Iwfal CNCE unlike CCXI failed its P2 diabetic nephropathy primary but did find some biomarker effects. Curious if you find any of these biomarker changes pertinent?
Abstract: [FR-PO899] Effect of CTP-499 on Biomarkers Associated with Chronic Kidney Disease in Patients with Type 2 Diabetes
Ara Aslanian, PhD, Kristine Hogan, Philip B. Graham, PhD, LuAnn A. Sabounjian, Lijun Wu, PhD. Concert Pharmaceuticals, Lexington, MA, United States.
Background:
The progression of CKD is intimately related to the pathophysiology of tubulointerstitial damage, as the severity of tubule injury predicts long-term clinical outcomes. Tubule cell dysfunction is mediated by pro-fibrotic and pro-inflammatory factors, thus therapeutic intervention that ameliorates these processes may be beneficial. CTP-499 is a novel, deuterium-containing, multi-subtype selective PDE inhibitor that had protective effects on renal function in patients with type 2 diabetic kidney disease in a 48-week Phase 2 clinical study. We have shown in non-clinical studies that CTP-499 has anti-fibrotic and anti-inflammatory activities consistent with inhibition of specific PDE subtypes. To investigate the mechanism of CTP-499 in diabetes-induced CKD, we examined a panel of biomarkers from this Phase 2 clinical trial patient population.
Methods: Results:
At 48 weeks, biomarkers associated with the severity of tubulointerstitial damage were significantly reduced in patients receiving CTP-499 compared to placebo, including IL-18 and clusterin (25% and 42%, respectively, P < 0.05; N = 65 CTP-499, 57-58 Placebo). In general, treatment-dependent changes were more prominent in patients with a baseline UACR = 850 mg/g, a group that shows more rapid decline in renal function than patients with lower baseline UACR. In this subgroup, the tubule injury markers MCP-1 and N-OPN were reduced by 34% and 55%, respectively (P < 0.05, N = 32 CTP-499, 27 Placebo) in addition to IL-18 and clusterin. Also, the extracellular matrix proteins fibronectin, collagen IV, and laminin, which undergo increased deposition in CKD, were significantly reduced in CTP-499-treated patients compared to placebo (13-68%; P < 0.05, N=65 CTP-499, 57-58 Placebo). These data are consistent with results showing that CTP-499 reduced tubule cell apoptosis and collagen deposition in the rat UUO kidney fibrosis model.
Conclusions:
Collectively, these data suggest CTP-499 has protective effects on renal tubules in diabetic kidney disease, and that anti-fibrotic mechanisms may contribute to this activity. These results further support continued development of this novel agent for the treatment of CKD.
Course: Annual Meeting: Abstract Sessions
Session: CKD: Epidemiology and Outcomes - II
Date/Time: Friday, November 14, 2014
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