A DOUBLE-BLIND, ASCENDING SINGLE AND MULTIPLE DOSE, SAFETY, TOLERABILITY, PHARMACOKINETIC, PHARMACODYNAMIC AND FOOD EFFECT STUDY OF EVP 0962 IN HEALTHY VOLUNTEERS

The drug to be given, EVP-0962, is a new, investigational compound that may
eventually be used to slow disease progression in patients with Alzheimer*s
disease (AD).The prevalence of diseases with learning and memory defects in
people of 65 years and older is approximately one in 10 people. Thus, diseases
with learning and memory defects represent a steadily growing problem of our
aging societies.
In Alzheimer*s disease (AD) brain cells die in areas of the brain that are
important for memory. One reason may be due to large fibers that are formed in
the brain, which are toxic to the brain cells. Abeta42 is a naturally occurring
protein in the human brain from which large fibers are formed. Abeta42 is
affected by gamma secretase, a protein that is found in the brain. Reducing
gamma secretase reduces the production of Abeta42 and thus reduces the
production of toxic large fibers. EVP-0962 is developed to treat Alzheimer*s
disease by reducing gamma-secretase, and thus the production of large toxic
fibers. Reducing the toxic Abeta42 may slow the progression of the disease and
thus delay the onset of the learning and memory defects seen in Alzheimer*s
Disease.

Primary :
to evaluate the safety and tolerability of EVP-0962 after single and multiple
ascending dose administrations in healthy subjects

Secondary :
to determine the pharmacokinetic profile of single and multiple oral doses of
EVP-0962 and to assess the pharmacokinetic profile of the acyl glucuronide
metabolite of EVP-0962
to assess the pharmacodynamic effects of EVP-0962 on the central nervous system
using quantitative electroencephalogram analysis and a subjective mood
measurement
to assess whether the bioavailability of EVP-0962 is affected by food

Design
A double-blind, randomized, placebo-controlled study, consisting of a single
ascending dose (SAD) with integrated food effect part, and a multiple ascending
dose (MAD) part. In the SAD part, Cohorts 1 and 2 with 8 subjects (6 subjects
on active and 2 on placebo) will be treated with escalating doses in an
alternating panel design with a washout of at least 14 days between dose
administrations. In the first dose cohort, for risk mitigating purposes,
initially 2 subjects (one active, one placebo) will be dosed and after a
24-hour safety monitoring window, the remainder of the first cohort will be
dosed. Cohort 3 with 8 subjects (6 subjects on active and 2 on placebo) will be
treated with one dose level; In the MAD part, 5 groups of 12 subjects (9
subjects on active and 3 on placebo) and 1 group of 12 elderly subjects (9
subjects on active and 3 on placebo) will be treated with escalating sequential
doses.

Procedures and assessments SAD part:
Screening :
demographics, medical history, clinical laboratory (including clinical
chemistry, hematology and urinalysis), pregancy test (females), fecal occult
blood test, physical examination (including height and body weight), vital
signs (including supine systolic and diastolic blood pressure, pulse rate, oral
body temperature and respiration rate), 12-lead electrocardiogram (ECG),
screening electroencephalogram (EEG), drug and alcohol screen, HBsAg, anti HCV,
anti-HIV 1/2, adverse events (AEs), previous and concomitant medication

Admission :
clinical laboratory (including clinical chemistry, hematology and urinalysis),
drug and alcohol screen, physical examination, vital signs (including supine
systolic and diastolic blood pressure, pulse rate, oral body temperature and
respiration rate), pregancy test (females), 12 lead ECG, AEs, previous and
concomitant medication

Follow-up:
clinical laboratory (including clinical chemistry, hematology and urinalysis),
fecal occult blood test, physical examination, vital signs (including supine
systolic and diastolic blood pressure, pulse rate, oral body temperature and
respiration rate), 12-lead ECG, AEs and concomitant medication

Observation period:
Groups 1 and 2: three periods in the clinic, each being from Day -1 until 48 h
(Day 3) after drug administration;Group 3: one period in the clinic from Day -1
until 48 h (Day 3) after drug administration

Blood sampling:
for pharmacokinetics (PK) of EVP-0962 and its acyl glucuronide metabolite in
plasma: each period at pre dose and at 0.5, 1, 2, 3, 4, 6, 8, 24, 36 and 48 h
post-dose
for potential future biomarkers analysis including amyloid peptides: each
period at pre dose and 1, 2, 4, 8 and 24 h post-dose

Urine sampling:
for PK of EVP-0962 and its acyl glucuronide metabolite: each period at pre-dose
and in the following collection intervals 0 4, 4- 8, 8-12, 12-24 and 24-48 h
post-dose
a sample of urine will be frozen for potential future analysis

Pharmacodynamic tests:
quantitative EEG (qEEG): each period at pre-dose and at 1, 2, 3, 4, 6, 8 and 24
h post dose
Bond and Lader Visual Analogue Scale (VAS): each period at pre-dose and at 1,
2, 4, 8 and 24 h post-dose

Safety assessments:
AEs: recorded from the time the Informed Consent Form (ICF) is signed until
completion of the follow up visit; clinical laboratory (including clinical
chemistry, hematology and urinalysis): each period at 48 h post-dose; vital
signs (including supine systolic and diastolic blood pressure, pulse rate, oral
body temperature and respiration rate): each period at pre-dose and at 1, 2, 3,
4, 5, 6, 8, 24 and 48 h post-dose; 12-lead ECG: each period at 1, 4, 8, 24, and
48 h post-dose, physical examination: each period at 48 h post dose

Bioanalysis:
analysis of plasma and urine samples for EVP 0962 and its acyl glucuronide
metabolite using validated methods by the Bioanalytical Laboratory of PRA

Procedures and assessments MAD part:
Screening and follow-up:
clinical laboratory, fecal occult blood, full physical examination, vital
signs, ECG; at eligibility screening: medical history, screening EEG, pregnancy
test (females only), , drug screen, urine alcohol test, HBsAg, anti HCV,
anti-HIV 1/2; drug screen and urine alcohol test, physical exam, clinical
laboratory, 12 lead ECG, pregnancy test (females only), and vital signs to be
repeated upon admission

Observation period:
one period in clinic from 17 h before the first dose administration on Day 1
until 72 h after the last dose administration on Day 14

Blood sampling:
for PK of EVP-0962 and its acyl glucuronide metabolite in plasma: pre-dose and
0.5, 1, 2, 3, 4, 6, 8, 24, 36 and 48 h post-dose on Days 1 and 14; additional
trough samples: pre dose on Days 7, 10 and 13
analysis including amyloid peptides: each period at pre dose and 1, 2, 4, 8 and
24 h post dose on Days 1 and 14

Urine sampling:
for PK of EVP-0962 and its acyl glucuronide metabolite: pre-dose and in the
following collection intervals 0 4, 4-8, 8 12, 12-24 and 24-48 h post-dose on
Days 1 and 14
a sample of urine will be frozen for potential future analysis

Pharmacodynamic tests
qEEG: pre-dose and 1, 2, 3, 4, 6, 8 and 24 h post-dose on Days 1 and 14
Bond and Lader VAS: pre-dose and 1, 2, 4, 8 and 24 h post dose on Days 1 and 14

Safety assessments:
adverse events: throughout the study; vital signs (including supine systolic
and diastolic blood pressure, pulse rate, oral body temperature and respiration
rate), 12-lead ECG: 1, 2, 3, 4, 5, 6, 8, 24 and 48 h post-dose on Days 1 and
14, and pre-dose on Days 7, 10 and 13; body weight: pre dose on Days 1 and 14;
clinical laboratory (including clinical chemistry, hematology and urinalysis):
pre dose on Days 7 and 14 in Groups 4-8, and pre-dose on Days 4 and 10 in
Groups 6-8 (for ALAT and ASAT); fecal occult blood test: once on Days 3, 6, 9
and 12


Bioanalysis:
analysis of plasma and urine samples for EVP 0962 and its acyl glucuronide
metabolite using validated methods by the Bioanalytical Laboratory of PRA

Treatments
SAD part: single oral dose administration of EVP-0962 or matching placebo, as
follows:
Cohort 1
Period 1 : 10 mg EVP 0962 or matching placebo in fasted conditions
Period 2 : 50 mg EVP 0962 or matching placebo in fasted conditions
Period 3 : 200 mg EVP 0962 or matching placebo in fasted conditions

Cohort 2
Period 1 : 20 mg EVP 0962 or matching placebo in fasted conditions
Period 2 : 100 mg EVP 0962 or matching placebo in fasted conditions
Period 3 : 100 mg EVP 0962 or matching placebo in fed conditions

Cohort 3 : 400 mg EVP 0962 or matching placebo in fasted conditions

MAD part: multiple oral dose administration of EVP-0962 or matching placebo, as
follows:
Cohort 1 20 mg EVP 0962 or matching placebo in fasted or fed conditions*
Cohort 2 50 mg EVP 0962 or matching placebo in fasted or fed conditions*
Cohort 3 100 mg EVP 0962 or matching placebo in fasted or fed conditions*
Cohort 4 200 mg EVP 0962 or matching placebo in fasted or fed conditions*
Cohort 5 MTD mg EVP 0962 or matching placebo in fasted or fed conditions*
(elderly cohort)
* Dose administration in either fasted or fed conditions will be determined
after completion of Cohort 2 in the SAD part

The dosis in Cphort 8 will be determined based on the maximum tollerated dose
in Groups 4-7, with a maximum of 400 mg.

Study Medication
Active substance : EVP 0962
Activity : Gamma secretase modulator (GSM)
Indication : Alzheimer*s disease/cognitive deficit
Strength : 10, 50 100 mg doses or placebo in formulated tablets
Dosage form : formulated tablets of EVP-0962 or placebo

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