Atrasentan demonstrated superiority versus placebo for reduction in proteinuria through 36 weeks.
Novartis has announced positive topline results from a 36-week interim analysis of the Phase 3 ALIGN study for atrasentan in patients with immunoglobulin A (IgA) nephropathy.
Announced on October 30, 2023, the study met its primary efficacy endpoint of superiority compared to placebo for reduction in proteinuria through 36 weeks, which Novartis plans to use to submit an application for possible accelerated approval in the US in 2024.1
“These positive topline Phase 3 data showcase the potential of atrasentan to improve outcomes for patients with IgAN by demonstrating clinically meaningful proteinuria reduction,” said Shreeram Aradhye, MD, president of development and chief medical officer at Novartis.1
An investigational oral endothelin A receptor antagonist, atrasentan is in development for IgA nephropathy and other rare kidney diseases. In the phase 2 AFFINITY study cohort of patients with IgA nephropathy, atrasentan demonstrated a 38.0% geometric mean reduction in 24-hour urine protein creatinine ratio in 20 patients at 6 weeks of treatment, 49.9% geometric mean reduction in 18 patients at 12 weeks of treatment, and 58.5% geometric mean reduction in 11 patients at 24 weeks of treatment.2
Atrasentan was added to the Novartis portfolio, along with zigakibart, through the acquisition of Chinook Therapeutics in August of 2023.3 An investigational humanized IgG4 monoclonal antibody, zigakibart blocks APRIL, a tumor necrosis factor-family cytokine involved in beta-cell signaling believed to be implicated in IgA nephropathy and other indications, from binding to its receptors. The first patient was enrolled in the phase 3 BEYOND trial on July 28, 2023.4
A randomized, multicenter, double-blind, placebo-controlled Phase 3 trial, ALIGN compared the efficacy and safety of atrasentan compared to placebo in patients with IgA nephropathy at risk of progressive loss of kidney function. For inclusion, patients were required to have biopsy-proven IgA nephropathy, receive a maximally tolerated dose of renin-angiotensin system (RAS) inhibitor therapy with 12 weeks of stability, have total urine protein ≥1 gram per day, and have an estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 m2.1
According to the release, approximately 340 patients with biopsy-proven IgA nephropathy with baseline total proteinuria more than 1 gram per day despite optimized RAS inhibitor treatment were randomized to receive once-daily oral doses of atrasentan 0.75 mg or placebo for 132 weeks. Participants continued receiving a maximally tolerated and stable dose of RAS inhibitor as supportive care. An additional group of up to 64 patients receiving a stable dose of SGLT2 inhibitor for at least 12 weeks were also enrolled in the study.1
The primary efficacy endpoint of the study was change in proteinuria as measured by urine protein to creatinine ratio from baseline to 36 weeks. Secondary and exploratory objectives include change in kidney function from baseline to week 136 as measured by eGFR, safety, and tolerability, with topline results from the confirmatory endpoint analysis expected in the first quarter of 2026.1
At week 36, atrasentan achieved a clinically meaningful and statistically significant reduction in proteinuria compared to placebo. Investigators also noted the safety profile of atrasentan was consistent with previously reported data from the phase 2 AFFINITY study cohort, where the treatment was well-tolerated. In total, 5 patients had a treatment-related adverse event, all of which were considered mild or moderate. No treatment-related SAEs were observed.1
“Along with investigational iptacopan, which recently also showed positive topline Phase 3 results, and investigational zigakibart, our development portfolio of 3 highly differentiated late-stage therapies in IgAN has the potential to provide much-needed treatment options for people living with this debilitating disease,” Aradhye said.1