Phase III ALIGN Trial Shows Atrasentan Significantly Reduces Proteinuria in High-Risk IgA Nephropathy Patients

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An interim analysis of the Phase III ALIGN trial (NCT04573478) demonstrated that 36 weeks of treatment with atrasentan significantly lowered proteinuria in patients with high-risk immunoglobulin A (IgA) nephropathy with a favorable safety profile compared to placebo, according to data published by The New England Journal of Medicine.^1,2 The trial is ongoing to determine the longer-term efficacy of atrasentan in lowering eGFR decline as a key secondary outcome, which will be presented after all patients in the main stratum finish the double-blind treatment duration of 136 weeks.

“In this prespecified interim analysis of an ongoing phase 3 clinical trial involving patients with IgA nephropathy, 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. “This benefit is clinically meaningful, especially in the context of a high-risk trial population (patients had a total urinary protein excretion of ≥1 g per day at baseline, despite appropriate supportive care) and a reassuring safety and side-effect profile.”¹

Worldwide, IgA nephropathy is the most common primary glomerular disease, with a global incidence rate of 2.5 cases per 100,000 person-years. The disease is typically diagnosed in men more frequently than women and is more common in patients of Asian descent and Caucasians.

Atrasentan, an endothelin receptor type A receptor inhibitor, has been found to lower albuminuria and correlates with reductions in low-density lipoprotein cholesterol and triglycerides in prior trials. A 2019 study published in The Lancet found that atrasentan lowered the risk of renal events in patients with diabetes and chronic kidney disease. The study authors noted that their findings support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes with a high risk of developing end-stage kidney disease.³

“In the IgA nephropathy stratum of the open-label AFFINITY basket trial, the addition of atrasentan to maximum tolerated doses of angiotensin-converting–enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) reduced the 24-hour urinary protein-to-creatinine ratio by 48% after 12 weeks of treatment,” the authors of the current study wrote. “Moreover, among patients with type 2 diabetes and chronic kidney disease, atrasentan reduced the risk of a composite of doubling of the serum creatinine level or kidney failure by 35%.”¹

The Phase III, multinational, double-blind, randomized, controlled ALIGN trial enrolled adult patients with biopsy-proven IgA nephropathy, 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.

Patients were randomly assigned to administration of either atrasentan at a dose of 0.75 mg per day or matched placebo across 132 weeks. The trial’s primary outcome was change in 24-hour urinary protein-to-creatinine ratio from baseline to week 36 assessed at a prespecified interim analysis of data from the first 270 patients in the main trial stratum.

Among the first 270 patients enrolled in the main stratum who completed the week 36 visit, the geometric mean percentage change in the urinary protein-to-creatinine ratio relative to baseline was −38.1% in the atrasentan cohort compared to −3.1% in the placebo cohort, showing a geometric mean between-group difference of −36.1 percentage points (95% confidence interval, −44.6 to −26.4; P<0.001). 

In terms of safety, the percentage of patients reporting adverse events (AEs) were similar between cohorts. Fluid retention was reported by 11.2% of patients administered atrasentan compared with 8.2% of patients in the placebo cohort, but this AE did not cause any patients to discontinue the trial regimen.

“The present prespecified interim analysis showed the efficacy of atrasentan using a surrogate outcome,” the study authors wrote. “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.”¹

References

1. Heerspink, H., et al. Atrasentan in Patients with IgA Nephropathy. N Engl J Med 2024. Published October 25, 2024. DOI: 10.1056/NEJMoa2409415.

2. Atrasentan in Patients With IgA Nephropathy (ALIGN). ClinicalTrials.gov. Updated October 15, 2024. Accessed November 7, 2024. https://clinicaltrials.gov/study/NCT04573478

3. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial. Heerspink, Hiddo J LElbert, Alicia et al. The Lancet, Volume 393, Issue 10184, 1937 - 1947