A Phosphodiesterase Inhibitor in Development for Diabetic Kidney Disease

CTP-499 may be a new tool for delaying diabetic kidney disease and ultimately ESRD…. 

Diabetic kidney disease is a leading cause of end-stage renal disease (ESRD) in the U.S. One of the first-line therapeutic options for delaying this complication is an ACE inhibitor. While these agents offer effective means for delaying the progression of diabetic kidney disease, they are not 100% effective in all patients therefore additional pharmacological options are desired.

In this phase II, multi-center, placebo-controlled trial, researchers at Concert Pharmaceuticals assessed CTP-499 – a phosphodiesterase inhibitor – in patients with diabetic kidney disease. The primary endpoint of this study was the change in urinary albumin-to-creatinine ratio after 24 week intervals of CTP-499 therapy. Secondary outcomes analyzed serum creatinine (SCr) levels as well as biomarkers of fibrosis.

Although the primary outcome of this study was not reached, researchers observed a favorable trend in urinary albumin-to-creatinine ratio after 48 weeks of CTP-499 therapy when compared to placebo – with urinary albumin-to-creatinine ratio increasing from 24 mg per gram from baseline compared to 223 mg per gram in study participants who received placebo (P = 0.097).

CTP-499 had a positive impact on serum creatinine (SCr) at 48 weeks. In study participants receiving CTP-499, the average SCr had increased by 0.08 mg/dL less than placebo – corresponding to a 38% improvement in SCr (0.13 mg/dL compared to 0.21 mg/dL in placebo group, P=0.057). In those receiving placebo, 10.3% experienced a ≥ 50% increase in SCr after 48 weeks compared only 1.5% of study participants who received the intervention (P = 0.026).

Statistically significant changes in 2 fibrotic biomarkers – urinary fibronectin and plasma collagen IV – were found at 48 weeks. When compared to placebo, study participants receiving CTP-499 for 48 weeks had 52% less urinary fibronectin and 18% less plasma collagen IV (P=0.0081 and P=0.022, respectively). It wasn’t until 48 weeks that significant changes in the biomarkers fibronectin and collagen IV were found – leading researchers to believe that CTP-499 works in anti-fibrotic pathway – as fibrosis is a relatively slow process.

CTP-499 was generally well-tolerated among study participants with the most common adverse effects being gastrointestinal in nature. No serious adverse events attributed to the study drug were reported.

• CTP-499 is a selective phosphodiesterase inhibitor which may be a new tool for delaying the progression of diabetic kidney disease and ultimately end-stage renal disease
• CTP-499 may protect against large spikes in serum creatinine levels as well as reduce fibrosis via a novel mechanism of action
• While larger clinical trials are needed during the next phase of clinical studies (Phase III), results from this study offer promising hope of a new treatment option for managing this debilitating and life-threatening condition