FDA Grants Accelerated Approval to Novartis’ Vanrafia (Atrasentan): First and Only Endothelin-1 Receptor Blocker for Proteinuria Reduction in IgA Nephropathy (IgAN)

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Written by: Priyanka Khamkar (M. Pharm., Pharmacology) and Sakshi Thakare (M. Pharm., Pharmacology)

IgAN
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The U.S. Food and Drug Administration (FDA) have granted accelerated approval to Novartis Pharmaceuticals Corporation for Vanrafia (atrasentan). It is a potent and highly selective Endothelin A (ETA) receptor antagonist. This once-daily, oral, non-steroidal medication is approved to reduce proteinuria in adults with primary Immunoglobulin A nephropathy (IgAN) who are at high risk of rapid disease progression. Disease progression typically indicated by a urine protein-to-creatinine ratio (UPCR) of ≥1.5 g/g. Vanrafia is intended for use alongside standard supportive treatments, including renin-angiotensin system (RAS) inhibitors, with or without sodium-glucose co-transporter-2 (SGLT2) inhibitors. FDA approved Vanrafia under accelerated approval based on reduction of proteinuria and it has not been confirmed yet that it slows kidney function decline in patient with IgAN. The confirmatory trial results and clinical benefits will be verified to continue this approval. This approval marks a significant advancement in the treatment of IgAN, a chronic kidney disease that can lead to kidney failure in up to 50% of patients within 10 to 20 years of diagnosis.

What is IgAN?

Immunoglobulin A (IgA) nephropathy, also known as IgAN or Berger’s disease, is one of the most common causes of glomerulonephritis and can lead to kidney failure. This widespread kidney disorder is marked by the build-up of IgA antibodies in the glomerular basement membrane, which triggers immune-related damage where the immune system attacks the kidneys. Clinically, it is commonly seen as blood in the urine (hematuria), protein in the urine (proteinuria), and a gradual decline in kidney function. On histological examination, a range of changes in the glomeruli might be observed, with mesangial cell proliferation and prominent IgA deposits being the most notable features.

In IgA nephropathy (IgAN), the accumulation of IgA in the kidneys happens due to a problem with how the body produces and handles a specific type of antibody called IgA1. It all started when the body produced an abnormal form of IgA1, known as galactose-deficient IgA1 (Gd-IgA1), which has a faulty sugar moiety attached to it. The immune system recognized this altered IgA1 as abnormal and generated autoantibodies that bind to it, forming immune complexes in the bloodstream.

These immune complexes travel to the kidneys and become deposited in the mesangium the central part of the glomeruli, which are the kidneys’ filtering units. This deposition triggers inflammation and immune-mediated injury, progressively damaging the kidney tissue. Over time, this leads to symptoms such as blood in the urine (hematuria), protein in the urine (proteinuria), and a gradual decline in kidney function. Due to this self-directed immune response, IgAN is considered an autoimmune-like kidney disease.

Background and Need for New Treatments

Conventional treatment for IgA nephropathy primarily involves supportive care, including blood pressure control and the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) to reduce proteinuria. However, these approaches are not very successful in significantly extending the progression of chronic kidney disease (CKD) to end-stage renal disease.

The role of sodium–glucose co transporter 2 (SGLT2) inhibitors in IgA nephropathy is not yet fully understood. Although nonspecific immunosuppressive treatments such as systemic or enteric-coated glucocorticoids have shown some benefit in high-risk patients, these effects are often not sustained without continued therapy. Long-term use is limited due to safety concerns and adverse side effects. As a result, there is a need for a safe and targeted therapy specifically for IgAN that can reliably slow disease progression in patients with IgA nephropathy.

Vanrafia (atrasentan): A Novel Approach

Vanrafia (atrasentan) is a once-daily, non-steroidal oral medication approved for adults with primary Immunoglobulin A Nephropathy (IgAN) to help lower protein levels in the urine (proteinuria), especially in those at high risk of fast disease progression. It works by blocking the Endothelin A (ETA) receptor, a key part of the pathway that contributes to kidney damage.

Endothelin-1 (ET-1) is elevated in IgA nephropathy (IgAN) due to ongoing inflammation and injury in the kidneys triggered by immune complex deposition. This immune activation leads to the release of various pro-inflammatory molecules, such as TNF-alpha, IL-6, TGF-beta, these substances stimulate the local production of endothelin-1 by endothelial and mesangial cells in the kidneys. Once produced, ET-1 worsens kidney injury by constricting blood vessels, reducing blood flow and oxygen to kidney tissue (ischemia), promoting mesangial cell proliferation and matrix expansion, increasing inflammation and fibrosis, and enhancing protein leakage into urine (proteinuria). This entire process is mediated by activation of Endothelin Type A Receptor (ETAR), a protein found on kidney cells.   Vanrafia belongs to a class of drugs known as ETA receptor antagonists. It works by selectively blocking the ETAR, thereby helping to protect kidney function and reduce proteinuria in patients with IgAN. This unique mechanism makes Vanrafia a specific drug of choice that selectively acts on the actual cause of the IgAN.

Clinical Trials and Approval

The efficacy and safety of Vanrafia is being studied in ALIGN trial (NCT04573478), is a Phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of atrasentan in patients with IgA nephropathy (IgAN) at risk of progressive loss of renal function. Participants receive either 0.75 mg of atrasentan or a placebo daily for 132 weeks. An open-label extension allows eligible participants to receive atrasentan for an additional 48 weeks. All participants are required to be on a stable dose of a renin-angiotensin system (RAS) inhibitor, unless contraindicated. A separate cohort includes participants on a stable dose of a sodium-glucose co-transporter-2 inhibitor (SGLT2) who have been under study. The primary endpoint of the trial is the change in proteinuria as measured by the urine protein-to-creatinine ratio (UPCR). Secondary endpoints include change in kidney function over time as measured by eGFR, safety and tolerability assessments, and quality of life evaluations.

The interim results of the Phase 3 ALIGN trial were presented at the European Reanl Association (ERA) Congress in May 2024. In the prespecified interim analysis involving 270 patients (135 per group), atrasentan achieved a 36.1% greater reduction in 24-hour urinary protein-to creatinine ratio (UPCR) compared to placebo at week 36. Specifically, the geometric mean percentage change from baseline was 38.1% in the atrasentan group versus 3.1% in the placebo group. This reduction in proteinuria is clinically meaningful, as persistent proteinuria is associated with a higher risk of progression to kidney failure in IgAN patients. 

Based on these interim results, Novartis submitted an application to the U.S. Food and Drug Administration (FDA) for accelerated approval of atrasentan. In May 2025, the FDA granted accelerated approval for atrasentan based on the condition of verification of the final results of the ALIGN study, which will serve as a confirmatory trial

Safety profile

Vanrafia exhibited a favourable safety profile consistent with previously reported data. The most frequently observed adverse events (occurring in ≥2% of patients and more often than with placebo) included peripheral edema, anemia, and elevated liver transaminases. Given the potential for hepatotoxicity associated with certain endothelin receptor antagonists, liver function should be assessed before initiating Vanrafia and monitored throughout treatment as clinically indicated.

Vanrafia is strictly contraindicated during pregnancy due to the risk of serious birth defects. Pregnancy must be ruled out before starting treatment with Vanrafia. Patients should be advised to use effective contraception before beginning therapy, throughout treatment, and for at least two weeks after discontinuing Vanrafia. If a patient becomes pregnant while on Vanrafia, the medication should be discontinued as soon as possible.

Conclusion

The FDA’s accelerated approval of Vanrafia represents a significant milestone in the management of primary IgA nephropathy. With its demonstrated efficacy in reducing proteinuria and favorable safety profile, Vanrafia offers a promising new option for patients at risk of rapid disease progression. As ongoing studies continue to evaluate its long-term benefits, Vanrafia may play a crucial role in transforming the care of individuals living with IgAN.

References

Novartis receives FDA accelerated approval for Vanrafia® (atrasentan), the first and only selective endothelin A receptor antagonist for proteinuria reduction in primary IgA nephropathy (IgAN), Novartis, https://www.novartis.com/news/media-releases/novartis-receives-fda-accelerated-approval-vanrafia-atrasentan-first-and-only-selective-endothelin-receptor-antagonist-proteinuria-reduction-primary-iga-nephropathy-igan

Heerspink HJL, Jardine M, Kohan DE, Lafayette RA, Levin A, Liew A, Zhang H, Lodha A, Gray T, Wang Y, Renfurm R, Barratt J; ALIGN Study Investigators. Atrasentan in Patients with IgA Nephropathy. N Engl J Med. 2025 Feb 6;392(6):544-554. doi: 10.1056/NEJMoa2409415. Epub 2024 Oct 25. PMID: 39460694.

Rout P, Limaiem F, Hashmi MF. IgA Nephropathy (Berger Disease) [Updated 2024 Apr 22]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK538214/

Highlights of Prescribing Information, VANRAFIA (atrasentan), https://www.novartis.com/us-en/sites/novartis_us/files/vanrafia.pdf

FDA Grants Accelerated Approval for Vanrafia (atrasentan) for Proteinuria Reduction in Primary IgA Nephropathy, Drugs.com, https://www.drugs.com/newdrugs/fda-grants-accelerated-approval-vanrafia-atrasentan-proteinuria-reduction-primary-iga-nephropathy-6493.html

Floege J, Rauen T, Tang SCW. Current treatment of IgA nephropathy. Semin Immunopathol. 2021 Oct;43(5):717-728. Doi: 10.1007/s00281-021-00888-3. Epub 2021 Sep 8. PMID: 34495361; PMCID: PMC8551131.


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