Novartis’ Phase III ALIGN trial shows Vanrafia® (atrasentan) slowed kidney function decline and sustained proteinuria reductions in IgA nephropathy, reinforcing long-term kidney protection and supporting regulatory submissions.
Written By: Fariha Sameen, PharmD
Reviewed By: Pharmacally Editorial Team
Novartis has reported final results from the Phase III ALIGN study (NCT04573478) showing that Vanrafia® (atrasentan) significantly slowed long-term kidney function decline and maintained proteinuria reductions for more than two years in adults with IgA nephropathy (IgAN).
A supportive analysis showed a roughly 34% slower rate of kidney function decline versus placebo. The findings were published in The Lancet and presented at the European Renal Association (ERA) Congress.
Trial Design and Patient Population
ALIGN was a global, randomized, double-blind, placebo-controlled Phase III trial that enrolled 340 adults with biopsy-confirmed IgAN who remained at risk of progressive kidney function loss despite optimized renin-angiotensin system (RAS) inhibitor therapy. Patients received once-daily oral Vanrafia 0.75 mg or placebo for approximately 132 weeks.
An additional cohort of 64 patients receiving background sodium-glucose co-transporter-2 (SGLT2) inhibitors was also evaluated.
Key Efficacy Outcomes
At Week 136, patients receiving Vanrafia experienced a mean estimated glomerular filtration rate (eGFR) decline of 7.5 mL/min/1.73 m² compared with 9.9 mL/min/1.73 m² for placebo. At the end of treatment, the difference reached statistical significance, with declines of 6.9 versus 9.5 mL/min/1.73 m², respectively (p=0.039).
The annualized eGFR slope was -2.7 mL/min/1.73 m² per year with Vanrafia compared with -4.1 mL/min/1.73 m² per year for placebo, representing an approximately 34% slower rate of kidney function decline (p=0.003).
Proteinuria reductions remained durable throughout treatment. At nine months, Vanrafia reduced urine protein-to-creatinine ratio (UPCR) by 38.3% relative to placebo. The benefit remained evident at Week 132, with a 28.4% relative reduction versus placebo.
Consistent Benefit with SGLT2 Inhibitors
Patients receiving background SGLT2 inhibitors also showed slower kidney function decline. At Week 136, eGFR decline was 1.5 mL/min/1.73 m² with Vanrafia compared with 10.6 mL/min/1.73 m² for placebo, supporting consistent benefit alongside current standard therapies.
Mechanism and Safety
Vanrafia is a potent and highly selective endothelin A (ETA) receptor antagonist that targets pathways involved in glomerular injury, fibrosis, and inflammation. By blocking ETA signaling, the therapy complements existing supportive care and offers an additional approach to slowing disease progression in IgAN.
Safety findings were consistent with previous studies. Adverse events were generally similar between treatment groups, and no new safety signals were reported during the 2.5-year treatment period.
Clinical Significance and Regulatory Outlook
Richard Lafayette, MD, an ALIGN investigator at Stanford University Medical Center, said the results reinforce earlier proteinuria findings and demonstrate that selective ETA receptor blockade can slow kidney function decline over more than two years of treatment.
Vanrafia received accelerated approval in the United States and China in 2025 for reducing proteinuria in adults with IgAN. Novartis plans to use the ALIGN data to support traditional approval submissions in 2026.
IgAN is a chronic autoimmune kidney disease that can progress to kidney failure in up to half of patients within 10 to 20 years.
The ALIGN results provide strong evidence that Vanrafia can preserve kidney function while delivering sustained reductions in proteinuria, supporting its role as a long-term treatment option for patients with IgAN.
Reference
About the Writer
Fariha Sameen, PharmD (LinkedIn), is a clinical pharmacy professional with hands-on experience in patient counselling, medication review, therapeutic monitoring, and clinical documentation across multiple departments. She has experience identifying and assessing drug-related problems and supporting medication safety practices. Her interests include pharmacovigilance, ADR reporting, clinical research, and medical writing focused on clear, evidence-based communication.