#3015 ALIGN post-hoc analyses: Reduction in proteinuria with atrasentan across subgroups by MEST-C score, baseline hematuria and baseline UPCR

Abstract Background and Aims Atrasentan is a potent and highly selective endothelin A receptor antagonist. In the prespecified 36-week interim analysis (IA) of the Phase 3 global ALIGN clinical trial, atrasentan demonstrated superiority versus placebo with a clinically meaningful and statistically significant reduction in proteinuria (primary endpoint) in patients with IgA Nephropathy (IgAN) receiving supportive care. Here, we report on additional post-hoc analyses from the ALIGN trial. Method ALIGN is an ongoing Phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of atrasentan vs placebo in adults with IgAN at risk of progressive loss of renal function. The main stratum of the ALIGN study included patients with biopsy-proven IgAN and proteinuria of ≥1g/day while on maximum tolerated dose of renin-angiotensin inhibitors. Patients were randomized to receive atrasentan 0.75 mg or placebo orally once daily for 132 weeks while continuing supportive care. These post-hoc analyses assessed the change from baseline in 24-hour UPCR at Week 36 based on baseline proteinuria (<1 or ≥1 g/g), MEST-C scores and baseline hematuria. The analyses were performed on the IA data set which included the first 270 of 340 patients randomized to the main stratum. For the analysis by MEST-C score, 160 of 270 patients from the IA data set were included (i.e. patients with MEST-C scores available at baseline). Results Atrasentan showed a statistically significant and clinically meaningful proteinuria reduction of 36.1% (95% CI: 26.4%, 44.6%; P < 0.0001) relative to placebo, after 36 weeks of treatment. The reduction in proteinuria in patients with baseline UPCR <1 g/g and ≥1 g/g (LS mean % UPCR change from baseline relative to placebo at Week 36) was −28.7 (95% CI: −47.5, −3.2)​ and −38.3 (95% CI: −47.4, −27.5), respectively (Fig.). In addition, efficacy benefit favoring atrasentan was shown irrespective of MEST-C score and baseline hematuria level (Fig.). Conclusion Consistent with the primary endpoint findings, atrasentan shows favorable efficacy versus placebo in patients with IgAN regardless of baseline UPCR (<1 g/g and ≥ 1g/g), MEST-C score, and baseline hematuria. These results add to previously presented subgroup analysis data, and further support the efficacy of atrasentan across a broad range of IgAN patients.

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