Atrasentan may be a treatment option for adults with IgAN.Results from the final analysis of the phase III ALIGN trial continue to support the efficacy and safety of atrasentan for the treatment of IgA nephropathy (IgAN).
“With 2.5 years of treatment … the totality of evidence shows that atrasentan leads to a clinically meaningful reduction in proteinuria and slowing of kidney function decline,” said Dr Hiddo Heerspink from the University Medical Center Groningen, Netherlands, at ERA 2026.
In the main stratum, the eGFR curves started to separate after 36 weeks of treatment. By week 136, eGFR* decline was greater with placebo than with atrasentan (–9.9 vs –7.5 mL/min/1.73 m2), yielding an adjusted mean difference (aMD) of 2.4 mL/min/1.73 m2 (p=0.057). Atrasentan reduced the annualized total eGFR slope by 1.4 mL/min/1.73 m2/year (nominal p=0.003).
Similar patterns were observed in the SGLT2i** stratum (aMD, 9.1 mL/min/1.73 m2; nominal p=0.004) and the pooled strata (aMD, 3.3 mL/min/1.73 m2; nominal p=0.005). [ERA 2026, abstract 101]
According to Heerspink, they selected the change in eGFR decline from baseline to week 136 as a key secondary endpoint because “we anticipated the endothelin receptor antagonist to cause haemodynamic acute eGFR reduction like other kidney protective drugs, and we know that this effect is reversible after treatment cessation. Hence, this is a clinically more interpretable estimate.”
Other outcomes
Compared with the placebo group, the atrasentan group had fewer patients who met the composite kidney outcomes with ≥30 percent eGFR reduction in the main stratum (15 percent vs 22 percent; hazard ratio [HR], 0.64), SGLT2i stratum (9 percent vs 28 percent; HR, 0.30), and pooled strata (14 percent vs 23 percent; HR, 0.57).
The effect of atrasentan on urine protein–creatinine ratio (UPCR) was sustained throughout the treatment period. The between-group relative reduction in 24-hr UPCR at week 36 was 38.3 percent. At week 132, the between-group relative reduction in first morning void UPCR was 28.4 percent.
More patients on atrasentan than placebo treatment achieved partial proteinuria remission at week 36 across both strata (main: 41.4 percent vs 15.3 percent; SGLT2i: 34.4 percent vs 21.9 percent) and the pooled strata (40.3 percent vs 16.3 percent).
Safety, tolerability
In the main stratum, the atrasentan and placebo groups had similar incidences of serious treatment-emergent adverse events (TEAEs; 14.2 percent vs 15.3 percent), severe TEAEs (13 percent vs 10 percent), and TEAEs leading to study drug discontinuation (3.6 percent vs 5.9 percent).
Moreover, the rate of TEAEs of special interest was higher in the atrasentan than the placebo group (28.4 percent vs 20 percent), but the rates of moderate or severe cases were similar (7.7 percent vs 8.8 percent). Only one serious TEAE of special interest was reported in the atrasentan group.
The most common TEAEs in the atrasentan group were COVID-19, nasopharyngitis, and peripheral oedema (23.1, 16, and 13 percent, respectively).
“There were no cases of potential hepatotoxicity using Hy’s law criteria, or study drug discontinuations due to hepatic AEs,” Heerspink said.
Persistent proteinuria common despite Tx
Up to 50 percent of IgAN patients with persistent proteinuria progress to kidney failure within 10–20 years of diagnosis. [PLoS One 2012;7:e38904; Clin J Am Soc Nephrol 2023;18:727-738] “Persistent proteinuria and declining kidney function remain common despite optimal use of RASi*** and SGLT2i therapies, representing an ongoing unmet need in IgAN,” Heerspink said.
The main stratum of ALIGN comprised 340 participants (mean age 44.9 years, 41 percent women, 54 percent Asian), while the exploratory SGLT2i stratum included 64 patients (mean age 47.2 years, 41 percent women, 40 percent Asian). Patients in each stratum were randomized 1:1 to atrasentan 0.75 mg QD or a matched placebo for 132 weeks. A 4-week off-treatment follow-up ensued.
The mean eGFR was 58.1 and 59.7 mL/min/1.73 m2 in the respective atrasentan and placebo groups in the main stratum. In the SGLT2i stratum, the corresponding values were 57.4 and 48.6 mL/min/1.73 m2. Almost all participants reported using a RASi (ACEi# and/or ARB##).
The current findings support the previously reported week 36 results, demonstrating a significant and clinically meaningful 36-percent reduction in proteinuria in the main stratum. [ERA 2024, abstract 109; N Engl J Med 2025;392:544-554]
The current results show the consistent treatment benefit of atrasentan irrespective of concurrent SGLT2i use. Atrasentan was well tolerated, and the safety results align with prior reports, Heerspink said. “These findings support the use of atrasentan for the treatment of adults with IgAN.”