Study of the Safety, Tolerability, Pharmacokinetics and Effect on Renal Potassium Clearance after Multiple Oral Dosing of LY2623091 in Healthy Volunteers

The drug to be given LY2623091 is a new, investigational compound that may
eventually be used for the treatment of chronic kidney disease. This compound
is in the development phase. Chronic kidney disease is characterized by ongoing
deterioration of kidney function. Ultimately, total loss of kidney function
may occur, requiring patients to use dialysis or renal transplant to survive.
Current treatments do not counter the deterioration of kidney function
sufficiently. Consequently, new therapies are urgently needed for these
patients. The experimental drug used in this study, LY2623091 is being
developed to safely improve kidney function in chronic kidney disease patients,
using a novel mechanism.

Primary:
- to investigate the safety and tolerability of the study drug after multiple
oral dosing in healthy volunteers

Secondary:
- to investigate the effect of the study drug on potassium clearance upon oral
potassium challenge after multiple oral dosing in healthy volunteers
to further explore the pharmacokinetics of the study drug after multiple oral
dosing in healthy volunteers

Exploratory:
- blood samples for DNA extraction will be collected and stored from all
subjects in this study to enable exploratory future analyses and
pharmacogenomic evaluations related to the compound activity/exposure during
later phase clinical development

Design:
a double-blind (for the study drug), placebo-controlled, four treatment,
two-period incomplete crossover, multiple-ascending dose study in two groups of
sixteen healthy male and/or healthy female (postmenopausal/sterilized) subjects
each receiving the study drug (eight subjects) or eplenerone (four subjects) or
placebo (four subjects) once daily for seven days, in the fed state on Day 1-6
and in the fasted state on Day 7; a washout of at least seven days between
dosing periods; each subject will follow a restricted sodium/potassium diet
from Day 2 until the end of the dosing period; a potassium challenge will take
place on Day 7 in fasted state

Procedures and assessments
Screening and follow-up:
clinical laboratory (including urinary albumin/creatinine ratio at screening),
vital signs, physical examination, weight, urine alcohol and drug screen,
12-lead ECG; at eligibility screening: medical history, height, temperature,
respiratory rate, serum pregnancy test (females only), HBsAg, anti HCV,
anti-HIV 1/2; clinical laboratory, directed physical examination, vital signs,
urine pregnancy test (females only), urine alcohol and drug screen to be
repeated upon each admission

Observation period:
2 periods, each period in clinic from -41 h drug administration on Day 1 up to
72 h after drug administration on Day 7; in each period, subjects will be on a
restricted 150 mEq/day sodium and 125 mEq/day potassium diet on Days 2 - 7

Blood sampling:
for pharmacokinetics of the study drug in plasma: pre-dose and 1, 2, 3, 4, 8,
12 and 24 h post-dose on Day 1, pre-dose and 1, 2, 3, 4, 8 and 12 h post-dose
on Day 6 and 24, 48 and 72 h post-dose on Day 7, during the 3rd dose level the
following additional samples will be taken: 1, 2, 3, 4, 8 and 12 h post-dose on
Day 7
for pharmacodynamics of sodium and potassium: -1.5 h pre-oral K+ challenge and
0 h (baseline) and 1, 2, 3, 4 and 5 h post-oral K+ challenge on Day 7
for future DNA extraction and genomics: pre-dose on Day 1 (Period 1 only)

Urine sampling:
for pharmacodynamics of sodium and potassium: 24 h pool starting at -2 h on Day
6 (relative to oral K+ challenge) and intervals -2 to -1, -1 to 0 h pre-oral K+
challenge and 0-1, 1-2, 2-3, 3-4, and 4-5 h post-oral K+ challenge on Day 7
for pharmacodynamics of aldosterone: 24 h pool starting at -2 h on Day 6
(relative to oral K+ challenge)

Safety assessments:
adverse events: throughout the study; clinical laboratory: pre-dose on Days 1,
2, 4 and 8; 12-lead ECG (in triplicate): pre-dose and at approximately Tmax and
24 h post-dose on Days 1 and 7; vital signs (blood pressure in triplicate):
pre-dose and 1, 4 and 24 h post-dose on Days 1, 3 and 7

Bioanalysis:
analysis of plasma LY2623091 samples using a validated method by PRA
analysis op serum and urine potassium and sodium samples using a clinical
chemistry method by PRA
analysis of urine aldosterone samples using a non-validated method by PRA
DNA extraction and genomics by Sponsor

Active substance: LY2623091
Comparator: eplerenone

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