A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, SINGLE ASCENDING DOSE STUDY TO EVALUATE SAFETY, TOLERABILITY, PHARMACOKINETIC AND FOOD EFFECT OF BCI 838 AND AN OPEN-LABEL MINIDOSE BIOAVAILABILITY STUDY TO COMPARE SEVERAL BCI-632 PRO-DRUG CANDIDATES IN HEALTHY MALE SUBJECTS

The drugs to be given, BCI-838, BCI-1038, BCI-1206 and BCI-1283 are new,
investigational compounds that may eventually be used for the treatment of mood
disorders. Mood disorders are mental disorders in which the mood or emotion of
a person is seriously disturbed (for example depression).
BCI-632, the active form of BCI-838, BCI-1038, BCI-1206 and BCI-1283, is a
specific and potent antagonist of the metabotropic glutamate receptors 2 and 3.
BCI-632 could potentially produce new brain tissue, including neurons, which
are responsible for transmitting signals in the brain.
It is expected that BCI-838, BCI-1038, BCI-1206 and BCI-1283 could have a
positive effect on mood disorders.
These new compounds are not registered as a drug. BCI-838 has been given to
humans before. BCI-1038, BCI-1206 and BCI-1283 are given to humans for the
first time.

- to evaluate the safety and tolerability of BCI-838 following oral
administration of single doses of BCI-838 in healthy male subjects
- to determine the pharmacokinetics of BCI-838 and metabolite BCI-632 following
oral administration of single ascending doses of BCI-838 in healthy male
subjects
- to determine the effect of food on the pharmacokinetics of BCI-838 and
metabolite BCI 632 following a single oral administration of BCI-838 in healthy
male subjects
- to evaluate and compare the relative bioavailability and pharmacokinetics of
metabolite BCI-632 following oral administration of several pro-drug candidates

Design:
This is a single-center study in healthy male subjects consisting of a single
ascending dose (SAD) part with an integrated food effect (FE) part with a
randomized, double-blind, placebo-controlled study design, and a minidose
bioavailability part with an open-label study design to compare several BCI-632
pro-drug candidates in healthy male subjects.
The SAD part will consist of 3 groups of 8 healthy male subjects each (Groups 1
and 2), each participating in 2 periods. Group 4 consists of 1 period. In each
group, 6 subjects will receive a single dose of BCI-838 and 2 subjects will
receive a single dose of placebo.
The FE part is integrated in the SAD part and will consist of 1 group of 8
healthy male subjects participating in 2 periods (Group 1) with a fixed
sequence. In the first period, 6 subjects will receive a single oral dose of
BCI 838 in the fasted state and 2 subjects will receive a single dose of
placebo in the fasted state. In the second period, 6 subjects will receive a
single oral dose of BCI 838 in the fed state and 2 subjects will receive a
single dose of placebo in the fed state. Subjects will receive the same study
treatment (BCI-838 or placebo) in both the fasted and fed periods.
The minidose bioavailability part consist of 1 group of 6 subjects a single
dose of 3 different BCI-632 pro-drugs (BCI-1038, BCI-1206 and BCI-1283) in 3
periods with a fixed sequence.

Procedures and assessments
Screening: demographics, body weight and height (including Body Mass Index
(BMI) calculation), medical history, drug and alcohol screen, HBsAg, anti HCV
and anti-HIV 1/2, clinical laboratory (including clinical chemistry, hematology
and urinalysis), physical examination, vital signs (including supine systolic
and diastolic blood pressure, pulse rate, respiratory rate and body
temperature), 12 lead electrocardiogram (ECG) (in triplicate), adverse events
(AEs) and previous medication
Each admission: clinical laboratory (including clinical chemistry, hematology
and urinalysis), drug and alcohol screen, AEs, and previous and concomitant
medication
Follow-up: clinical laboratory (including clinical chemistry, hematology and
urinalysis), physical examination, vital signs (including supine systolic and
diastolic blood pressure, pulse rate, respiratory rate and body temperature),
12 lead ECG (in triplicate), AEs and concomitant medication

Observation period: Groups 1 and 2: two periods in the clinic, each being from
Day -1 until 48 h (Day 3) after drug administration
Group 3: three periods in the clinic from Day -1 until 48 h (Day 3) after drug
administration. For Group 2 Period 2 and group 4 up to 72 h (Day 4) after drug
administration.

Blood sampling: for pharmacokinetics (PK) of BCI-838 (only for Groups 1 and 2)
and metabolite BCI-632 in plasma: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12,
16, 24, 36 and 48 hours post-dose. At 72 h post-dose an extra PK blood sample
will be collected for Period 2 of Group 2 and group 4 only. Safety assessments:
AEs: recorded from the time the Informed Consent Form is signed until
completion of the follow up visit; clinical laboratory (including clinical
chemistry, hematology and urinalysis): pre-dose and 12 and 48 hours post-dose;
vital signs (including supine systolic and diastolic blood pressure, pulse
rate, respiratory rate and body temperature) and 12-lead ECG (in triplicate):
pre-dose and 1, 2.5, 3.5, 4.5, 7, 12.5, 23, 35 and 47 hours post-dose
Bioanalysis: Analysis of plasma PK samples for BCI-838 and metabolite BCI-632
by the bioanalytical laboratory at PRA International using a validated liquid
chromatography-mass spectrometry/mass spectrometry method

Study Medication
Active medication:
Active substance: BCI-838
Activity: antagonism of metabotropic glutamate receptors 2 and 3
Indication: mood disorders or cognitive impairment
Dosage form: oral capsule

Active medication:
Active substance: BCI-1038
Activity: antagonism of metabotropic glutamate receptors 2 and 3
Indication: mood disorders or cognitive impairment
Dosage form: oral capsule

Active medication:
Active substance: BCI-1206
Activity: antagonism of metabotropic glutamate receptors 2 and 3
Indication: mood disorders or cognitive impairment
Dosage form: oral capsule

Active medication:
Active substance: BCI-1283
Activity: antagonism of metabotropic glutamate receptors 2 and 3
Indication: mood disorders or cognitive impairment
Dosage form: oral capsule

Placebo:
Substance: microcrystalline cellulose
Activity: none
Indication: not applicable
Dosage form: oral capsule

Criteria for evaluation
Safety: AEs, vital signs, 12-lead ECG, clinical laboratory and physical
examination
PK: plasma concentrations of BCI-838 and metabolite BCI-632; PK parameters in
plasma


Treatments
SAD part
Group 1(integrated FE part):
Period 1: a single oral dose of 30 mg BCI-838 (n=6) or placebo (n=2) on Day 1
in the fasted state
Period 2: a single oral dose of 30 mg BCI-838 (n=6) or placebo (n=2) on Day 1
in the fed state

Group 2:
Period 1: a single oral dose of 100 mg BCI-838 (n=6) or placebo (n=2) on Day 1
in the fasted state
Period 2: a single oral dose of 300 mg BCI-838 (n=6) or placebo (n=2) on Day 1
in the fasted state

Minidose bioavailability part
Group 3:
Period 1: a single oral dose of 1 mg BCI-1038 (n=6) on Day 1 in the fasted state
Period 2: a single oral dose of 1 mg BCI-1206 (n=6) on Day 1 in the fasted state
Period 3: a single oral dose of 1 mg BCI-1283 (n=6) on Day 1 in the fasted state

For each individual subject, there will be a washout of at least 5 days between
dosing in each period.

In a previous study in healthy volunteers, with single doses up to 3 mg,
BCI-838 was considered safe and well tolerated. The adverse events that were
reported were mild, transient and were considered not related to study drug.
As BCI-1038, BCI-1206 and BCI-1283 will be administered to man for the first
time in this study, to date adverse effects in man has not been reported.
The insertion of the indwelling canula and the venepuncture may cause some
pain, and sometimes lead to a bruise, but the actual collection of blood will
not be painful. Light bleeding and possibly an infection may occur. However,
chances these complications will occur are limited.