Atrasentan with Current Optimal Therapy Reduces Albuminuria in Type 2 Nephropathy

Atrasentan, an oral endothelin receptor antagonist, reduces albuminuria and improves the lipid profile in patients with diabetic nephropathy when given with optimal therapy using an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB), a recent study shows.

“It has a nearly 40 percent reduction of albuminuria over the full 12-week stretch [of the trial], with minimal side effects,” Dick de Zeeuw, MD, PhD, professor and chair of the department of clinical pharmacology at University Medical Center Groningen in The Netherlands, reported at the 50th Congress of the European Renal Association—European Dialysis and Transplant Association in Istanbul. Besides being a marker of kidney damage, albuminuria is also a promoter of kidney damage and a cardiovascular risk factor, possibly because it indicates generalized vascular and endothelial dysfunction.

Atrasentan is an investigational compound that blocks the effect of endothelin-1 at the endothelin-A receptor. Endothelin-1 is a peptide that constricts blood vessels in the kidney and has a negative effect on kidney function.

Although optimal therapy with compounds that target the renin-angiotensin-aldosterone system, such as ACE inhibitors and ARBs, help protect the kidneys and reduce albuminuria, some risk persists. “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,” de Zeeuw said.

He presented the results of two parallel, double blind, placebo-controlled, multinational phase 2b studies (total n = 211) in which patients with type 2 diabetes and nephropathy received maximum tolerated labeled doses of ACE inhibitors or ARBs. They also received atrasentan at 0.75 mg/day (n = 78), 1.25 mg/day (n = 83), or placebo (n = 50) to evaluate the efficacy of the compound in lowering albuminuria and its safety. At baseline, patients in the three groups all had macroalbuminuria, as determined by the urinary albumin-to-creatinine ratio (878 mg/g, 826 mg/g, and 671 mg/g, respectively).

At the end of the 12-week trials, patients experienced sustained reductions in the primary endpoint of the urinary albumin-to-creatinine ratio: a 36 percent geometric mean decrease in the group receiving the 0.75-mg dose and a 44 percent decrease at the 1.25-mg dose versus a 2 percent increase in the placebo group (both p < 0.001 vs. placebo). Just over half of the patients in each group experienced a decrease of more than 30 percent in urinary albumin-to-creatinine ratio. Significant decreases (p < 0.001) were evident as early as 2 weeks for the atrasentan groups. There were also decreases in low-density lipoprotein cholesterol and triglyceride levels in the active drug groups.

Adverse events similar to placebo

The rates of adverse events were similar among the three groups. Peripheral edema occurred in 35 percent of patients in the 0.75-mg group and in 42 percent in the 1.25-mg and placebo groups. Diarrhea and constipation occurred in 13, 21, and 14 percent of the people in the three arms, respectively. Adverse events caused 8 percent of participants to drop out of the low-dose group and 15 percent to discontinue the study in the high-dose group. Edema was the most common reason for participants to discontinue the study. None discontinued in the placebo group.

Estimated GFRs dropped by less than 1 mL/min per 1.73 m2 in both of the atrasentan groups, but these changes were no different from those in the placebo group (p = 0.412 and p = 0.355 for the 0.75-mg and 1.25-mg doses, respectively).

A phase 3 randomized, double-blind, placebo-controlled trial is planned using the 0.75-mg daily dose of atrasentan, which was determined in the phase 2b trials to have the best balance of efficacy and safety. The trial will investigate renal as well as cardiovascular outcomes when atrasentan is given on top of current optimal standard of care to patients with type 2 diabetic nephropathy. It is planned to involve more than 4000 patients and to run for 4 years.

As noted by de Zeeuw, other endothelin antagonists have been tested in type 2 diabetes and have lowered albuminuria. A trial of avosentan was stopped early because of fluid retention leading to congestive heart failure. He said that this adverse effect was blamed on the high dose of the drug, and current trials are looking at a lower dose that might retain the albumin-lowering effects but avoid fluid retention.

July 2013 (Vol. 5, Number 7)