NVS Novartis AG

• Vanrafia can be seamlessly added to supportive care in IgAN and used as a foundational therapy with no requirement for a REMS (Risk Evaluation Mitigation Strategy) program¹
  
• Phase III data showed Vanrafia achieved proteinuria reduction of 36.1% (P<0.0001) vs. placebo with improvements seen at Week 6 and sustained through Week 36 and favorable safety^1,2
  
• IgAN is a progressive, rare kidney disease; up to 50% of patients with persistent proteinuria progress to kidney failure within 10 to 20 years of diagnosis^3-9
  
• With third FDA approval in under 1 year across its renal portfolio, Novartis is uniquely positioned to lead a transformation in kidney care

EAST HANOVER, N.J., April 2, 2025 /PRNewswire/ -- Novartis today announced the US Food and Drug Administration (FDA) has granted accelerated approval for Vanrafia^® (atrasentan), a potent and selective endothelin A (ETA) receptor antagonist, for the reduction of proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression. This is generally defined as a urine protein-to-creatinine ratio (UPCR) ≥1.5 g/g¹. Vanrafia is a once-daily, non-steroidal, oral treatment that can be added onto supportive care, including a renin-angiotensin system (RAS) inhibitor with or without a sodium-glucose co-transporter-2 (SGLT2) inhibitor^1,2.

Vanrafia was granted accelerated approval based on a prespecified interim analysis of the Phase III ALIGN study measuring the reduction of proteinuria at 36 weeks compared to placebo¹. It has not been established whether Vanrafia slows kidney function decline in patients with IgAN. The continued approval of Vanrafia may be contingent upon the verification of clinical benefit from the ongoing Phase III ALIGN study evaluating whether Vanrafia slows disease progression as measured by estimated glomerular filtration rate (eGFR) decline at week 136¹. The eGFR data are expected in 2026 and intended to support traditional FDA approval.

"Today's approval marks an important milestone for people living with IgA nephropathy, offering a new option that can be seamlessly integrated into their existing treatment plan, with no REMS requirement," said Richard Lafayette, M.D., F.A.C.P., Professor of Medicine, Nephrology and Director of the Glomerular Disease Center at Stanford University Medical Center, and Vanrafia ALIGN Study Investigator and Steering Committee Member. "Vanrafia is a selective ETA receptor antagonist that effectively reduces proteinuria, a major risk factor in IgAN. Taking early, decisive action is critical to help improve outcomes for these patients who too often progress toward kidney failure."

IgAN is a progressive, rare kidney disease in which the immune system attacks the kidneys, often causing glomerular inflammation and proteinuria¹⁰. With almost 13 out of every million people in the US diagnosed per year, it is one of the most common autoimmune kidney diseases, and each person's journey is unique^11,12. Up to 50% of IgAN patients with persistent proteinuria progress to kidney failure within 10 to 20 years of diagnosis, often requiring maintenance dialysis and/or kidney transplantation^3-10, and response to treatment can vary^12,13. Effective, targeted therapies with different mechanisms of action can help physicians select the most appropriate treatment for patients¹².

"My son was diagnosed with IgA nephropathy long before there were any medicines approved to treat this condition, so the availability of multiple treatment options is incredibly meaningful for this community," said Bonnie Schneider, Director and Co-Founder, IgA Nephropathy Foundation. "The approval of Vanrafia broadens the treatment landscape and expands the opportunity to tailor care in a disease that can impact each patient so differently."

Data supporting approval
In the ongoing Phase III ALIGN study, patients receiving Vanrafia in combination with a RAS inhibitor achieved clinically meaningful and statistically significant proteinuria reduction of 36.1% (P<0.0001) compared to placebo, with results seen as early as week 6 and sustained through week 36^1,2,14. The effect of Vanrafia on UPCR was consistent across subgroups, including age, sex, race, and baseline disease characteristics, such as eGFR and proteinuria levels, in the main study cohort¹. A similar treatment effect of Vanrafia was seen in an additional group of patients treated with both a RAS inhibitor and an SGLT2 inhibitor (37.4% reduction in UPCR vs. placebo)¹.

The ALIGN study showed that Vanrafia has a favorable safety profile consistent with previously reported data¹. Adverse events reported in ≥2% of patients treated with Vanrafia, and more frequently than placebo, include peripheral edema, anemia, and liver transaminase elevation¹. 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 defects¹. Vanrafia does not require a REMS program.

Transforming care in kidney disease
"We are proud to expand the treatment landscape in IgA nephropathy with today's FDA accelerated approval of Vanrafia. IgAN is a heterogenous condition that requires differentiated therapies with unique mechanisms of action, and with our multi-asset kidney disease portfolio, we are well positioned to support a broad patient population and advance care for this disease," said Victor Bultó, President, US, Novartis. "Building on our longstanding legacy in nephrology, we continue to rapidly grow our capabilities in this space. Each launch enables us to more effectively reach patients with the most suitable treatment option and deliver on our promise to transform kidney disease care." 

This is the third US approval received by Novartis for its kidney disease portfolio in the last year, with Fabhalta^® having been granted FDA approval in C3 glomerulopathy (C3G) in March 2025 and accelerated approval in IgAN in August 2024¹⁵. Fabhalta is also being studied in a broad range of rare kidney diseases, including atypical hemolytic uremic syndrome (aHUS), immune complex membranoproliferative glomerulonephritis (IC-MPGN) and lupus nephritis (LN). Studies are ongoing to evaluate the safety and efficacy profiles in these investigational indications and support potential regulatory submissions. An investigational subcutaneously administered anti-APRIL monoclonal antibody, zigakibart, is currently in Phase III development in IgAN, with results expected in 2026¹⁶. 

About ALIGN
The ALIGN study (NCT04573478) is a global, randomized, multicenter, double-blind, placebo-controlled Phase III clinical trial comparing the efficacy and safety of Vanrafia versus placebo in patients with IgAN at risk of progressive loss of kidney function^1,14. In total, 340 individuals with biopsy-proven IgAN with baseline total proteinuria ≥1 g/day despite optimized RAS inhibitor treatment were randomized to receive once-daily, oral Vanrafia (0.75 mg) or placebo for approximately 132 weeks^1,2. Patients continue receiving a maximally tolerated and stable dose of a RAS inhibitor as supportive care (unless they are unable to tolerate RAS inhibitor therapy)^1,2. An additional group of 64 patients receiving an SGLT2 inhibitor for at least 12 weeks was also enrolled^1,2. The primary efficacy endpoint for the interim analysis is change in proteinuria, a marker of kidney damage, as measured by 24-hour UPCR from baseline to 36 weeks^1,2,14. Secondary and exploratory objectives include evaluating the change in kidney function from baseline to 136 weeks as measured by eGFR, as well as safety and tolerability^1,14.

Novartis in kidney disease
Building on a 40-year legacy that began in transplant, Novartis is on a mission to empower breakthroughs and transform care in kidney health, starting with kidney conditions that have significant unmet need. Historically, these conditions have had considerably less funding and research, leading to a treatment landscape largely focused on reactive or end-stage disease management, often with significant physical, emotional, and financial burdens. Our pipeline targets the underlying causes of disease, with an aim to protect kidney health and delay or prevent dialysis and/or transplantation. Our goal is to help patients get back to living life on their terms—whether at work, in school, or with loved ones, and by partnering with patients, advocates, clinicians and policymakers, we aim to raise awareness, accelerate diagnosis and get patients the right care, sooner.

VANRAFIA Indications
VANRAFIA is a prescription medicine used to reduce protein in the urine (proteinuria) in adults with a kidney disease called primary immunoglobulin A nephropathy (IgAN) who are at risk of their disease getting worse quickly. It is not known if VANRAFIA is safe and effective in children.

VANRAFIA is approved based on a reduction of proteinuria. Continued approval may require results from an ongoing study to determine whether VANRAFIA slows decline in kidney function.

VANRAFIA Important Safety Information
VANRAFIA can cause serious birth defects if taken during pregnancy. Females should not be pregnant when they start taking VANRAFIA, become pregnant during treatment, or for 2 weeks after stopping treatment. Females who can become pregnant should have a negative pregnancy test before starting VANRAFIA.

Patients who can become pregnant are those who have entered puberty, even if they have not started their menstrual period, and have a uterus, and have not gone through menopause. Menopause means that patients have not had a menstrual period for at least 12 months for natural reasons, or that patients have had their ovaries removed. Patients who cannot become pregnant are those who have not yet entered puberty, or do not have a uterus, or have gone through menopause. Females who can become pregnant should use effective birth control before starting treatment with VANRAFIA, during treatment with VANRAFIA and for 2 weeks after stopping VANRAFIA because the medicine may still be in their body. Patients should talk to their health care provider or gynecologist (a health care provider who specializes in reproduction) to find out about options for effective forms of birth control that they may use to prevent pregnancy during treatment with VANRAFIA. If the patient decides that they want to change the form of birth control that they use, they should talk to their health care provider or gynecologist to be sure that they choose another effective form of birth control. Patients should not have unprotected sex. Patients should talk to their health care provider or pharmacist right away if they have unprotected sex or if patients think their birth control has failed. Their health care provider may talk to them about using emergency birth control.

Patients should tell their health care provider right away if they miss a menstrual period or think that they may be pregnant. Patients should not take VANRAFIA if they are pregnant, plan to become pregnant, or become pregnant during treatment with VANRAFIA. VANRAFIA can cause serious birth defects. Patients should not take VANRAFIA if they are allergic to atrasentan or any of the ingredients in VANRAFIA.

Before taking VANRAFIA, patients should tell their health care provider about all their medical conditions, including if they have liver problems, are pregnant or plan to become pregnant during VANRAFIA treatment (VANRAFIA can cause serious birth defects) or if they are breastfeeding or plan to breastfeed. It is not known if VANRAFIA passes into their breast milk. Patients should not breastfeed during treatment with VANRAFIA. Patients should talk to their health care provider about the best way to feed their baby if they take VANRAFIA. 

Patients should tell their health care provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking VANRAFIA with certain medications may affect the way VANRAFIA, and the other medicine works and may increase their risk for side effects. Patients should not start any new medicine until they check with their health care provider.

VANRAFIA may cause serious side effects, including those mentioned above as well as liver problems, fluid retention and decreased sperm counts. Medicines like VANRAFIA can cause liver problems, including liver failure. VANRAFIA can increase liver enzymes in the patients' blood. The patients' healthcare provider will do blood tests to check their liver enzymes before starting treatment and if needed during treatment. The patients' healthcare provider may temporarily stop or permanently stop treatment with VANRAFIA if their liver enzymes increase or if they develop symptoms of liver problems. Patients should tell their health care provider if they have any of the following symptoms of liver problems while taking VANRAFIA; nausea or vomiting, pain in the upper right stomach, tiredness, loss of appetite, yellowing of their skin or whites of their eyes, dark urine, fever, itching. VANRAFIA can cause their body to hold too much water (fluid retention). Patients should tell their healthcare provider if they develop any unusual weight gain, trouble breathing, or swelling of their ankles or legs during treatment. Their healthcare provider may prescribe other medicines (diuretics) and may temporarily stop VANRAFIA if they develop fluid retention. VANRAFIA may cause decreased sperm counts in males and may affect the ability to father a child. Patients should tell their doctor if being able to have children is important to them.

The most common side effects of VANRAFIA include swelling of the hands, legs, ankles, and feet (peripheral edema) and low red blood cell count (anemia).

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

FABHALTA Indications
FABHALTA is a prescription medicine used to:

• Treat adults with paroxysmal nocturnal hemoglobinuria (PNH).
• Reduce protein in the urine (proteinuria) in adults with a kidney disease called primary immunoglobulin A nephropathy (IgAN), who are at risk of their disease progressing quickly.
  FABHALTA is approved based on a reduction of proteinuria. Continued approval may require results from an ongoing study to determine whether FABHALTA slows decline in kidney function.
• Treat adults with a kidney disease called complement 3 glomerulopathy (C3G), to reduce protein in the urine (proteinuria).

It is not known if FABHALTA is safe and effective in children with PNH, IgAN, or C3G.

FABHALTA Important Safety Information
FABHALTA is a medicine that affects part of the immune system and may lower one's ability to fight infections. FABHALTA increases the chance of getting serious infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b. These serious infections may quickly become life-threatening or fatal if not recognized and treated early. Patients must complete or update vaccinations against Streptococcus pneumoniae and Neisseria meningitidis at least 2 weeks before the first dose of FABHALTA. If patients have not completed vaccinations and FABHALTA must be started right away, they should receive the required vaccinations as soon as possible. If patients have not been vaccinated and FABHALTA must be started right away, they should also receive antibiotics to take for as long as their health care provider tells them. If patients have been vaccinated against these bacteria in the past, they might need additional vaccinations before starting FABHALTA. Their health care provider will decide if they need additional vaccinations. Vaccines do not prevent all infections caused by encapsulated bacteria. Patients should call their health care provider or get emergency medical care right away if they have any of these signs and symptoms of a serious infection: fever with or without shivers or chills; fever with chest pain and cough; fever with high heart rate; headache and fever; confusion; clammy skin; fever and rash; fever with breathlessness or fast breathing; headache with nausea or vomiting; headache with stiff neck or stiff back; body aches with flu-like symptoms; or eyes sensitive to light. Health care providers will give their patients a Patient Safety Card about the risk of serious infections. Patients must carry it with them at all times during treatment and for 2 weeks after the last dose of FABHALTA. The risk of serious infections may continue for a few weeks after their last dose of FABHALTA. It is important for patients to show this card to any health care provider who treats them. This will help health care providers diagnose and treat patients quickly.

FABHALTA is only available through a program called the FABHALTA Risk Evaluation and Mitigation Strategy (REMS). Before patients can take FABHALTA, their health care provider must enroll in the FABHALTA REMS program, counsel their patients about the risk of serious infections caused by certain bacteria, give their patients information about the symptoms of serious infections, make sure that their patients are vaccinated against serious infections caused by encapsulated bacteria and that they receive antibiotics if they need to start FABHALTA right away and are not up-to-date on vaccinations, as well as give patients a Patient Safety Card about the risk of serious infections.

Patients should not take FABHALTA if they are allergic to FABHALTA or any of the ingredients in FABHALTA. Patients should not take FABHALTA if they have a serious infection caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, or Haemophilus influenzae type b, when starting FABHALTA.

Before taking FABHALTA, patients should tell their health care provider about all their medical conditions, including if they have an infection or fever, have liver problems, are pregnant or plan to become pregnant (it is not known if FABHALTA will harm an unborn baby), or are breastfeeding or plan to breastfeed as it is not known if FABHALTA passes into breast milk. Patients should not breastfeed during treatment and for 5 days after the final dose of FABHALTA.

Patients should tell their health care provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking FABHALTA with certain other medicines may affect the way FABHALTA works and may cause side effects. Patients should know the medicines they take and the vaccines they receive. Patients should keep a list of them to show their health care provider and pharmacist when they get a new medicine.

FABHALTA may cause serious side effects, including those mentioned above as well as increased cholesterol and triglyceride (lipid) levels in the blood. Health care providers will do blood tests to check patients' cholesterol and triglycerides during treatment with FABHALTA. Health care providers may start patients on medicine to lower cholesterol if needed.

The most common side effects of FABHALTA in adults include: headache; nasal congestion, runny nose, cough, sneezing, and sore throat (nasopharyngitis); diarrhea; pain in the stomach (abdomen); infections (bacterial and viral); nausea; and rash.

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

Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "may," "could," "expected," "investigational," "pipeline," "launch," "transformation," "continue," "continued," "opportunity," "ongoing," "to evaluate," "progressive," "aim," "goal," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for Vanrafia (atrasentan), or regarding potential future revenues from Vanrafia. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that Vanrafia will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that Vanrafia will be commercially successful in the future. In particular, our expectations regarding Vanrafia could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise. 

About Novartis
Novartis is an innovative medicines company. Every day, we work to reimagine medicine to improve and extend people's lives so that patients, healthcare professionals and societies are empowered in the face of serious disease. Our medicines reach nearly 300 million people worldwide.

Reimagine medicine with us: Visit us at https://www.novartis.com and https://www.novartis.us and connect with us on LinkedIn, LinkedIn US, Facebook, X/Twitter, X/Twitter US and Instagram.

References

1. VANRAFIA prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corp; April 2025.
2. Heerspink HJL, Jardine M, Kohan DE, et al. Atrasentan in Patients with IgA Nephropathy. N Engl J Med. 2025;392(6):544-554. doi:10.1056/NEJMoa2409415
3. Xie J, Kiryluk K, Wang W, et al. Predicting progression of IgA nephropathy: new clinical progression risk score. PLoS One. 2012;7(6):e38904. doi:10.1371/journal.pone.0038904
4. Rodrigues JC, Haas M, Reich HN. IgA Nephropathy. Clin J Am Soc Nephrol. 2017;12(4):677-686. doi:10.2215/CJN.07420716
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6. Hastings MC, Bursac Z, Julian BA, et al. Life Expectancy for Patients From the Southeastern United States With IgA Nephropathy. Kidney Int Rep. 2017;3(1):99-104. Published 2017 Aug 24. doi:10.1016/j.ekir.2017.08.008
7. Sim JJ et al. Poster TH-PO615 presented at: ASN Kidney Week 2023; November 2-5, 2023; Philadelphia, PA.
8. Bobart SA, Alexander MP, Shawwa K, et al. The association of microhematuria with mesangial hypercellularity, endocapillary hypercellularity, crescent score and renal outcomes in immunoglobulin A nephropathy. Nephrol Dial Transplant. 2021;36(5):840-847. doi:10.1093/ndt/gfz267
9. Saha MK et al. Poster TH-PO1016 presented at: ASN Kidney Week 2019; November 5-10, 2019; Washington, DC.
10. National Institute of Diabetes and Digestive and Kidney Diseases. IgA nephropathy. Available from: https://www.niddk.nih.gov/health-information/kidney-disease/iga-nephropathy. Accessed March 2025.
11. 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
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13. 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.
14. ClinicalTrials.gov. NCT04573478. A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Atrasentan in Patients With IgA Nephropathy at Risk of Progressive Loss of Renal Function. Available from https://clinicaltrials.gov/study/NCT04573478. Accessed March 2025.
15. FABHALTA prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2024.
16. ClinicalTrials.gov. A Study of BION-1301 in Adults With IgA Nephropathy. Identifier NCT05852938. Available at: https://clinicaltrials.gov/ct2/show/NCT05852938. Accessed March 2025.

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