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LY3045697: Results from two randomized clinical trials of a novel inhibitor of
aldosterone synthase
#MMPMID28814143
Sloan-Lancaster J
; Raddad E
; Flynt A
; Jin Y
; Voelker J
; Miller JW
J Renin Angiotensin Aldosterone Syst
2017[Jul]; 18
(3
): 1470320317717883
PMID28814143
show ga
INTRODUCTION: LY3045697 is a potent and selective aldosterone synthase (CYP11B2)
inhibitor that was developed as a safer alternative to mineralocorticoid receptor
antagonists. Effects of LY3045697 on aldosterone and cortisol synthesis, as well
as potassium ion homeostasis, were evaluated in two clinical studies in healthy
subjects. MATERIALS AND METHODS: Two incomplete, placebo-controlled
crossover-design clinical studies examined safety, pharmacodynamics, and
pharmacokinetics under single and repeated dose conditions in healthy subjects.
Pharmacodynamics was assessed following oral potassium challenge and intravenous
adrenocorticotropic hormone procedures with spironolactone 25 mg/d as an active
comparator. RESULTS: A total of 51 subjects participated in the two studies,
which included 38 males and 13 females (of non-childbearing potential), from
18-65 years old. LY3045697 caused rapid dose and concentration-dependent
unstimulated plasma aldosterone concentration reduction seen as early as 4 h
after the first dose at dose levels as low as 1 mg, and reaching near complete
suppression at high doses. The potency (IC(50)) decreased significantly upon
multiple dosing. After eight days of dosing, post-adrenocorticotropic hormone
challenge plasma aldosterone concentration increase was dose-dependently blunted
by LY3045697 with high potency with a dose as low as 0.1 mg resulting in
substantial effect, and with an overall IC(50) of 0.38 ng/ml. Minor reductions in
cortisol were observed only at the top dose of 300 mg. LY3045697 is generally
safe and tolerated, and exhibits linear pharmacokinetics. CONCLUSIONS: LY3045697
is a potent and highly selective aldosterone synthase inhibitor with selectivity
for CYP11B2, offering a substantial potential advantage over previous aldosterone
synthase inhibitors evaluated in the clinic.
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