ATRASENTAN VS PLACEBO IN SUBGROUPS OF PATIENTS FROM EAST ASIA WITH IgA NEPHROPATHY (IgAN): INTERIM DATA FROM THE PHASE III ALIGN TRIAL

The endothelin system is a key contributor to the progression of IgAN, which is a disease with a particularly high incidence and risk of progression to kidney failure in people from East Asia. At the prespecified Week 36 interim analysis (IA) of the Phase III ALIGN trial (NCT04573478), treatment with atrasentan, a highly potent and highly selective endothelin A receptor antagonist, led to a statistically significant and clinically meaningful 36.1% reduction in 24-hour urine protein–creatinine ratio (24h-UPCR) vs placebo (primary endpoint). Reduction in 24h-UPCR consistently favored atrasentan over placebo across subgroups based on baseline (BL) disease characteristics and demographics, including in patients (pts) from East Asia. Based on the IA results, atrasentan (VANRAFIA®) received accelerated approval by the US Food and Drug Administration and conditional approval by the China National Medical Products Administration for proteinuria reduction in adults with primary IgAN at risk of rapid disease progression. Considering the clinical burden of IgAN in East Asia, proteinuria reduction was analyzed in subgroups of pts from this region in ALIGN.

ALIGN is a double-blind, Phase III trial in adults with biopsy-proven IgAN, total urinary protein ≥1 g/day and estimated glomerular filtration rate of ≥30 mL/min/1.73 m2 who were on stable, maximally tolerated renin–angiotensin system inhibition for ≥12 weeks prior to screening. Pts were randomized to receive atrasentan 0.75 mg/day or placebo. An IA was conducted after the first 270 pts from the main stratum completed the Week 36 visit or discontinued from the trial. The relative percentage reduction from BL in 24h-UPCR was assessed in pts from the main stratum who lived in East Asia; subgroup analyses based on BL 24h-UPCR and first-morning void (FMV) hematuria, and individual or combined components of the MEST-C (mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy or interstitial fibrosis, and [fibro]cellular crescents) system scored at biopsy were post hoc.

At the ALIGN IA, 59 and 61 pts from East Asia were receiving atrasentan and placebo, respectively. Pts lived in mainland China (45.0%; n=54), Japan (18.3%; n=22), South Korea (26.7%; n=32) or other (10.0%; n=12). In pts with BL 24h-UPCR ≥1 g/g or <1 g/g, the relative percentage change in 24h-UPCR at Week 36 with atrasentan vs placebo was –45.7% (95% confidence interval [CI] –58.3, –29.3) and –22.7% (95% CI –53.9, 29.6), respectively (Figure). For pts with baseline FMV hematuria classed as negative/trace, 1+/2+ or 3+, the relative percentage change in 24h-UPCR at Week 36 with atrasentan vs placebo was –30.2% (95% CI –50.9, –0.9), –44.1% (95% CI –61.9, –18.1), and –59.3% (95% CI –79.1, –20.7), respectively (Figure). Regardless of the individual or grouped components of the MEST-C scoring system, the relative percentage reduction in 24h-UPCR favored atrasentan over placebo (Figure).

In pts from East Asia, clinically meaningful reductions in 24h-UPCR were observed with atrasentan vs placebo at Week 36 of the ALIGN trial, supporting atrasentan as a potential foundational treatment for pts from East Asia with IgAN. Despite small sample sizes across some of the subgroups, the benefits appeared consistent irrespective of BL proteinuria, hematuria and MEST-C score components at kidney biopsy.