Novartis IgAN data in The Lancet show clinically meaningful slowing of kidney function decline with Vanrafia® over 2.5 years

Novartis' Vanrafia Shows Clinically Meaningful Kidney Function Slowing in IgAN

Novartis reported final 2.5-year Phase III ALIGN results for Vanrafia (atrasentan) in adults with IgA nephropathy (IgAN). The study showed a clinically meaningful slowing of kidney function decline, with an annualized total eGFR slope reduction of 1.4 mL/min/1.73 m²/year (approximately 34% slower decline) compared to placebo (p=0.003). Vanrafia also significantly reduced protein in urine by 38.3% vs placebo at 9 months, with reductions sustained through the end of treatment. These benefits were consistent, even in patients also receiving SGLT2 inhibitors. The data reinforces Vanrafia's potential as a foundational IgAN therapy and supports future traditional approval submissions.

• The ALIGN study demonstrated that Vanrafia significantly slowed kidney function decline, with an annualized total eGFR slope of -2.7 mL/min/1.73 m²/year compared to -4.1 mL/min/1.73 m²/year for placebo (p=0.003), representing a ~34% slower decline over 2.5 years. Additionally, Vanrafia achieved a 38.3% relative reduction in urine protein-to-creatinine ratio (UPCR) at 9 months, with reductions sustained through the end of treatment.
• The positive effects of Vanrafia on kidney function decline were consistent across different measures and notably observed in patients also receiving SGLT2 inhibitors, where eGFR change from baseline at Week 136 favored Vanrafia by 9.1 mL/min/1.73 m² (p=0.004). Safety data were consistent with prior studies, showing adverse events similar to placebo and no new safety signals, supporting its long-term use.
• Vanrafia received accelerated approval in the U.S. and China in 2025 for proteinuria reduction in adults with IgAN. Novartis plans to use these final 2.5-year data to support submissions for traditional approval in 2026, positioning Vanrafia as the first and only selective endothelin A receptor antagonist approved for primary IgAN, offering a once-daily oral treatment that can be integrated with existing supportive care.

Addressing the Unmet Needs in IgA Nephropathy Treatment

IgA nephropathy treatment faces significant challenges that limit optimal patient outcomes. Current therapeutic approaches are hampered by incomplete understanding of disease pathogenesis, inadequate efficacy of standard treatments, and safety concerns with existing immunosuppressive regimens.

• Insufficient efficacy of standard care: Current first-line treatments (ACEIs and ARBs) do not adequately mitigate the risk of disease progression, with 20%-50% of patients developing progressive renal failure and up to 40% reaching end-stage renal disease after 20 years

• Corticosteroid treatment dilemma: Systemic corticosteroids demonstrate hard outcome benefits (HR 0.37 [95% CI: 0.26, 0.52]) but carry the highest adverse event risk (RR 3.28 [95% CI: 2.11, 5.09]), leading to growing efforts to reduce cumulative exposure or avoid glucocorticoids altogether

• Limited evidence base for immunosuppressive therapies: There are limited controlled data on the efficacy of potentially toxic immunosuppressive therapies, with unclear efficacy for agents like mycophenolate mofetil despite several small controlled trials

• Significant global heterogeneity: Substantial variability exists worldwide in management strategies and outcomes, with evidence-based clinical studies being few and leading to huge variations in treatment approaches

• Incomplete validation of novel therapies: While novel targeted therapies (B-cell/plasma-cell-targeted agents and complement pathway inhibitors) show promising risk-benefit profiles with projected favorable effects (B-cell: HR 0.38; complement: HR 0.42), longer-term data and standardized eGFR slope reporting are needed for comprehensive validation

• Outdated treatment guidelines: Most KDIGO guideline recommendations, particularly those dealing with therapy, require revision by guideline-updating work groups to reflect current evidence and emerging treatment options

• Disease complexity and diagnostic challenges: The variability of IgAN disease presentation and progression, complex diagnostic pathways, and evolving treatment landscape pose significant challenges for both patients and healthcare providers throughout the clinical journey

ALIGN Study: Vanrafia's Long-Term Efficacy in IgA Nephropathy

Recent clinical studies in IgA nephropathy have demonstrated promising efficacy across multiple therapeutic approaches, from complement inhibitors to APRIL/BAFF modulators. These trials showcase substantial improvements in proteinuria reduction and eGFR preservation, with varying safety profiles depending on the intervention class.

Vanrafia's Impact on the Evolving IgA Nephropathy Landscape

The treatment landscape for IgA nephropathy has undergone a fundamental transformation over the past five years, marked by the approval of three novel disease-specific therapies: nefecon, sparsentan, and iptacopan. This represents a paradigm shift from traditional supportive care and non-specific immunosuppression toward targeted, disease-modifying treatments. The evolution has been driven by favorable regulatory changes and an enhanced understanding of IgAN pathogenesis, leading to an explosion of clinical drug development with several additional therapies currently in late-stage development.

Recent clinical trial data has demonstrated the efficacy of novel therapeutic approaches targeting specific pathogenic pathways. A phase 2 trial of SC0062, a selective endothelin receptor type A antagonist, showed promising results in 131 patients, with placebo-corrected geometric mean reductions in proteinuria ranging from -27.6% to -38.1% at 12 weeks and -22.4% to -51.6% at 24 weeks across different dose groups. Similarly, cemdisiran, a complement C5 inhibitor, demonstrated a 37.4% placebo-adjusted reduction in proteinuria at week 32 in a phase 2 study. A controlled-release budesonide trial in an Indian population showed significant improvements in both proteinuria and eGFR preservation, further expanding the evidence base for targeted interventions.

The emerging therapeutic pipeline encompasses diverse mechanisms of action, including APRIL and BAFF inhibitors (sibeprenlimab, atacicept, povetacicept, telitacicept), complement pathway modulators (iptacopan, cemdisiran, ravulizumab), and novel agents such as felzartamab. Treatment approaches have evolved toward precision medicine strategies incorporating biomarker-guided therapy, individualized risk stratification, and combination regimens. The International IgA Nephropathy Prediction Tool, endorsed by 2021 KDIGO guidelines, exemplifies this shift, while next-generation tools utilizing machine learning and multi-omics data enable real-time, AI-driven decision support for personalized IgAN management.

Atrasentan's Long-Term Data Reshapes IgA Nephropathy Treatment

The latest 2.5-year Phase III ALIGN results for Vanrafia (atrasentan) mark a pivotal moment for patients living with IgA nephropathy (IgAN), a progressive and often debilitating kidney disease. The data, demonstrating a significant 34% reduction in the annualized eGFR slope and sustained proteinuria reduction, underscore atrasentan's potential to fundamentally alter the disease trajectory. This is particularly impactful given that these benefits were observed even in patients already on SGLT2 inhibitors, suggesting a complementary mechanism of action that could lead to a new paradigm in combination therapy.

For clinical teams, this means a powerful new tool to combat kidney function decline in IgAN, an area with considerable unmet need despite advances in RAS inhibition and SGLT2i. The evidence supports atrasentan as a strong candidate for traditional approval, moving beyond proteinuria as a surrogate endpoint to demonstrate tangible long-term renal protection. This positions atrasentan not just as another option, but potentially as a foundational component of IgAN management.

However, strategic considerations must account for the known class effects of endothelin receptor antagonists. While the ALIGN trial reported fluid retention events as uncommon and not leading to discontinuation, the broader literature on ERAs highlights a risk of fluid retention and heart failure, particularly in patients with more severe CKD or type 2 diabetes. Furthermore, individual patient responses to atrasentan can vary due to genetic factors, specifically OATP1B1 polymorphisms, which influence drug exposure and, consequently, efficacy and safety. This suggests that personalized medicine approaches, potentially involving genetic screening or careful titration, might be crucial for optimizing patient outcomes and mitigating risks. As the IgAN therapeutic landscape rapidly evolves with other agents like sparsentan, demonstrating clear differentiation and optimizing patient selection will be key to Vanrafia's long-term success.