ATRASENTAN REDUCES PROTEINURIA IN PATIENTS WITH IgA NEPHROPATHY TREATED WITH SODIUM GLUCOSE CO-TRANSPORTER 2 INHIBITORS: A PHASE II RANDOMIZED, PLACEBO-CONTROLLED, CROSSOVER TRIAL (ASSIST)

Atrasentan is a highly selective endothelin-A receptor antagonist for proteinuria reduction in adults with primary IgA nephropathy (IgAN) at risk of rapid disease progression. Renin–angiotensin system inhibitors (RASi) and sodium glucose co-transporter 2 inhibitors (SGLT2i) are recommended as background therapies in IgAN, and preliminary evidence suggests atrasentan may further reduce proteinuria when added to concomitant RASi and SGLT2i use.

We performed a double-blind, placebo-controlled crossover study of atrasentan in adults with biopsy-proven IgAN, estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 and total urinary protein >0.5 g/day derived from a 24-hour urine collection while on a stable dose of RASi for ≥12 weeks and SGLT2i for ≥8 weeks (NCT05834738). Participants not on a stable dose of SGLT2i at screening entered an 8-week run-in period to initiate and stabilize SGLT2i therapy. Eligible participants were randomized 1:1 to either sequence AB or sequence BA, in which they received 0.75 mg atrasentan (A) once daily during Period 1 and matching placebo (B) during Period 2, with a 12-week wash-out period in between. The primary endpoint was the change in proteinuria (urinary protein–creatinine ratio [UPCR] from 24-hour collection) from baseline to Week 12 during periods 1 and 2. The secondary endpoint was the change in proteinuria (UPCR from a 24-hour urine collection) from baseline to Week 24 during Period 2. Safety endpoints included the incidence, severity, seriousness, and relatedness of adverse events (AEs).

We recruited 54 participants (47 on stable and 7 run-in SGLT2i) from six countries. Participant mean age was 47.7 years (standard deviation [SD] 11.9), 42.6% were female, mean eGFR was 63.3 mL/min/1.73 m2 (SD 22.2), and median UPCR was 0.97 g/g (Q1–Q3: 0.73–1.37). Treatment with atrasentan and placebo resulted in a geometric mean percentage change from baseline in UPCR at Week 12 of −30.7% (95% confidence interval [CI] −38.5%, −21.9%) and −7.2% (95% CI −17.7%, 4.7%), respectively, corresponding to a difference in geometric mean percentage change in UPCR with atrasentan versus placebo at Week 12 of −25.3% (95% CI −36.8%, −11.7%; P=0.0006; Figure A). The treatment difference in UPCR between atrasentan and placebo during the second treatment period at Week 24 was −26.4% (95% CI −45.8%, −0.0%; P<0.05). During the 12-week washout period, geometric mean UPCR increased in the atrasentan arm and remained stable in the placebo arm (Figure B). There was one unrelated serious AE. In Treatment Period 1, fluid retention AEs occurred in five participants (18.5%) in the atrasentan arm and one participant (3.7%) in the placebo arm. In Treatment Period 2, fluid retention AEs occurred in three patients (11.1%) in the atrasentan arm and three patients (11.1%) in the placebo arm. None of these fluid retention AEs were severe or led to hospitalizations. During the study there were no cases of liver function abnormalities meeting criteria for Hy’s law, no study drug discontinuations due to a
treatment-related adverse event, and no deaths.

Atrasentan provided a robust and clinically meaningful reduction in proteinuria in adults with IgAN and proteinuria ≥0.5 g/day treated with maximal background RASi and SGLT2i therapy. Atrasentan was well tolerated and no new safety signals emerged.