EFFICACY OF ATRASENTAN BY RENIN–ANGIOTENSIN SYSTEM INHIBITOR DOSE IN IgA NEPHROPATHY PATIENTS FROM EAST ASIA: POST HOC ANALYSIS FROM THE PHASE III ALIGN TRIAL

Atrasentan is a highly potent and highly selective endothelin A receptor antagonist that is being investigated alongside existing renin–angiotensin system inhibitor (RASi) treatment in patients (pts) with IgA nephropathy (IgAN). At the prespecified Week (W) 36 interim analysis of the Phase III ALIGN trial (NCT04573478), atrasentan led to a statistically significant and clinically meaningful 36.1% reduction in the primary endpoint of 24-hour urine protein–creatinine ratio (24h-UPCR) vs placebo; results were consistent regardless of baseline (BL) RASi dose. Based on the interim analysis 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. Here, we assessed the effect of atrasentan on proteinuria by BL RASi dose in ALIGN pts from East Asia. 

ALIGN is a Phase III trial in adults with biopsy-proven IgAN, total urine protein ≥1 g/day, and estimated glomerular filtration rate ≥30 mL/min/1.73 m2 who were on stable, maximally tolerated RASi for ≥12 weeks prior to screening. Alongside their existing RASi, pts were randomized to receive atrasentan 0.75 mg/day or placebo. An interim analysis (IA) was conducted after the first 270 pts in the main stratum completed the W36 visit or discontinued from the trial. In this post hoc analysis, mean change from BL in 24h-UPCR at W36 was assessed by BL RASi dose (≤50% or >50% of the maximum labeled dose [MLD]). Data were used from pts in the main stratum who lived in East Asia.

At the time of the IA, 120 pts from East Asia received atrasentan (n=59) or placebo (n=61) (Table). The pts lived in mainland China (45.0%), Japan (18.3%), South Korea (26.7%) or other (10.0%). At BL, angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors were prescribed to 89.2% and 9.2% of pts, respectively; 1.7% of pts were RASi intolerant. Pts received a mean of 51.6% and 60.6% of the MLD of RASi at BL in the atrasentan and placebo arms, respectively. In the atrasentan arm at BL, 67.8% of pts received ≤50% and 28.8% received >50% of the MLD of RASi. In the placebo arm at BL, 55.7% of pts received ≤50% and 31.1% received >50% of the MLD of RASi. At W36 in pts who received ≤50% of the MLD of RASi, atrasentan and placebo led to 24h-UPCR mean changes of –42.7% (95% confidence interval [CI] –53.3, –29.8) and –11.9% (95% CI –29.3, 9.8), respectively; the between-group difference was –35.0% (95% CI –51.9, –12.2) favoring atrasentan. At W36 in pts who received >50% of the MLD of RASi, atrasentan and placebo led to 24h-UPCR mean changes of –48.7% (95% CI –62.1, –30.5) and +5.2% (95% CI –23.3, 44.1), respectively; the between-group difference was –51.2% (95% CI –68.5, –24.4) favoring atrasentan (Figure).

At W36 of ALIGN, when analyzing the pts from East Asia, atrasentan led to a clinically meaningful proteinuria reduction irrespective of BL RASi dose, as shown previously in the overall population of the main stratum. These data support atrasentan as a potential IgAN treatment in pts from East Asia regardless of their RASi dose. Our findings further reinforce the potential of atrasentan as a foundational therapy in IgAN.