AbbVie, a global, research-based biopharmaceutical company, has initiated a phase III clinical study called SONAR (Study Of Diabetic Nephropathy with Atrasentan) to assess the effects of the investigational compound atrasentan - when added to standard of care - on progression of kidney disease in patients with stage 2 to 4 chronic kidney disease (CKD) and type 2 diabetes. SONAR is a large, multinational, double-blind, placebo-controlled clinical study that is expected to enroll more than 4,000 patients with diabetic nephropathy.

This study will evaluate atrasentan's impact on renal outcomes, such as the onset of end-stage renal disease (ESRD), as defined by need for chronic dialysis, transplant or death due to renal failure progression.

The initiation of the phase III study follows results from phase IIb studies, which were presented during a late breaking clinical trials scientific session at the 2013 European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Congress in Istanbul, Turkey.

"There is a pressing need for new medications to treat nephropathy in patients with type 2 diabetes, who have a high risk to end up in dialysis," said Dick de Zeeuw, MD, Ph.D., professor and chair of the Department of Clinical Pharmacology and Department of Nephrology at the University of Groningen, the Netherlands, and co-chair of the SONAR steering committee. "Phase II studies of atrasentan in this patient population have shown encouraging results, and we look forward to further evaluating this investigational treatment in the phase III SONAR study."

Diabetic nephropathy, or diabetic kidney disease, is a common complication of diabetes and the leading cause of CKD in the developed world. Albuminuria - protein in the urine, as measured by urine albumin-to-creatinine ratio (UACR) - is the main sign of diabetic nephropathy. As kidney function decreases, the level of protein in the urine rises, leading to further damage to the kidney.iv Previous research has suggested that endothelin receptors play a role in this process and drugs that target this receptor system, such as atrasentan, may have the potential to delay progression of CKD.

"We are committed to improving renal outcomes for patients with type 2 diabetes, where there is significant unmet need," said James Stolzenbach, Ph.D., divisional vice president, dyslipidemia and renal, AbbVie. "If validated in phase III, atrasentan has the potential to provide a novel treatment option for type 2 diabetic kidney disease patients worldwide."

The phase IIb studies of atrasentan were conducted to evaluate the efficacy and safety of atrasentan in lowering albuminuria in subjects with type 2 diabetes and nephropathy receiving maximum tolerated labeled doses of angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB). Two parallel, double-blind, placebo-controlled, multinational studies were conducted: one in Japan with 58 patients and a second in the US, Canada and Taiwan with 153 patients. Findings from the 12-week studies of two doses of atrasentan (0.75 mg, n=78; 1.25 mg, n=83) vs. placebo (n=50) showed sustained reductions in UACR (primary endpoint): 36 per cent in the 0.75 mg, 44 per cent in 1.25 mg group vs. increase of two per cent in placebo group (P<0.001).

Additionally, as secondary endpoints: a more than 30 per cent albuminuria reduction was observed in 51 and 55 percent of the atrasentan subjects, respectively (P=0.001). Changes in estimated glomerular filtration rate (eGFR), another important measure of kidney function, were measured  compared to placebo in both groups (0.75mg= -0.81/min/1.73m2; p=0.412 and 1.25mg= -0.91 ml/min/1.73m2; p=0.355), and did not change significantly compared to placebo. In the phase II b studies, the observed adverse events were similar among the three treatment and placebo groups.  The most commonly observed adverse events included peripheral edema (35 per cent in 0.75mg arm, 42 per cent in 1.25 mg arm vs. 42 per cent on placebo), diarrhoea and constipation (13 per cent in 0.75mg arm, 21 per cent in 1.25 mg arm vs. 14 per cent on placebo). There were no significant differences in the rate of peripheral edema or diarrhea and constipation among the treatment and placebo arms. A small percentage of subjects discontinued the study due to adverse events (8 per cent on 0.75 mg, 15 per cent on 1.25mg vs. 0 on placebo), with edema as the most commonly cited reason. Importantly, the study concluded that the 0.75 mg dose of atrasentan administered orally once daily showed the best efficacy-safety balance, informing the dosing of atrasentan selected for further investigation in the phase III clinical study.

Atrasentan is an investigational compound that belongs to a class of drugs known as selective endothelin-A receptor antagonists, which block the effect of endothelin-l (ET-l), a peptide that constricts blood vessels in the kidney to negatively impact kidney functions. Atrasentan is a highly selective endothelin-A receptor antagonist that was discovered and is being developed internally at AbbVie.

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