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.