Atrasentan in patients with IgA nephropathy (ALIGN): final 2·5-year results from a randomised, double-blind, placebo-controlled, phase 3 trial

Background Atrasentan, a selective endothelin A receptor antagonist, reduced proteinuria in the prespecified interim analysis (week 36) of the ALIGN trial in adults with IgA nephropathy. We assessed whether atrasentan slowed estimated glomerular filtration rate (eGFR) decline after 2·5 years’ treatment. Methods We performed a randomised, double-blind, placebo-controlled, phase 3 trial (133 sites, 20 countries). Adults with biopsy-proven IgA nephropathy, eGFR of at least 30 mL/min per 1·73 m2, and urinary protein excretion of at least 1·0 g/day while receiving renin–angiotensin system inhibition were enrolled (main stratum). An exploratory stratum enrolled participants also receiving an SGLT2 inhibitor. Participants were randomly assigned (1:1) to oral atrasentan 0·75 mg once daily or placebo for 132 weeks, followed by a 4-week off-treatment follow-up. The key secondary endpoint was change from baseline to week 136 in eGFR in the main stratum, assessed in all randomised patients (excluding data after intercurrent events, defined as initiation of restricted or alternative IgA nephropathy medications or kidney replacement therapy). Safety was assessed in all randomised patients who received at least one dose of study treatment. ALIGN is registered with ClinicalTrials.gov , NCT04573478 ; the double-blind section is complete, and the open-label extension is ongoing. Findings Between March 15, 2021, and April 28, 2023, 404 participants were randomly assigned (main stratum: 340; SGLT2 inhibitor stratum: 64). In the main stratum, change from baseline in eGFR at week 136 was −7·5 mL/min per 1·73 m2 (95% CI −9·2 to −5·8) with atrasentan and −9·9 mL/min per 1·73 m2 (−11·7 to −8·1) with placebo (between-group difference 2·4 mL/min per 1·73 m2; 95% CI −0·1 to 4·8; p=0·057). The between-group difference in eGFR change from baseline at end of treatment (week 132) was 2·6 mL/min per 1·73 m2 (95% CI 0·1–5·0), and the difference in total eGFR slope (baseline to week 136) was 1·4 mL/min per 1·73 m2 per year (95% CI 0·5–2·3). In the SGLT2 inhibitor stratum, the difference in eGFR change from baseline at week 136 between atrasentan and placebo was 9·1 mL/min per 1·73 m2 (95% CI 3·0–15·2). Treatment-emergent adverse events were well balanced between atrasentan and placebo, with no new safety signals. In the main stratum, fluid retention adverse events occurred in 24 (14%) of 169 patients receiving atrasentan and 20 (12%) of 170 receiving placebo. Interpretation Atrasentan reduced proteinuria and preserved kidney function after 2·5 years. This effect was present with or without concomitant SGLT2 inhibitor use. Atrasentan was well tolerated. Funding Novartis.