Managing IgA Nephropathy: A Clinician's View on Two Distinct Approaches

The immunoglobulin A nephropathy treatment landscape has been evolving rapidly in recent years, providing nephrologists with multiple treatment options to select the best option for each patient.

Sponsored by Novartis Pharmaceuticals Corporation

Please note that Dr. Rastogi has been compensated by Novartis Pharmaceuticals Corporation for his time.

The treatment options mentioned herein, FABHALTA® (iptacopan) and
VANRAFIA® (atrasentan), are two different drugs and were not studied for combination use. The Prescribing Information for each drug does not mention the other drug, nor that the drugs can be used together.

Please see full Prescribing Information, including Boxed WARNING and Medication Guide for FABHALTA and Prescribing Information, including Boxed WARNING and Medication Guide for VANRAFIA.

IgA nephropathy (IgAN) is a progressive, rare kidney disease in which the immune system attacks the kidneys in multiple ways, often causing proteinuria.1,2 Although IgAN is considered a rare disease, almost 13 of every 1 million people in the United States are diagnosed each year, making it one of the most common forms of primary glomerulonephritis.3,4 Taking early action in identifying these patients and helping reduce their proteinuria is critical.5,6

A hallmark of the disease is its heterogeneity.7 IgAN’s “multi-hit” model of disease pathology results in the deposition of immune complexes in the kidneys, which can trigger multiple pathways of disease.8,9 The heterogeneity of IgAN is also seen clinically, in the variety of symptoms patients may experience and in their responses to treatment.3,10 These factors underscore the importance of identifying the most appropriate therapy for each individual patient.7,11

Treatment options for IgAN have expanded in recent years, giving clinicians more options to tailor treatment to the individual.

“The treatment landscape has changed rapidly, and we have multiple approved therapies for IgA nephropathy,” says Anjay Rastogi, MD, PhD, a board-certified nephrologist in Los Angeles. “As a nephrologist and pharmacologist, it’s been wonderful to see the growing number of treatment options we can offer our patients when just a few years ago we had none.”

One of the most important clinical goals for nephrologists treating patients with IgAN is to reduce proteinuria.3 Persistent elevated proteinuria may be difficult to manage in patients with IgAN, “so we really want to focus on getting it low and keeping it low,” says Dr. Rastogi.12

With a number of therapies granted approval by the FDA in the last few years, the growing treatment landscape has given physicians more options to help patients with IgAN, including FABHALTA and VANRAFIA.

FABHALTA® (iptacopan), a complement Factor B inhibitor

One treatment option is twice-daily oral FABHALTA, indicated to reduce proteinuria in adults with primary IgAN at risk of rapid disease progression, generally defined as a urine protein-to-creatinine ratio (UPCR) ≥1.5 g/g.13 This indication was granted accelerated approval by the FDA in 2024 based on reduction of proteinuria. It has not been established whether FABHALTA slows kidney function decline in patients with IgAN. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial.

FABHALTA is the first and only treatment in IgAN to target the alternative complement pathway. The immune system’s alternative complement pathway is thought to contribute to the pathogenesis of IgAN when activated in the kidneys.8,14,15 FABHALTA binds to Factor B and inhibits the alternative complement pathway.

FABHALTA increases the risk of serious infections, especially those caused by encapsulated bacteria, such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b. Life-threatening and fatal infections with encapsulated bacteria have occurred in patients treated with complement inhibitors. These infections may quickly become life threatening or fatal if not recognized and treated early.

Because of this risk, patients must complete or update vaccination for encapsulated bacteria, including Streptococcus pneumoniae and Neisseria meningitidis (serogroups A, C, W, Y, and B), according to current ACIP* recommendations at least two weeks prior to starting FABHALTA. If urgent FABHALTA therapy is indicated in a patient who is not up to date with these vaccinations, physicians should provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible.13

The phase 3 APPLAUSE-IgAN study is an ongoing, multicenter, randomized, double-blind study of adults with biopsy-proven IgAN, elevated proteinuria (UPCR >/= 1 g/g) and
eGFR >/= 20mL/min/1.73 m2 who were on supportive care before and throughout the study (renin-angiotensin system inhibitor [RASi] with or without sodium-glucose cotransporter-2 inhibitor [SGLT2i]). The interim efficacy analysis was based on the first 250 patients with eGFR >/= 30 mL/min/1.73 m2 who completed or discontinued the study prior to the Month 9 visit. Patients were randomized 1:1 to either FABHALTA 200 mg bid (n=125) or placebo bid (n=125).15 The most common adverse reactions (≥5%) in adults with IgAN receiving FABHALTA were upper respiratory tract infection, lipid disorder, and abdominal pain. FABHALTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called FABHALTA REMS. See full Important Safety Information below.

VANRAFIA® (atrasentan), an endothelin A (ETA) receptor antagonist

VANRAFIA is a once-daily nonsteroidal oral treatment that can be added to your patient’s current maximally tolerated and stable RASi ± SGLT2i regimen.16 It was granted accelerated approval by the FDA in April 2025 for the reduction of proteinuria in adults with primary IgAN at risk of rapid disease progression, generally defined as a UPCR ≥1.5 g/g, based on a reduction of proteinuria. It has not been established whether VANRAFIA slows kidney function decline in patients with IgAN. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial.

VANRAFIA is an endothelin receptor antagonist (ERA).16 Activation of the ETA receptor by ET-1 is thought to contribute to the pathogenesis of IgAN. Because some ERAs 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.16 Use of VANRAFIA is contraindicated in patients who are pregnant and patients with hypersensitivity. Serious warnings associated with VANRAFIA include embryo-fetal toxicity, hepatotoxicity, fluid retention, and decreased sperm counts.

The phase 3 ALIGN study is a multicenter, randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of VANRAFIA in 340 adult patients with biopsy-proven primary IgAN, urine protein ≥1 g/day, and an estimated glomerular filtration rate (eGFR) of ≥30 mL/min/1.73 m2 on a maximally tolerated and stable dose of RASi. In a separate exploratory cohort, 64 adult patients received an SGLT2i in addition to RASi therapy. In an interim analysis of 270 patients from the main cohort (n=340) at 9 months, patients on VANRAFIA and maximally tolerated and stable RASi had a 38% (95% CI: 32%, 44%) reduction from baseline versus 3% (95% CI: -7%, 12%) with RASi alone, with a statistically significant relative reduction of 36% (95% CI: 26%, 45%; P<0.0001). Adverse events reported in ≥2% of patients treated with VANRAFIA, and more frequently than placebo, include peripheral edema, anemia, and liver transaminase elevation.16 See additional Important Safety Information below.

A Clinician’s Perspective

“Managing IgAN requires a broad, patient-centric approach, given it can present differently in each patient,” says Dr. Rastogi. “It is important to approach diagnosis and potential treatment options based on individual patient needs.”

"Wherever a person is in their treatment journey, they should be closely monitored,” he says. “If a patient is not responding over a period of 3 to 6 months, it may be time to reevaluate.”

Dr. Rastogi acknowledges that the decision isn’t always straightforward and may require additional consultation with specialists. “It's exciting to have a growing number of treatment options, but it can also be challenging for primary nephrologists to stay informed, given how rapidly therapies have become available,” he says. “Working with a variety of partners, such as specialized centers, and having a multidisciplinary care team can help with treatment management.”

The main goal is to identify the treatment option most appropriate for the individual with the aim of reducing proteinuria.7,10,12 This is especially critical, says Dr. Rastogi. “It’s important to keep in mind that IgA nephropathy is a systemic disease that impacts kidneys and often affects young adults,” he says. “It is important to address IgAN early. It’s an exciting time in nephrology and, given the variety of treatment options available, physicians should feel empowered to find the right care plan for their patients.”

Learn more about FABHALTA or VANRAFIA.

*Advisory Committee on Immunization Practices.

Indication and Important Safety Information for FABHALTA® (iptacopan) capsules, for oral use

INDICATION

FABHALTA is indicated to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression, generally a urine protein-to-creatinine ratio (UPCR) ≥1.5 g/g.

This indication is approved under accelerated approval based on reduction of proteinuria. It has not been established whether FABHALTA slows kidney function decline in patients with IgAN. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

• In patients with serious hypersensitivity to FABHALTA or any of the excipients.
• For initiation in patients with unresolved serious infection caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, or Haemophilus influenzae type b.

WARNINGS AND PRECAUTIONS

Serious Infections Caused by Encapsulated Bacteria

• FABHALTA, a complement inhibitor, increases a patient’s susceptibility to serious, life-threatening, or fatal infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis (caused by any serogroup, including nongroupable strains), and Haemophilus influenzae type b. Life-threatening and fatal infections with encapsulated bacteria have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The initiation of FABHALTA is contraindicated in patients with unresolved serious infections caused by encapsulated bacteria.
• Complete or update vaccination against encapsulated bacteria at least 2 weeks prior to the start of FABHALTA, according to the current ACIP recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations considering the duration of therapy with FABHALTA. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent FABHALTA therapy is indicated in a patient who is not up to date with vaccinations against encapsulated bacteria according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. The benefits and risks of treatment with FABHALTA, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by encapsulated bacteria.
• Vaccination does not eliminate the risk of serious encapsulated bacterial infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of serious infection and evaluate patients immediately if an infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if they occur. Promptly treat known infections. Serious infection may become rapidly life threatening or fatal if not recognized and treated early. Consider interruption of FABHALTA in patients who are undergoing treatment for serious infections, depending on the risks of interrupting treatment in the disease being treated.

FABHALTA REMS

• FABHALTA is available only through a restricted program under a REMS called FABHALTA REMS because of the risk of serious infections caused by encapsulated bacteria.
• Under the FABHALTA REMS, prescribers must enroll in the program; counsel patients about the risks, signs, and symptoms of serious infections caused by encapsulated bacteria; provide patients with the REMS educational materials; ensure patients are vaccinated against encapsulated bacteria; prescribe antibacterial drug prophylaxis if patients’ vaccination status is not up to date and treatment must be started urgently; and provide instructions to always carry the Patient Safety Card during treatment and for 2 weeks following the last dose of FABHALTA.
• Further information is available by telephone: 1-833-993-2242 or online at
  www.FABHALTA-REMS.com.

Hyperlipidemia

• FABHALTA may increase total cholesterol, LDL cholesterol, and serum triglycerides. Some patients required cholesterol-lowering medications.
• Monitor serum lipid parameters periodically during treatment with FABHALTA and initiate cholesterol-lowering medications, if indicated.

ADVERSE REACTIONS

• The most common adverse reactions (≥5%) in adults with IgAN receiving FABHALTA were upper respiratory tract infection, lipid disorder, and abdominal pain.

DRUG INTERACTIONS

• Concomitant use of CYP2C8 inducers (eg, rifampin) may decrease iptacopan exposure, which may result in loss of or reduced efficacy of FABHALTA. Monitor the clinical response and discontinue use of the CYP2C8 inducer if loss of efficacy of FABHALTA is evident.
• Concomitant use of strong CYP2C8 inhibitors (eg, gemfibrozil) may increase iptacopan exposure, which may result in an increased risk for adverse reactions with FABHALTA. Coadministration with a strong CYP2C8 inhibitor is not recommended.

USE IN SPECIFIC POPULATIONS

• Because of the potential for serious adverse reactions in a breastfed child, breastfeeding should be discontinued during treatment and for 5 days after the final dose.
• FABHALTA is not recommended in patients with severe hepatic impairment (Child-Pugh class C). No dose adjustment is required for patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment.

Please see full Prescribing Information, including Boxed WARNING and Medication Guide for FABHALTA.

Indication and Important Safety Information for VANRAFIA® (atrasentan) tablets, for oral use

INDICATION

VANRAFIA is indicated to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression, generally a urine protein-to-creatinine ratio
(UPCR) ≥1.5 g/g.

This indication is approved under accelerated approval based on a reduction of proteinuria. It has not been established whether VANRAFIA slows kidney function decline in patients with IgAN. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

Pregnancy

Use of VANRAFIA is contraindicated in patients who are pregnant.

Hypersensitivity

VANRAFIA is contraindicated in patients with a history of a hypersensitivity reaction to atrasentan or any component of the product.

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity

Based on data from animal reproduction studies, VANRAFIA may cause fetal harm when administered to a pregnant patient and is contraindicated during pregnancy. The available human data for endothelin receptor antagonists (ERAs) do not establish the presence or absence of major birth defects related to the use of VANRAFIA. Counsel patients who can become pregnant of the potential risk to a fetus. Exclude pregnancy prior to initiation of treatment with VANRAFIA. Advise patients to use effective contraception prior to initiation of treatment, during treatment, and for 2 weeks after discontinuation of treatment with VANRAFIA. When pregnancy is detected, discontinue VANRAFIA as soon as possible.

Hepatotoxicity

Some ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure. Asymptomatic and transient transaminase elevations have been observed with VANRAFIA. Obtain liver enzyme testing before initiating VANRAFIA, and repeat during treatment as clinically indicated. In patients with elevated aminotransferases at baseline (>3 × upper limit of normal [ULN]), consider periodic liver test monitoring. Do not initiate VANRAFIA in patients with severe hepatic impairment.

Advise patients to report symptoms suggesting hepatic injury (eg, nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching). If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin
>2 × ULN, or by clinical symptoms of hepatotoxicity, discontinue VANRAFIA. Consider reinitiation of VANRAFIA when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity or jaundice.

Fluid Retention

Fluid retention may occur with ERAs and has been observed in clinical studies with VANRAFIA. VANRAFIA has not been evaluated in IgAN patients with heart failure. If clinically significant fluid retention develops, consider initiating or increasing diuretic treatment and interrupting VANRAFIA treatment.

Decreased Sperm Counts

VANRAFIA, similar to other ERAs, may have an adverse effect on spermatogenesis. Counsel men about the potential effects on fertility.

ADVERSE REACTIONS

The most common adverse reactions (incidence ≥5%) with VANRAFIA were peripheral edema and anemia.

EFFECT OF OTHER DRUGS ON VANRAFIA

Strong or Moderate CYP3A Inducers: Avoid concomitant use with a strong or moderate CYP3A inducer. Atrasentan is a CYP3A substrate. Concomitant use with a strong and moderate CYP3A inducer is expected to decrease atrasentan exposure, which may reduce VANRAFIA efficacy.

OATP1B1/1B3 Inhibitors: Avoid concomitant use with organic anion transporting polypeptides (OATP) 1B1/1B3 (OATP1B1/1B3) inhibitors. Atrasentan is an OATP1B1/1B3 substrate. Concomitant use with an OATP1B1/1B3 inhibitor increases atrasentan exposure, which may increase the risk of VANRAFIA adverse reactions.

Please see full Prescribing Information, including Boxed WARNING and Medication Guide for VANRAFIA.

References:

1IgA Nephropathy Foundation. IgAN FAQs. Accessed September 2025. https://igan.org/faq/

2 Rodrigues JC, Haas M, Reich HN. IgA nephropathy. Clin J Am Soc Nephrol. 2017;12(4):677-686. doi:10.2215/CJN.07420716

3 Rovin, Brad H et al. KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV). Kidney Int. 2005;108(4):S1-S71. doi:10.1016/j.kint.2025.04.004

4 Kwon CS, Daniele P, Forsythe A, Ngai C. A systematic literature review of the epidemiology, health-related quality of life impact, and economic burden of immunoglobulin A nephropathy. J Health Econ Outcomes Res. 2021;8(2):36-45. doi:10.36469/001c.26129

5 Gomes AM, Schau B, Farina A. Emerging perspectives in the management of IgA nephropathy: a comprehensive review. Porto Biomed J. 2024;9(6):264. doi:10.1097/j.pbj.0000000000000264

6 American Kidney Fund. IgA Nephropathy (IgAN). Accessed September 2025. https://www.kidneyfund.org/all-about-kidneys/other-kidney-diseases/iga-nephropathy

7 Lim RS, Yeo SC, Barratt J, Rizk DV. An update on current therapeutic options in IgA nephropathy. J Clin Med. 2024;13(4):947. doi:10.3390/jcm13040947

8 Rizk DV, Maillard N, Julian BA, et al. The emerging role of complement proteins as a target for therapy of IgA nephropathy. Front Immunol. 2019;10:504. doi:10.3389/fimmu.2019.00504

9 Kohan DE, Barratt J, Heerspink HJL, et al. Targeting the endothelin A receptor in IgA nephropathy. Kidney Int Rep. 2023;8:2198-2210. doi:10.1016/j.ekir.2023.07.023

10 Boyd JK, Cheung CK, Molyneux K, Feehally J, Barratt J. An Update on the Pathogenesis and Treatment of IgA Nephropathy. Kidney Int. 2012;81(9):833-843. doi:10.1038/ki.2011.501

11 Glassock RJ. An Expert Opinion on Current and Future Treatment Approaches in IgA Nephropathy. Adv Ther. 2025;42(6):2545-2558. doi:10.1007/s12325-025-03187-7

12 Pitcher D, Braddon F, Hendry B, et al. Long-Term Outcomes in IgA Nephropathy. Clin J Am Soc Nephrol. 2023;18(6):727-738. doi:10.2215/CJN.0000000000000135

13 Fabhalta. Prescribing information. Novartis Pharmaceuticals Corp. https://www.novartis.com/us-en/sites/novartis_us/files/fabhalta.pdf

14 Lafayette RA, Kelepouris E. lmmunoglobulin A nephropathy: advances in understanding of pathogenesis and treatment. Am J Nephrol. 2018;47(suppl 1):43-52. doi:10.1159/000481636

15 Perkovic V, Kollins D, Renfurm R, et al. Efficacy and Safety of Iptacopan in Patients with IgA Nephropathy: Interim Results from the Phase 3 APPLAUSE-IgAN Study. Presented at the World Congress of Nephrology (WCN); April 15, 2024; Buenos Aires, Argentina. doi:10.1016/j.ekir.2024.02.1414

16 Vanrafia. Prescribing information. Novartis Pharmaceuticals Corp. https://www.novartis.com/us-en/sites/novartis_us/files/vanrafia.pdf

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