PET dopamine receptor occupancy study in healthy volunteers: design

“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) with 11C raclopride as a radiotracer.” (opens the source at this quote in a new tab)
“Sixteen healthy volunteers (7 female, 9 male) ages 18 to 55 years and with a body mass index (BMI) between 18 and 30 kg/m2 were enrolled in the study.” (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)

Striatal D2/D3 receptor occupancy at steady state by dose

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

“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)

Time course of receptor occupancy relative 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 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)
“Additionally, it is possible that this prolonged receptor occupancy is due to a metabolite of LB-102, though data to date indicate that LB-102 is not appreciably (<5%) metabolized.” (opens the source at this quote in a new tab)

“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)

“A correlation between dopamine RO and plasma LB-102 concentration could not be established.” (opens the source at this quote in a new tab)

Target occupancy window of 60% to 80%

“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.” (opens the source at this quote in a new tab)
“Receptor occupancy above 80% can be associated with an increased risk of EPS.” (opens the source at this quote in a new tab)

“This aligns with PET data showing that while 50 mg achieves approximately 70% D2/D3 occupancy, 100 mg exceeds 80%.” (opens the source at this quote in a new tab)
“Notably, the level of receptor occupancy with LB-102 100 mg was not accompanied by a disproportionate increase in any antipsychotic-induced parkinsonism, suggesting LB-102 maintains a favorable therapeutic index even at high levels of receptor engagement.” (opens the source at this quote in a new tab)

Occupancy compared with published amisulpride doses

“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)

“The dopamine receptor occupancy levels seen in the imaging trial at 50 mg of LB-102 are approximately equivalent to those observed with 300 to 400 mg of amisulpride.” (opens the source at this quote in a new tab)

“This modification allows LB-102 to attain therapeutically relevant levels of D2/D3 receptor occupancy (60%-80%) over 24 hours at 5- to 8-fold lower systemic exposures, also enabling once-daily dosing.” (opens the source at this quote in a new tab)

PET study limitations

“Limitations of this study include a small number of RO observations at steady state but allowed bracketing 50 and 100 mg.” (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)

Prolactin elevation in healthy volunteers

“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)

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

“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)

“Prolactin elevation, a common laboratory finding of most antipsychotic drugs that act as dopamine antagonists that is believed to be the result of inhibition of dopamine receptors in the pituitary, was observed at all those doses.” (opens the source at this quote in a new tab)

Prolactin elevation in NOVA-1

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

QTc interval in healthy volunteers

“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)

“Additionally, because QTcF interval was fairly prolonged from pre-dose values (20- 46 msec) in all healthy volunteers 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)
“1 case of mild ECG QTcF prolongation (458 msec, 200 mg LB-102 QD)” (opens the source at this quote in a new tab)
“At the highest dose (200 mg LB-102), QTcF prolongation was noted; however, predefined stopping criteria were not met.” (opens the source at this quote in a new tab)

“There were no abnormal ECG readings; the average change in QTcf from baseline was -1 ms.” (opens the source at this quote in a new tab)

QTc interval in NOVA-1

Parameter	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)	Placebo (n = 108)
QTc, mean (SD) change from baseline to day 28, millisecond	“4.9 (13.39)”	“4.3 (12.55)”	“5.4 (9.44)”	“1.2 (12.56)”
Mean change ≥30 millisecond, No. participants (%)	“5 (4.7)”	“1 (0.9)”	“1 (2.8)”	“1 (0.9)”
Mean change ≥60 millisecond, No. participants (%)	“0”	“0”	“0”	“0”

“Stopping criteria were not met at any dose level.” (opens the source at this quote in a new tab)

Concentration-QTc modeling and a thorough QT study

No evidence found.

Preclinical behavioral models

“LB-102 had equivalent or better results than similar doses of amisulpride in the LMA model of hyperactivity.” (opens the source at this quote in a new tab)
“In our head-to-head preclinical rat model of cognition, the Novel Object Recognition model, and in a mouse model of stereotypy or excessive repetition, the Apomorphine Induced Climbing model, we observed that the effects of treatment with LB-102 were statistically indistinguishable from that of amisulpride.” (opens the source at this quote in a new tab)

“In scPCP treated rats in a catalepsy test to measure EPS potential, no catalepsy was observed and LB-102 and LB-103 were indistinguishable from amisulpride” (opens the source at this quote in a new tab)

Preclinical receptor occupancy in mice

“Dopamine D2/3 receptor occupancies in mice, presented below, resulting from 100 mg/kg oral doses of LB-102 and amisulpride in mice were determined to be 68% and 38%, respectively, consistent with greater Log P and increased plasma concentrations of LB-102 observed in a Phase 1 clinical study” (opens the source at this quote in a new tab)

Preclinical pharmacokinetic, receptor occupancy, and efficacy model

“Direct measurement of rodent brain concentrations indicates that blood brain barrier permeation is rate limiting and that brain concentrations lag behind and then persist beyond observed plasma concentrations.” (opens the source at this quote in a new tab)
“As modeled in rodents, a 30 mg/kg dose of LB- 102 achieves D2 occupancy of 74% at peak occupancy and provides for 16 out of 24 hours of D2 occupancy when analyzed as the Area Under the Response Curve (AURC).” (opens the source at this quote in a new tab)

“Receptor occupancy and behavioral responses are delayed relative to plasma concentrations and persist much longer than predicted by plasma levels.” (opens the source at this quote in a new tab)