• Hiddo J L Heerspink, Meg Jardine, Donald E Kohan, Richard A Lafayette, Adeera Levin, Adrian Liew, Hong Zhang, Amit Lodha, Todd Gray, Yi Wang, Ronny Renfurm, Jonathan Barratt, and ALIGN Study Investigators.
• From the Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands (H.J.L.H.); the National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (M.J.); the Division of Nephrology, University of Utah Health, Salt Lake City (D.E.K.); Stanford University, Stanford, CA (R.A.L.); the University of British Columbia, Vancouver, Canada (A. Levin); Mount Elizabeth Novena Hospital, Singapore (A. Liew); Peking University First Hospital, Beijing (H.Z.); Chinook Therapeutics, Seattle (T.G.); Novartis, East Hanover, NJ (A. Lodha, Y.W.); Novartis, Basel, Switzerland (R.R.); and the University of Leicester, Leicester, United Kingdom (J.B.).
• N. Engl. J. Med. 2024 Oct 25.

BackgroundPatients with IgA nephropathy and severe proteinuria have a high lifetime risk of kidney failure. The efficacy and safety of the selective endothelin type A receptor antagonist atrasentan in reducing proteinuria in patients with IgA nephropathy are incompletely understood.MethodsWe are conducting a phase 3, multinational, double-blind, randomized, controlled trial involving adults 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 receive atrasentan (0.75 mg per day) or matched placebo for 132 weeks. The primary outcome, assessed at a prespecified interim analysis of data from the first 270 patients in the main stratum, was the change in the 24-hour urinary protein-to-creatinine ratio from baseline to week 36; the change was estimated with the use of a repeated-measures model. (An exploratory stratum of patients who were receiving a sodium-glucose cotransporter 2 inhibitor were included in a separate analysis.) Safety analyses were based on adverse events across the entire main stratum.ResultsA total of 340 patients were recruited into the main stratum. Among the first 270 patients in the main stratum (135 per trial group) who completed the week 36 visit, the geometric mean percentage change in the urinary protein-to-creatinine ratio relative to baseline was significantly greater with atrasentan (-38.1%) than with placebo (-3.1%), with a geometric mean between-group difference of -36.1 percentage points (95% confidence interval, -44.6 to -26.4; P<0.001). The percentage of patients with adverse events did not differ substantially between the two groups. Fluid retention was reported by 19 of 169 patients (11.2%) in the atrasentan group and in 14 of 170 (8.2%) in the placebo group but did not lead to discontinuation of the trial regimen. No apparent cases of cardiac failure or severe edema occurred.ConclusionsIn this prespecified interim analysis, atrasentan resulted in a significant and clinically meaningful reduction in proteinuria as compared with placebo in patients with IgA nephropathy. (Funded by Novartis; ALIGN ClinicalTrials.gov number, NCT04573478.).Copyright © 2024 Massachusetts Medical Society.

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