Atrasentan Shows Long-Term Kidney Benefit in IgA Nephropathy

Key Takeaways

• In the main stratum, atrasentan was associated with a smaller eGFR decline over 2.5 years than placebo.
• An exploratory stratum that included participants receiving an SGLT2 inhibitor also showed a between-group eGFR difference favoring atrasentan.
• Treatment-emergent adverse events were well balanced, no new safety signals were reported, and fluid retention events occurred in both groups.

In adults with biopsy-proven IgA nephropathy, the ALIGN phase 3 trial found a week 136 between-group eGFR difference of 2.4 mL/min per 1.73 m2 favoring atrasentan. The prespecified key secondary endpoint was change from baseline to week 136 in eGFR in the main stratum. After 132 weeks of treatment and 4 weeks off treatment, eGFR decline was smaller with atrasentan than with placebo. The estimate included a confidence interval crossing zero, and p=0.057. The abstract also described findings in an exploratory stratum receiving an SGLT2 inhibitor.

ALIGN was a randomised, double-blind, placebo-controlled phase 3 trial conducted at 133 sites in 20 countries. Adults with biopsy-proven IgA nephropathy were enrolled, and 404 participants were randomly assigned overall, including 340 in the main stratum and 64 in the exploratory SGLT2 inhibitor stratum. Main-stratum eligibility required eGFR of at least 30 mL/min per 1.73 m2, urinary protein excretion of at least 1.0 g/day, and background renin–angiotensin system inhibition. Participants were assigned 1:1 to oral atrasentan 0.75 mg once daily or placebo. Randomisation occurred between March 15, 2021, and April 28, 2023, and the week 136 eGFR assessment followed 132 weeks of treatment and 4 weeks off treatment.

In the main stratum, change from baseline in eGFR at week 136 was −7.5 mL/min per 1.73 m2 with atrasentan and −9.9 with placebo. The between-group difference was 2.4 mL/min per 1.73 m2, with a 95% CI of −0.1 to 4.8 and p=0.057. The end-of-treatment week 132 difference was 2.6 mL/min per 1.73 m2, with a 95% CI of 0.1 to 5.0. The total eGFR slope difference from baseline to week 136 was 1.4 mL/min per 1.73 m2 per year, with a 95% CI of 0.5 to 2.3. Efficacy analyses excluded data after intercurrent events, defined as starting restricted or alternative IgA nephropathy medications or kidney replacement therapy, and investigators observed slower decline over 2.5 years.

The exploratory stratum included participants already receiving an SGLT2 inhibitor at study entry. In that stratum, the week 136 between-group difference in eGFR change was 9.1 mL/min per 1.73 m2, with a 95% CI of 3.0 to 15.2. The authors interpreted the findings as showing reduced proteinuria and preserved kidney function after 2.5 years, with effects reported in participants with or without concomitant SGLT2 inhibitor use. That stratum remained exploratory.

Safety was assessed in all randomised patients who received at least one dose of study treatment. Treatment-emergent adverse events were well balanced between groups, no new safety signals were identified, and atrasentan was described as well tolerated. In the main stratum, fluid retention adverse events occurred in 24 of 169 patients given atrasentan and 20 of 170 given placebo, corresponding to 14% and 12%. The open-label extension is ongoing.