How a Rare Kidney Disease Gained a Robust New Therapy Pipeline
核心洞察
The FDA approved the first therapy for primary IgA nephropathy (搜索) in December 2021, and since then multiple novel drugs have received accelerated approval, transforming the treatment landscape.
A 2016 Kidney Health Initiative partnership redefined surrogate endpoints, establishing proteinuria reduction at 9 months as an acceptable marker, which made clinical trials feasible and affordable.
Currently, five therapies are approved in the U.S., including sparsentan, atrasentan, budesonide, sibeprenlimab, and iptacopan, with additional agents like atacicept and povetacicept under FDA review.
In December 2021, the FDA approved the first therapy indicated to treat primary immunoglobulin A nephropathy. Since then, several novel drugs have received accelerated approval for the disease, and more are in the pipeline — a transformation that experts describe as nothing short of remarkable.
"In just the last few years, there's been an explosion in therapies available to us," Jackson Kim, MD, clinical assistant professor in the division of nephrology at Stanford Health Care, told Healio.
Kim, who graduated from medical school in 2017, said he was taught that IgA nephropathy (搜索) "was not a big deal." The disease progressed slowly, if at all, and was treated with kidney supportive measures. "At the time, it was poorly understood, and traditional teaching hadn't caught up to what [researchers] were realizing: that it wasn't such a benign disease," he said. "Since then, we've undergone a big change. It turns out that a significant portion of these patients will end up with kidney failure. Early on, all we had were steroids. These [new] therapies have certainly changed the landscape."
Why the Pipeline Accelerated
IgA nephropathy (搜索) is considered a rare disease, affecting one to two per 100,000 people in the United States. The incidence is higher in East Asia, lower in Europe, and "very rare" in Central Africa, according to Dana Rizk, MD, professor of medicine in the division of nephrology at the University of Alabama at Birmingham. Although the disease was first described in 1968, research into therapies had been limited.
"Traditional clinical trials needed patients to reach certain hard endpoints — dialysis — and so for diseases like IgA nephropathy (搜索), which happens mostly in young folks, that timeline will have been too long and none of the clinical trials would have been feasible," Rizk told Healio.
That changed in 2016 with the support of the Kidney Health Initiative (KHI), a partnership among the American Society of Nephrology, the FDA, and multiple member companies and organizations, which began a project to identify surrogate endpoints for clinical trials in IgA nephropathy (搜索).
"There's a publication that came out of that, which the FDA signed up to, which showed that if you measure proteinuria change at 9 months, that's a pretty good indicator that that drug is likely to protect kidney function 2, 3, 5 years later," said Jonathan Barratt, PhD, FRCP, professor of renal medicine at the University of Leicester in the United Kingdom, who was part of the KHI working group.
Based on those data, the FDA agreed to an accelerated approval pathway for drugs that showed reduction in proteinuria at 9 months and full approval based on 2-year eGFR data when they become available. "You could do that with around 350 to 450 patients, and you only need 200 patients for the proteinuria [data]," Barratt said. "So suddenly, it became a trial design that was affordable."
The Four-Hit Hypothesis and Targeted Therapies
At the same time, researchers were developing an understanding of the pathogenesis of IgA nephropathy (搜索) referred to as the "four-hit hypothesis," according to Kim: Hit 1, galactose-deficient IgA1 is elevated; Hit 2, autoantibodies form in response; Hit 3, pathogenic IgA and antibodies form circulating immune complexes; and Hit 4, these complexes deposit in the glomeruli and cause inflammation, scarring, and kidney damage. Pharmaceutical companies are developing drugs that target different points in the disease process.
"Knowing where to target in terms of therapeutics, then, of course, industry was interested in investing in this new approval pathway," Rizk said.
Currently Approved Agents
Currently, two nonimmunosuppressive and three immunologic therapies are approved in the United States for proteinuria reduction for adults with primary IgA nephropathy (搜索) at risk for rapid progression:
- Sparsentan (Filspari, Travere): A first-in-class dual endothelin A and angiotensin II receptor antagonist. Based on data from the PROTECT trial, FDA accelerated approval was granted in February 2023 and full approval in September 2024.
- Atrasentan (Vanrafia, Novartis): A first-in-class selective endothelin A receptor antagonist. Based on data from the ALIGN trial, accelerated approval was granted in April 2025. Final 2.5-year data were published in The Lancet in June.
- Budesonide (Tarpeyo, Calliditas): A targeted-release oral corticosteroid. Based on data from the NefIgArd trial, accelerated approval was granted in December 2021 and full FDA approval in December 2023.
- Sibeprenlimab-szsi (Voyxact, Otsuka): The first approved a proliferation-inducing ligand (APRIL) blocker. Based on data from the VISIONARY trial, accelerated approval was granted in November 2025. Twelve-month eGFR data were presented at the European Renal Association Congress in Glasgow in June.
- Iptacopan (Fabhalta, Novartis): A first-in-class factor-B complement inhibitor. Based on data from the APPLAUSE-IgAN trial, accelerated approval was granted in August 2024. Final 24-month data were published in The New England Journal of Medicine in March.
A Rich Pipeline Ahead
The pipeline for therapies remains robust. In July, the FDA is scheduled to consider atacicept (Vera Therapeutics), a novel human transmembrane activator and calcium-modulator and cyclophilin ligand interactor-Fc fusion protein that inhibits B-cell activating factor (BAFF (搜索)) and APRIL (搜索). That agent is "likely to get approved," Barratt said.
Positive data have also been reported for povetacicept (Vertex), an investigational recombinant fusion protein therapy and dual BAFF (搜索) and APRIL (搜索) antagonist, which the FDA is scheduled to consider later this year. Telitacicept (RemeGen), a dual BAFF and APRIL antagonist approved for systemic lupus erythematosus in China, will likely also be approved for IgA nephropathy (搜索) in the near future, he said.
Ravulizumab-cwvz (Ultomiris, AstraZeneca), a terminal C5 complement (搜索) inhibitor approved for other indications, is in phase 3 trials "as a disease-modifying treatment option" for IgA nephropathy (搜索). In addition, phase 3 trials are underway for two drugs targeting CD38 (搜索) depletion — felzartamab (Biogen) and mezagitamab (Takeda (搜索)).
"Stay tuned because there's more to come. Some of the new drugs still being tested have different mechanisms of action, targeting the disease differently," Rizk said. "There are more complement inhibitors targeting different spots on the complement cascade. And then there are new therapies called 'degraders' that would degrade, or chew up, the galactose-deficient IgA1 — harnessing your own system to eat up this abnormal IgA. We've never done anything like that before, so we'll see."
Also in the early stage is a potential gene therapy from Purespring Therapeutics (搜索), according to Kim. "It would deliver gene therapy to the podocytes and will sort of engineer them to be more complement activation-resistant, or complement-modulating," Kim said. "Basically, the podocytes themselves, the filtering cells, will not only serve a filter function, but also have an anti-complement effect — like your own built-in pharmacy. That's really exciting."
Managing IgA Nephropathy (搜索) Today
When treating IgA nephropathy (搜索), Kim said he follows the Kidney Disease: Improving Global Outcomes guideline. The 2021 guideline was updated in October 2025 to include new therapies. Ultimately, the goal is to preserve kidney function, and treatment success is assessed in terms of proteinuria.
"In general, I will push the [non-immunologic], supportive care as hard as tolerated," Kim said. "Depending on blood pressure, I'll start adding, step-by-step, renin-angiotensin system inhibition, potentially upgrading to a dual endothelin A and angiotensin II receptor (搜索) antagonist [sparsentan or atrasentan] and an SGLT2 inhibitor. Then, if potassium and creatinine are OK, I'll think about a mineralocorticoid receptor antagonist or a GLP-1 receptor agonist if there are concurrent comorbidities, such as obesity or diabetes with proteinuria. At that point, if proteinuria remains uncontrolled above 0.5 g per day, I'll try to get a targeted delayed-release steroid [budesonide], a B-cell inhibitor modulating class [sibeprenlimab-szsi] or the complement inhibition class [iptacopan] approved."
An Embarrassment of Riches — and Remaining Challenges
How to choose which therapy to use for which patient is now the "million dollar question," Rizk said. Researchers need to determine whether there is an optimal drug sequence or combination. Currently, there are no data to show any one of these new drugs is better than another, according to Barratt.
"I think you might see some differences over the longer term. At the moment, it's too tough to call. It's going to be a crowded marketplace," he said.
Still, the marketplace may be able to support many therapies, even though IgA nephropathy (搜索) remains a rare disease. "There's never one size that fits all. Some people respond to medications or don't respond, they have side effects with one and not the other, they don't like taking injections or don't like taking pills. So, we need a multitude of drugs," Rizk said. "Which ones and in what sequence, we have to figure out, but it's an embarrassment of riches."
Barratt also emphasized that long-term risks and benefits need careful assessment. "All of these drugs come with a cost because they're targeting the immune system," he said. "All the data at the moment would suggest none of these are curative, which means we're committing young people to potentially life-long therapy taking out two very important components of your immune system. We've never done it before."
Until a therapy is developed to increase kidney function — to cure the disease — screening will remain the biggest challenge, Barratt said. "The future of IgA nephropathy (搜索) will be that we live in a world where there are many available treatments. But it's only going to make a difference if we get to patients earlier. The bottom line is patients present too late."
Beyond IgA nephropathy (搜索), these agents are also expanding into other indications. In March 2025, the FDA approved iptacopan for treatment of adults with complement 3 glomerulopathy (搜索). In April (搜索), the FDA approved sparsentan for proteinuria reduction in adults and children with focal segmental glomerulosclerosis (搜索). "With nearly all of these drugs, we are under no illusion that these were developed to treat IgA nephropathy alone. They were developed to target a pathway that is also relevant in all the other antibody-mediated kidney diseases," Barratt said.