Rising Single Dose Safety, Tolerability and Pharmacokinetic Study of SCH 900229 in Healthy Adult Subjects

The drug to be given, SCH900229, is a new investigational compound that may
eventually be used for the treatment of Alzheimer*s disease. This compound is
still in the development phase. Alzheimer*s disease is characterized by
specific plaques in the brain, composed primarily of certain proteins. These
plaques contribute to the progress of the disease. The experimental drug used
in this study, SCH900229, has shown (in animals) to significantly reduce this
specific protein in the blood, brain and spinal fluid with possible beneficial
effects on disease course in Alzheimer*s disease, both on the effects on the
nervous system and on complaints.

- to evaluate the safety and tolerability of a single oral dose of SCH 900229
administered to healthy adult volunteers
- to characterize the pharmacokinetic (PK) profile of SCH 900229 in plasma of
healthy adult volunteers after a single oral dose
- to evaluate the potential effects of a high fat diet on the safety,
tolerability, bioavailability and pharmacokinetics of SCH 900229 administered
to healthy adult volunteers as a single oral dose
- to evaluate the relative bioavailability of SCH 900229 when administered as
blend in capsule formulation
- to evaluate the relative bioavailability of SCH 900229 when administered as
an active (liquid emulsion) in capsule formulation
- to explore the utility of whole blood Hes1 gene expression levels as a safety
biomarker
- to explore the utility of pooled hair follicle-based Notch signalling gene
expression levels as a safety biomarker.

Design:
a randomized, placebo-controlled, third party blind, rotating panel, single
ascending dose study with four cohorts of ten healthy male and/or female
(postmenopausal/sterilized) subjects each receiving a single oral dose of SCH
900229 or placebo (eight verum and two placebo) in three periods(two periods
for Cohort 4); in the third period one cohort will receive SCH 900229 after a
high fat meal, the other two panels will receive SCH 900229 in capsule form;
one panel will receive a blend in capsule formulation and the other an active
liquid emulsion in capsule formulation; a washout of approximately two weeks
between successive dose levels; in the first dose level two subjects will be
dosed at least one day prior to the rest of the cohort (one verum and one
placebo).

Procedures and assessments
Screening and follow-up:
clinical laboratory, occult blood, vital signs (including oral temperature),
physical examination, 12-lead ECG; at eligibility screening: medical history,
elbow breadth measurement, height, weight, drug screen, FSH and estradiol
(females only), HBsAg, anti HCV, anti-HIV 1/2 and pregnancy test (females
only); drug screen, clinical laboratory, 12-lead ECG and vital signs (including
oral temperature) to be repeated upon each admission.

Observation period:
3 periods (2 periods for Cohort 4), first and second period in clinic from -17
h up to 72 h after drug administration followed by ambulatory visits on Days 6
and 8 and third period in clinic from -17 h up to 72 h after drug
administration with optional ambulatory visits on Days 6 and 8.

Blood sampling:
for pharmacokinetics of SCH 900229 in plasma: pre-dose and 0.25, 0.5, 0.75, 1,
1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, 24, 36, 48, 72 (all periods), 120 (Periods 1
and 2 only) and 168 h (Periods 1 and 2 only, optional in period 3) post-dose
for pharmacodynamics of A*40 in plasma: pre-dose and 1, 2, 4, 6, 10, 14, 24, 48
and 72 h post-dose and once on Day 8 (Periods 1 and 2 only)
for metabolite profiling in plasma: pre-dose and 1, 3, 6, 12, 24, 36, 48, 72
and 120 h post-dose (Period 2 only)
for Hes1 gene expression: once on Days -1 to 4 and once on Day 8 (Periods 1 and
2)
for genotyping: pre-dose (Period 1 only)

Urine sampling:
For metabolite profiling: pre-dose and interval 0-48 h post-dose (in 24 h block
intervals; Period 2 only).

Hair sampling:
15 hair follicles will be collected at Predose (0 hour), and at 8, 24, 48, and
72 hours post-dose. An additional sample will be collected on Day 8.

Safety assessments:
adverse events: throughout the study; clinical laboratory: pre-dose and once on
Days 2-4 (all periods) and once on Day 8 (Periods 1 and 2); occult blood: on
all stool samples from Days -1 to 4 (all periods) and once on Day 8 (Periods 1
and 2 only); 12-lead ECG: pre-dose and 1, 2, 4, 8, 12, 24, 48 and 72 h
post-dose and once on Day 8 (Periods 1 and 2 only); vital signs (including oral
temperature): pre-dose and 1, 2, 4, 8, 12, 24, 48 and 72 h post-dose (all
periods) and once on Days 6 and 8 (Periods 1 and 2 only, optional for Period
3).

Bioanalysis:
- analysis of plasma SCH 900229 samples using a validated method by Sponsor
- analysis of plasma A*40 samples using a validate method by Sponsor
- genotyping by Sponsor
- metabolite profiling in plasma and urine using validated methods by Sponsor
- analysis of Hes1 gene expression using validated method by Sponsor

Study Medication:
Active substance: SCH 900229
Activity: *-secretase (GS) inhibitor
Indication: Alzheimer*s disease (AD)
Strength: 0.1 and 1 mg/mL (oral solution); 2 mg (powder capsule) and 12 mg
(liquid emulsion capsule)
Dosage form: oral solution, powder capsule (Period 3) and liquid emulsion
capsule (Period 3)

Treatments:
Cohort 1
Period 1: a single oral dose of A mg SCH 900229 or placebo on Day 1
Period 2: a single oral dose of D mg SCH 900229 or placebo on Day 1
Period 3: a single oral dose of G mg SCH 900229 or placebo on Day 1*

Cohort 2
Period 1: a single oral dose of B mg SCH 900229 or placebo on Day 1
Period 2: a single oral dose of E mg SCH 900229 or placebo on Day 1
Period 3: a single oral dose of H mg SCH 900229 or placebo on Day 1*

Cohort 3
Period 1: a single oral dose of C mg SCH 900229 or placebo on Day 1
Period 2: a single oral dose of F mg SCH 900229 or placebo on Day 1
Period 3: a single oral dose of I mg SCH 900229 or placebo on Day 1*

Cohort
Period 1: a single oral dose of J mg SCH 900229 or placebo on Day 1
Period 2: a single oral dose of K mg SCH 900229 or placebo on Day 1


*In this period subjects will participate in two formulations investigations
and a food effect investigation. The assignment of investigations of (Food or
Formulation) to a particular cohort will be determined based upon available PK,
safety and tolerability results from previous periods and considerations

Formulation 1: SCH 900229 blend in capsule or placebo
Formulation 2: SCH 900229 active (liquid emulsion) in capsule or placebo
Food effect: SCH 900229 or placebo in the fed state

Procedures: pain, light bleeding, heamatoma, possibly an infection.

Medication: As SCH900229 will be administered to man for the first time in this
study, adverse effects in man have not been reported up to now. In previous
studies with mice, in which SCH900229 was administered daily in (very) high
doses over a period of one month, an increase of mean body weight was observed.
In previous studies with dogs (dosing for 8 days) there were abnormal stool
findings in higher doses (lack of stool, soft/loose, red streaked stool). In a
one month study with dogs these stool findings were also present.