Novartis announced that it will pursue traditional approval from the U.S. Food and Drug Administration (FDA) for Vanrafia (atrasentan) in IgA nephropathy (IgAN), despite the Phase 3 ALIGN trial narrowly missing its primary kidney function endpoint.
In the ALIGN trial, Vanrafia demonstrated a difference of 2.39 ml/min/1.73m² in estimated glomerular filtration rate (eGFR) change from baseline compared with placebo at Week 136, which occurred four weeks after the end of treatment. The p-value for this key secondary endpoint was 0.057, falling short of statistical significance.
At Week 132, marking the conclusion of treatment, the difference in eGFR change from baseline between Vanrafia and placebo was 2.59 ml/min/1.73m², with a nominal two-sided p-value of 0.039, according to the company. Novartis also reported clinically meaningful findings at Week 132 and within a prespecified exploratory subgroup of patients who were also receiving sodium-glucose co-transporter-2 (SGLT2) inhibitors.
“Progressive and complex diseases such as IgAN present an urgent need for medicines that can target the different drivers of the disease. Vanrafia can be seamlessly integrated into patients’ existing treatment plans, with a consistent safety profile,” said Ruchira Glaser, M.D., Global Head, Cardiovascular, Renal & Metabolic Development Unit at Novartis, in a February 13 statement. She added that the ALIGN data contribute to the body of evidence supporting Vanrafia as a potential foundational therapy aimed at slowing kidney function decline.
ALIGN represents the longest follow-up period among pivotal Phase 3 studies conducted in IgAN. The company stated that the safety findings were consistent with earlier observations.
Vanrafia received accelerated FDA approval in April 2025. The therapy, a selective endothelin A receptor antagonist (ERA), was obtained through Novartis’ 2023 acquisition of Chinook Therapeutics and became the company’s second IgAN treatment to secure FDA clearance. Unlike Filspari, Vanrafia does not carry a Risk Evaluation and Mitigation Strategy (REMS) requirement mandated by the FDA.
Novartis’ IgAN portfolio also includes Fabhalta (iptacopan), a complement inhibitor that demonstrated statistically significant superiority over placebo in reducing IgAN progression as measured by eGFR changes over two years in the Phase 3 Applause-IgAN study. The company disclosed positive final results from that trial in October and plans to submit regulatory filings this year.
Fabhalta was first approved by the FDA in December 2023 for paroxysmal nocturnal hemoglobinuria. It subsequently received accelerated approval in IgAN in 2024 and, in March 2025, became the first FDA-approved therapy for C3 glomerulopathy. The drug generated $505 million in sales last year, nearly tripling its prior performance. Novartis has projected peak annual sales across multiple indications to exceed $3 billion.
IgAN is described by the company as a progressive autoimmune kidney disorder, with approximately 25 million new diagnoses globally each year.
In addition to Vanrafia and Fabhalta, Novartis is evaluating zigakibart, an anti-APRIL antibody, in the Phase 3 Beyond trial. The study protocol was recently amended to emphasize eGFR as a primary focus to potentially support a full approval. An interim analysis of eGFR data is expected in the first half of 2027.
Vanrafia Regulatory Path Moves Forward After ALIGN Results
Novartis announced plans to pursue full FDA approval for Vanrafia in IgA nephropathy, even after the Phase 3 ALIGN study did not meet its primary endpoint. Despite the ALIGN miss, Vanrafia demonstrated clinically meaningful trends in kidney function preservation, encouraging the company to continue discussions with regulators.
The Phase 3 ALIGN trial evaluated Vanrafia in patients with IgA nephropathy, a chronic kidney disease characterized by progressive renal decline. Although the primary endpoint was not statistically achieved, secondary measures and subgroup analyses suggested that Vanrafia may still offer benefit in slowing disease progression.
Novartis confirmed it will continue engaging with the U.S. Food and Drug Administration following results from the Phase 3 ALIGN trial in IgA nephropathy. While the primary endpoint was not met, the company highlighted encouraging signals in secondary endpoints and long-term kidney function trends.
Executives stated that regulators often consider the totality of evidence, including safety profile, biomarker shifts, and consistency across studies. The therapy’s tolerability remained aligned with previous clinical data, with no unexpected safety concerns emerging during the late-stage trial.
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