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.