approximately 8 weeks and included an inpatient screening period of up to 14 days, 28-day inpatient treatment period, an inpatient stabilization period, and an outpatient final safety follow-up approximately 2 weeks after completion of the treatment period.” (opens the source at this quote in a new tab)

Randomization, allocation ratio, and blinding

“Eligible participants were randomized according to a computer-generated randomization schedule using a site-based block size of 4.” (opens the source at this quote in a new tab)
“The randomization ratio was 3:3:3:1 to oral once-daily placebo; LB-102 50 mg; LB-102 75 mg; or LB-102 100 mg, with a smaller sample planned in the arm receiving 100 mg.” (opens the source at this quote in a new tab)
“Randomization was fully blinded, with assignments concealed from participants, trial personnel, investigators, sponsor, contract research organization, and clinical site teams.” (opens the source at this quote in a new tab)

Registry design fields

Field	Registry record
Allocation	“Randomized”
Interventional model	“Parallel Assignment”
Masking	“Quadruple”
Phase	“Phase 2”

Sponsor rationale for the smaller exploratory 100 mg arm

“Based on previous results, we believed that there was a potential for the 100 mg dose to result in receptor occupancy above 80%. As a result, we chose to limit the number of participants enrolled at this dose level while maintaining enough patients to provide insight into the therapeutic potential of this dose.” (opens the source at this quote in a new tab)
“The 100 mg dose cohort was exploratory and was intended to characterize safety at the higher dose. However, we analyzed the 100 mg cohort with the same statistical rigor, including sensitivity analyses, applied to the 50 and 75 mg cohorts.” (opens the source at this quote in a new tab)

Protocol rationale for the 4-week duration, fixed doses, and inpatient setting

“A 4-week double-blind Treatment Period is of adequate length to determine whether an antipsychotic effect has been demonstrated. Since efficacy in schizophrenia is dependent on both treatment duration and dose, a fixed dose approach represents the optimal study design to evaluate efficacy. To facilitate enrollment of acutely ill patients and optimize treatment compliance, a 4-week inpatient hospitalization is required following the initial screening phase.” (opens the source at this quote in a new tab)

Protocol dose rationale

“Based on the mechanism of action of LB-102 at dopamine D2 and 5HT7 receptors, data from animal models, and PET dopamine RO data, it is hypothesized that LB-102 will have antipsychotic effects at doses ranging from 50 mg/day to 100 mg/day.” (opens the source at this quote in a new tab)

Central review of ratings

“PANSS and MINI screening assessments, as well as PANSS assessments at baseline and week 4, were reviewed by an independent central reviewer.” (opens the source at this quote in a new tab)

Measures intended to limit placebo response

“We included a number of measures in this Phase 2 trial to reduce the risk of an elevated placebo rate including consistent, frequent, and close engagement with clinical sites, the use of a third-party vendor to help identify and exclude professional patients from the trial, and a centralized review of PANSS ratings to ensure consistency and quality control throughout the trial.” (opens the source at this quote in a new tab)

“The PANSS Rater will read the PCRS before administering the PANSS at each study visit.” (opens the source at this quote in a new tab)

Safety oversight, individual stopping criteria, and interim analysis

“A Safety Review Committee (SRC) will be established to review available safety data; details are included in the safety data plan.” (opens the source at this quote in a new tab)
“Dosing of an individual patient will cease if any of the following criteria are met:” (opens the source at this quote in a new tab)
“An increase in QTcF to >500 msec for male and female patients.” (opens the source at this quote in a new tab)
“An increase in QTcF of >60 msec over Baseline.” (opens the source at this quote in a new tab)
“No interim analysis is planned for this study.” (opens the source at this quote in a new tab)

Pharmacokinetic sampling subset

“PK analyses will include the first 60 patients randomized in the study regardless of cohort.” (opens the source at this quote in a new tab)

Sponsor statement on the regulatory role of the trial

“Based on the design of this clinical trial, the results discussed below, and positive feedback from FDA as part of our end-of-Phase 2 interaction, we believe this Phase 2 trial may serve as one of two adequate well-controlled clinical trials of LB-102 required for approval.” (opens the source at this quote in a new tab)

Key inclusion criteria

Criterion	Quoted registry text
Age and diagnosis	“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”
Body mass index	“Body mass index (BMI) must be ≥18 and ≤40 kg/m2.”
PANSS total score	“Total PANSS score between 80 and 120, inclusive, and”
PANSS positive items	“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	“CGI-S score ≥4 (moderately to severely ill).”
Prior antipsychotic response	“Have 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.”
Relapse history	“Have history of relapse and/or exacerbation of symptoms when they were not receiving antipsychotic treatment.”
Hospitalization	“Must be willing to be hospitalized for the duration of the inpatient period of the study.”
Living situation	“Have stable living environment when not in a hospital.”

Acute exacerbation window and antipsychotic-free interval

“At screening, participants were required to need hospitalization, or continued hospitalization, for a current acute exacerbation of psychotic symptoms, with symptom onset less than or equal to 6 weeks prior; if already an inpatient at screening, the participant must have been hospitalized for onset less than or equal to 2 weeks for the current exacerbation.” (opens the source at this quote in a new tab)
“Participants must have been free from antipsychotic treatment for 2 or more weeks (or ≥5 times the treatment half-life) before baseline assessment.” (opens the source at this quote in a new tab)

Key exclusion criteria: psychiatric history and illness course

“Patients who presented with a first episode of schizophrenia.” (opens the source at this quote in a new tab)
“Improvement of ≥20% in total PANSS score between the Screening and Baseline assessments.” (opens the source at this quote in a new tab)
“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.” (opens the source at this quote in a new tab)
“Current DSM-5 Axis I diagnosis other than schizophrenia.” (opens the source at this quote in a new tab)
“Patients who met DSM-5 criteria for substance abuse or dependence within the past 1 year.” (opens the source at this quote in a new tab)
“Patients with clinically significant tardive dyskinesia.” (opens the source at this quote in a new tab)
“Prisoners or patients who were compulsorily detained (involuntarily hospitalized) for treatment of either a psychiatric or physical illness or have been in the last 6 months prior to the Screening Visit” (opens the source at this quote in a new tab)

Exclusion of recently diagnosed schizophrenia

“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.” (opens the source at this quote in a new tab)

Key exclusion criteria: medical conditions and laboratory values

“Patients with insulin-dependent diabetes mellitus (i.e., any patient using insulin) are excluded.” (opens the source at this quote in a new tab)
“Patients with known ischemic heart disease or any history of myocardial infarction, congestive heart failure.” (opens the source at this quote in a new tab)
“Patients with epilepsy or a history of seizures.” (opens the source at this quote in a new tab)
“AST and ALT >2 × upper limit of normal (ULN)” (opens the source at this quote in a new tab)
“HbA1c ≥7.0%” (opens the source at this quote in a new tab)
“Patients with a history of neuroleptic malignant syndrome.” (opens the source at this quote in a new tab)

Electrocardiographic exclusion threshold

“Interval between Q and T wave corrected for heart rate using Fridericia’s formula (QTcF) interval >450 msec for males and females” (opens the source at this quote in a new tab)

Rescreening

“Participants were able to be rescreened on a case-by-case basis with approval of the sponsor and medical monitor.” (opens the source at this quote in a new tab)

Treatment arms

Arm	Quoted registry description
LB-102 50 mg once daily	“Oral LB-102: 50 mg (n ~ 105)”
LB-102 75 mg once daily	“Oral LB-102: 75 mg (n ~ 105)”
LB-102 100 mg once daily	“Oral LB-102: 100 mg (n ~ 35)”
Placebo	“Matched placebo tablets”

Dosing frequency, duration, and titration

“LB-102 will be dosed orally once a day.” (opens the source at this quote in a new tab)
“The duration of treatment of the study is 28 days (4 weeks).” (opens the source at this quote in a new tab)

“All patients started at the planned dose level without titration.” (opens the source at this quote in a new tab)

Tablet strength, matched placebo, and supervised administration

“LB-102 and placebo will be administered as visually matched tablets for the treatment of adult patients with an acute exacerbation of schizophrenia. LB-102 tablets are 50 mg in strength. The placebo tablets will match the 50-mg tablets in appearance.” (opens the source at this quote in a new tab)
“Administration of study drug will be supervised by study personnel to ensure compliance.” (opens the source at this quote in a new tab)

Discontinuation of prior psychotropic medication

“Starting on the first day of the screening phase, after written informed consent for the study has been provided, all antipsychotic or other psychotropic medications will be stopped with clinically appropriate titration down as per the Investigator’s clinical judgment.” (opens the source at this quote in a new tab)

Permitted concomitant psychotropic medication

“Psychotropic medications are 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.” (opens the source at this quote in a new tab)

Medication and study period	Dose permitted
Lorazepam, screening phase through day 7	“Maximum of 6 mg/day”
Lorazepam, day 8 through day 14	“Maximum of 4 mg/day”
Lorazepam, day 15 through day 28	“Maximum of 2 mg/day”
Benztropine, screening phase through day 28	“Maximum 4 mg/day”
Propranolol, screening phase through day 28	“Maximum of 40 mg/day”

Post-treatment stabilization on standard antipsychotic medication

“an inpatient Stabilization Period of up to 5 days (during which patients will be stabilized on standard antipsychotic medication)” (opens the source at this quote in a new tab)

Concomitant medication use during the trial by treatment arm

No evidence found.

Primary endpoint and the sponsor's stated rationale

“The primary end point was change from baseline to week 4 in PANSS total score.” (opens the source at this quote in a new tab)

“The scale utilized for the primary study endpoint, Positive and Negative Syndrome Scale (PANSS) is validated and widely used in this patient population.” (opens the source at this quote in a new tab)

PANSS structure and scoring range

“The PANSS rating is composed of 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. Patients are scored from 1 to 7 on each symptom scale. The total score of the PANSS is a minimum of 30 and a maximum of 210.” (opens the source at this quote in a new tab)
“A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms whereas a higher PANSS total value represents a worse outcome” (opens the source at this quote in a new tab)

“The PANSS consists of 3 subscales containing a total of 30 symptom constructs. For each symptom construct, severity is 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.” (opens the source at this quote in a new tab)
“The PANSS will be administered using the clinician rated semi-structured interview via the SCI-PANSS.” (opens the source at this quote in a new tab)

Development and validation of the PANSS

“Based on two established psychiatric rating systems, the 30-item PANSS was conceived as an operationalized, drug-sensitive instrument that provides balanced representation of positive and negative symptoms and gauges their relationship to one another and to global psychopathology.” (opens the source at this quote in a new tab)
“Review of five studies involving the PANSS provided evidence of its criterion-related validity with antecedent, genealogical, and concurrent measures, its predictive validity, its drug sensitivity, and its utility for both typological and dimensional assessment.” (opens the source at this quote in a new tab)

European Medicines Agency guidance on the primary efficacy measure

“To support an indication for the treatment of schizophrenia, efficacy on a broad range of schizophrenia symptoms, as captured by the total score on instruments such as the PANSS or BPRS, has to be demonstrated in short-term studies (see section 4.4.3.1.) and maintenance of treatment effectiveness has to be shown in at least one long term study (see section 4.4.4.).” (opens the source at this quote in a new tab)
“The primary efficacy measure should be a composite measure of the symptoms of schizophrenia. For this, the widely accepted measurement scales are the PANSS (Positive and Negative Symptom Scale) and BPRS (Brief Psychiatric Rating Scale), which are still considered to be reliable and validated.” (opens the source at this quote in a new tab)
“Primary efficacy measure(s) should be presented as the numerical change in schizophrenia symptom score from baseline to study endpoint (final measurement). The results should be discussed not only in terms of statistical significance but also in terms of clinical relevance.” (opens the source at this quote in a new tab)

PANSS total score as the primary efficacy measure in FDA-approved labeling for xanomeline and trospium chloride

“The primary efficacy measure was the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score at Week 5.” (opens the source at this quote in a new tab)
“The PANSS is a 30-item scale that measures symptoms of schizophrenia. Each item is rated by a clinician on a seven-point scale. A score of 1 indicates the absence of symptoms, and a score of 7 indicates extremely severe symptoms. The PANSS total score may range from 30 to 210 with higher scores reflecting greater overall symptom severity.” (opens the source at this quote in a new tab)

FDA guidance document specific to efficacy endpoints in schizophrenia trials

No evidence found.

Clinical meaning of PANSS total scores and percentage reductions

“Being considered "mildly ill" according to the CGI approximately corresponded to a PANSS total score of 58, "moderately ill" to a PANSS of 75, "markedly ill" to a PANSS of 95 and severely ill to a PANSS of 116.” (opens the source at this quote in a new tab)
“To be "minimally improved" according to the CGI score was associated with a mean percentage PANSS reduction of 19%, 23%, 26% and 28% at weeks 1, 2, 4 and 6, respectively. The corresponding figures for a CGI rating "much improved" were 40%, 45%, 51% and 53%.” (opens the source at this quote in a new tab)

Absolute PANSS change corresponding to minimal clinical improvement

“An absolute reduction of the BPRS/PANSS by approximately 10/15 points corresponded to a CGI change of 'minimally improved' and to a change of the CGI severity score by one severity step.” (opens the source at this quote in a new tab)
“Less severely ill patients required less BPRS/PANSS total score reduction to achieve the same CGI-improvement score than more severely ill patients.” (opens the source at this quote in a new tab)

Responder thresholds recommended for acute schizophrenia trials

“In short term trials in patients with acute/exacerbated symptoms at least a 30% reduction on the total PANSS score compared to baseline is generally considered to be clinically relevant and can be accepted as a definition of responder.” (opens the source at this quote in a new tab)

“When the Brief Psychiatric Rating Scale (BPRS) or the Positive and Negative Syndrome Scale (PANSS) are used for definitions of response, a cut-off of at least 50% reduction of the baseline score should be used for acutely ill, non-refractory patients and a cut-off of at least 25% reduction for refractory patients.” (opens the source at this quote in a new tab)

Correction of percentage change for the 30-point minimum score

“All 30 items range from 1 to 7 leading to a minimum total score of 30, implying that the PANSS is an interval scale. For such interval scales straightforward calculation of relative changes is not appropriate.” (opens the source at this quote in a new tab)
“This systematic literature research shows that the majority of authors (62%) actually appear to use incorrect calculations.” (opens the source at this quote in a new tab)

“In the prespecified analysis, PANSS total score was derived from the standard item rating scale (1-7, total score range: 30-210). In the post hoc analysis, item scores were rescaled (0-6; total score range: 0-180) to adjust for the mathematical floor effect.” (opens the source at this quote in a new tab)

Placebo response trends in acute schizophrenia trials: FDA analysis of new drug applications

“the mean placebo response (change from baseline in PANSS score) increased from -6.4 to -10.5” (opens the source at this quote in a new tab)
“In North American trials, placebo response increased from -4.3 (pre-2009) to -8.5 (post-2009), and treatment effect decreased from -9.0 (pre-2009) to -3.4 (post-2009).” (opens the source at this quote in a new tab)
“Baseline disease severity remained similar in the pre- and post-2009 time periods, with PANSS scores ranging between 85 and 100.” (opens the source at this quote in a new tab)

Placebo response trends in acute schizophrenia trials: meta-analyses

“The standardized mean difference (SMD) for overall efficacy was 0.47 (95% credible interval 0.42, 0.51), but accounting for small-trial effects and publication bias reduced the SMD to 0.38.” (opens the source at this quote in a new tab)
“However, in a multivariable meta-regression, only industry sponsorship and increasing placebo response were significant moderators of effect sizes.” (opens the source at this quote in a new tab)

“The average treatment change associated with placebo treatment in antipsychotic trials rose since 1960, while the change associated with medication treatment decreased.” (opens the source at this quote in a new tab)

Secondary efficacy endpoints

“Secondary end points included changes from baseline to week 4 in CGI-S, PANSS Positive Symptoms subscale, PANSS Negative Symptoms subscale, and PANSS Marder factor scores” (opens the source at this quote in a new tab)
“CGI-S responder rate (ie, proportion of participants with a score of 1 [normal], 2 [borderline ill], or 3 [mildly ill])” (opens the source at this quote in a new tab)
“greater than or equal to 20% PANSS responder rate (ie, proportion of participants with ≥20% reduction from baseline in PANSS total score; using the original item scores [range, 1-7]) at week 4” (opens the source at this quote in a new tab)
“Post hoc analyses evaluated the greater than or equal to 20% PANSS responder rate using a floor adjustment (ie, item scores rescaled from 1-7 to 0-6), to provide context for indirect comparisons with prior data.” (opens the source at this quote in a new tab)

Clinical Global Impressions-Severity of Illness scale

“The Clinical Global Impressions-Severity (CGI-S) rates illness severity on a scale from 1 to 7 and has been shown to correlate with PANSS.” (opens the source at this quote in a new tab)
“The scoring is for the CGI-S:1-normal, not at all ill, 2-Borderline mentally ill, 3-Mildly ill, 4-Moderately ill, 5-Markedly ill, 6-Severely ill, and 7-Extremely ill.” (opens the source at this quote in a new tab)

“Clinical global impression (CGI) data should also be presented, both CGI-severity and CGI-improvement.” (opens the source at this quote in a new tab)

PANSS Marder factor scores

“PANSS Marder is a way to group the 30 individual items of the PANSS into five broader categories or dimensions. This factor structure is widely used in clinical trials and research to assess and analyze symptoms of schizophrenia.” (opens the source at this quote in a new tab)

Negative symptom measurement in regulatory guidance

“Satisfactory reliability and validity has been demonstrated for the negative symptoms subscale of the PANSS and for the SANS (Scale for the Assessment of Negative Symptoms).” (opens the source at this quote in a new tab)

Exploratory cognition endpoint: Cogstate battery

“The Cogstate Computerized Schizophrenia Battery of Tests is a measure of cognitive ability in subject with Schizophrenia in both the acute and chronic stages and will take approximately 22 to 35 minutes to complete.” (opens the source at this quote in a new tab)

“Changes from baseline in the individual tests were prespecified exploratory endpoints, with composite scores generated post hoc in the total population:” (opens the source at this quote in a new tab)
“Based on previously published literature, the threshold for clinical importance of the treatment effect size was pre-determined as 0.2.” (opens the source at this quote in a new tab)

Safety and tolerability assessments

“Safety was evaluated through AEs, assessment of body weight/waist circumference, vital signs, clinical laboratory parameters, and 12-lead electrocardiograms. Suicidal ideation was evaluated using the Columbia-Suicide Severity Rating Scale (C-SSRS).” (opens the source at this quote in a new tab)
“The evaluation of neuromotor AEs was assessed using the Simpson-Angus Scale (SAS; range, 0-40).” (opens the source at this quote in a new tab)
“Akathisia was evaluated using the Barnes Akathisia Rating Scale (BARS; range, 0-14).” (opens the source at this quote in a new tab)
“The Abnormal Involuntary Movement Scale (AIMS; total dyskinesia score range, 0-28) assessed the presence and severity of tardive dyskinesia and other involuntary motor AEs.” (opens the source at this quote in a new tab)
“defined as any AE that began on or after the first dose of trial medication or any preexisting condition that reappeared during the treatment period and 14 days or less after the last dose” (opens the source at this quote in a new tab)

Planned sample size and power

“A sample size of 350 participants was estimated to provide greater than or equal to 85% power at a 2-sided 5% significance level to detect an assumed between-group treatment difference of 8 points in change from baseline in PANSS total score between either LB-102 50 mg or 75 mg and placebo, assuming an SD of 18, overall dropout rate of 25%, and a multiplicity adjustment using the Hochberg procedure.” (opens the source at this quote in a new tab)

Planned allocation by arm

“~105 patients will get placebo, ~105 will get 50 mg LB-102 QD, ~105 will get 75 mg LB-102 QD, ~35 will get 100 mg LB-102 QD” (opens the source at this quote in a new tab)

Participants screened and randomized

“Of 622 individuals screened, 263 (42.3%) were excluded. The primary reasons for screen failure included not meeting randomization criteria (229 [87.1%]) and study withdrawal (27 [10.3%]).” (opens the source at this quote in a new tab)
“There were 359 participants randomized (mean [SD] age, 39.1 [9.3] years; 69 female [19.2%]; 290 male [80.8%]; placebo, 108 [30.1%]; LB-102 50 mg, 107 [29.8%]; 75 mg, 108 [30.1%]; 100 mg, 36 [10.0%]), with all receiving 1 or more treatment doses and no protocol exceptions” (opens the source at this quote in a new tab)

Participants with observed week 4 data in the efficacy table

Measure	Placebo (n = 108)	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)
PANSS total score, No.	“93”	“91”	“84”	“23”
CGI-S score, No.	“94”	“91”	“83”	“23”

Participants analyzed in the registry results

Measure	Placebo	LB-102 50 mg	LB-102 75 mg	LB-102 100 mg
Started	“108”	“107”	“108”	“36”
Primary outcome, overall number of participants analyzed	“108”	“107”	“108”	“36”
CGI-S outcome, overall number of participants analyzed	“94”	“91”	“83”	“23”

“N for analyzed participants reflects all participants (i.e., including those with missing data imputed). Missing PANNS total scores were imputed using a mixture of MAR and MNAR approaches depending on the reason for missingness.” (opens the source at this quote in a new tab)
“N for Analyzed participants reflects observed CGI-S data at Week 4.” (opens the source at this quote in a new tab)

Safety and modified intention-to-treat populations

“The safety population comprised all randomized participants who received 1 or more doses of LB-102 or placebo, with participants grouped according to actual treatment received.” (opens the source at this quote in a new tab)
“Efficacy analyses were conducted in the modified intention-to-treat population (mITT), comprising all randomized participants who received 1 or more doses of LB-102 or placebo, according to randomized treatment.” (opens the source at this quote in a new tab)

Analysis sets defined in the statistical analysis plan

“The ITT Analysis Set will include all randomized patients, irrespective of whether they received the drug or not. This will be the main analysis population for efficacy analysis purposes and patients will be analyzed based on the treatment they were randomized to.” (opens the source at this quote in a new tab)
“The mITT Analysis Set will include all randomized patients with at least 1 dose of study drug.” (opens the source at this quote in a new tab)
“This will be a secondary analysis set for the analysis of the primary endpoint, however should the ITT and the mITT substantially overlap (i.e. at least 95% of ITT patients are also in the mITT), the latter will be used as primary efficacy analysis set for all efficacy endpoints.” (opens the source at this quote in a new tab)
“The Safety Analysis Set will include all patients who received any study drug. Analyses based on this population will use the actual treatment received rather than the randomized one.” (opens the source at this quote in a new tab)

Per-protocol analysis set in the protocol

“Per-Protocol (PP) Analysis Set: all patients included in the mITT Analysis Set that do not have a major protocol violation. The PP Analysis Set will be used for supportive analyses of the primary and key secondary efficacy endpoints.” (opens the source at this quote in a new tab)

Primary analysis model and handling of missing data

“The primary efficacy end point was analyzed using a mixed model for repeated measures (MMRM), including treatment group, study site, visit, and treatment × visit interaction as fixed effects, baseline PANSS total score as a covariate, and an unstructured covariance matrix to account for within-patient correlation.” (opens the source at this quote in a new tab)
“Missing data due to a discontinuation related to either lack of efficacy or a drug-related AE were imputed assuming a missing-not-at-random mechanism.” (opens the source at this quote in a new tab)
“Missing data due to discontinuation for any other reason or nonmonotone missing data were imputed under a missing-at-random mechanism.” (opens the source at this quote in a new tab)

Estimand and intercurrent events in the protocol

“Taking a prohibited medication prior to Week 4” (opens the source at this quote in a new tab)
“Starting an emergency treatment prior to Week 4” (opens the source at this quote in a new tab)
“The primary estimand for all the above events will follow the treatment-policy strategy” (opens the source at this quote in a new tab)

Multiplicity control and status of the 100 mg arm

“Formal statistical testing of LB-102 50 mg and 75 mg compared with placebo was performed for the primary end point only and included a multiplicity strategy (Hochberg correction) to control the familywise error rate at the 5% significance level” (opens the source at this quote in a new tab)
“No formal hypothesis was tested for LB-102 100 mg; however, data were analyzed using identical methods as prespecified for 50 mg and 75 mg across all end points for descriptive purposes.” (opens the source at this quote in a new tab)
“Hereafter, P values were not multiplicity controlled.” (opens the source at this quote in a new tab)

“No formal hypothesis will be tested for the LB-102 100 mg arm, but data will be included in any analysis model for all the primary and secondary efficacy endpoints and CIs and p-values provided for descriptive purposes.” (opens the source at this quote in a new tab)

“Results from the analysis of the primary endpoint will be adjusted for multiplicity using a standard Hochberg procedure.” (opens the source at this quote in a new tab)

Analysis of secondary endpoints

“All continuous secondary efficacy variables will be 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.” (opens the source at this quote in a new tab)
“which will only be displayed for informative/descriptive purposes (i.e., no multiplicity correction will be implemented)” (opens the source at this quote in a new tab)
“This endpoint will be 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.” (opens the source at this quote in a new tab)

Sensitivity analyses of the primary endpoint

“Three sensitivity analyses evaluated the robustness of the primary outcome across all 3 doses” (opens the source at this quote in a new tab)

“The primary analysis will be repeated but including PANNS values obtained during early termination assessments in the analysis” (opens the source at this quote in a new tab)
“For this sensitivity analysis, all missing data due to drop-out will be imputed using a pattern-mixture model, whereby data will be imputed only using data from patients with no missing data from the Placebo (reference) arm” (opens the source at this quote in a new tab)

“As a sensitivity analysis, missing data that was imputed under a MAR mechanism in the primary analysis will be imputed under a MNAR mechanism using a tipping-point approach to check robustness of the main analysis results.” (opens the source at this quote in a new tab)

Post hoc effect size calculations

“A post hoc calculation of Hedges g effect size (bias-corrected standardized mean differences) was conducted on 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 SD.” (opens the source at this quote in a new tab)

Prespecified subgroups

“BMI at Baseline: ≤ 25 kg/m2, 25 to 30 kg/m2, ≥ 30 kg/m2” (opens the source at this quote in a new tab)
“Baseline PANSS (disease severity): ≤95, > 95” (opens the source at this quote in a new tab)

Population used for the post hoc cognition analysis

“290 participants completed week 4, and provided both valid PANSS and Cogstate testing scores, with data included in the assessment of the Global Cognition composite score.” (opens the source at this quote in a new tab)

Screening and randomization

“Of 622 individuals screened, 263 (42.3%) were excluded.” (opens the source at this quote in a new tab)
“Initially, 270 participants did not pass screening; however, after rescreening 13 participants, 7 were found to be eligible and were randomized.” (opens the source at this quote in a new tab)

Overall completion and reasons for early termination

“The completion rate after 4 weeks of treatment was 81.6% across all arms, with 72.7% completing the end-of-study visit.” (opens the source at this quote in a new tab)
“The most common reasons for early termination were participant withdrawal (56 [57.1%]), lost to follow-up (26 [26.5%]), and AEs (10 [10.2%]).” (opens the source at this quote in a new tab)

Completion of week 4 and of the study by arm

Milestone	Placebo	LB-102 50 mg	LB-102 75 mg	LB-102 100 mg
Randomized	“108 randomized to placebo”	“107 randomized to LB-102 50 mg”	“108 randomized to LB-102 75 mg”	“36 randomized to LB-102 100 mg”
Completed week 4	“94 (87%)”	“91 (85%)”	“85 (79%)”	“23 (64%)”
Completed study	“83 (77%)”	“76 (71%)”	“80 (74%)”	“22 (61%)”

Registry participant flow and reasons for not completing

Milestone or reason	Placebo	LB-102 50 mg	LB-102 75 mg	LB-102 100 mg
Started	“108”	“107”	“108”	“36”
Completed	“83”	“76”	“80”	“22”
Not completed	“25”	“31”	“28”	“14”
Withdrawal by subject	“11”	“16”	“19”	“10”
Lost to follow-up	“9”	“12”	“4”	“1”
Adverse event	“2”	“2”	“3”	“3”
Protocol violation	“1”	“0”	“1”	“0”
Physician decision	“0”	“1”	“1”	“0”
Lack of efficacy	“1”	“0”	“0”	“0”
Death	“1”	“0”	“0”	“0”

Discontinuation rate described by the sponsor

“The discontinuation rate reached approximately 18% during the treatment period (four weeks) and approximately 27% when taking into account up to 14 days following the last dose.” (opens the source at this quote in a new tab)

Demographics and ongoing medical history, safety analysis set

Characteristic	Placebo (n = 108)	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)	Overall (N = 359)
Age at informed consent, mean (SD), y	“39.1 (9.11)”	“39.0 (9.64)”	“39.2 (9.17)”	“39.1 (9.19)”	“39.1 (9.26)”
Female, No. (%)	“23 (21.3)”	“20 (18.7)”	“18 (16.7)”	“8 (22.2)”	“69 (19.2)”
Male, No. (%)	“85 (78.7)”	“87 (81.3)”	“90 (83.3)”	“28 (77.8)”	“290 (80.8)”
Hispanic or Latino, No. (%)	“17 (15.7)”	“12 (11.2)”	“8 (7.4)”	“6 (16.7)”	“43 (12.0)”
Black or African American, No. (%)	“80 (74.1)”	“87 (81.3)”	“83 (76.9)”	“25 (69.4)”	“275 (76.6)”
White, No. (%)	“24 (22.2)”	“17 (15.9)”	“18 (16.7)”	“9 (25.0)”	“68 (18.9)”
Weight at screening, mean (SD), kg	“85.6 (17.2)”	“84.0 (19.5)”	“88.4 (18.5)”	“85.9 (18.0)”	“86.0 (18.4)”
BMI at screening, mean (SD)	“28.2 (5.2)”	“27.4 (6.0)”	“28.8 (5.6)”	“28.0 (6.0)”	“28.1 (5.7)”
Insomnia, No. (%)	“79 (73.1)”	“83 (77.6)”	“75 (69.4)”	“29 (80.6)”	“266 (74.1)”
Anxiety, No. (%)	“59 (54.6)”	“68 (63.6)”	“63 (58.3)”	“21 (58.3)”	“211 (58.8)”
Depressive symptoms, No. (%)	“36 (33.3)”	“43 (40.2)”	“34 (31.5)”	“5 (13.9)”	“118 (32.9)”
Agitation, No. (%)	“32 (29.6)”	“41 (38.3)”	“26 (24.1)”	“9 (25.0)”	“108 (30.1)”
Headache, No. (%)	“41 (38.0)”	“49 (45.8)”	“37 (34.3)”	“17 (47.2)”	“144 (40.1)”

Baseline symptom severity

Baseline measure, mean (SD)	Placebo	LB-102 50 mg	LB-102 75 mg	LB-102 100 mg
PANSS total score	“93.8 (8.17)”	“93.9 (7.53)”	“93.6 (7.79)”	“93.9 (9.01)”
PANSS total score, median (range)	“93 (80 to 118)”	“92 (82 to 115)”	“92 (81 to 116)”	“92 (82 to 114)”
CGI-S score	“4.8 (0.57)”	“4.8 (0.57)”	“4.9 (0.53)”	“4.8 (0.61)”
PANSS Positive Symptoms subscale	“25.1 (3.61)”	“25.2 (2.92)”	“25.5 (2.88)”	“25.0 (3.46)”
PANSS Negative Symptoms subscale	“23.3 (3.50)”	“23.4 (3.35)”	“22.8 (3.20)”	“23.4 (3.60)”

Race and ethnicity of the randomized population

“Participants self-reported the following races: 2 American Indian or Alaska Native (0.6%), 3 Asian (0.8%), 275 Black or African American (76.6%), 4 multiracial (1.1%), 68 White (18.9%), and 7 other (1.9%).” (opens the source at this quote in a new tab)
“Participants self-reported the following ethnicities: 43 Hispanic or Latino (12.0%) and 316 not Hispanic or Latino (88.0%).” (opens the source at this quote in a new tab)

Years since diagnosis

Characteristic	Placebo (n=108)	LB-102 50 mg (n=107)	LB-102 75 mg (n=108)	LB-102 100 mg (n=36)	Overall (N=359)
Years since diagnosis, mean (range)	“16.4 (2–41)”	“15.2 (2–38)”	“16.2 (2–39)”	“13.5 (2–36)”	“15.8 (2–41)”

Baseline CGI-S categories

“All participants were categorized at least as moderately ill, or a 4 on the CGI-S scale, with the majority of participants (range of 61.1% to 70.4% across the four cohorts) categorized as being markedly ill, or a 5 on the CGI-S scale, at baseline.” (opens the source at this quote in a new tab)

Participants with a baseline PANSS Negative Symptoms subscale score of 24 or more

“171 participants (47.6% of the total population) had a PANSS Negative Symptoms subscale score ≥24 at baseline.” (opens the source at this quote in a new tab)

Baseline cognitive impairment

“No cognitive impairment assessment was used to determine clinical trial eligibility.” (opens the source at this quote in a new tab)

Prior antipsychotic treatment, number of prior hospitalizations, and smoking status at baseline

No evidence found.

Primary endpoint: change from baseline to week 4 in PANSS total score, modified intention-to-treat analysis set

Statistic	Placebo (n = 108)	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)
Baseline, mean (SD)	“93.8 (8.17)”	“93.9 (7.53)”	“93.6 (7.79)”	“93.9 (9.01)”
Day 28, mean (SD)	“83.4 (12.24)”	“77.6 (12.25)”	“79.5 (13.49)”	“77.2 (8.91)”
LS mean change (SE)	“−9.3 (1.08)”	“−14.3 (1.10)”	“−14.0 (1.11)”	“−16.1 (1.91)”
LS mean difference from placebo (SE) and 95% CI	“NA”	“−5.0 (1.51) [−8.0 to −2.1]”	“−4.7 (1.53) [−7.7 to −1.7]”	“−6.8 (2.17) [−11.1 to −2.6]”
P value	“NA”	“<.001”	“.002”	“.002”

“Results from the analysis of the primary endpoint for 50 mg and 75 mg were adjusted for multiplicity using a standard Hochberg procedure.” (opens the source at this quote in a new tab)
“LB-102 100 mg treatment resulted in a significant LS mean (SE) change from baseline to week 4 in PANSS total score of −16.1 (1.91; P = .002 vs placebo; post hoc Hedges g = 0.83 [Δ = 0.64]).” (opens the source at this quote in a new tab)

Primary endpoint: P values to four decimal places

“The 50 mg dose arm (n=107) achieved an effect size of 0.61 and participants experienced a 5.0-point reduction in PANSS total score compared to placebo (p=0.0009). Treatment with the 75 mg dose arm (n=108) achieved an effect size of 0.41 and led to a 4.7-point reduction in PANSS total score compared to placebo (p=0.0022). The study also included an exploratory dose of 100 mg (n=36), which demonstrated an effect size of 0.83 with a 6.8-point reduction in PANSS total score compared to placebo (p=0.0017).” (opens the source at this quote in a new tab)

Primary endpoint in the registry results

Statistic	Placebo	LB-102 50 mg	LB-102 75 mg	LB-102 100 mg
Overall number of participants analyzed	“108”	“107”	“108”	“36”
Least squares mean (standard error), score on a scale	“-9.27(1.078)”	“-14.28(1.097)”	“-13.95(1.108)”	“-16.08(1.906)”

Effect sizes for the primary endpoint

“The primary end point of the change from baseline to week 4 in PANSS total score showed statistical superiority with LB-102 50 mg and 75 mg compared with placebo using the Hochberg correction (least-squares [LS] mean change [SE]: placebo, −9.3 [1.08]; 50 mg, −14.3 [1.10], P < .001; post hoc Hedges g = 0.61 [Δ = 0.50]; 75 mg, −14.0 [1.11], P = .002; post hoc Hedges g = 0.41 [Δ = 0.45])” (opens the source at this quote in a new tab)
“Post hoc analysis of MMRM-based effect sizes yielded directionally consistent results as Hedges g (LB-102 50 mg, Δ = 0.50; 75 mg, Δ = 0.45; 100 mg, Δ = 0.64)” (opens the source at this quote in a new tab)

“Effect size is calculated by taking the difference in average observed PANSS change among completers between two groups (an active treatment arm and placebo) and dividing it by a single measure of variability that combines both groups’ spreads” (opens the source at this quote in a new tab)
“We also calculated effect size versus placebo based on all patients with at least one post-baseline PANSS assessment combining both observed and imputed data and yielding effect sizes of 0.50 at 50 mg, 0.45 at 75 mg, and 0.64 at 100 mg.” (opens the source at this quote in a new tab)

Sensitivity analyses of the primary endpoint

“Sensitivity analyses supported the primary findings” (opens the source at this quote in a new tab)

Time course of the PANSS total score

“The effect of LB-102 on PANSS total score was observed as early as week 1 and maintained throughout the 4-week treatment period” (opens the source at this quote in a new tab)

“(p-values) for 50, 75 and 100 mg at Day 8 (<.0001, 0.0032, 0.0181); Day 15 (0.0006, 0.0344, 0.0276); Day 21 (0.0006, 0.0025, 0.0050)” (opens the source at this quote in a new tab)

Least squares mean change in PANSS total score at weeks 1, 2, and 3 by arm

No evidence found.

Placebo response

“Although LB-102 demonstrated a statistically significant improvement in PANSS total score vs placebo, the 9-point reduction observed with placebo may reflect inpatient stabilization or design-related factors (eg, number of treatment arms and site participation).” (opens the source at this quote in a new tab)

CGI-S score change and CGI-S responder rate at week 4

Statistic	Placebo (n = 108)	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)
Baseline, mean (SD)	“4.8 (0.57)”	“4.8 (0.57)”	“4.9 (0.53)”	“4.8 (0.61)”
Day 28, mean (SD)	“4.3 (0.74)”	“3.9 (0.77)”	“4.1 (0.85)”	“4.0 (0.60)”
LS mean change (SE)	“−0.39 (0.07)”	“−0.72 (0.08)”	“−0.67 (0.08)”	“−0.84 (0.14)”
LS mean difference from placebo (SE) and 95% CI	“NA”	“−0.33 (0.10) [−0.52 to −0.14]”	“−0.28 (0.10) [−0.47 to −0.09]”	“−0.45 (0.15) [−0.74 to −0.16]”
P value for score change	“NA”	“<.001”	“.005”	“.003”
CGI-S responders, No. (%) and 95% CI	“8 (7.4) [2.0 to 12.8]”	“25 (23.4) [14.9 to 31.9]”	“19 (17.6) [10.0 to 25.2]”	“4 (11.1) [0.0 to 22.8]”
Responder difference vs placebo (95% CI)	“NA”	“16.0 (6.5 to 25.4)”	“10.2 (1.5 to 18.9)”	“3.7 (−7.7 to 15.1)”
P value for responder rate	“NA”	“.001”	“.02”	“.35”

“A 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 50 mg, n = 2 of 91 [2.2%]; LB-102 75 mg, n = 1 of 83 [1.2%]; LB-102 100 mg, n = 0 of 23; and placebo, n = 1 of 94 [1.1%]) and none rated normal, not at all ill.” (opens the source at this quote in a new tab)

Shift in CGI-S category from baseline to week 4

“With these changes, the majority of participants shifted from markedly ill (CGI-S of 5) at baseline to moderately ill (CGI-S of 4, range of 45.8% to 65.2% of participants across all three dose cohorts) or mildly ill (CGI-S of 3, range of 17.4% to 25.3% of participants across all three dose cohorts).” (opens the source at this quote in a new tab)

PANSS Positive and Negative Symptoms subscale scores at week 4

Statistic	Placebo (n = 108)	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)
Positive Symptoms subscale, LS mean change (SE)	“−3.1 (0.41)”	“−4.8 (0.43)”	“−4.9 (0.43)”	“−5.3 (0.76)”
Positive Symptoms subscale, LS mean difference (SE) and 95% CI	“NA”	“−1.7 (0.59) [−2.8 to −0.5]”	“−1.7 (0.59) [−2.9 to −0.6]”	“−2.2 (0.86) [−3.8 to −0.5]”
Positive Symptoms subscale, P value	“NA”	“.005”	“.004”	“.01”
Negative Symptoms subscale, LS mean change (SE)	“−1.1 (0.31)”	“−2.2 (0.31)”	“−1.7 (0.32)”	“−1.8 (0.55)”
Negative Symptoms subscale, LS mean difference (SE) and 95% CI	“NA”	“−1.1 (0.43) [−1.9 to −0.2]”	“−0.6 (0.44) [−1.5 to 0.3]”	“−0.7 (0.63) [−1.9 to 0.5]”
Negative Symptoms subscale, P value	“NA”	“.01”	“.16”	“.26”

“Analysis of the PANSS Negative Symptoms subscale score showed a numerical improvement from baseline to week 4 for all LB-102 doses, with significant improvement for 50 mg compared with placebo” (opens the source at this quote in a new tab)

PANSS Marder factor scores at week 4

Marder factor and statistic	Placebo (n = 108)	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)
Positive Symptoms, LS mean change (SE)	“−2.5 (0.42)”	“−4.4 (0.43)”	“−4.4 (0.44)”	“−5.4 (0.82)”
Positive Symptoms, LS mean difference (SE) and 95% CI	“NA”	“−1.9 (0.60) [−3.0 to −0.7]”	“−1.9 (0.60) [−3.1 to −0.7]”	“−2.8 (0.91) [−4.6 to −1.1]”
Positive Symptoms, P value	“NA”	“.002”	“.002”	“.002”
Negative Symptoms, LS mean change (SE)	“−1.6 (0.36)”	“−2.5 (0.37)”	“−1.9 (0.37)”	“−3.0 (0.70)”
Negative Symptoms, LS mean difference (SE) and 95% CI	“NA”	“−0.9 (0.50) [−1.9 to 0.1]”	“−0.4 (0.51) [−1.4 to 0.7]”	“−1.4 (0.78) [−3.0 to 0.1]”
Negative Symptoms, P value	“NA”	“.08”	“.50”	“.07”
Disorganized Thought, LS mean change (SE)	“−2.0 (0.30)”	“−3.6 (0.31)”	“−2.9 (0.31)”	“−3.3 (0.58)”
Disorganized Thought, LS mean difference (SE) and 95% CI	“NA”	“−1.6 (0.42) [−2.5 to −0.8]”	“−0.9 (0.43) [−1.8 to −0.1]”	“−1.3 (0.65) [−2.6 to 0.0]”
Disorganized Thought, P value	“NA”	“<.001”	“.03”	“.04”
Uncontrolled Hostility/Excitement, LS mean change (SE)	“−0.7 (0.26)”	“−1.5 (0.26)”	“−1.5 (0.27)”	“−1.9 (0.50)”
Uncontrolled Hostility/Excitement, LS mean difference (SE) and 95% CI	“NA”	“−0.8 (0.36) [−1.6 to −0.1]”	“−0.8 (0.37) [−1.5 to −0.1]”	“−1.2 (0.56) [−2.3 to −0.1]”
Uncontrolled Hostility/Excitement, P value	“NA”	“.02”	“.02”	“.03”
Anxiety/Depression, LS mean change (SE)	“−2.4 (0.31)”	“−2.7 (0.32)”	“−3.2 (0.32)”	“−3.5 (0.60)”
Anxiety/Depression, LS mean difference (SE) and 95% CI	“NA”	“−0.3 (0.43) [−1.1 to 0.6]”	“−0.7 (0.44) [−1.6 to 0.1]”	“−1.0 (0.67) [−2.3 to 0.3]”
Anxiety/Depression, P value	“NA”	“.54”	“.09”	“.13”

“For PANSS Marder factor scores for Negative Symptoms and Anxiety/Depression, each LB-102 dose demonstrated numerically greater improvements vs placebo that did not reach statistical significance” (opens the source at this quote in a new tab)

PANSS total score responder rates at week 4

Analysis and statistic	Placebo	LB-102 50 mg	LB-102 75 mg	LB-102 100 mg
Prespecified 20% or greater response, No. (%) and 95% CI	“17 (18.3) [10.4 to 26.1]”	“29 (31.9) [22.3 to 41.4]”	“27 (32.1) [22.2 to 42.1]”	“10 (43.5) [23.2 to 63.7]”
Prespecified, OR (95% CI)	“NA”	“1.91 (0.98 to 3.74)”	“2.27 (1.16 to 4.41)”	“2.87 (1.17 to 7.05)”
Prespecified, P value	“NA”	“.06”	“.02”	“.02”
Post hoc floor-adjusted 20% or greater response, No. (%) and 95% CI	“36 (38.7) [28.8 to 48.6]”	“52 (57.1) [47.0 to 67.3]”	“45 (53.6) [42.9 to 64.2]”	“18 (78.3) [61.4 to 95.1]”
Post hoc floor-adjusted, OR (95% CI)	“NA”	“1.92 (1.08 to 3.40)”	“1.95 (1.10 to 3.46)”	“4.75 (1.83 to 12.34)”
Post hoc floor-adjusted, P value	“NA”	“.03”	“.02”	“.001”

Responder rates at 30% or 50% PANSS reduction

No evidence found.

Post hoc analysis in participants with a baseline PANSS Negative Symptoms subscale score of 24 or more

“LB-102 50 mg, −3.4 (Δ −1.70, p=0.0045 vs placebo; effect size=0.67)” (opens the source at this quote in a new tab)
“LB-102 75 mg, −2.6 (Δ −1.00, p=0.1501 vs placebo, effect size=0.34)” (opens the source at this quote in a new tab)
“LB-102 100 mg, −3.3 (Δ −1.70, p=0.0658 vs placebo, effect size=0.60)” (opens the source at this quote in a new tab)

“We also conducted an exploratory post-hoc analysis of our Phase 2 data on the treatment effect in patients with negative symptoms at baseline (i.e., those patients with a PANSS Negative Subscore greater than or equal to 24). In patients with negative symptoms at baseline, the LS Mean change in negative symptom scores at Week 4 was -1.6 (placebo), -3.4 (50 mg, Δ -1.7, p=0.0045 versus placebo; effect size=0.67), -2.6 (75 mg, Δ -1.00, p=0.1501, effect size=0.34), and -3.3 (100 mg, Δ -1.70, p=0.0658, effect size=0.60).” (opens the source at this quote in a new tab)

Exploratory cognition results: post hoc Cogstate composite scores after 4 weeks

Composite score	LB-102 50 mg vs placebo, effect size	P value	LB-102 75 mg vs placebo, effect size	P value	LB-102 100 mg vs placebo, effect size	P value
Global Cognition (N=290)	“0.26”	“0.0476”	“0.41”	“0.0027”	“0.66”	“0.0018”
Attention (Psychomotor Function) (n=290)	“0.13”	“0.3331”	“0.29”	“0.0277”	“0.24”	“0.2062”
Memory (Executive Function) (n=265)	“0.15”	“0.3128”	“0.19”	“0.1957”	“0.53”	“0.0273”

“Post hoc analysis. Analysis of Effect Size was calculated via ANCOVA with visit, treatment, and visit by treatment as fixed effects, and with baseline Global Cognition composite score as a covariate.” (opens the source at this quote in a new tab)
“Mediation analysis highlighted a significant and direct effect of LB-102 on cognitive performance in all NOVA1 participants with acute schizophrenia, with no impact mediated by the improvement in schizophrenia symptoms (r=0.05, p=0.44).” (opens the source at this quote in a new tab)

Dose response described by the authors

“LB-102 produced significant reductions at all doses, with broadly similar effects at 50 to 75 mg, with a numerically larger (but less certain) signal with 100 mg with no clear dose-related increase from 50 to 100 mg in extrapyramidal symptoms.” (opens the source at this quote in a new tab)

Indirect comparison with established antipsychotics described by the authors

“The magnitude of effect falls within the range reported for established oral antipsychotics in multiepisode acute schizophrenia in a large network meta-analysis (eg, standardized mean difference [95% credible interval]: amisulpride, −0.73 [−0.89 to −0.58]; olanzapine, −0.56 [−0.62 to −0.50]; risperidone, −0.55 [−0.62 to −0.48])” (opens the source at this quote in a new tab)

Results of prespecified subgroup analyses by baseline body mass index and baseline PANSS total score

No evidence found.

Pharmacokinetic results from the first 60 randomized participants

No evidence found.

Patient-reported outcome and health-related quality of life results

No evidence found.

Overview of adverse events by arm

Outcome, No. (%)	Placebo (n = 108)	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)
Any AE	“67 (62.0)”	“77 (72.0)”	“68 (63.0)”	“28 (77.8)”
Any TEAE	“60 (55.6)”	“74 (69.2)”	“62 (57.4)”	“27 (75.0)”
Any treatment-related TEAE	“23 (21.3)”	“49 (45.8)”	“34 (31.5)”	“17 (47.2)”
Any serious TEAE	“2 (1.9)”	“1 (0.9)”	“1 (0.9)”	“1 (2.8)”
Serious treatment-related TEAE	“0”	“1 (0.9)”	“1 (0.9)”	“0”
TEAE leading to early withdrawal	“2 (1.9)”	“2 (1.9)”	“3 (2.8)”	“3 (8.3)”
TEAE leading to death	“1 (0.9)”	“0”	“0”	“0”

“TEAEs were reported in 223 participants (62.1%; 560 events), with a higher incidence in the groups receiving LB-102 100 mg (27 [75.0%]; 60 events) and 50 mg (74 [69.2%]; 204 events) than the groups receiving 75 mg (62 [57.4%]; 139 events) and placebo (60 [55.6%]; 157 events).” (opens the source at this quote in a new tab)
“Treatment-related TEAEs occurred in 123 participants (34.3%; 212 events), with the most common being insomnia, weight increase, headache, and blood prolactin increased” (opens the source at this quote in a new tab)

Treatment-emergent adverse events occurring in 5% or more of participants

TEAE, No. (%)	Placebo (n = 108)	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)
Insomnia	“24 (22.2)”	“27 (25.2)”	“23 (21.3)”	“14 (38.9)”
Headache	“10 (9.3)”	“12 (11.2)”	“9 (8.3)”	“2 (5.6)”
Anxiety	“9 (8.3)”	“10 (9.3)”	“9 (8.3)”	“4 (11.1)”
Agitation	“10 (9.3)”	“11 (10.3)”	“6 (5.6)”	“4 (11.1)”
Weight (increase)	“4 (3.7)”	“13 (12.1)”	“8 (7.4)”	“3 (8.3)”
Blood prolactin (increase)	“0”	“7 (6.5)”	“6 (5.6)”	“3 (8.3)”
Hyperprolactinemia	“0”	“4 (3.7)”	“2 (1.9)”	“3 (8.3)”
Blood creatine phosphokinase (increase)	“3 (2.8)”	“4 (3.7)”	“1 (0.9)”	“2 (5.6)”
Alanine aminotransferase (increase)	“1 (0.9)”	“3 (2.8)”	“1 (0.9)”	“2 (5.6)”
Somnolence	“0”	“1 (0.9)”	“4 (3.7)”	“2 (5.6)”
Constipation	“0”	“4 (3.7)”	“1 (0.9)”	“2 (5.6)”

Treatment-related adverse events occurring in 5% or more of participants

Treatment-related TEAE, No. (%)	Placebo (n = 108)	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)
Insomnia	“5 (4.6)”	“11 (10.3)”	“6 (5.6)”	“3 (8.3)”
Weight (increase)	“2 (1.9)”	“11 (10.3)”	“6 (5.6)”	“3 (8.3)”
Headache	“5 (4.6)”	“9 (8.4)”	“6 (5.6)”	“1 (2.8)”
Blood prolactin (increase)	“0”	“7 (6.5)”	“6 (5.6)”	“3 (8.3)”
Somnolence	“0”	“1 (0.9)”	“4 (3.7)”	“2 (5.6)”
Alanine aminotransferase (increase)	“0”	“3 (2.8)”	“1 (0.9)”	“2 (5.6)”
Agitation	“2 (1.9)”	“2 (1.9)”	“0”	“2 (5.6)”

Severe and serious adverse events and deaths

“Most TEAEs were mild or moderate. Severe TEAEs were reported in 5 participants (1.4%), including dystonia (75 mg, n = 1), psychotic disorder (100 mg, n = 1), schizophrenia (placebo, n = 2), and death (placebo, n = 1).” (opens the source at this quote in a new tab)
“One death was reported in the placebo group.” (opens the source at this quote in a new tab)

“There were five reported serious adverse events, or SAEs, overall with two SAEs in the placebo cohort (psychotic disorder and death), one SAE in the 50 mg cohort (suicidal ideation – deemed possibly related to treatment), one SAE in the 75 mg cohort (dystonia – deemed possibly related to treatment) and one SAE in the 100 mg cohort (psychotic disorder – deemed not related to treatment).” (opens the source at this quote in a new tab)

Serious adverse events and all-cause mortality in the registry results

Event, affected / at risk (%)	Placebo	LB-102 50 mg	LB-102 75 mg	LB-102 100 mg
All-cause mortality	“1/108 (0.93%)”	“0/107 (0.00%)”	“0/108 (0.00%)”	“0/36 (0.00%)”
Serious adverse events, total	“2/108 (1.85%)”	“1/107 (0.93%)”	“1/108 (0.93%)”	“1/36 (2.78%)”
Death	“1/108 (0.93%)”	“0/107 (0.00%)”	“0/108 (0.00%)”	“0/36 (0.00%)”
Dystonia	“0/108 (0.00%)”	“0/107 (0.00%)”	“1/108 (0.93%)”	“0/36 (0.00%)”
Psychosis	“1/108 (0.93%)”	“0/107 (0.00%)”	“0/108 (0.00%)”	“1/36 (2.78%)”
Suicidal ideation	“0/108 (0.00%)”	“1/107 (0.93%)”	“0/108 (0.00%)”	“0/36 (0.00%)”

Adverse events leading to discontinuation

“TEAEs leading to trial drug discontinuation occurred in 10 participants (placebo, n = 2; 50 mg, n = 2; 75 mg, n = 3; 100 mg, n = 3) with 5 serious TEAEs (placebo, n = 2 [including 1 death]; each LB-102 arm, n = 1)” (opens the source at this quote in a new tab)
“The only TEAE leading to trial discontinuation occurring in more than 1 participant was worsening schizophrenia (placebo, n = 2; LB-102 50 mg, n = 1). Other discontinuation-related TEAEs included psychotic disorder, suicidal ideation, alanine aminotransferase increase, lipase increase, toothache, COVID-19, and dystonia.” (opens the source at this quote in a new tab)

Extrapyramidal symptoms, dystonia, and akathisia

“Extrapyramidal symptom incidence was low across all groups (placebo, 2 [1.9%]; LB-102 50 mg, 0 [0%]; 75 mg, 1 [0.9%]; 100 mg, 1 [2.8%]), as was dystonia (placebo, 1 [0.9%]; LB-102 50 mg, 0 [0%]; 75 mg, 3 [2.8%]; 100 mg, 1 [2.8%]).” (opens the source at this quote in a new tab)
“Evaluation of the SAS, BARS, and AIMS demonstrated values that remained stable over time, with little to no emergence of any antipsychotic-induced parkinsonism, akathisia, tardive dyskinesia, or other involuntary motor AEs.” (opens the source at this quote in a new tab)

TEAE related to extrapyramidal symptoms, n (%)	Placebo (n=108)	LB-102 50 mg (n=107)	LB-102 75 mg (n=108)	LB-102 100 mg (n=36)
Dystonia	“1 (0.9%)”	“0”	“3 (2.8%)”	“1 (2.8%)”
Akathisia	“1 (0.9%)”	“1 (0.9%)”	“2 (1.9%)”	“0”
Extrapyramidal disorder	“2 (1.9%)”	“0”	“1 (0.9%)”	“1 (2.8%)”
Total related to EPS	“4 (3.7%)”	“1 (0.9%)”	“6 (5.6%)”	“2 (5.6%)”

Prolactin concentrations

“Elevated prolactin levels at day 28 were reported across all arms (placebo, 5.2%, mean [SD] increase, 1.3 [6.0] ng/mL; 50 mg, 91.0%, mean [SD] increase, 59.9 [55.1] ng/mL; 75 mg, 94.0%, mean [SD] increase, 51.4 [52.0] ng/mL; 100 mg, 87.5%, mean [SD] increase, 51.2 [48.1] ng/mL; to convert to micrograms per liter, multiply by 1)” (opens the source at this quote in a new tab)

Clinical adverse events related to prolactin increase

“Clinical AEs related to prolactin increase were reported in 5 participants, including galactorrhea (50 mg, n = 2; 75 mg, n = 1), breast enlargement (100 mg, n = 1), and erectile dysfunction (100 mg, n = 1).” (opens the source at this quote in a new tab)

TEAE related to prolactin increase, n (%)	Placebo (n=108)	LB-102 50 mg (n=107)	LB-102 75 mg (n=108)	LB-102 100 mg (n=36)
Galactorrhea	“0”	“2 (1.9%)”	“1 (0.9%)”	“0”
Breast enlargement	“0”	“0”	“0”	“1 (2.8%)”
Erectile dysfunction	“0”	“0”	“0”	“1 (2.8%)”
Total related to prolactin	“0”	“2 (1.9%)”	“1 (0.9%)”	“2 (5.6%)”

“Prolactin-related AEs Low rate (~1-5.6%); AEs were mild to moderate and did not result in discontinuation” (opens the source at this quote in a new tab)

Prolactin change by sex and course of prolactin after treatment discontinuation

No evidence found.

Change from baseline to day 28 in weight, prolactin, glucose, cholesterol, and QTc

Parameter	Placebo (n = 108)	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)
Weight, mean (SD), kg	“2.0 (2.9)”	“4.3 (3.2)”	“3.3 (2.8)”	“2.9 (2.5)”
Weight increase ≥7%, No. participants (%)	“11 (10%)”	“27 (26%)”	“20 (19%)”	“3 (9%)”
Prolactin, mean (SD), ng/mL	“1.3 (6.03)”	“59.9 (55.11)”	“51.4 (52.02)”	“51.2 (48.07)”
Fasting glucose, mean (SD), mg/dL	“0.2 (12.07)”	“2.3 (24.52)”	“2.0 (13.62)”	“7.0 (19.39)”
Total cholesterol, mean (SD), mg/dL	“0.8 (25.06)”	“7.7 (24.75)”	“5.4 (23.98)”	“5.8 (25.52)”
QTc, mean (SD), millisecond	“1.2 (12.56)”	“4.9 (13.39)”	“4.3 (12.55)”	“5.4 (9.44)”
QTc mean change ≥30 millisecond, No. participants (%)	“1 (0.9)”	“5 (4.7)”	“1 (0.9)”	“1 (2.8)”

“Analyzed using a last-observation-carried-forward approach in participants with postbaseline weight data (placebo, n=106; 50 mg, n=105; 75 mg, n=107; 100 mg, n=34).” (opens the source at this quote in a new tab)

Weight gain

“Weight increase was the only TEAE to occur in 5% or more of the total population at a rate at least twice that observed with placebo but was not dose-dependent (placebo, 4 [3.7%], mean increase, 2.1 kg; 50 mg, 13 [12.1%], mean increase, 4.3 kg; 75 mg, 8 [7.4%], mean increase, 3.3 kg; 100 mg, 3 [8.3%], mean increase, 2.9 kg).” (opens the source at this quote in a new tab)
“A 7% or greater weight increase, using a last-observation-carried-forward approach, was reported by 61 participants (placebo, 11 [10.4%], mean increase, 6.9 kg; 50 mg, 27 [25.7%], mean increase, 8.2 kg; 75 mg, 20 [18.7%], mean increase, 7.2 kg; 100 mg, 3 [8.8%], mean increase, 7.2 kg)” (opens the source at this quote in a new tab)

“There was an increase in weight across all treatment arms by the end of Week 4 (placebo, 2.1 kg; 50 mg, 4.6 kg; 75 mg, 3.5 kg; 100 mg, 3.7 kg).” (opens the source at this quote in a new tab)

“Over the course of the trial, we observed approximately 1.6 kg placebo-adjusted weight gain on a last observation carried forward basis.” (opens the source at this quote in a new tab)

“Average placebo-adjusted weight gain for treated subjects was 2 kg.” (opens the source at this quote in a new tab)

Metabolic laboratory parameters

“Despite the weight gain observed in the four-week trial, no clinically meaningful signal in metabolic parameters such as cholesterol, LDL, HDL, triglycerides or fasting glucose were observed.” (opens the source at this quote in a new tab)

Change in triglycerides, LDL cholesterol, HDL cholesterol, and HbA1c by arm

No evidence found.

QTc interval and vital signs

“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 (Fridericia-corrected QT interval) values” (opens the source at this quote in a new tab)

QTcF, ms	Placebo (n=108)	LB-102 50 mg (n=107)	LB-102 75 mg (n=108)	LB-102 100 mg (n=36)
Baseline QTcF	“393.5”	“393.3”	“394.8”	“390.0”
Change at day 28	“1.2”	“4.9”	“4.3”	“5.4”

“QTc Prolongation Minimal QT prolongation (4.3-5.4 ms); no patients met pre-specified stopping criteria” (opens the source at this quote in a new tab)

“there were no reports of orthostasis among patients treated with LB-102 in the trial” (opens the source at this quote in a new tab)

Sedation and somnolence

TEAE, n (%)	Placebo (n=108)	LB-102 50 mg (n=107)	LB-102 75 mg (n=108)	LB-102 100 mg (n=36)
Sedation	“0”	“0”	“1 (0.9%)”	“0”
Somnolence	“0”	“1 (0.9%)”	“4 (3.7%)”	“2 (5.6%)”

“Across 251 dosed subjects, only one case of sedation was reported.” (opens the source at this quote in a new tab)

Insomnia and other events that were common baseline conditions

“TEAEs were generally balanced across treatment arms, except insomnia (more frequent with 75 mg) and weight increase.” (opens the source at this quote in a new tab)
“Common baseline comorbidities (ie, insomnia, anxiety, headache, and agitation) were among the most common TEAEs, suggesting that some TEAEs may represent the re-emergence, exacerbation, or fluctuation of preexisting symptoms rather than new, drug-related effects.” (opens the source at this quote in a new tab)

Suicidal ideation and behavior

“There was no change in suicidal ideation or behavior at the end of Week 4, as measured by the Columbia–Suicide Severity Rating Scale (C-SSRS).” (opens the source at this quote in a new tab)

Authors' comparison of tolerability with other antipsychotics

“Elevated prolactin was reported from 6.5% of those receiving LB-102 50 mg to 8.3% of those receiving LB-102 100 mg; by comparison, data for amisulpride indicate significantly higher rates of hyperprolactinemia (25%-100%).” (opens the source at this quote in a new tab)
“Extrapyramidal symptoms, QTc prolongation, and hepatic enzyme changes with LB-102 remained similar to placebo.” (opens the source at this quote in a new tab)

Summary

NOVA-1 was a 4-week inpatient trial conducted at 25 sites in the United States. The authors state that it was not designed to evaluate long-term durability of treatment and that further studies are needed to assess generalizability to outpatients. The trial had no active comparator, so the comparisons with amisulpride, olanzapine, risperidone, and xanomeline and trospium chloride in the publication are indirect. European Medicines Agency guidance names 6 weeks as the preferred duration for short-term efficacy trials and states that a 4-week trial could also be considered.

Formal hypothesis testing with multiplicity control covered the primary endpoint for the 50 mg and 75 mg doses only. The 100 mg arm was exploratory, with 36 participants randomized and 23 with an observed week 4 PANSS total score, and P values for the 100 mg dose and for all secondary endpoints were not controlled for multiplicity. The placebo group improved by 9.3 points on the PANSS total score. The differences from placebo were 5.0 points for 50 mg and 4.7 points for 75 mg, compared with the 8-point difference assumed in the sample size calculation. The Hedges g values of 0.61, 0.41, and 0.83 were calculated post hoc in participants who completed the trial, and the model-based values in the modified intention-to-treat population were 0.50, 0.45, and 0.64. The prespecified 20% PANSS responder comparison for 50 mg had a P value of .06, and the floor-adjusted responder analysis was post hoc. On negative symptoms, the difference from placebo had a P value below .05 for the 50 mg dose on the PANSS Negative Symptoms subscale and for no dose on the Marder Negative Symptoms factor; the authors state that negative symptom improvement in a 4-week acute trial may be secondary to resolution of positive symptoms. Cognition results are post hoc composite scores in the 290 participants who completed week 4 with valid PANSS and Cogstate scores. No patient-reported or quality of life endpoint appears among the protocol endpoints.

Completion of week 4 was 81.6% overall and 64% (23 of 36 participants) in the 100 mg arm. Of 359 participants, 290 (80.8%) were male and 275 (76.6%) were Black or African American, and eligibility was limited to ages 18 to 55 years and excluded first-episode and treatment-resistant illness. Elevated prolactin levels at day 28 were reported in 87.5% to 94.0% of participants in the LB-102 arms and 5.2% in the placebo arm, with mean increases of 51.2 to 59.9 ng/mL and 1.3 ng/mL. Weight increase of 7% or more occurred in 25.7% (50 mg), 18.7% (75 mg), 8.8% (100 mg), and 10.4% (placebo) of participants, and the authors state that smoking restrictions, limited physical activity, and minimal dietary restrictions at the sites may have contributed. Four weeks of treatment do not characterize long-term endocrine or metabolic outcomes; an investigator quoted in a news report stated that clinical value will depend on phase 3 data, longer-term metabolic and endocrine outcomes, relapse prevention, functioning, adherence, and head-to-head comparisons.

Sources differ on some figures. Table 3 of the publication reports mean weight change of 2.0 kg with placebo and 2.9 to 4.3 kg with LB-102, while the discussion of the publication and a 2025 poster report 2.1 kg with placebo and 3.5 to 4.6 kg with LB-102; the sponsor reported placebo-adjusted weight gain of 2 kg in January 2025 and approximately 1.6 kg in its Form 10-K. The registry lists primary completion on December 4, 2024, and the publication states that the trial was conducted between December 2023 and August 2024. The sponsor funded the trial and the medical writing and participated in the design, conduct, analysis, and interpretation.

Limitations stated by the authors: duration, setting, and comparator

“was conducted over 4 weeks and was not designed to evaluate the long-term durability of treatment.” (opens the source at this quote in a new tab)
“The inpatient setting minimized risks related to nonadherence, illicit substance use, and unauthorized concomitant medications; further studies are needed to assess whether these findings are generalizable to an outpatient population.” (opens the source at this quote in a new tab)
“The trial did not include an active comparator group, and thus, no direct comparison can be made with other medications.” (opens the source at this quote in a new tab)

Limitations stated by the authors: weight gain, negative symptoms, and study population

“Site-level 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.” (opens the source at this quote in a new tab)
“Additionally, although LB-102 demonstrated broad symptomatic efficacy, it is possible that, in an acute 4-week trial, improvements in negative symptoms may be secondary to the resolution of positive symptoms (pseudospecificity); further studies are required to disentangle these effects.” (opens the source at this quote in a new tab)
“Many sites had a trial population that was predominantly Black, reflecting the urban US clinical settings in which recruitment for many sites occurred.” (opens the source at this quote in a new tab)

Caution on cross-trial comparisons

“although methodological differences warrant cautious interpretation” (opens the source at this quote in a new tab)

Sponsor role and medical writing support

“In collaboration with the academic authors, the funder participated in the design and conduct of the trial and in the collection, management, analysis, and interpretation of the data.” (opens the source at this quote in a new tab)
“The preparation, review, and approval of the manuscript were undertaken by all authors and the sponsor, with support from professional medical writers funded by the sponsor.” (opens the source at this quote in a new tab)

Investigator comment on what remains to be shown

“He noted, however, that NOVA-1 was a short, 4-week phase 2 inpatient study without an active comparator.” (opens the source at this quote in a new tab)
“The real and full clinical value will depend on phase 3 data, longer-term metabolic/endocrine outcomes, relapse prevention, functioning, adherence, and head-to-head comparisons” (opens the source at this quote in a new tab)

Comment from a psychiatrist not involved in the study

“It’s a promising new asset that seems to have replicated efficacy across psychotic, negative, and depressive symptoms” (opens the source at this quote in a new tab)

Regulatory guidance on short-term trial duration and comparators

“The preferred design for demonstrating short term efficacy is a 6 week clinical trial.” (opens the source at this quote in a new tab)
“Shorter study duration (e.g. 4 weeks) could also be considered, especially for drugs with a similar profile to existing antipsychotic drugs. This carries the risk of negative results if maximal therapeutic effect is not obtained at 4 weeks and the shorter duration is disadvantageous in terms of the ability to demonstrate stability of effect.” (opens the source at this quote in a new tab)
“If the aim of the study is to demonstrate non-inferiority to an active comparator, then a three-arm study of placebo, test product and active comparator is recommended” (opens the source at this quote in a new tab)

Registered study purpose

“This is a Phase 3, randomized, double blind, placebo controlled, fixed dose, multicenter study designed to assess the efficacy, safety, tolerability, and pharmacokinetics (PK) of LB-102 100 mg once daily (QD) and LB-102 50 mg QD versus placebo QD for the treatment of adult patients with an acute exacerbation of schizophrenia” (opens the source at this quote in a new tab)

Role in the registration program

“We initiated a six-week Phase 3 trial (NOVA-2) of LB-102 in participants with acute schizophrenia in March 2026, which we believe, if positive, may be sufficient to support a regulatory approval application along with our Phase 2 trial and other NDA-enabling activities.” (opens the source at this quote in a new tab)

“Based on positive results and prior FDA feedback, we believe NOVA-2, together with the open label extension trial, and data from our Phase 2 (NOVA-1) trial, will support the potential U.S. approval of LB-102 for the treatment of schizophrenia.” (opens the source at this quote in a new tab)
“Our Phase 3 trial, NOVA-2, is designed to further elucidate the potential multidimensional benefits of LB-102 across the positive, negative, and cognitive symptom domains of schizophrenia.” (opens the source at this quote in a new tab)

Study dates and status

Item	Registry record
Protocol number	“LB-102-008”
Study start (actual)	“2026-03-25”
Primary completion (estimated)	“2027-06”
Study completion (estimated)	“2027-10”
Last update posted	“2026-07-27”

Sites: United States only

“We are conducting this trial entirely in the United States at approximately 25 sites, a similar number of sites as were utilized in our Phase 2 acute schizophrenia trial and there is a significant overlap between the sites utilized in our Phase 2 trial and those we are utilizing in the Phase 3 trial.” (opens the source at this quote in a new tab)

“This study has 13 locations” (opens the source at this quote in a new tab)

Topline results timing: guidance at initiation

“Topline results from NOVA-2 are anticipated in the second half of 2027 and if positive, the company expects to hold a pre-NDA meeting with FDA thereafter.” (opens the source at this quote in a new tab)

Topline results timing: guidance revised in July 2026

“based on enrollment projections, it now expects to report topline results from the pivotal Phase 3 NOVA-2 clinical trial of LB-102 in patients with schizophrenia in the first half of 2027 and to schedule a pre-NDA meeting with the FDA thereafter in the second half of 2027.” (opens the source at this quote in a new tab)
“Enrollment in our pivotal Phase 3 NOVA-2 trial has been more rapid than we expected” (opens the source at this quote in a new tab)

“Phase 3 topline data read out expected in 1H 2027” (opens the source at this quote in a new tab)

Official title and registered design

“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” (opens the source at this quote in a new tab)
“Patients will be randomized 1:1:1 to one of three treatments” (opens the source at this quote in a new tab)

Three-arm, inpatient, fixed-dose design without titration

“The Phase 3 trial is a three-arm, inpatient, double-blinded, placebo-controlled, oral once-daily dose of LB-102 in patients with acute schizophrenia, with a six-week treatment duration.” (opens the source at this quote in a new tab)
“All patients will start at their assigned dose level without titration.” (opens the source at this quote in a new tab)
“We designed our Phase 3 to leverage the operational framework of our Phase 2 trial.” (opens the source at this quote in a new tab)

Changes from the phase 2 trial

“Primary changes: 6-week duration; 3 versus 4 arms” (opens the source at this quote in a new tab)
“Doses selected to inform use in commercial setting” (opens the source at this quote in a new tab)

Measures to limit placebo response

“To mitigate the risk of an elevated placebo response in this trial, we are employing the same strategies which proved effective in our Phase 2 acute schizophrenia trial including consistent, frequent, and close engagement with clinical sites, the use of two third-party vendors (including the one used in our Phase 2 trial) to help identify and exclude professional patients from the trial, and a centralized review of PANSS ratings to ensure consistency and quality control throughout the trial.” (opens the source at this quote in a new tab)

Inclusion criteria

Criterion	Quoted registry text
Age	“18 Years to 65 Years”
Diagnosis	“Diagnosis of schizophrenia as defined by DSM-5”
Symptom severity	“PANSS 80-120”
Body mass index	“BMI - 18-40”
Setting	“Willing to be hospitalized for duration of the study”

Exclusion criteria

Criterion	Quoted registry text
Treatment resistance	“History of resistant treatment to schizophrenia medications”
Symptom change before randomization	“Increase in PANSS of > 20% between screening and baseline”
Other psychiatric diagnosis	“DSM-5 diagnosis other than schizophrenia”
Suicide risk	“Risk of suicidal behavior”
Violence risk	“Risk of violent or destructive behavior”
Tardive dyskinesia	“Clinically significant tardive dyskinesia determined by a score of ≥3 on Item 8 of the AIMS at Screening”
Akathisia	“Score of ≥3 on the BARS global clinical assessment of akathisia at Screening”
Diabetes	“Insulin dependent diabetes”
Cardiac disease	“Known ischemic heart disease or any history of myocardial infarction, congestive heart failure (whether controlled or uncontrolled), angioplasty, stenting, or coronary artery bypass surgery”

Treatment arms

Arm	Quoted registry text
LB-102 50 mg	“LB-102 50 mg given orally for 6 weeks”
LB-102 100 mg	“LB-102 100 mg given orally for 6 weeks”
Placebo	“Placebo given orally for 6 weeks”
Dosage form	“LB-102 oral tablet given for six weeks”

Dose selection and randomization ratio

“To better inform potential future commercial use of LB-102, we are studying the effects of two doses, 50 mg LB-102 or 100 mg LB-102, versus placebo in this trial, and patients will be randomized in a 1:1:1 ratio across the three arms of the trial.” (opens the source at this quote in a new tab)

Permitted concomitant and rescue medications

No evidence found.

Primary outcome definition

“Change from baseline to Week 6 on the Positive and Negative Syndrome Scale” (opens the source at this quote in a new tab)
“Determine whether LB-102, demonstrates antipsychotic efficacy, as determined by a change from Baseline on the Positive and Negative Syndrome Scale (PANSS) total score, compared to placebo: increase in scale indicates worsening while a decrease in the scale likely indicates a response to treatment” (opens the source at this quote in a new tab)

“The primary endpoint of the trial is change from baseline in total PANSS score at Day 42.” (opens the source at this quote in a new tab)

Company rationale for the 6-week assessment

“potential to further improve PANSS reductions observed following treatment with LB-102 given that in our Phase 2 trial, the PANSS score in the LB-102 treated arms declined at a faster rate than placebo through the 28-day duration of our Phase 2 trial.” (opens the source at this quote in a new tab)

Secondary outcomes: registry record

Secondary outcome	Time frame
“Evaluate the Safety and Tolerability of LB-102”	“10 weeks”
“Change in Clinical Global Impressions-Severity of Illness scale (CGI-S)”	“6 weeks”

Secondary endpoints: company statements

“Secondary endpoints include Clinical Global Impression-Severity (CGI-S), PANSS positive and negative subscales, Marder factor scores, cognitive performance, and Personal and Social Performance (PSP) scale.” (opens the source at this quote in a new tab)

Key secondary endpoint hierarchy and multiplicity control

No evidence found.

Planned enrollment: registry record

Enrollment type	Participants
Estimated	“456”

Planned enrollment: company statements

“The trial is designed to enroll approximately 460 patients with acute exacerbation of schizophrenia at approximately 25 sites in the U.S.” (opens the source at this quote in a new tab)

“The sample size will be approximately 460 patients.” (opens the source at this quote in a new tab)

Power and effect size assumptions

No evidence found.

Analyzed population

No evidence found.

Summary

NOVA-2 is recruiting and has reported no results. The registry record lists an estimated primary completion of June 2027, and the company expects topline results in the first half of 2027. Planned enrollment is 456 participants in the registry record and approximately 460 in company statements, randomized 1:1:1 to LB-102 50 mg, LB-102 100 mg, or placebo for 6 weeks of inpatient treatment at sites in the United States only. The 75 mg dose studied in NOVA-1 is absent from this trial. The trial has no active comparator, lasts 6 weeks, and excludes participants with a history of treatment resistance, so it will provide no comparative, maintenance, or treatment-resistant evidence. The registry record lists 2 secondary outcomes (adverse events and CGI-S), and company statements add PANSS subscales, Marder factor scores, cognitive performance, and the Personal and Social Performance scale. The testing hierarchy, power assumptions, and analysis sets have not been disclosed. The registry record listed 13 locations at its July 2026 update, and company statements describe approximately 25 sites.

Registered study purpose

“Phase 3, open label, multicenter study designed to assess the long term safety and tolerability of LB-102 for the treatment of adult patients with stable schizophrenia” (opens the source at this quote in a new tab)

Accrual of the safety population for the new drug application

“Concurrently with the Phase 3 NOVA-2 trial, we are enrolling an outpatient, open label trial (NOVA-3) to accrue the requisite safety population required to support NDA submission as well as other clinical trials and non-clinical studies typically required by FDA for an NDA approval.” (opens the source at this quote in a new tab)

“Although the primary objective of this trial is to collect the requisite safety data required for an NDA submission, we also expect to collect efficacy data in certain subsets of patients enrolled in this trial.” (opens the source at this quote in a new tab)

Study dates and status

Item	Registry record
Protocol number	“LB-102-010”
Study start (actual)	“2026-04-23”
Primary completion (estimated)	“2028-12”
Study completion (estimated)	“2029-04”
Last update posted	“2026-09-09”

Registered locations

“This study has 23 locations” (opens the source at this quote in a new tab)

Enrollment status in August 2026

“The 52-week open-label safety and tolerability trial (NOVA-3), evaluating the long-term safety and tolerability of LB-102 in patients with stable schizophrenia, is enrolling eligible patients who have completed NOVA-2, as well as de novo patients.” (opens the source at this quote in a new tab)

Official title and registered design

“A 52 Week, Open Label Safety and Tolerability Study of LB-102 in Adult Patients With Schizophrenia” (opens the source at this quote in a new tab)
“Open label study” (opens the source at this quote in a new tab)

Enrollment of NOVA-2 completers and new participants

“Patients who complete NOVA-2 will be able to continue in the Open Label Extension trial that will also enroll de novo patients.” (opens the source at this quote in a new tab)

“we expect to initiate an open label trial in patients with stable schizophrenia that will enroll both patients who participated in the Phase 3 trial as well as patients who did not.” (opens the source at this quote in a new tab)

“~900 patients – rollover from Phase 3 trial + new patients” (opens the source at this quote in a new tab)

Target population

“adult patients with stable schizophrenia who are experiencing inadequate response or who are having issues with side effects, general tolerability, or overall effectiveness of their current antipsychotic medication and desire to change medications, or who have completed their participation in current LB-102 clinical studies” (opens the source at this quote in a new tab)

Inclusion criteria

Criterion	Quoted registry text
Age	“18 Years to 65 Years”
Symptom severity	“Patients clinically stable PANSS </= 80 at screening”
Global severity	“CGI-S </+ 3 at screening”
Medical status	“Medically stable”
Body mass index	“BMI 18 -40”
Current treatment	“Taking oral antipsychotic treatment for at least 30 days”
Living situation	“Have stable living environment”

Exclusion criteria

Criterion	Quoted registry text
Treatment resistance	“History of treatment resistance to schizophrenia medications”
Other psychiatric diagnosis	“DSM-5 current diagnosis other than schizophrenia”
Suicide risk	“Risk of suicidal behavior”
Breastfeeding	“Breast feeding”

Flexible dosing between 50 mg and 100 mg

“LB-102 flexible dosing 50 mg - 100 mg” (opens the source at this quote in a new tab)

Switching from the prior antipsychotic

No evidence found.

Primary outcome definition

“Evaluate long term safety and tolerability of LB-102 by evaluating the number of adverse event, incidence of treatment emergent events.” (opens the source at this quote in a new tab)
“Overall adverse events, serious adverse events, incidence of treatment emergent events and adverse events which lead to study discontinuation” (opens the source at this quote in a new tab)
“52 weeks” (opens the source at this quote in a new tab)

Exposure requirements for the safety database

“To support approval, the safety population must include at least 1,500 cumulative patient exposures to LB-102, including at least 100 patients with greater than or equal to one year of exposure and 300 patients with greater than or equal to six months of exposure.” (opens the source at this quote in a new tab)

Secondary outcomes

Secondary outcome description	Time frame
“Evaluating the safety of treatment by number of adverse events”	“52 weeks”
“Evaluating the safety of treatment by change in vital signs, electrocardiogram (QTC), and weight/height for BMI”	“52 weeks”
“Evaluating the safety of treatment by conducting physical examinations”	“52 weeks”
“Assess the long-term effectiveness determined by Positive and Negative Syndrome Scale (PANSS)”	“52 weeks”

Open-label efficacy assessments

“Efficacy measures will include periodic assessments of cognitive performance as well as open label assessments of improvements in positive and negative symptoms, including in patients with prominent negative symptoms at enrollment in the trial.” (opens the source at this quote in a new tab)
“Although we do not expect data from this open label trial to lead to product label claims without additional randomized clinical trials, we believe these data have the potential to further support the differentiation of LB-102” (opens the source at this quote in a new tab)

Planned enrollment: registry record

Enrollment type	Participants
Estimated	“900”

Planned enrollment: company statement

“As a result, we expect to enroll approximately 900 patients in our planned open label safety trial.” (opens the source at this quote in a new tab)

Number of participants entering from NOVA-2

No evidence found.

Analyzed population

No evidence found.

Summary

NOVA-3 is a single-group, open-label trial with no concurrent control and has reported no results. The registry record lists an estimated primary completion of December 2028. Planned enrollment is 900 participants, drawn from participants who completed NOVA-2 and from newly enrolled adults with stable schizophrenia who have taken an oral antipsychotic for at least 30 days. Dosing is flexible between 50 mg and 100 mg, so the long-term exposure at each dose will depend on investigator dose selection. PANSS and cognitive assessments are unblinded, and the company states that it does not expect these data to support label claims without additional randomized trials. The number of participants expected to enter from NOVA-2, the visit schedule, and the analysis sets have not been disclosed.

Primary objectives

“To evaluate the safety and the tolerability of a single oral dose of LB-102 compared to placebo” (opens the source at this quote in a new tab)
“To evaluate the safety and the tolerability of multiple oral doses of LB-102 compared to placebo” (opens the source at this quote in a new tab)

Secondary objectives

“To evaluate the PK of a single dose of LB-102” (opens the source at this quote in a new tab)
“To evaluate the PK of multiple oral doses of LB-102” (opens the source at this quote in a new tab)

First-in-human study

“This was a first-in-human study examining single and multiple doses of LB-102 administered orally in 64 healthy volunteers.” (opens the source at this quote in a new tab)

Site and registered dates

Item	Registry record
Protocol number	“LB-102-001”
Site	“Medpace Clinical Pharmacology LLC”
Site location	“Cincinnati, Ohio, United States, 45227”
Study start (actual)	“2020-01-22”
Primary completion (actual)	“2020-07-01”
Study completion (actual)	“2020-11-09”

Dates in the clinical study report

Item	Clinical study report
Sites	“Single US center”
First subject enrolled	“06 January 2020”
Last subject completed	“10 July 2020”
Release date of report	“09 November 2020”

Randomized, double-blind, placebo-controlled single and multiple ascending dose design

“This was a Phase 1, randomized double-blind, placebo-controlled study designed to evaluate the safety, tolerability, and PK of LB-102 in healthy subjects. The study consisted of two parts: Part A (SAD) and Part B (MAD). There were 5 cohorts in Part A and 3 cohorts in Part B.” (opens the source at this quote in a new tab)
“Subjects were discharged on Day 3 (Part A) or Day 9 (Part B) and returned for a Follow-up Visit (Day 8 or Day 15, respectively) for safety review.” (opens the source at this quote in a new tab)

Sentinel dosing and safety review between cohorts

“In Cohort 1 (Part A), dosing of the first 2 subjects (1 active and 1 placebo) commenced at least 24 hours prior to the remaining 6 subjects.” (opens the source at this quote in a new tab)
“The blinded available study results for a cohort were reviewed by a Safety Review Committee (SRC) and it was agreed whether the safety profile was sufficiently acceptable to support proceeding with the evaluation of the next higher dose level.” (opens the source at this quote in a new tab)

Randomization and blinding

“Part A: In each cohort, eight (8) new participants were enrolled, randomized 3:1 (LB-102 capsule: placebo capsules, i.e., 6 receiving LB-102 capsules and 2 receiving placebo capsules).” (opens the source at this quote in a new tab)
“Study randomization was computer generated.” (opens the source at this quote in a new tab)
“All study personnel, sponsor personnel, and vendors were blinded. Only the unblinded pharmacist knew which study participants were randomized to LB-102 or placebo.” (opens the source at this quote in a new tab)

Dose escalation guided by safety and plasma concentrations

“Dosing in the single ascending dose (SAD) portion of the study was initially planned to be 50, 100, 200, and 400 mg, with doses in the multiple ascending dose (MAD) portion to be determined based on observations in the SAD portion.” (opens the source at this quote in a new tab)
“Dose escalation was guided by safety and plasma concentrations of LB-102 compared to a translational model.” (opens the source at this quote in a new tab)

Dose reductions during the study

“Cohort 2 was reduced from 100 mg to 10 mg. Cohort 3 was reduced from 200 mg to 100 mg. Cohort 4 was reduced from 400 mg to 200 mg. Cohort 5 was reduced from 800 mg to 150 mg.” (opens the source at this quote in a new tab)

Key inclusion criteria

“Healthy adult male and female subjects between 18 to 55 years of age inclusive at the screening visit.” (opens the source at this quote in a new tab)
“Subjects must be in good general health as determined by medical history and physical examination with no clinically significant medical findings and no history of significant medical disease (e.g., cardiovascular, pulmonary, renal, etc.) or acute condition with the past 30 days.” (opens the source at this quote in a new tab)

Key exclusion criteria

“History or presence of psychiatric or neurological disease or condition.” (opens the source at this quote in a new tab)
“Recent history of alcohol or drug abuse (within the last two years).” (opens the source at this quote in a new tab)
“The subject has a history of QT prolongation or dysrhythmia or a family history of prolonged QT interval or sudden death.” (opens the source at this quote in a new tab)
“QTcF interval > 450 msec for males and females” (opens the source at this quote in a new tab)
“Use of any prescription or over the counter medication, herbal medications, vitamins, or supplements within 14 days prior to study drug administration.” (opens the source at this quote in a new tab)

Treatment by cohort

Cohort	Clinical study report
Part A, cohort 1	“LB-102 50 mg (n=6) or Matching Placebo (n=2) QD x 1 day”
Part A, cohort 2	“LB-102 10 mg (n=6) or Matching Placebo (n=2) QD x 1 day”
Part A, cohort 3	“LB-102 100 mg (n=6) or Matching Placebo (n=2) QD x 1 day”
Part A, cohort 4	“LB-102 200 mg (n=6) or Matching Placebo (n=2) QD x 1 day”
Part A, cohort 5	“LB-102 150 mg (n=6) or Matching Placebo (n=2) QD x 1 day”
Part B, cohort 6	“LB-102 (n=6) 50 mg BID (100 mg/day) x 6 days (Days 1-6) and QD x 1 day (Day 7)”
Part B, cohort 7	“LB-102 (n=6) 100 mg BID (200 mg/day) x 6 days (Days 1-6) and QD x 1 day (Day 7)”
Part B, cohort 8	“LB-102 (n=6) 75 mg BID (150 mg/day) x 6 days (Days 1-6) and QD x 1 day (Day 7)”

Formulation and duration

“N-methyl amisulpride (LB-102) Powder in Capsule in dosage strengths of 10 mg, 25 mg, 50 mg, 75 mg, and 100 mg, Oral administration.” (opens the source at this quote in a new tab)
“Part A: 1 day; Part B: 7 days.” (opens the source at this quote in a new tab)

Fasting before the first dose in Part B

“Subjects were required to fast for approximately 12 hours prior to the first Day 1 dose.” (opens the source at this quote in a new tab)

Extent of exposure in the cohorts that stopped early

“Therefore, 7 out of 8 subjects in this cohort received doses of 100 mg LB-102 (N=5) or placebo (N=2) twice daily on Days 1-2 and QD on Day 3, totaling 5 doses.” (opens the source at this quote in a new tab)
“The one subject (01S2092) who did not complete the treatment course received twice daily doses of 75 mg LB-102 on Days 1-2 and one dose on Day 3 before treatment was halted due to an AE (acute dystonic reaction).” (opens the source at this quote in a new tab)

Primary outcome definition

“Percentage of participants who experience at least one treatment-emergent adverse event (TEAE)” (opens the source at this quote in a new tab)
“Day 8 (Part A) or Day 15 (Part B)” (opens the source at this quote in a new tab)

Safety parameters

“Safety parameters include AEs, hematology, chemistry, urinalysis, prolactin, ECG, physical examination, vital signs, and C-SSRS.” (opens the source at this quote in a new tab)

Individual and cohort stopping criteria

“An increase in QTcF to > 500 msec or > 60 msec over baseline.” (opens the source at this quote in a new tab)
“two or more LB-102 or placebo- treated subjects experience a ≥ Grade 2 AE in the same system organ class that is not clearly unrelated to LB-102 or placebo” (opens the source at this quote in a new tab)

Secondary pharmacokinetic outcomes

“PK parameters of LB-102 and amisulpride include maximum plasma concentrations (Cmax), time to reach Cmax (Tmax), area under the plasma concentration-time curve from 0 hours to a specified time (AUC0-t), area under the plasma concentration time curve from 0 hours to 24 hours (AUC0-24), area under the plasma concentration time curve from 0 hours to infinity (AUC0-inf)” (opens the source at this quote in a new tab)

Planned sample size

“A total of 64 subjects were planned to be enrolled into the study with 8 subjects (6 active, 2 placebo) randomized for each of the 8 cohorts (exclusive of possible replacements).” (opens the source at this quote in a new tab)
“The sample size for the study was based on clinical rather than statistical rationale. No formal sample size calculations were made.” (opens the source at this quote in a new tab)

Screened, enrolled, and treated

“There were 288 subjects screened for the study. A total of 64 subjects enrolled and 224 failed screening.” (opens the source at this quote in a new tab)
“A total of 64 subjects were randomized into the study, with 48 receiving at least one dose of LB-102 and 16 receiving placebo (Table 14.1.1).” (opens the source at this quote in a new tab)

Pharmacokinetic population

“The PK Population (N= 48) included all of the subjects who were randomized, had received at least one dose of LB-102, and had at least one post-dose measureable concentration of LB-102.” (opens the source at this quote in a new tab)
“No subjects were excluded from PK analysis.” (opens the source at this quote in a new tab)

Descriptive analysis with pooled placebo

“No inferential statistics was performed, and no subgroup analysis was performed. Each cohort was evaluated separately for safety. All placebo subjects from the different cohorts were combined into a single group for summary purposes.” (opens the source at this quote in a new tab)

Disposition by cohort

Group	Randomized	Treated	Completed the study	Withdrawal by subject	Other reason
Cohort 1, 50 mg once daily	“6”	“6”	“6 (100.0%)”	“0”	“0”
Cohort 2, 10 mg once daily	“6”	“6”	“6 (100.0%)”	“0”	“0”
Cohort 3, 100 mg once daily	“6”	“6”	“6 (100.0%)”	“0”	“0”
Cohort 4, 200 mg once daily	“6”	“6”	“6 (100.0%)”	“0”	“0”
Cohort 5, 150 mg once daily	“6”	“6”	“6 (100.0%)”	“0”	“0”
Cohort 6, 50 mg twice daily	“6”	“6”	“6 (100.0%)”	“0”	“0”
Cohort 7, 100 mg twice daily	“6”	“6”	“0 (0.0%)”	“3 (50%)”	“3 (50%)”
Cohort 8, 75 mg twice daily	“6”	“6”	“5 (83.3%)”	“1 (16.7%)”	“0”
Placebo	“16”	“16”	“14 (87.5%)”	“0”	“2 (12.5%)”

Early stopping of cohort 7 (100 mg twice daily)

“No subject in Cohort 7 completed the treatment course because one subject (01S2069) withdrew from the study after receiving their morning dose on Day 2 for personal/family reasons and because 2 subjects (01S2066 and 01S2079) each had an acute dystonic reaction on Day 3.” (opens the source at this quote in a new tab)
“Treatment was halted for all subjects in Cohort 7, including the two subjects receiving placebo.” (opens the source at this quote in a new tab)

Protocol deviations

“There were no major protocol deviations reported in this study, and all deviations (30) were considered non-CSR reportable.” (opens the source at this quote in a new tab)

Demographics by cohort

Group	Age, mean (years)	Male	Black or African American	White	BMI, mean (kg/m2)
Cohort 1, 50 mg once daily	“37.2”	“2 (33.3%)”	“2 (33.3%)”	“3 (50.0%)”	“25.7”
Cohort 2, 10 mg once daily	“31.3”	“4 (66.7%)”	“3 (50.0%)”	“3 (50.0%)”	“23.9”
Cohort 3, 100 mg once daily	“35.0”	“4 (66.7%)”	“4 (66.7%)”	“2 (33.3%)”	“25.3”
Cohort 4, 200 mg once daily	“28.8”	“4 (66.7%)”	“6 (100.0%)”	“0 (0.0%)”	“24.2”
Cohort 5, 150 mg once daily	“31.0”	“4 (66.7%)”	“5 (83.3%)”	“1 (16.7%)”	“24.3”
Cohort 6, 50 mg twice daily	“31.7”	“6 (100.0%)”	“4 (66.7%)”	“2 (33.3%)”	“26.0”
Cohort 7, 100 mg twice daily	“34.8”	“5 (83.3%)”	“5 (83.3%)”	“1 (16.7%)”	“22.8”
Cohort 8, 75 mg twice daily	“44.0”	“4 (66.7%)”	“2 (33.3%)”	“4 (66.7%)”	“24.1”
Placebo	“40.1”	“12 (75.0%)”	“9 (56.3%)”	“7 (43.8%)”	“25.1”

Pharmacokinetics of LB-102 after a single dose (Part A)

Dose	n	Cmax, mean (SD), ng/mL	Tmax, median (min, max), h	Half-life, mean (SD), h	AUC0-inf, mean (SD), ng∙h/mL	CL/F, mean (SD), L/h
10 mg	“6”	“24.1 (10.728)”	“3 (3, 3)”	“13.675 (3.9375)”	“252.637 (69.857)”	“42.44 (12.598)”
50 mg	“6”	“176 (52.786)”	“3 (2, 4)”	“11.933 (1.7797)”	“1595.938 (189.1599)”	“31.7 (3.794)”
100 mg	“6”	“348.167 (141.832)”	“3.01 (1, 4)”	“14.146 (3.9617)”	“2809.785 (477.7622)”	“36.56 (6.935)”
150 mg	“6”	“596.5 (117.527)”	“3 (3, 4)”	“11.969 (1.8897)”	“4636.577 (745.7299)”	“33.05 (5.25)”
200 mg	“6”	“975.667 (253.995)”	“1.75 (1.5, 3)”	“12.997 (3.5854)”	“7002.109 (820.7252)”	“28.89 (3.381)”

Absorption, half-life, and dose proportionality after a single dose

“Following administration of a single oral dose, LB-102 was rapidly absorbed, with mean peak plasma concentrations of LB-102 obtained within 3.01 hours post-dose (median Tmax ranged from 1.75 to 3.01 hours).” (opens the source at this quote in a new tab)
“Plasma concentrations of LB-102 generally declined from peak in an apparent biphasic manner, with mean t½ ranged from 11.933 to 14.146 hours across treatment groups. Mean t½ did not appear to increase with increasing dose.” (opens the source at this quote in a new tab)
“increased in a slightly greater than dose-proportional manner.” (opens the source at this quote in a new tab)
“Apparent clearance (CL/F) appeared to decrease as dose increased (42.44 L/h to 28.89 L/h).” (opens the source at this quote in a new tab)

Pharmacokinetics of LB-102 after twice-daily dosing (Part B)

Parameter	50 mg twice daily	75 mg twice daily	100 mg twice daily
Day 1 Cmax, mean (SD), ng/mL	“125.467 (22.721)”	“267.333 (69.373)”	“325.167 (67.744)”
Day 1 AUC0-12, mean (SD), h•ng/mL	“787.967 (117.2242)”	“1524.015 (323.0305)”	“1783.039 (323.7988)”
Multiple dose, n	“6”	“5”	“-”
Multiple dose Cmax, mean (SD), ng/mL	“224 (39.8798)”	“309.4 (149.1452)”	“-”
Multiple dose AUC0-12, mean (SD), h•ng/mL	“1490.091 (130.1117)”	“2290.849 (708.461)”	“-”
Multiple dose half-life, mean (SD), h	“14.311 (3.7449)”	“-”	“-”
Clearance at steady state, mean (SD), L/h	“33.78 (3.082)”	“34.85 (8.792)”	“-”
Accumulation ratio for Cmax, mean (SD)	“1.798 (0.215)”	“1.121 (0.4118)”	“-”
Accumulation ratio for AUC, mean (SD)	“1.925 (0.3251)”	“1.472 (0.2833)”	“-”

Steady state and accumulation

“In Part B (MAD), trough concentrations of LB-102 and amisulpride plateaued before the morning dose on Day 4.” (opens the source at this quote in a new tab)
“After multiple doses, there was slight to moderate accumulation of LB-102 across dose levels with mean accumulation ratio based on Cmax after the first dose and last dose (RCmax) values ranged from 1.121 to 1.798 and with mean RAUC values ranged from 1.472 to 1.925.” (opens the source at this quote in a new tab)
“Exposure (as measured by Cmax, D7 and AUC0-12, D7) to LB-102 increased in a dose proportional manner.” (opens the source at this quote in a new tab)

Amisulpride as a minor metabolite

“As a function of Cmax, the percentage of amisulpride to LB-102 was on average about 2.5% across the doses, making amisulpride a minor metabolite of LB-102.” (opens the source at this quote in a new tab)
“In fact, amisulpride was not detected in subjects taking 10 mg LB-102 QD (Cohort 2).” (opens the source at this quote in a new tab)
“Amisulpride had a higher accumulation than LB-102 across dose levels with mean RCmax values ranged from 1.317 to 2.016 and with mean RAUC values ranged from 1.801 to 2.232.” (opens the source at this quote in a new tab)

Maximum tolerated dose

“The maximum tolerated dose of LB-102 was identified as 150 mg per day as either 150 mg QD or 75 mg BID.” (opens the source at this quote in a new tab)

Company comparison of exposure with amisulpride

“We observed the plasma exposure of 50 mg of LB-102 to be 1,648 ng*h/mL. In a previous third-party study of amisulpride, plasma exposure was reported at 667 ng*h/mL.” (opens the source at this quote in a new tab)

Effect of food on pharmacokinetics

No evidence found.

Treatment-emergent adverse events: overall

“Out of the 64 subjects, 28 subjects (50 mg QD, N=4; 10 mg QD, N=2; 100 mg QD, N=3; 200 mg QD, N=3; 150 mg QD, N=1; 50 mg BID, N=2; 100 mg BID, N=3; 75 mg BID, N=5; Placebo, N=5) experienced at least one treatment-emergent adverse event (TEAE), with a total of 43 TEAEs.” (opens the source at this quote in a new tab)
“All TEAEs were mild or moderate intensity (37 mild, 6 moderate) as individually described in Data Listing 16.2.7.” (opens the source at this quote in a new tab)
“There were no deaths or other serious AEs.” (opens the source at this quote in a new tab)

Adverse events considered definitely related to LB-102

“Of the TEAEs definitely related to study drug, there were 11 cases of elevated prolactin (≥100 µg/L; 50 mg QD, N=3; 10 mg QD, N=1; 100 mg QD, N=1; 150 mg QD, N=1; 50 mg BID, N=2; 100 mg BID, N=1; 75 mg BID, N=2), 4 cases of moderate dystonia (200 mg QD, N=1; 100 mg BID, N=2; 75 mg BID, N=1), and 1 case of mild ECG QTcF prolongation (41 msec, 200 mg LB-102 QD) that all resolved.” (opens the source at this quote in a new tab)

Acute dystonia: dose-limiting events

“Due to 2 TEAEs in the same system organ class (acute dystonic reaction), treatment was halted in all subjects taking 100 mg LB-102 BID (Cohort 7) and the 2 subjects in Cohort 7 taking placebo. As a result, the SRC concluded to reduce the dose for Cohort 8 to 75 mg LB-102 BID.” (opens the source at this quote in a new tab)
“Two (2) moderate, Grade 2 AEs (acute dystonic reaction) were experienced by 2 subjects on Day 3, 1 and 3 hours post dose, respectively.” (opens the source at this quote in a new tab)
“Subject 01S0119 (20-year-old male) was randomized and enrolled on 03 March 2020 and received 200 mg LB-102 QD in Cohort 4. The subject experienced an acute dystonic reaction on Day 1 (03 March 2020) that was definitely related to study drug.” (opens the source at this quote in a new tab)
“In subjects taking 75 mg LB-102 BID (Cohort 8), 1 subject (01S2092) similarly experienced an acute dystonic reaction on Day 3 after the first dose.” (opens the source at this quote in a new tab)

Acute dystonia: doses reported in the publication abstract

“As a result of two cases of EPS (acute dystonia) at 200 mg in the MAD portion of the study, dosing of that arm was discontinued and doses for the remaining cohort were decreased to 150 mg/day.” (opens the source at this quote in a new tab)
“There were four instances of EPS (acute dystonia), typically associated with dopamine receptor occupancy in excess of 80%, one at 100 mg QD, one at 75 mg BID, and two at 100 mg BID.” (opens the source at this quote in a new tab)

QTcF interval

“No subject reached the QT prolongation stopping criteria of an increase in QTcF interval to >500 msec for male and female subjects or an increase in QTcF of >60 msec over baseline.” (opens the source at this quote in a new tab)
“Subject 01S0116 (31-year-old female) receiving 200 mg LB-102 QD (Cohort 4) experienced an AE of increased QTcF prolongation (41 msec) at 2 hours post-dose that was definitely related to study drug (pre-dose= 417 msec; 2 hours post-dose= 458 msec). The QTcF prolongation resolved by 4 hours post-dose (437.9 msec) without any concomitant medications.” (opens the source at this quote in a new tab)
“Additionally, because QTcF interval was fairly prolonged from pre-dose values (20-46 msec) in all subjects taking 200 mg LB-102 QD (Cohort 4), the dosage for Cohort 5 was reduced to 150 mg LB-102 QD.” (opens the source at this quote in a new tab)
“There were 5 additional subjects (01S0042, 10 mg QD; 01S0063, 100 mg QD; 01S0156, 150 mg QD; 01S0165, 150 mg QD) with an increase in prolonged QTcF interval from pre-dose (40-46 msec), but none rose >450 msec.” (opens the source at this quote in a new tab)

“There was evidence of transient QT interval prolongation at the 200 mg dose, none of which resulted in clinical observation or triggered stopping criteria.” (opens the source at this quote in a new tab)

Prolactin

“Prolactin levels increased in all subjects treated with at least one dose of LB-102 (N=48) and increased to clinically significant levels (≥100µg/L) in 11 subjects. In the Placebo group, 10 subjects (out of 16) had elevated prolactin levels on at least 1 visit, but no concentration reached a clinically significant level.” (opens the source at this quote in a new tab)
“Normal prolactin levels for non-pregnant females is 4.9-23.2 µg/L and for males is 4.1-15.1 µg/L.” (opens the source at this quote in a new tab)

“LB-102 was generally safe and well-tolerated, and clinical lab values were unremarkable at all doses, save for prolactin which was transiently elevated in the majority of subjects treated with LB-102; there were no clinical observations associated with the increases in prolactin elevation.” (opens the source at this quote in a new tab)

Other adverse events considered probably or possibly related

“Of the TEAEs probably or possibly related to study drug, there were 4 cases of nausea (100 mg LB-102 QD, N=1; 200 mg LB-102, N=1; 100 mg LB-102 BID, N=1; 75 mg LB-102 BID, N=1) and 1 case of vomiting (100 mg LB-102 BID), urticaria (100 mg LB-102 QD), gastroesophageal disease (200 mg LB-102), insomnia (75 mg LB-102 BID), dizziness (75 mg LB-102 BID), and” (opens the source at this quote in a new tab)

Vital signs, laboratory results, and suicidality

“Vital signs and physical examination results were largely unchanged from baseline. Other than increases in prolactin, chemistry laboratory results were also relatively unchanged throughout study treatment. C-SSRS did not change during study treatment.” (opens the source at this quote in a new tab)
“There were no clinically significant changes in hematology laboratory results during the study.” (opens the source at this quote in a new tab)

Company summary at the doses studied in later trials

“At 50 mg and 100 mg QD, two of the doses evaluated in our Phase 2 trial (and the doses being evaluated in our Phase 3 trial) we observed no adverse events associated with QT prolongation, sedation, weight gain or EPS in our Phase 1 trial.” (opens the source at this quote in a new tab)

Summary

LB-102-001 enrolled 64 healthy adults at 1 site in the United States; 48 received LB-102, with 6 participants per dose cohort, and none had schizophrenia. Dosing lasted 1 day in Part A and up to 7 days in Part B. Part B used twice-daily dosing, and the phase 2 and phase 3 trials use once-daily dosing. The analysis was descriptive, with no inferential statistics and no formal sample size calculation. Cohort 7 (100 mg twice daily) stopped on day 3 after 2 cases of acute dystonia, so multiple-dose pharmacokinetic parameters exist for the 50 mg and 75 mg twice-daily cohorts only (6 and 5 participants). The study report attributes the shorter day 1 half-life in Part B to limited sampling between doses. The study used powder in capsule, and the NOVA-2 registry record describes a tablet; no food-effect or relative bioavailability data were found. The sources differ on 2 details: the registry record lists 15 mg for Part A cohort 2 where the study report states 10 mg, and the publication abstract places 1 dystonia case at 100 mg once daily where the study report places it at 200 mg once daily. The publication was read as an abstract because its full text is closed access.

Measurement of dopamine receptor occupancy

“The goal of this study was to measure the dopamine receptor occupancy of orally administered LB-102 at three different doses (50, 75, and 100 mg as single doses and 50 and 100 mg as multiple doses) and at different timepoints in healthy volunteers using positron emission tomography (PET)” (opens the source at this quote in a new tab)
“The relationship between RO and plasma LB-102 concentration was measured, as were safety and tolerability of LB-102 after single and multiple dose(s).” (opens the source at this quote in a new tab)

Dose selection for the phase 2 trial

“This study was conceived both as proof of concept that LB-102 would be an effective dopamine inhibitor in humans and also to inform dosing in a Phase 2 clinical study of LB-102 in schizophrenia patients.” (opens the source at this quote in a new tab)

Site and registered dates

Item	Registry record
Protocol number	“LB-102-002”
Site	“Washington University School of Medicine”
Site location	“St Louis, Missouri, United States, 63110”
Study start (actual)	“2021-01-05”
Primary completion (actual)	“2021-09-17”
Study completion (actual)	“2021-11-15”

Site and study period in the publication

“This study was conducted at the Mallinckrodt Institute of Radiology (MIR) PET facility at Washington University School of Medicine (WUSM) in St. Louis during 2020” (opens the source at this quote in a new tab)

Open-label, adaptive, four-cohort design

“An Open Label Positron Emission Tomography (PET) Study to Evaluate Dopamine Receptor Occupancy of LB-102 Administered Orally to Healthy Subjects” (opens the source at this quote in a new tab)
“This will be an adaptive study and doses in cohorts 2-4 will be determined after PET data from Cohort 1 are obtained.” (opens the source at this quote in a new tab)

“The 75 mg and 100 mg doses were determined empirically after observation of prior doses and were determined empirically with the goal of bracketing 60–80% dopamine RO.” (opens the source at this quote in a new tab)

Timing of PET scans

“All cohorts underwent four PET scans, including one baseline scan prior to administration of LB-102 followed by three post-dose scans at varying timepoints. In cohorts 1 and 2, post-dose scans started at 2.5 h, 7.5 h, and 23.5 h after dosing. For cohort 3, post-dose scans started at 2.5 h, 23.5 h, and 47.5 h after dosing. Subjects in Cohort 4 underwent post-dose scans following the final dose (day 4) of LB-102 at 2.5 h, 7.5 h, and 23.5 h after final dosing.” (opens the source at this quote in a new tab)
“PET scans were acquired over 90 min and values reported are a time-weighted average of values obtained.” (opens the source at this quote in a new tab)

Regions of interest and occupancy calculation

“Receptor occupancy in four regions of the brain (caudate, putamen, thalamus, and temporal cortex) was measured starting at 2.5, 7.5, and 23.5 h post-dose (for 50 mg and 100 mg doses) and starting at 2.5, 23.5, and 47.5 h post dose for (75 mg doses).” (opens the source at this quote in a new tab)
“There were no meaningful statistical differences between the respective methods and data obtained using the SRTM are presented as representative.” (opens the source at this quote in a new tab)

Healthy adults aged 18 to 55 years

“Sixteen healthy volunteers (7 female, 9 male) ages 18 to 55 years” (opens the source at this quote in a new tab)

Registered inclusion and exclusion criteria

“Body Mass Index (BMI) ≥ 18 and ≤ 30 kg/m2 at screening visit.” (opens the source at this quote in a new tab)
“History or presence of psychiatric or neurological disease or condition, as determined by the Investigator.” (opens the source at this quote in a new tab)
“Individuals with pacemakers, aneurysm clips, shrapnel, or other restricted implanted metallic devices will be excluded from study.” (opens the source at this quote in a new tab)
“The subject has a history of QT prolongation or dysrhythmia or a family history of prolonged QT interval or sudden death.” (opens the source at this quote in a new tab)

Doses by cohort

“In Cohort 1, all four subjects were dosed with 50 mg LB-102. In Cohort 2, all subjects were dosed with 100 mg LB-102, and in Cohort 3 all subjects were dosed with 75 mg LB-102.” (opens the source at this quote in a new tab)
“Subjects in Cohorts 1 to 3 received single doses and subjects in Cohort 4 received once daily doses over 4 days” (opens the source at this quote in a new tab)
“The 4-day dosing was designed to capture receptor occupancy under steady state conditions.” (opens the source at this quote in a new tab)

Dose reduction in the multiple-dose cohort

“Initially, all four subjects in Cohort 4 were to receive 100 mg LB-102; the first two subjects demonstrated higher than expected dopamine receptor occupancy at 100 mg QD for four days, approaching 90%. It was decided to reduce dosing to 50 mg for the final two subjects out of an abundance of caution.” (opens the source at this quote in a new tab)

Formulation and administration

“In Cohorts 1-3, a single dose of LB-102 was administered orally as a powder in capsule on day 1 of the study and in Cohort 4 once a day for four days.” (opens the source at this quote in a new tab)
“The dose was given with water and subjects had the option to eat breakfast after dosing.” (opens the source at this quote in a new tab)

Primary outcome definition

“Brain Receptor Occupancy as Measured by Positron Emission Tomography” (opens the source at this quote in a new tab)
“PET scan of D2/D3 receptor occupancy using raclopride as a tracer” (opens the source at this quote in a new tab)

Target occupancy of 60% to 80% for antipsychotic effect

“For first and most second generation antipsychotics dopamine receptor occupancy (RO) in the 60–80% range is typically desired to maximize improvements in symptoms of schizophrenia” (opens the source at this quote in a new tab)
“Importantly, this 70% RO is in the midpoint of the 60–80% range typically sought for dopamine inhibitors in the treatment of schizophrenia and shows very little variability (~10%) over the course of 24 h.” (opens the source at this quote in a new tab)

“Previous reports analyzing receptor occupancy of multiple antipsychotic drugs have found that occupancies of 60% to 80% correlate with maximum efficacy and tolerability in the treatment of schizophrenia. Receptor occupancy above 80% can be associated with an increased risk of EPS.” (opens the source at this quote in a new tab)

Occupancy thresholds for response and adverse effects: haloperidol in first-episode schizophrenia

“The likelihood of clinical response, hyperprolactinemia, and extrapyramidal side effects increased significantly as D(2) occupancy exceeded 65%, 72%, and 78%, respectively.” (opens the source at this quote in a new tab)

Occupancy with classical neuroleptics and relation to extrapyramidal syndromes

“In 22 patients treated with conventional dosages of classical neuroleptics, the D2 occupancy was 70% to 89%. Patients with acute extrapyramidal syndromes had a higher D2 occupancy than those without side effects.” (opens the source at this quote in a new tab)

Applicability of healthy volunteer occupancy to schizophrenia

“Data from studies of dopamine RO in healthy volunteers have demonstrated fidelity to data obtained in schizophrenia patients” (opens the source at this quote in a new tab)

Secondary outcome

“Safety and Tolerability as Measured by Reported Adverse Events” (opens the source at this quote in a new tab)
“Up to 14 days” (opens the source at this quote in a new tab)

Planned cohorts

“There will be 4 cohorts consisting of 4 subjects each.” (opens the source at this quote in a new tab)

Screened, enrolled, and analyzed

“Twenty-four volunteers were screened and sixteen were enrolled based on inclusion/exclusion criteria. All enrolled participants completed the study and were included in the analyses.” (opens the source at this quote in a new tab)
“Sizing of this study was based on prior experience with PET imaging studies and did not take statistical powering assumptions into account.” (opens the source at this quote in a new tab)

All enrolled participants analyzed

“A total of 64 PET scans were acquired, 4 per subject.” (opens the source at this quote in a new tab)

Completion

“No enrolled subjects dropped out of the study.” (opens the source at this quote in a new tab)

Demographics by dose group

Dose group	n	Age, years	Weight, kg	BMI, kg/m2
50 mg, single dose	“4”	“31 (4)”	“68 (7)”	“23 (1)”
75 mg, single dose	“4”	“37 (10)”	“73 (15)”	“26 (3)”
100 mg, single dose	“4”	“28 (8)”	“82 (7)”	“26 (3)”
50 mg, 4 doses	“2”	“23 (1)”	“82 (8)”	“27 (4)”
100 mg, 4 doses	“2”	“45 (11)”	“85 (3)”	“27”

Striatal occupancy at steady state

“steady-state once daily oral dosing of 50 mg LB-102 afforded striatal dopamine occupancy (RO) in the desired 60–80% range consistently over the course of 24 h.” (opens the source at this quote in a new tab)
“Single oral doses, based on prior experience and analogy to amisulpride, had RO of 60–80% at ~400 mg and the chronic dosing of LB-102 replicated this at only 50 mg.” (opens the source at this quote in a new tab)

“4 QD oral doses (steady state) of 100 mg LB-102 demonstrated D2/3 RO of 80% in caudate/putamen” (opens the source at this quote in a new tab)
“4 QD oral doses (steady state) of 50 mg LB-102 demonstrated D2/3 RO of 75% in caudate/putamen” (opens the source at this quote in a new tab)

“Under steady-state conditions, at the 50 mg dose of LB-102, the average receptor occupancy was approximately 70%, and at the 100 mg dose, it was approximately 80%.” (opens the source at this quote in a new tab)

Occupancy after single doses

“Single 50 mg, 75 mg, and 100 mg oral doses of LB-102 demonstrated dopamine D2/3 RO approaching 50%-75% in striatal regions (caudate/putamen)” (opens the source at this quote in a new tab)
“RO ranges of ~50%-80% were observed in caudate/putamen, with additional RO < 50 % in extra-striatal regions” (opens the source at this quote in a new tab)

Time course of occupancy

“We observed that single doses of LB-102 led to a linear, dose-dependent dopamine receptor occupancy that achieved maximal levels at approximately eight hours post-dose and persisted for at least 24 hours” (opens the source at this quote in a new tab)
“We observed that the receptor occupancy following the Day 4 dose was relatively consistent over 24 hours in all four volunteers.” (opens the source at this quote in a new tab)

“the observation of 40% dopamine RO a full two days after a single 75 mg dose of LB-102 was unexpected.” (opens the source at this quote in a new tab)

Relation of occupancy to plasma concentration

“Contrary to the often observed relationship between RO vs plasma concentrations, maximum dopamine RO significantly lagged maximum plasma concentration and showed little variability under steady state conditions.” (opens the source at this quote in a new tab)
“dopamine RO remains significant after plasma concentrations have dropped below 10 ng/mL.” (opens the source at this quote in a new tab)
“the relationship between plasma concentration and dopamine receptor occupancy is not linear and higher plasma concentrations of LB-102 are not always associated with higher receptor occupancy, for example, up to 80% dopamine RO with a plasma LB-102 concentration of 10 ng/mL” (opens the source at this quote in a new tab)
“Calculated SEM values for RO were < 3%, markedly lower than the SEMs observed for PK measurements for which they approached 20%.” (opens the source at this quote in a new tab)

Implication for dosing frequency and phase 2 dose selection

“Results from the study did suggest that once-a-day dosing of LB-102 could be effective in treating schizophrenia (amisulpride is typically dosed twice daily).” (opens the source at this quote in a new tab)

“Cohort 4 data indicates that at steady state dosing, 50 - 75 mg LB-102 QD will achieve 65-75% D2/3 RO.” (opens the source at this quote in a new tab)

Treatment-emergent adverse events

Adverse event	Occurrence	Relation to treatment
Headache	“3”	“Possibly”
Dizziness	“1”	“Possibly”
Restlessness	“2”	“Unlikley”
Anxiety	“1”	“Unlikley”
Acid reflux	“1”	“Not Related”
Nasal congestion	“1”	“Not Related”
Sore throat	“1”	“Not Related”

Severity and extrapyramidal symptoms

“Treatment-related adverse events reported by participants in this study were mild or moderate in severity, similar to previous reports. No episodes of acute dystonia were reported or observed, consistent with a prior study in healthy adults in which acute EPS was observed at higher doses of LB-102 (75 mg twice daily i.e. 150 mg/day).” (opens the source at this quote in a new tab)

“Two instances of restlessness occurred during the multidose cohort. These were likely not akathisia and instead a consequence of the five day stay in the research unit.” (opens the source at this quote in a new tab)

Prolactin

“Prolactin was measured at baseline and at last visit, average prolactin at baseline was 7.5 ng/mL (SD 2.9) which increased, on average, to 30.8 (SD 13.0) at final visit.” (opens the source at this quote in a new tab)
“there were no clinically observable effects of prolactin elevation (for example: galactorrhea or menstrual irregularities).” (opens the source at this quote in a new tab)

Electrocardiogram and laboratory findings

“There were no abnormal ECG readings” (opens the source at this quote in a new tab)
“No changes in blood cell counts or tests of liver or kidney function nor suicidal ideation were observed.” (opens the source at this quote in a new tab)

Summary

LB-102-002 was an open-label study in 16 healthy adults at 1 site, with 4 participants in each single-dose cohort and 2 participants at each steady-state dose. The sample size was set without statistical power assumptions, and the authors list the small number of steady-state observations as a limitation. Occupancy was measured with a raclopride tracer after 1 dose or after 4 once-daily doses; occupancy in people with schizophrenia, after longer treatment, and at 5-HT7 receptors was not measured. The article text gives approximate occupancy values, and the per-participant values by region and time point are in its figures and supplementary tables. Steady-state occupancy at 50 mg is described as approximately 70% in the article and the Form 10-K and as 75% in the 2021 poster. The article states that the study was conducted during 2020, and the registry record lists a study start in January 2021. The registry description of twice-daily dosing for 5 days in the final cohort differs from the once-daily dosing for 4 days reported in the article. The article and the 2021 poster assign the mean ages of the 75 mg and 100 mg single-dose groups in opposite order. LB Pharmaceuticals funded the study, and the competing interests statement lists 3 authors as company employees and 3 as consultants to the company.