AbbVie Initiates Phase 3 Study of Its Investigational Compound Atrasentan on Renal Outcomes in Patients with Diabetic Nephropathy

-- AbbVie presents results of Phase 2b studies

NORTH CHICAGO, Illinois, May 20, 2013 /PRNewswire/ -- AbbVie (NYSE: ABBV) announced today the initiation of a Phase 3 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.  The 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.[i]

The initiation of the Phase 3 study follows results from Phase 2b studies, which were presented today 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.[ii]

"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, M.D., 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 2 studies of atrasentan in this patient population have shown encouraging results, and we look forward to further evaluating this investigational treatment in the Phase 3 SONAR study."

Diabetic nephropathy, or diabetic kidney disease, is a common complication of diabetes and the leading cause of CKD in the developed world.  In the US, approximately 40 percent of patients with diabetes develop diabetic nephropathy.  Albuminuria - protein in the urine, as measured by urine albumin-to-creatinine ratio (UACR) - is the main sign of diabetic nephropathy.[iii] 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.[i]

"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 3, atrasentan has the potential to provide a novel treatment option for type 2 diabetic kidney disease patients worldwide."

About Phase 2b Studies

The Phase 2b 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 percent in the 0.75 mg, 44 percent in 1.25 mg group vs. increase of 2 percent in placebo group (P<0.001).[ii]

Additionally, as secondary endpoints:

• A more than 30 percent albuminuria reduction was observed in 51 and 55 percent of the atrasentan subjects, respectively (P=0.001).[ii]
• 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.[ii]

In the Phase 2b studies, the observed adverse events were similar among the three treatment and placebo groups.  The most commonly observed adverse events included peripheral edema (35 percent in 0.75mg arm, 42 percent in 1.25 mg arm vs. 42 percent on placebo), diarrhea and constipation (13 percent in 0.75mg arm, 21 percent in 1.25 mg arm vs. 14 percent on placebo).  There were no significant differences in the rate of peripheral edema or diarrhea and constipation among the treatment and placebo arms.[ii] 

A small percentage of subjects discontinued the study due to adverse events (8 percent on 0.75 mg, 15 percent on 1.25mg vs. 0 on placebo), with edema as the most commonly cited reason.[ii]

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 3 clinical study.[ii]

About SONAR Study

SONAR is a randomized, double-blind, parallel, placebo-controlled, multicenter study designed to assess the effects of atrasentan (0.75 mg administered orally once a day) on renal outcomes in patients with type 2 diabetic nephropathy (diabetic kidney disease) while they continue to be treated with the current standard of care: the maximum tolerated labeled daily dose of a RAS inhibitor, such as an ACE inhibitor or an ARB, and a diuretic.[i]  

Inclusion criteria for patients includes estimated GFR (another important indicator of kidney disease progression) of 25 to 75 mL/min/1.73 m2, UACR >300 and <5,000 mg/g, and systolic blood pressure within 110 and 160 mgHg.[i]

The primary endpoint will evaluate the effect of atrasentan on time to doubling of serum creatinine or the onset of ESRD, as defined by need for chronic dialysis, transplant or death due to renal failure. Secondary endpoints will assess the effects of atrasentan on urine albumin excretion, eGFR and cardiovascular events including cardiovascular death, heart attack and stroke.  Quality of life evaluations also will be conducted.[i]

After initial screening, patients will be enrolled in a run-in period to optimize RAS inhibitor and diuretic doses.  Eligible patients will then enter an enrichment period, in which they will receive atrasentan 0.75 mg/day for six weeks to determine their UACR response and to assess tolerability of atrasentan.  Approximately 3,150 responders (UACR reduction > 30 percent from baseline) and approximately 1,000 non-responders (UACR < 30 percent reduction from baseline) will then be randomized 1:1 into a double-blind treatment period, which will continue for approximately 48 months.[i]

About Diabetic Nephropathy

Diabetic nephropathy is kidney disease or damage that is a common complication of diabetes.[iv] Worldwide, approximately 171 million people are living with diabetes and the global burden is expected to double between 2000 and 2030.[v] Complications add greatly to the already substantial costs of medical care for patients with type 2 diabetes.[vi] 

In the US, diabetic kidney disease occurs in approximately 40 percent of all patients with diabetes.[iii] Diabetes is the most common cause of kidney failure or ESRD, accounting for nearly 44 percent of new cases in the US.[vii] The number of people with diabetes continues to rise and as a result, the number of people with kidney failure caused by diabetes is growing.[iii]  Some experts predict that diabetes might soon account for half the cases of kidney failure.[vii]

About Atrasentan

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.

About AbbVie

AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. In 2013, AbbVie employs approximately 21,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

[i] Clinical Study Protocol M11-352. AbbVie. Date Accessed: April 1, 2013.

[ii] European Renal Association - European Dialysis and Transplantation Association (ERA-EDTA). Oral Presentation 034932, "The Selective Type A Endothelin Antagonist Atrasentan Reduces Residual Albuminuria in Patients with Type 2 Diabetes and Nephropathy."

[iii] Temporal Trends in the Prevalence of Diabetic Kidney Disease in the United States. The Journal of the American Medical Association. Date Accessed: October 28, 2011.

[iv] Diabetic Nephropathy. Cleveland Clinic. Available at: http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/nephrology/diabetic-nephropathy/. Date Accessed: April 22, 2013.

[v] IDF Diabetes Atlas: Global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Atlas. Date Accessed: May 2, 2013.

[vi] Medical Care Costs Associated With Progression of Diabetic Nephropathy. Diabetes Care. Date Accessed:  May 2, 2013.

[vii] Kidney Disease of Diabetes. National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC). Accessed:  May 2, 2013