A First in Human, Single-dose Escalation Study of LY2562175 In Healthy Subjects

The drug to be given, LY2562175, is a new, investigational compound that may
eventually be used in the treatment of high cholesterol (too high percentage of
fat in the blood). High cholesterol is associated with a higher risk of
developing Coronary Heart Disease (CHD).

Cholesterol can build up in the walls of your arteries. This buildup of
cholesterol is called plaque. Over time, plaque can cause narrowing of the
arteries. This is called atherosclerosis, or hardening of the arteries.
Narrowing of your coronary arteries due to plaque can stop or slow down the
flow of blood to your heart. When the arteries narrow, the amount of
oxygen-rich blood is decreased. This is called coronary heart disease (CHD). By
lowering the percentage of fat in the blood, LY2562175 reduces the risk of high
cholesterol and subsequently the risk of CHD.

The purpose of the study is to investigate how safe the compound is and how
well the compound is tolerated. The study will also investigate how quickly and
to what extent the drug is absorbed, metabolised (broken down into smaller
parts) and eliminated from the body (this is called pharmacokinetics). This
study is not intended to improve your health, but is necessary for the further
development of the drug.

Design:
a double-blind, placebo-controlled, single-dose escalation study with two
groups of nine healthy male and/or female (postmenopausal/sterilized) subjects
each receiving a single oral dose of LY2562175 or placebo (six verum and three
placebo) on three occasions; a wash-out of at least fourteen days between
dosing within a cohort
Procedures and assessments

Screening and follow-up:
clinical laboratory, creatinine, hepatic profile, blood glucose, total
cholesterol, vital signs, physical examination, ECG (in triplicate at
screening);
at eligibility screening: medical history, oral temperature and respiratory
rate height, weight, BUN, PT, aPTT, alcohol and drug screen, HBsAg, anti HCV,
anti-HIV 1/2 and pregnancy test (females only); urinalysis and drug screen to
be repeated upon each admission

Observation period:
3 periods, each period in clinic from -17 h up to 48 h after drug administration

Blood sampling:
for pharmacokinetics of LY2562175 in plasma: pre-dose and 0.25, 0.5, 1, 2, 4,
6, 7, 8, 11, 12, 24, 36, and 48 h post-dose
for pharmacodynamics of fasting lipid panel (TG, LDL-C, VLDL-C, directed HDL,
HDL-C and TC): once on Day 1 and 24 h post-dose
for pharmacodynamics of bile acid panel: once on Day 1 and 24 h post-dose and
at follow-up

Safety assessments :
adverse events: throughout the study; physical examination, biochemistry,
haematology, PT and aPTT and vital signs: once on Day 1 and 24 and 48 h
post-dose (including oral temperature and respiratory rate: pre-dose); weight:
once on Day 1; ECG (in triplicate): pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 h
post-dose;

Bioanalysis:
analysis of plasma LY2562175 samples using LC/MC method by PRA
analysis of fasting lipid panel using a clinical laboratory method by PRA
analysis of bile acid panel using a validated method by PRA

Study medication
Active substance: LY2562175
Activity : potent farnesoid x receptor agonist
Indication : dyslipidemia
Strength : 5, 25 and 100 mg
Dosage form: capsules

Treatments
Group 1
period 1: a single oral dose of 5 mg LY2562175 or placebo on Day 1 in the
fasted state
period 2: a single oral dose of 75 mg LY2562175 or placebo on Day 1 in the
fasted state
period 3: a single oral dose of 400 mg LY2562175 or placebo on Day 1 in the
fasted state

Group 2
period 1: a single oral dose of 25 mg LY2562175 or placebo on Day 1 in the
fasted state
period 2: a single oral dose of 200 mg LY2562175 or placebo on Day 1 in the
fasted state
period 3: a single oral dose of 600 mg LY2562175 or placebo on Day 1 in the
fasted state

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