Atrasentan Reduces Proteinuria in IgA Nephropathy

Introduction

On April 2, 2025, the FDA granted accelerated approval for atrasentan (Vanrafia), an endothelin type A receptor antagonist for reducing proteinuria in adults with primary IgA nephropathy (IgAN) at risk for rapid disease progression. IgAN, a common form of primary glomerulonephritis, is a chronic, autoimmune disease. Current treatment strategies include slowing the progression of kidney dysfunction and reducing proteinuria through lifestyle modifications and renin-angiotensin system inhibition.¹ The risk for kidney failure remains high, emphasizing the need for novel therapies targeting other pathophysiological mechanisms of the disease. By blocking the binding of endothelin 1 to endothelin receptor A, atrasentan exhibits anti-inflammatory, antiproliferative, and antifibrotic effects in IgAN.¹

Efficacy

ALIGN (NCT04573478) is a phase 3 randomized controlled trial that evaluated the efficacy of atrasentan vs placebo in reducing proteinuria. It also evaluated the decline in estimated glomerular filtration rate (eGFR) in patients with IgAN. The trial is ongoing; however, results from the prespecified interim analysis were published.¹ Individuals 18 years or older with a biopsy-driven diagnosis of IgAN, a urinary protein excretion of at least 1 g/d, and an eGFR of at least 30 mL/min/1.73 m² were included in the trial. The individuals had to be on a maximally tolerated and optimized dose of an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker for at least 12 weeks prior to screening. Eligible individuals were randomly assigned 1:1 to receive atrasentan 0.75 mg daily or matching placebo. The primary outcome for efficacy was the change in 24-hour urinary protein-to-creatinine ratio for the first 270 individuals from baseline to week 36. Atrasentan had a geometric mean urinary protein-to-creatinine difference of –38.1% (95% CI, –43.9% to –31.7%) vs placebo, with a difference of –3.1% (95% CI, –12.4% to 7.3%%). The geometric mean group difference between atrasentan and placebo was statistically significant with a difference of –36.1 percentage points (95% CI, –44.6 to –26.4; P < .001).¹ The longer-term efficacy of atrasentan in the key secondary outcome of eGFR decline is being evaluated and will be reported once the main stratum population finishes the treatment period.

Safety

Safety outcomes were evaluated in ALIGN, inclusive of all adverse events (AEs), any serious AEs, or AEs identified as special interest from the first dose up to 30 days following the last dose received. Any AE occurred in 82.2% in the atrasentan group compared with 84.7% in the placebo group. The most common AEs reported in the atrasentan group included nasopharyngitis (10.1%), peripheral edema (8.9%), anemia (6.5%), pyrexia (6.5%), and upper respiratory tract infections (6.5%). The occurrence of any AE of special interest—anemia, cardiac failure, fluid retention, and hypotension—was higher in the atrasentan group compared with placebo (22.5% vs 14.1%). None of these AEs led to discontinuation of treatment, and there were no reports of cardiac failure or death during the trial.¹

Dosing and administration

Atrasentan is available as 0.75-mg tablets. The recommended dosing is 0.75 mg daily with or without food. Tablets should not be crushed, chewed, or cut. Atrasentan is contraindicated in patients who are pregnant due to concerns of embryo-fetal toxicity. Pregnancy should be excluded before initiating this medication, and patients should be advised to use effective contraception measures before initiating, during treatment, and for 2 weeks following discontinuation of atrasentan. Atrasentan should not be initiated in patients with severe hepatic impairment. Concomitant use with moderate or strong CYP3A4 inducers and organic anion transporting polypeptides 1B1/1B3 inhibitors should be avoided.²

References

1. Heerspink HJL, Jardine M, Kohan DE, et al; ALIGN Study Investigators. Atrasentan in patients with IgA nephropathy. N Engl J Med. 2025;392(6):544-554. doi:10.1056/NEJMoa2409415

2. Vanrafia (atrasentan) tablets. Prescribing information. Novartis Pharmaceuticals Corporation; 2025. Accessed March 2, 2026. https://www.tarpeyohcp.com/prescribinginformation.pdf