FC052: Atrasentan for the Treatment of IGA Nephropathy: Interim Results from the Affinity Study

Abstract

BACKGROUND AND AIMS: IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the developed world. Up to 40% of patients with IgAN are at risk of progressing to end-stage kidney disease (ESKD), with proteinuria being a strong predictor of disease progression. Treatments that reduce proteinuria in IgAN are accompanied by eGFR preservation and improved kidney outcomes.[1] Endothelin A (ETA) receptor activation is a key driver of proteinuria, inflammation and fibrosis in patients with glomerular diseases.[2] Therefore, ETA receptor blockade has potential to be of therapeutic benefit for patients with proteinuric glomerular diseases, including IgAN. Atrasentan, a potent and selective ETA receptor antagonist that has demonstrated clinically significant reductions in proteinuria and risk of ESKD in a study of over 5300 patients with diabetic kidney disease (DKD), represents a potential therapy to reduce proteinuria and preserve kidney function in patients with IgAN and other glomerular diseases.[3] AFFINITY is a global, phase 2, open-label basket study to evaluate the efficacy and safety of atrasentan in patients with proteinuric glomerular diseases due to IgAN, Alport syndrome, focal segmental glomerulosclerosis and DKD. Here we present interim results from the first 17 patients enrolled in the IgAN cohort of the AFFINITY study, through week 12 of treatment. METHOD(S): Approximately 20 patients will be enrolled in the IgAN cohort. They must have biopsy proven IgAN, be receiving a maximally tolerated and stable dose of renin angiotensin system inhibitor and have a urine protein creatinine ratio [UPCR] between 0.5 and <1.0 g/g from a first morning void urine sample. Patients are treated orally with 0.75 mg atrasentan daily. The primary endpoint is the change in 24-h UPCR from baseline to Week 12. Key exploratory endpoints include changes in eGFR from baseline to Week 56. RESULT(S): A total of 17 patients have enrolled in the IgAN cohort as of 4 January 2022. A total of 12 and 8 patients have completed visits through Week 6 and Week 12, respectively. The median age is 47 years and 41% are women. The geometric mean (GM) baseline proteinuria is 1.2 g/day, and median eGFR is 41 mL/min/1.73 m² (Table 1). The 8 patients on treatment through Week 12 had a GM % reduction from baseline in 24-h UPCR of 43.6% [95% confidence interval (95% CI) 29.0-55.2] (Figure 1). Pharmacokinetic data are currently available for nine patients and showed a mean trough plasma atrasentan concentration in the targeted therapeutic range. Adverse events (AE) were observed in nne patients (53%), all mild or moderate in Table 1. Demographics Parameter (range) IgAN (n=17) Age (years) median 47 (23, 71) Women, n (%) 7 (41%) Race, White, n (%) 9 (53%) Weight (kg), median 75.3 (61.5, 135.2) BMI (kg/m²), median 26.6 (21.8, 45.2) Baseline 24-h UPCR (mg/g) GM 1 889 (537, 1632) Baseline 24-h total protein (mg/day) GM 1205 (637, 2306) eGFR (mL/min/1.73 m²), median2 41 (28, 94) SBP (mmHg), median 3 128 (109, 156) DBP (mmHg), median 3 83 (65, 92) 1Based on 24-h collections using the GM of the two baseline samples. 2Based on the average of screening and baseline samples. 3Based on the average of three assessments at the visit on/prior to Day 1. severity, most of which have resolved. One patient experienced an unrelated serious adverse event of traffic accident without long-term injuries. All patients remain on treatment with study drug except for one patient who discontinued drug due to an unrelated AE at week 13. CONCLUSION(S): Treatment of patients with IgAN with atrasentan in addition to standard of care provided a >43% GM reduction in proteinuria after 12 weeks and was well tolerated, strongly supporting a key role of the endothelin pathway in the pathogenesis of IgAN. The ongoing phase 3 ALIGN study for patients with IgAN and proteinuria >=1g/day will provide further assessment of the proteinuria lowering effects of atrasentan in this high-risk patient population. (Figure Presented).