The selective endothelin A receptor antagonist atrasentan reduces proteinuria and preserves kidney function in adults with IgA nephropathy (IgAN), final results from the multinational ALIGN study have shown.

The long-term results at 2.5 years of follow-up also confirm the tolerability and safety of atrasentan was consistent with the known safety profile in shorter studies, with no new safety signals observed.

The investigators, including Professor Meg Jardine from the Concord Repatriation General Hospital and NHMRC Clinical Trials Centre, said atrasentan offers a clinically meaningful addition to supportive care for patients with IgA nephropathy.

The phase 3 study, published in The Lancet [link here], randomised 404 participants from 20 countries including Australia, to either oral atrasentan or placebo for 132 weeks.

Patients had biopsy-confirmed IgAN, proteinuria of at least 1·0 g/day, and an eGFR of at least 30 mL/min per 1·73 m^² despite an optimised dose of a RAS inhibitor for at least 12 weeks before screening. Patients receiving a stable dose of an SGLT2 inhibitor, in addition to a stable dose of a RAS inhibitor, were enrolled in an exploratory arm to the study.

A prespecified interim analysis, previously published in the NEJM [link here], reported that atrasentan resulted in a 36% reduction in proteinuria over 9 months compared with placebo.

At week 132, the geometric mean percentage change from baseline in first morning void UPCR was −28·8% with atrasentan versus −0·6% with placebo.

“The long-term results of ALIGN demonstrate that the proteinuria reduction was maintained throughout the double-blind treatment phase, confirming that the proteinuria-lowering effect of atrasentan is sustained over time.”

The study found eGFR trajectories in both atrasentan and placebo groups started to separate at week 36. By week 136, there was a “clinically meaningful” but not statistically significant difference in eGFR change from baseline between the groups of 2·4 mL/min per 1·73 m^².

The rate of eGFR decline (total eGFR slope) over time was also reduced with atrasentan compared with placebo, with a between-group difference of 1·4 mL/min per 1·73 m^² per year.

“This effect is clinically meaningful based on a meta-analysis of randomised controlled trials indicating that an eGFR slope difference of 1·4 mL/min per 1·73 m^² per year will translate into a more than 40% relative risk reduction for kidney failure,” the study said.

The study found the results in the exploratory arm of patients also taking SGLT2 inhibitors was similar to the main cohort.

“The totality of the evidence from ALIGN provides a valid rationale to use atrasentan on top of current supportive care including a RAS inhibitor, with or without an SGLT2 inhibitor, to reduce proteinuria and eGFR decline,” it said.

Clinical relevance

Associate Professor Muh Geot Wong

A comment article in the journal [link here], authored by Dr Peter-Joon Lee and Associate Professor Muh Geot Wong from Concord Repatriation General Hospital and the University of Sydney, said the ALIGN findings closely paralleled those from the phase 3 PROTECT trial of the dual endothelin–angiotensin receptor antagonist sparsentan.

“PROTECT demonstrated substantial and sustained proteinuria reduction (around 40%) and a modest improvement in chronic eGFR slope (1·1 mL/min per 1·73 m^² per year), yet did not show statistical significance for total eGFR slope over 2 years (p=0·058),” they said.

“Taken together, ALIGN and PROTECT provide complementary evidence supporting endothelin pathway inhibition, with consistent reductions in proteinuria and concordant effects on eGFR slope.”

They said meta-analytic data in IgA nephropathy suggest that the observed differences in annual eGFR slope were of a magnitude associated with “…meaningful reductions in the risk of kidney failure.”

“Kidney Disease: Improving Global Outcomes (KDIGO) 2025 guidelines now emphasise combination therapy targeting multiple mechanistic pathways, aiming for deep proteinuria reduction (<0·5 g/day, ideally <0·3 g/day) and slowing of eGFR decline,” they said.

“Within this framework, dual endothelin–angiotensin receptor antagonists (eg, sparsentan) are positioned as non-immunosuppressive foundational therapies alongside RAS and SGLT2 inhibition, whereas selective ETA antagonists (eg, atrasentan) are likely to be incorporated as adjunctive agents.”

However, they said the consistent failure of pivotal trials to meet prespecified statistical thresholds for eGFR endpoints “…introduces unresolved uncertainty.”

“Until robust, unequivocal evidence demonstrates sustained and statistically confirmed preservation of kidney function, alongside mechanistic biomarkers of disease modification, the role of ERAs should be viewed as additive rather than transformative in high-risk IgA nephropathy,” they concluded.

The ALIGN study was sponsored by Novartis.