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2017 ; 5
(1
): e00292
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Novel SGLT2 inhibitor: first-in-man studies of antisense compound is associated
with unexpected renal effects
#MMPMID28596840
van Meer L
; van Dongen M
; Moerland M
; de Kam M
; Cohen A
; Burggraaf J
Pharmacol Res Perspect
2017[Feb]; 5
(1
): e00292
PMID28596840
show ga
The antisense compound ISIS 388626 selectively inhibits renal glucose
reabsorption by inhibiting the sodium-glucose cotransporter-2 (SGLT2) mRNA
expression. It is developed as an insulin-independent treatment approach for type
2 diabetes mellitus (T2DM). The safety, tolerability, pharmacokinetics, and
pharmacodynamics after subcutaneous administration of the drug were planned to be
evaluated in healthy volunteers in a single-ascending-dose study (50-400 mg) and
a multiple-ascending-dose study (6 weeks; weekly doses of 50-400 mg with loading
dose regimen of three doses during the first week). The study was halted early
because increases in serum creatinine occurred in the subjects participating in
the 100 mg multiple-dose cohort. The pronounced changes in serum creatinine were
accompanied by increased urinary excretion of beta-2-microglobulin and KIM1. The
possible mechanisms for these findings remain elusive and are in contrast to
preclinical findings as comparable treatment with ISIS 388626 of animals did not
reveal similar changes. Although exposure was limited, there was an indication
that glucosuria increased upon active treatment. Before the concept of
antisense-mediated blocking of SGLT2 with ISIS 388626 can be explored further,
more preclinical data are needed to justify further investigations.