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2015 ; 4
(6
): 1325-47
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gab.com Text
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English Wikipedia
Horizon 2020 in Diabetic Kidney Disease: The Clinical Trial Pipeline for Add-On
Therapies on Top of Renin Angiotensin System Blockade
#MMPMID26239562
Perez-Gomez MV
; Sanchez-Niño MD
; Sanz AB
; Martín-Cleary C
; Ruiz-Ortega M
; Egido J
; Navarro-González JF
; Ortiz A
; Fernandez-Fernandez B
J Clin Med
2015[Jun]; 4
(6
): 1325-47
PMID26239562
show ga
Diabetic kidney disease is the most frequent cause of end-stage renal disease.
This implies failure of current therapeutic approaches based on renin-angiotensin
system (RAS) blockade. Recent phase 3 clinical trials of paricalcitol in early
diabetic kidney disease and bardoxolone methyl in advanced diabetic kidney
disease failed to meet the primary endpoint or terminated on safety concerns,
respectively. However, various novel strategies are undergoing phase 2 and 3
randomized controlled trials targeting inflammation, fibrosis and signaling
pathways. Among agents currently undergoing trials that may modify the clinical
practice on top of RAS blockade in a 5-year horizon, anti-inflammatory agents
currently hold the most promise while anti-fibrotic agents have so far
disappointed. Pentoxifylline, an anti-inflammatory agent already in clinical use,
was recently reported to delay estimated glomerular filtration rate (eGFR) loss
in chronic kidney disease (CKD) stage 3-4 diabetic kidney disease when associated
with RAS blockade and promising phase 2 data are available for the pentoxifylline
derivative CTP-499. Among agents targeting chemokines or chemokine receptors, the
oral small molecule C-C chemokine receptor type 2 (CCR2) inhibitor CCX140
decreased albuminuria and eGFR loss in phase 2 trials. A dose-finding trial of
the anti-IL-1? antibody gevokizumab in diabetic kidney disease will start in
2015. However, clinical development is most advanced for the endothelin receptor
A blocker atrasentan, which is undergoing a phase 3 trial with a primary outcome
of preserving eGFR. The potential for success of these approaches and other
pipeline agents is discussed in detail.