Objectives: Endothelin A (ETA) receptor activation drives proteinuria, inflammation, and fibrosis in patients with glomerular diseases. Atrasentan, a potent and selective ETA receptor antagonist, represents a potential therapy to reduce proteinuria and preserve kidney function in patients with IgA nephropathy (IgAN) and other glomerular diseases. AFFINITY is a phase 2, open-label study evaluating efficacy and safety of atrasentan in adult patients with proteinuric glomerular diseases. Methods: Eligibility criteria for the IgAN cohort include adults with biopsy-proven IgAN; eGFR ≥30 mL/min/1.73m2, UPCR ≥0.5 to <1.0 g/g (first morning void) and on maximally-tolerated/stable RASi. Patients are treated orally with 0.75 mg atrasentan daily for 52 weeks. The primary endpoint is change in 24-hour UPCR from baseline to Week 12. Results: Twenty patients have enrolled in the IgAN cohort. Median age was 45 years, with 50% women, 45% White and 45% Asian. Median baseline 24-hour total urine protein was 1.2 g/day (geometric mean; GM), 70% of patients had total urine protein of >1 g/day, and median eGFR was 46 mL/min/1.73m2. Mean (range) treatment duration was 45 (13-53) weeks as of data cut-off (19 October 2022). Atrasentan was generally well-tolerated with no serious and notreatment-related severe adverse events (AEs). Treatment-emergent AEs observed in 16 patients were mild or moderate; most have resolved. One patient discontinued due to a related AE of headache. No significant fluid retention was observed. GM reduction from baseline in 24-hour UPCR was 48.3% at week 12 (95% CI 38.9,56.3; n=20) and 54.7% at week 24 (95% CI 46.1,61.9; n=19; Figure). Conclusions: Treatment with atrasentan in addition to standard of care was generally well-tolerated and resulted in durable and clinically meaningful reduction in proteinuria at weeks 12 and 24, strongly supporting the therapeutic potential of ETA receptor blockade with atrasentan in patients with IgAN.