Atrasentan Significantly Reduces Proteinuria in IgA Nephropathy Patients: Phase III ALIGN Trial
Key Insights
Interim analysis of the Phase III ALIGN trial shows atrasentan significantly reduced proteinuria in high-risk IgA nephropathy (search) patients after 36 weeks.
The study demonstrated a 36.1 percentage point reduction in the urinary protein-to-creatinine ratio compared to placebo (P<0.001).
Atrasentan's safety profile was favorable, with fluid retention being the most common adverse event but not leading to trial discontinuation.
An interim analysis of the Phase III ALIGN trial has revealed that atrasentan significantly reduces proteinuria in patients with high-risk immunoglobulin A (IgA) nephropathy. The study, published in The New England Journal of Medicine, showed that 36 weeks of treatment with atrasentan led to a clinically meaningful reduction in proteinuria compared to placebo, with a favorable safety profile. The trial is ongoing to evaluate the long-term impact of atrasentan on eGFR decline.
The study enrolled adult patients with biopsy-proven IgA nephropathy (search), a total urinary protein excretion of at least 1 g per day, and an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m2 of body-surface area. Participants were randomized to receive either atrasentan at a dose of 0.75 mg per day or a matched placebo for 132 weeks. The primary outcome was the change in 24-hour urinary protein-to-creatinine ratio from baseline to week 36.
Significant Reduction in Proteinuria
Results from the first 270 patients who completed the week 36 visit showed a geometric mean percentage change in the urinary protein-to-creatinine ratio of -38.1% in the atrasentan group compared to -3.1% in the placebo group. This represents a significant between-group difference of -36.1 percentage points (95% confidence interval, -44.6 to -26.4; P<0.001).
"In this prespecified interim analysis of an ongoing phase 3 clinical trial involving patients with IgA nephropathy (search), 36 weeks of treatment with atrasentan (0.75 mg per day) as compared with placebo reduced the urinary protein-to-creatinine ratio by 36.1 percentage points (P<0.001)," the study authors wrote.
Safety Profile
The percentage of patients reporting adverse events was similar between the atrasentan and placebo groups. Fluid retention was more common in the atrasentan group (11.2%) compared to the placebo group (8.2%), but it did not lead to treatment discontinuation in any patients.
Atrasentan's Mechanism and Prior Studies
Atrasentan is an endothelin receptor type A (search) receptor inhibitor. Previous studies have indicated that atrasentan can lower albuminuria and is associated with reductions in low-density lipoprotein cholesterol and triglycerides. A prior study in The Lancet found that atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease.
Implications for IgA Nephropathy Treatment
IgA nephropathy (search) is the most common primary glomerular disease worldwide, with an incidence rate of 2.5 cases per 100,000 person-years. The current study authors noted, "Although the final results of the ALIGN trial will be needed to confirm that the proteinuria reduction seen with atrasentan translates to a reduction in eGFR decline, there is growing confidence in the urinary protein-to-creatinine ratio as a surrogate biomarker in IgA nephropathy."