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 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. RESULTS 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 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 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.

Novel Treatment Paradigms: Primary IgA Nephropathy

“…Interim analysis of AFFINITY demonstrated a 58.5% mean proteinuria reduction in patients with IgAN treated with atrasentan at 24 weeks, and a favorable safety profile. 57 ALIGN also met its primary endpoint on interim analysis, with treatment with atrasentan resulting in a statistically significant reduction in proteinuria compared to placebo at 36 weeks. 58…”

Endothelin receptor antagonists in kidney protection for diabetic kidney disease and beyond?

“…A protocol prespecified interim analysis of the IgAN cohort of the AFFINITY trial reported the baseline characteristic of this cohort at the European Renal Association meeting, 2022. Following a 12 and 24‐week of treatment with atrasentan, there was a mean 24‐h urine protein reduction from baseline of 50% and 59%, respectively with no significant weight gain or acute change in eGFR 79 . Finally, aprocitentan, an orally active, daily dosing, non‐selective ERA has an ongoing phase 3 randomized clinical trial (PRECISION) evaluating its efficacy and safety in patients with treatment resistant hypertension receiving multiple antihypertensives (NCT03541174).…”

“…Following a 12 and 24‐week of treatment with atrasentan, there was a mean 24‐h urine protein reduction from baseline of 50% and 59%, respectively with no significant weight gain or acute change in eGFR. 79 Finally, aprocitentan, an orally active, daily dosing, non‐selective ERA has an ongoing phase 3 randomized clinical trial (PRECISION) evaluating its efficacy and safety in patients with treatment resistant hypertension receiving multiple antihypertensives (NCT03541174). A press release recently reported the PRECISION study achieved its primary endpoint measure of systolic blood pressure reduction at 4 weeks in both the aprocitentan 12.5 mg ( p < .005) and 25 mg ( p < .005) groups compared with placebo, and was well‐tolerated.…”