New Orleans — New understanding about the pathophysiology of immunoglobulin A nephropathy (IgAN) and a two-phase approval pathway have led to a recent dramatic rise in the number of new therapies for treating the condition. 

“IgA nephropathy is not a trivial disease. It can progress in a large number of patients to kidney failure. Now we have drugs that can slow or halt that progression, and this is just the first wave of therapies — there are several innovative and exciting therapies that are in development and will be coming out to clinical trials in the coming months,” Brad H. Rovin, MD, director of the Division of Nephrology at the Ohio State University, Columbus, told Medscape Medical News. 

“This really makes IgA nephropathy to me one of the hottest therapeutic fields. It allows us to now start thinking about precision medicine, because we have so many drugs to try and figure out what combinations are best for individual patients,” said Rovin, who presented 2-year data from the phase 3 APPLAUSE-IgAN study here at the National Kidney Foundation (NKF) 2026 Spring Clinical Meetings. 

Rovin’s study was just one of many presentations on IgAN at the meeting, including five industry-sponsored symposia on the disease, along with new study data presented orally and in posters on several individual agents targeting IgAN pathogenesis. 

Framework for Accelerated Approval 

IgAN is an autoimmune disease characterized by deposition of immune complexes in the glomerulus, diagnosed by biopsy. It is the most common primary glomerulonephritis worldwide, with an incidence of at least 2.5 per 100,000. Despite the routine use of renin-angiotensin aldosterone inhibitors and corticosteroids, IgAN progresses to kidney failure within 10-20 years from onset in up to half of patients. 

While more recent recommendations also advise use of SGLT2 inhibitors as add-on therapy to manage the consequences of existing IgAN-induced nephron loss, the newer therapies address various steps in the pathogenesis of the disease process itself. 

In 2019, the American Society of Nephrology and the FDA developed a framework for accelerated approval of IgAN treatments based on the surrogate endpoint reduction of proteinuria, assessed as the urine protein-to-creatinine ratio, at 9 months. Subsequent full approval is based on long-term improvement in kidney function, measured as estimated glomerular filtration (eGFR), at 2 years. 

The first drug granted accelerated approval, delayed-release budesonide capsules (Tarpeyo, Calliditas Therapeutics), received full approval in December 2023. Another oral agent, sparsentan (Filspari, Travere Therapeutics), received full approval in September 2024 as the first non-immunosuppressant IgAN treatment. 

Three additional agents have received accelerated approval so far: the oral complement inhibitor iptacopan (Fabhalta, Novartis), approved in August 2024, oral atrasentan (Vanrafia, Novartis), approved in April 2025, and the injectable monoclonal antibody sibeprenlimab-szsi (Voyxact, Otsuka), approved in November 2025. 

The field is evolving so rapidly that even the most recent Kidney Disease: Improving Global Outcomes (KDIGO) revised IgAN guidelines published in 2025 are already out of date. In March 2026, Rovin and colleagues published a commentary to position these three new agents into the treatment strategy outlined in the KDIGO publication.

4-Hit Hypothesis 

Except for budesonide, each of the other agents targets specific points in the now-accepted “four hit” or “multi-hit” hypothesis of IgAN development, derived over the past several years from genome-wide association studies and experimental models. 

1. Excessive production of galactose-deficient IgA1
2. Production of antiglycan autoantibodies targeting galactose-deficient IgA1
3. Formation of circulating immune complexes consisting of IgG autoantibodies bound to galactose-deficient IgA1 and complement C3
4. Deposition of galactose deficient IgA1-antiglycan immune complexes on mesangial cells in the glomerulus, activating inflammation and leading to glomerular injury

More recently, B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) have been identified as key mediators in the production of galactose-deficient IgA1 and its corresponding autoantibodies. Elevated levels of both BAFF and APRIL correlate with disease severity in people with IgAN, and their inhibition is now pursued as a therapeutic drug target. 

Confirmatory Data for Iptacopan 

Rovin presented the confirmatory 2-year eGFR data from APPLAUSE-IgAN which enrolled 518 adults who were randomized to twice-daily oral iptacopan 200 mg or placebo. The 9-month results (n = 477) showed a significant 38.3% reduction in 24-h urinary protein-to-creatinine ratio compared to placebo with an acceptable safety profile. The FDA accelerated approval was based on these initial results. 

At 24 months, the annualized total eGFR decline was 3.02 ml/min/1.73m² per year slower with iptacopan than placebo, a significant difference (adjusted P < .001). A composite kidney failure endpoint event occurred in 21.4% of the iptacopan group, versus 33.5% of the placebo group (hazard ratio, 0.57; adjusted P = .003). 

There were no significant differences in adverse events or discontinuation due to adverse events, and no deaths occurred, Rovin reported. 

Interim Analysis From VISIONARY 

Dana V. Rizk, MD, professor of medicine in the Division of Nephrology at the University of Alabama, Birmingham, presented results of a prespecified interim post hoc analysis from the phase 3 VISIONARY randomized trial of once-monthly subcutaneous sibeprenlimab, a humanized IgG2 monoclonal antibody that selectively blocks APRIL. A previous interim analysis showed a 51.2% placebo-adjusted reduction in urine protein-to-creatinine ratio at 9 months. 

This new analysis of VISIONARY examined the treatment response to sibeprenlimab compared to placebo in 320 study participants across different proteinuria thresholds. At 9 months, 25.5% of patients receiving sibeprenlimab achieved the KDIGO recommended target of < 0.5 g/day urine total protein, compared with just 6.2% on placebo. At 12 months, those percentages were 34.3% and 12.7%, respectively. The number needed to treat (NNT) was 6, decreasing to 5 by month 12. 

Approximately half of those receiving sibeprenlimab achieved a 50% or greater reduction in urinary protein creatinine ratio at month 9, vs less than 10% with placebo. That response rate increased by about 10% at month 12 with sibeprenlimab. The NNT was 3 at both time points, Rizk reported. 

“The low NNT values and consistent benefit across all proteinuria thresholds reinforce the clinically meaningful efficacy of sibeprenlimab in IgA nephropathy,” she said. 

Which Drug for Which Patients, and in What Order? 

Rizk, who is an investigator for several IgAN drug trials, told Medscape Medical News that exactly how each of the new agents will be used clinically has yet to be sorted out. 

“All the drugs seem to reduce proteinuria well enough, and for some we’ve already seen their eGFR preservation results, which is important. We’ll need to have the results from the other trials that are still ongoing, because at the end of the day, the ultimate goal is preservation of kidney function,” she said. 

Next steps will be to figure out where to start, if the drugs can be used in combination, or if certain sequences of treatment will benefit certain patients, Rizk explained. “The science is just not there yet,” she noted, adding that “there’s also the reality of accessibility, as in, what the patient’s insurance allows them to have.” 

She also pointed out that diagnosing people earlier as now recommended by KDIGO might allow treatments targeting earlier points in the pathogenesis to work better. 

“We used to wait until they had a gram of [urine] protein before we would biopsy them. Now the guidelines say 500 mg. So, if we increase awareness about screening, checking urine to detect proteinuria and hematuria, we’ll start capturing people earlier in their disease, before they have significant scar tissue. And then, drugs that address the immunologic aspect of the disease should play a big role, as opposed to catching somebody who already has a lot of fibrosis, and has already lost a lot of kidney function,” she told Medscape. 

Severity and Side Effect Profiles 

Also asked to comment, NKF Chief Medical Officer Joseph A. Vassalotti, MD, said that influencing factors might include IgAN severity — as assessed by the Oxford Classification MEST scores— and side effect profiles. He pointed out that both sparsentan and iptacopan have FDA-required Risk Evaluation and Mitigation Strategy labeling, the former for liver function monitoring and the latter for the increased risk of serious encapsulated bacterial infections associated with the use of all complement inhibitors.

“I think some of this will be thinking about the side effect profile. There are steroid side effects with the budesonide that maybe some patients won’t tolerate. Some of it may be personal preference. I think it’s reasonable to discuss with patients what they’re willing to do in terms of monitoring,” Vassalotti said. 

Indeed, Rizk added that some patients may not want to take an injection, while others might prefer once-monthly shots to daily or twice-daily pills. Thus, “some of the patient factors also have to be taken into account.” 

Rovin has received grant/research support, travel reimbursement and fees for educational events from GSK, and consulting fees from GSK, Roche/Genentech, Bristol Myers Squibb, Artiva, Kyverna, AstraZeneca, Novartis, Biogen and Alexion. Rizk has received research support, consulting fees, and/or honoraria from Travere Therapeutics, Calliditas Therapeutics, Otsuka Pharmaceutical, Vertex Pharmaceuticals, Vera Therapeutics, LaRoch, Novartis, Sanofi, Dimerix, Takeda, Emerald Clinical, BioCryst, Chugai, Timberlyne Therapeutics, Jade Biosciences, Climb Bio, Argenx, and Alpine Immune Science. She has ownership in Reliant Glycosciences. Vassalotti is an employee of NKF with no further disclosures. 

Miriam E. Tucker is a freelance journalist based in the Washington DC area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR’s Shots blog, and Diatribe. She is on X (formerly Twitter) @MiriamETucker and BlueSky @miriametucker.bsky.social