Atrasentan slowed IgA nephropathy, but narrowly missed its mark

Atrasentan, a drug that blocks the blood-vessel-constricting signal endothelin, slowed the loss of kidney function over two and a half years in people with IgA nephropathy — but the key measure of that benefit narrowly missed the trial's threshold for statistical significance in the final ALIGN results [s1]. The nuance matters: an earlier look at the same trial had already shown atrasentan sharply cuts protein leakage into the urine, the finding that won it accelerated approval, so the open question was whether that would translate into preserved kidney function — and the answer is "probably, but not proven at the primary timepoint" [s1][s2].

IgA nephropathy is a rare autoimmune kidney disease in which deposits of the antibody immunoglobulin A inflame the kidney's filtering units. It is a leading cause of kidney failure in young adults, and its damage shows up first as protein in the urine and then as a steady decline in the estimated glomerular filtration rate (eGFR), the standard gauge of how well the kidneys clear waste. Standard care is a blocker of the renin–angiotensin system, increasingly paired with an SGLT2 inhibitor, but many patients still progress [s1]. Atrasentan targets a different pathway — the endothelin A receptor — that contributes to kidney scarring and protein loss.

What the trial did

ALIGN was a randomised, double-blind, placebo-controlled phase 3 trial run at 133 sites in 20 countries and funded by Novartis, which markets atrasentan [s1]. It enrolled adults with biopsy-proven IgA nephropathy, an eGFR of at least 30 mL/min per 1.73 m², and urinary protein of at least 1.0 g/day despite renin–angiotensin blockade; a smaller exploratory group also taking an SGLT2 inhibitor was analysed separately [s1]. Participants were randomly assigned 1:1 to oral atrasentan 0.75 mg once daily or placebo for 132 weeks [s1]. In all, 404 patients were randomised — 340 in the main group and 64 in the SGLT2 stratum [s1].

The trial reported in two stages. Its prespecified interim analysis, published in 2025, measured the change in urinary protein at week 36 and was the basis for the drug's early approval [s2]. The final analysis, reported here, tested the harder endpoint: the change in eGFR from baseline to week 136 in the main stratum [s1].

What it found

Kidney function fell in both groups, as expected in a progressive disease, but less steeply on the drug. eGFR declined by 7.5 mL/min per 1.73 m² with atrasentan (95% confidence interval −9.2 to −5.8) versus 9.9 with placebo (95% CI −11.7 to −8.1) [s1]. The between-group difference of 2.4 mL/min per 1.73 m² carried a confidence interval of −0.1 to 4.8 and a P value of 0.057 — a hair above the conventional 0.05 threshold, so the primary comparison did not reach statistical significance [s1].

Two supporting measures did land on the significant side. The difference at the end of treatment (week 132, before a four-week washout) was 2.6 mL/min per 1.73 m² (95% CI 0.1 to 5.0), and the difference in the total rate of eGFR decline across the trial was 1.4 mL/min per 1.73 m² per year (95% CI 0.5 to 2.3) [s1]. In the exploratory group also taking an SGLT2 inhibitor, the eGFR difference was larger, at 9.1 mL/min per 1.73 m² (95% CI 3.0 to 15.2), suggesting the benefit holds on top of that newer background therapy [s1]. Safety was reassuring for a drug class historically dogged by fluid retention: such events occurred in 14% of the atrasentan group and 12% of the placebo group, with no new safety signals [s1].

How to read it

This is a case where the headline P value and the weight of the evidence point in slightly different directions, and honesty requires holding both. On the one hand, the trial's own primary eGFR comparison at week 136 did not cross the significance line, and a difference whose interval touches zero is formally compatible with no benefit [s1]. On the other, the washout appears to have narrowed the gap — the effect at the end of active treatment was significant — and the overall slope of decline, the SGLT2 subgroup, and the already-established reduction in proteinuria all lean the same way [s1][s2]. The proteinuria result from the interim analysis was itself large: a 36.1-percentage- point greater reduction in the urine protein-to-creatinine ratio versus placebo at week 36 [s2].

For a reader, the practical translation is that atrasentan looks like a genuine but modest addition to kidney protection in IgA nephropathy, with the caveat that its clearest effect is on a surrogate (protein) while the effect on the outcome patients care about (preserved filtration) is real but statistically borderline. That is precisely the kind of distinction that gets flattened in drug marketing. Related coverage has examined the FDA approval of the anti-APRIL antibody sibeprenlimab for IgA nephropathy, an earlier endothelin-blocking drug, sparsentan, in a related kidney disease, and how SGLT2 inhibitors protect the kidneys beyond diabetes.

What to watch

An open-label extension of ALIGN is ongoing and may clarify the durability of the benefit [s1]. The larger question for the field is where atrasentan sits in a treatment landscape that has expanded fast — endothelin blockers, SGLT2 inhibitors, and drugs targeting the immune drivers of IgA nephropathy — and whether these can be combined to bend the trajectory toward kidney failure more than any one of them does alone [s1][s2].

This article describes research and regulatory context and is not medical advice. Treatment of IgA nephropathy is a decision for treating clinicians.

Sources

• Atrasentan in patients with IgA nephropathy (ALIGN): final 2·5-year results — The Lancet, 4 June 2026
• Atrasentan in Patients with IgA Nephropathy — New England Journal of Medicine, 6 February 2025