ALIGN Study: Atrasentan Shows Significant Benefit on Proteinuria in IgAN at 36 Weeks

Hiddo Heerspink, PhD, PharmD
Credit: George Institute for Global Health

Data from the phase 3 ALIGN trial suggests use of atrasentan was associated with a 36.1% reduction in proteinuria relative to placebo therapy among patients with IgA nephropathy.

Presented at the 61st European Renal Association Congress (ERA 24), results of the trial analysis, which included the first 270 patients form the 340-patient trial, indicate use of atrasentan was associated with significant reductions in proteinuria. If approved, the endothelin A (ETA) receptor agonist could provide an additional option for patients with IgA nephropathy. According to a release from Novartis, the company expects to file a submission for atrasentan in IgAN during the first half of 2024.^1,2

“ETA receptor activation causes proteinuria, which is usually one of the first clinical signs of IgAN. Patients with persistent proteinuria have a poorer prognosis and are more likely to progress to kidney failure,” said prinicpal investigator Hiddo Heerspink, PhD, PharmD, a professor of Clinical Trials and Personalized Medicine at the Department of Clinical Pharmacy and Pharmacology at the University Medical Center Groningen.² “We need targeted treatment options that can support patients with IgAN across the care pathway. These data from the ALIGN study further demonstrate the ability of atrasentan to significantly reduce proteinuria and, if approved, its potential to become a new foundational treatment for people living with IgAN that can be seamlessly added to current supportive therapy.”

An ongoing, global, randomized, double-blind, placebo-controlled, parallel-group phase 3 trial, ALIGN was launched in 2020 to explore the efficacy and safety of atrasentan in patients with IgA nephropathy considered at high risk of kidney function loss. The full trial is designed to detail the effects over 132 weeks.¹

In total, 340 patients were enrolled and to receive atrasentan 0.75 mg or placebo daily for 132 weeks, in addition to their baseline medication regimen, which could include SGLT2 inhibitors. The trial’s primary outcome of interest was the change in urine protein to creatinine ratio (UPCR), based on 24-hour urine collection, from baseline. At ERA 24, Heerspink, presented the results of an analysis of the first 270 patients using this same endpoint from baseline to week 36.¹

Of the 270 patients included in the analysis, 135 received atrasentan and 135 received placebo therapy. investigators noted both groups had similar baseline characteristics. Among the atrasentan arm, the meanage was 45.7 (SD, 12.94) years, the median 24-hr UPCR was 1435.7 (IQR, 1006.7 to 1988.6) mg/g, and the mean eGFR was 58.28 (SD, 23.750) mL/min/1.73m2. Among the placebo arm, the mean age was 44.1 (SD, 11.03) years, the median 24-UPCR was 1429.2 (IQR, 1100.9 to 1918.3) mg/g, and the mean eGFR was 59.49 (SD, 24.417) mL/min/1.73m2.

Upon analysis, results suggested those in the atrasentan group experienced a 36.1% (95% CI, 26.4 to 44.6; P <.0001) relative reduction in mean percentage change in UPCR compared to their counterparts receiving placebo therapy. Additional analysis indicated UPCR reductions among those receiving atrasentan experienced UPCR reductions as early as the first 6 weeks of treatment, which were maintained through week 36.¹

Safety analysis of the trial revealed treatment-emergent adverse events were similar among the atrasentan and placebo arms (82.2% vs 84.7%). Investigators also pointed out the numbers of moderate and/or severe and serious treatment-emergent adverse events were similar between groups (36.7% vs 37.6%). Investigators highlighted there were no serious events related to treatment observed among either group. However, safety analysis indicated a greater proportion of special interest events in patients treated with atrasentan relative to placebo therapy(22.5% vs 14.1%). Specific event types are highlighted below:¹

• Fluid retention: 11.2% vs 8.2%
• Anemia: 8.3% vs 2.4%
• Hypotension: 5.9% vs 4.1%

Of note, none of the patients with anemia required blood transfusion, there were 0 cases of cardiac failure observed in the trial, and none of the events of interest led to discontinuation of atrasentan.¹

“For those living with IgAN and their families, the disease can have a significant impact not only physically, but also mentally. When my son Eddie was diagnosed with IgAN 20 years ago, there were no FDA-approved medicines developed to treat IgAN. That was as devastating as the diagnosis itself because we felt completely in the dark about how to manage the condition,” said Bonnie Schneider, Director and Co-Founder, IgAN Foundation. “It’s a disease that affects people differently, and what works for one person may not work for another. We’re pleased to see ongoing research into different treatments and are excited for a future where the community will have options to meet their individual needs."

References:

1. Heerspink HJ, Jardine M, Kohan D, et al. ALIGN Phase 3 primary endpoint analysis: atrasentan shows significant reduction in proteinuria in patients with IgA nephropathy. Abstract presented at 61st European Renal Association Congress. Stockholm, Sweden. May 23-26, 2024.
2. Novartis. Novartis Atrasentan Phase III data show clinically meaningful proteinuria reduction further advancing company’s IGA nephropathy (IgAN) portfolio. Novartis. May 25, 2024. Accessed May 25, 2024. https://www.novartis.com/news/media-releases/novartis-atrasentan-phase-iii-data-show-clinically-meaningful-proteinuria-reduction-further-advancing-companys-iga-nephropathy-igan-portfolio.