Novartis reported final 2.5-year Phase III ALIGN results showing slower kidney function decline with Vanrafia (atrasentan) versus placebo in adults with IgA nephropathy (IgAN). Results were published in The Lancet and presented at the European Renal Association (ERA) Congress. Estimated glomerular filtration rate (eGFR) change from baseline favored Vanrafia, alongside sustained reductions of protein in the urine through end of treatment.

Benefits were consistent across different measures of kidney function and in patients additionally receiving sodium-glucose co-transporter-2 (SGLT2) inhibitors. Key efficacy results: Main cohort: Change from baseline in eGFR at end of study (Week 136): -7.5 for Vanrafia, -9.9 for placebo, effect vs placebo 2.4 (p=0.057). Change from baseline in eGFR at end of treatment (Week 132): -6.9 for Vanrafia, -9.5 for placebo, effect vs placebo 2.6 (p=0.039).

Annualized total eGFR slope (Weeks 0-136): -2.7 for Vanrafia, -4.1 for placebo, effect vs placebo 1.4 (~34% slower decline; p=0.003). Change from baseline in urine protein-to-creatinine ratio (UPCR) at 9 months (Week 36): -39.5% for Vanrafia, -1.9% for placebo, 38.3% relative reduction. Change from baseline in UPCR at end of treatment (Week 132): -28.8% for Vanrafia, -0.6% for placebo, 28.4% relative reduction.

SGLT2 inhibitor cohort: Change from baseline in eGFR at end of study (Week 136): -1.5 for Vanrafia, -10.6 for placebo, effect vs placebo 9.1 (p=0.004). Week 132 plus a 4-week off-treatment follow-up. UPCR at Week 36 assessed using 24-hour urine collection; UPCR at Week 132 assessed using first-morning void samples.

All p values are nominal except for the change from baseline in eGFR at the end of study in the main cohort; all p values are two-sided; eGFR change from baseline is expressed in mL/min/1.73 m²; annualized eGFR slope is expressed in mL/min/1.73 m²/year. Safety was consistent with prior studies, with adverse events similar to placebo and no new signals observed. Vanrafia received accelerated approval in the U.S. and China for reduction of proteinuria in adults with IgAN in 2025.

Novartis intends to use these data to support submission for traditional approval in 2026. The ALIGN study (NCT04573478) is a global, randomized, multicenter, double-blind, placebo-controlled Phase III clinical trial comparing the efficacy and safety of Vanrafia vs placebo in patients with IgAN at risk of progressive loss of kidney function. In total, 340 patients with biopsy-proven IgAN with baseline total proteinuria =1 g/day despite optimized renin-angiotensin system (RAS) inhibitor treatment were randomized to receive once-daily, oral Vanrafia (0.75 mg) or placebo for approximately 132 weeks.

Patients continue receiving a maximally tolerated and stable dose of a RAS inhibitor as supportive care. An additional cohort of 64 patients receiving an SGLT2 inhibitor in addition to RAS inhibitor for at least 12 weeks was also enrolled. The primary efficacy endpoint for the interim analysis (in 270 patients) was change in protein in urine, as measured by 24-hour UPCR from baseline to 36 weeks.

The key secondary endpoint for the final analysis is the change from baseline to 136 weeks in kidney function as measured by eGFR. Other secondary efficacy endpoints as well as safety and tolerability are also assessed. Vanrafia (atrasentan) is a potent and highly selective endothelin A (ETA) receptor antagonist, which is part of the endothelin system, a key system involved in the progression of IgAN.

Vanrafia is the first and only selective ETA receptor antagonist approved for primary IgAN, a once-daily, oral treatment and can be seamlessly added to, or used alongside, existing supportive care (e.g. RAS inhibitor with or without SGLT2 inhibitor) without the need for titration. Vanrafia does not require a Risk Evaluation and Mitigation Strategy (REMS) program. Because some endothelin receptor antagonists have caused elevations of aminotransferases, hepatotoxicity, and liver failure, clinicians should obtain liver enzyme testing before initiating Vanrafia and during treatment when clinically indicated.

Vanrafia may cause serious birth defects.