A STUDY OF THE SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF LY3045697 AFTER MULTIPLE ORAL DOSING IN HEALTHY SUBJECTS

LY3045697 is a new investigational compound that may eventually be used for the
treatment of chronic kidney disease. LY3045697 is not registered as a drug but
has been given to humans before.

Primary:
To evaluate the safety and tolerability of LY3045697 after multiple oral dosing
in healthy subjects

Secondary:
To investigate the pharmacokinetics of LY3045697 after multiple oral dosing in
healthy subjects

This is a randomized, double blind, placebo and positive comparator
(spironolactone) controlled, multiple dose escalating, incomplete cross-over
design study in 24 healthy males and females of non-child bearing potential.
Subjects will be divided into 2 groups of 12 subjects, which will be dosed in
an alternating fashion during 3 separate admission periods per group. There
will be a wash-out period of at least 7 days between dosing periods for an
individual subject. Dosing will be in the fed state. Within each treatment
period, subjects will be randomized 8:2:2 to LY3045697:placebo:spironolactone,
and each subject will have received 2 LY3045697 levels and either placebo or
spironolactone at the end of the study. To maintain the blind, the study will
be conducted in a double dummy format, with subjects taking a solution vial
(either LY3045697 or placebo) and a capsule (either spironolactone or placebo)
on each day of dosing. There will be an oral K+ challenge on Day 7 and an
intravenous (IV) ACTH challenge on Day 8 in each period.

Multiple oral doses of LY3045697 or placebo,
spironolactone or placebo

The study where LY3045697 was given to humans for the first time is still
ongoing. Thus far, subjects were treated with a single oral dose of 0.1 mg, 0.3
mg and 1 mg of LY3045697. The most reported adverse events include tiredness,
headache, common cold and abdominal pain. All adverse events were of mild
intensity and none were considered to be related to the study medication by the
investigator.

Animal studies showed that LY3045697 was well tolerated in rats for 28 days at
very high doses (1000 mg/kg). In monkeys this was the case for doses of 30
mg/kg. In both species there was a slight increase in weight and volume of the
liver and adrenal glands. LY3045697 may reduce a substance in your blood called
aldosterone. Aldosterone helps your body to regulate sodium and potassium
levels and blood pressure. LY3045697 may cause increased potassium levels,
which could cause abnormal heart rhythm. LY3045697 may also cause your blood
pressure to drop. LY3045697 may reduce a substance in your blood called
cortisol which helps your body survive stressful situations. Lack of cortisol
can result in abdomen pain, nausea and vomiting, muscles aches, loss of
appetite and weight, lack of energy and a low blood pressure. LY3045697 may
reduce the amount of sodium in your blood. You may also experience increased
urination.
LY3045697 has not been studied in animals for any effects on pregnancy or on
sperm function. In women who get pregnant while taking LY3045697, there may be
bad effects on the embryo or fetus.
Women of childbearing potential or who are breast-feeding must not take
LY3045697.

The most frequently reported adverse effect of the registered drug
spironolactone is hyperkalemia (abnormally high levels of potassium in the
blood). Symptoms of hyperkalemia are muscle weakness, nausea, dizziness and
headache. Please refer to page 8 of the instruction manual of spironolactone
for more information on adverse effects.

With the dose(s) used in this study no serious adverse effects are expected.
The occurrence of known or other effects cannot be excluded. All potential
drugs cause adverse events to some extent. Therefore you should take into
account that some risks are still unknown at this moment.