• 1.

    Lafayette R, et al.; NeflgArd Trial Investigators. Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NeflgArd): 2-Year results from a randomized phase 3 trial. Lancet 2023; 402:859780. doi: 10.1016/S0140-6736(23)01554-4

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  • 2.

    Wimbury D, et al. Targeted-release budesonide modifies key pathogenic biomarkers in immunoglobulin A nephropathy: Insights from the NEFIGAN trial. Kidney Int (published online November 25, 2023) doi: 10.1016/j.kint.2023.11.003

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    • Search Google Scholar
    • Export Citation
  • 3.

    Sunny ME, Santhosh C. US FDA approves Sweden-based Calliditas’ kidney disease drug. Reuters. December 21, 2023. https://www.reuters.com/business/healthcare-pharmaceuticals/us-fda-approves-sweden-based-calliditas-kidney-disease-drug-2023-12-20/

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FDA Gives Full Approval to First IgA Nephropathy Drug. Tarpeyo to Target Underlying Mechanism of Action

Eric Seaborg
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Several glomerular disease specialists used the word “excited” to describe their reaction to the US Food and Drug Administration (FDA) granting full approval to a drug for treatment of immunoglobulin A (IgA) nephropathy. After giving Tarpeyo (budesonide) accelerated approval in December 2021, the FDA followed it up with full approval on December 21, 2023, based on clinical trial results for treatment of adults with primary IgA nephropathy.

“This approval is an incredibly big thing because in the world of primary kidney [diseases] we have had too few breakthroughs with medications designed to treat the mechanism of action,” said Richard Lafayette, MD, professor of medicine at Stanford University, Stanford, CA, and principal investigator in the clinical trial underpinning the approval.

Lafayette said the disease is an autoimmune disorder in which the patient makes too much of an aberrant form of IgA: “The patients develop auto-antibodies to those elevated levels of circulating IgA. The kidneys both specifically and nonspecifically try to remove the immune complexes, which get caught in the glomerular mesangium, leading to inflammation. Patients who are predisposed develop hematuria, proteinuria, and progressive loss of kidney structure and function. Roughly half of them will be approaching dialysis within just 10 years.”

In the past, treatment relied on “supportive care,” according to Shikha Wadhwani, MD, MS, FASN, assistant professor of medicine in the Division of Nephrology and Hypertension at the Northwestern University Feinberg School of Medicine, Chicago, IL. “All we really had for decades were medications to lower protein in the urine—which also happen to be blood pressure medications—as well as steroids we use in a variety of different auto-immune diseases. Steroids come with their own problems—a lot of potential side effects.”

In contrast, Tarpeyo is a B cell immunomodulator designed to target a source of the disease by reducing the production of pathogenic galactose-deficient IgA1 antibodies. The manufacturer describes it as an oral, delayed-release formulation of the corticosteroid budesonide. It is designed to remain intact until it reaches the ileum, where it targets mucosal B cells, including in the Peyer’s patches, which are responsible for the production of the galactose-deficient IgA1 believed to underlie IgA nephropathy.

Successful clinical trials

The approval was based on the results of the phase 3 Efficacy and Safety of Nefecon in Patients with Primary IgA (Immunoglobulin A) Nephropathy (NeflgArd) clinical trial, a randomized, double-blind, multicenter, international study published in The Lancet (1). Approximately 360 participants were randomly assigned to receive daily oral Tarpeyo (referred to in the trial as Nefecon, its investigational drug name) or matching placebo for 9 months, followed by a 15-month follow-up period. All of the patients also received a renin-angiotensin-aldosterone system (RAAS) inhibitor throughout.

The study authors reported that the drug provided “a clinically relevant reduction in eGFR [estimated glomerular filtration rate] decline and a durable reduction in proteinuria versus placebo. [Tarpeyo] was also well-tolerated, with a safety profile as expected for a locally acting oral budesonide product.” In the treatment group, the decline in eGFR was one-half that of patients who received placebo.

Kidney International published an analysis of another clinical trial aimed at exploring how Tarpeyo exerts its effects (2). The trial found that Nefecon led to significant reductions in serum levels of galactose-deficient IgA1 and pathogenic IgA-containing immune complexes, which the authors said was “supportive of Nefecon having a disease-modifying action in IgA nephropathy.”

“For many years we have been primarily treating IgA nephropathy with drugs that target intra-renal injury, [such as] RAAS inhibitors,” according to Brad H. Rovin, MD, FASN, director of the Division of Nephrology at The Ohio State University, Columbus, and a co-author of the study in The Lancet. “However, I have always been concerned that in the background, galactose-deficient IgA was still being made in abundance and still depositing in the kidney, so we were not stopping the root cause of IgA nephropathy. With Tarpeyo, based on its presumptive mechanism of action, we may, for the first time, be targeting a very early step in the pathogenesis of IgA nephropathy, potentially allowing us to control the disease and decrease further risk to the kidneys. While this remains to be proven, data so far are encouraging,” said Rovin.

An underdiagnosed disease?

IgA nephropathy affects 130,000 to 150,000 people in United States, and the FDA has granted Tarpeyo orphan drug status. Wadhwani noted, however, that epidemiological data indicate that there may be more patients at risk for the disease than previously believed. “We are probably missing cases because a primary care doctor, internist, or family practice doctor has to check the urine, which a lot of people don’t do, and then think it is worth making a referral if they find blood or protein,” she said.

She hopes that increased education about the availability of a more effective and safer drug will give doctors more incentive to screen for it. “We are going to be biopsying people with blood in the urine much more often now that we have something to treat them with,” Wadhwani shared.

She said that the disease is much more prevalent in the Asia Pacific region, and in Japan, children are routinely screened by testing urine. Lafayette agrees: “Too many of our patients, particularly in North America and Europe, are diagnosed very, very late. There is a lot of advocacy going around for better screening and for encouraging primary care doctors to do more blood pressure checks and more laboratory testing of the urine, at least with dipsticks, during routine primary care visits to try to find patients earlier. These things are done in China and Japan. It results in earlier diagnosis, and all of our therapies work much better if they are deployed early.”

Encouraging early results

In the 2 years since Tarpeyo’s accelerated approval, many specialists have been using it and have been pleased with the results. Wadhwani had two patients in the clinical trial that led to the drug’s approval. When the trial was unblinded, she learned that both had been receiving the drug. “Both of my patients did remarkably well. One is in complete remission,” she said.

Rovin has treated five or six patients and found it to be “well-tolerated with declines in proteinuria. Judging the stability of eGFR will take longer, but so far I have not had anyone progress to end stage kidney disease.” Lafayette also expressed that the several patients he has treated have tolerated the drug well.

Wadhwani noted that, because the clinical trial compared Tarpeyo with placebo, “we don’t know how it compares directly to corticosteroids—traditionally prednisone or prednisolone—that were given to people deemed at high risk of progression. But anecdotally, what I have seen in terms of side effects and what other nephrologists are seeing are that people are tolerating this medication better. To have a new drug that potentially mitigates some of the adverse reactions to steroids and is effective is really exciting.”

Although it seems to be tolerated better than prednisone, Tarpeyo is still an immunosuppressive steroid that was tested in a 9-month course. “While a single, 9-month treatment course is not curative, the tolerability and toxicity profiles of Tarpeyo are such that it [Tarpeyo] is suitable for use as a cyclical treatment to chronically suppress pathogenic IgA production,” according to Jonathan Barratt, PhD, professor of renal medicine at the University of Leicester in the United Kingdom and a co-author of both The Lancet and Kidney International articles.

“Tarpeyo is currently the only available treatment that has been shown to suppress the production of pathogenic IgA in IgA nephropathy. The now full approval opens up the opportunity for far more patients with IgA nephropathy to access this disease-modifying therapy and start treatment while they have good kidney function and will gain the maximum benefit from suppressing this disease early and preserving kidney function over the long term,” he said.

Wadhwani has already begun fielding questions about its use from nephrologists who are not glomerular disease specialists. “[This drug] is safe and efficacious and is certainly something that any nephrologist can use in their [patients with IgA nephropathy] with monitoring as they would with any immune-modulatory drugs. So I think it is going to be used not just by academic institutions. It is already being used in community nephrology practices.”

Another IgA nephropathy drug

The full approval of Tarpeyo came less than 1 year after the February 2023 accelerated FDA approval of another IgA nephropathy drug, Filspari (sparsentan).

Rovin said he is also excited about using Filspari, which he considers complementary to Tarpeyo. “While Tarpeyo is likely modulating the immune system and affecting IgA at an early step in its pathogenesis, Filspari is working, presumably, at the level of the kidney parenchyma to attenuate the kidney injury caused by the deposition of IgA immune complexes in the mesangium. We know that it does this better than our current standard of care (RAAS inhibitors). Because each drug works on a different part of the IgA nephropathy disease pathway, I believe that the combination may provide additive benefits for patients.”

Wadhwani agrees that the drugs can be layered on top of each other: “One of my patients got Tarpeyo first, and after the 9 months had a partial remission. Then I started him on Filspari, which is nonimmunosuppressive, so he can stay on it long term.”

Both drugs are expensive, with Reuters (3) reporting that Tarpeyo costs over $15,000 per month, and Filspari costs almost $10,000 per month, but the specialists interviewed reported no problems with getting insurance coverage approval.

Patients are also excited about the approval of Tarpeyo, according to Bonnie Schneider, director and co-founder of the IgA Nephropathy Foundation (https://igan.org/). “This first-ever IgA nephropathy treatment to get a full approval based on kidney function represents a beacon of hope for the entire IgA nephropathy community and signifies a critical step forward in the battle against IgA nephropathy,” Schneider reflected.

Wadhwani does not expect the drug to be a panacea, but its development makes her optimistic for the future. “We refer to IgA nephropathy as though it is one disease, but it is actually very heterogeneous. Every patient’s kidney biopsy looks a little bit different, and everyone is different in how they respond to treatment. It is naïve for us to think that one drug is going to be the answer to every single [problem for a patient with IgA nephrology], but it is really exciting that there are two drugs that have now gotten accelerated approval.

“There is a ton of interest by pharmaceutical companies in investing money and resources in drug development, which was not there 10 or 15 years ago. So I think what we are going to be able to offer patients is going to change dramatically in the course of even just the next 5 years because there are so many ongoing trials right now,” Wadhwani concluded.

References

  • 1.

    Lafayette R, et al.; NeflgArd Trial Investigators. Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NeflgArd): 2-Year results from a randomized phase 3 trial. Lancet 2023; 402:859780. doi: 10.1016/S0140-6736(23)01554-4

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Wimbury D, et al. Targeted-release budesonide modifies key pathogenic biomarkers in immunoglobulin A nephropathy: Insights from the NEFIGAN trial. Kidney Int (published online November 25, 2023) doi: 10.1016/j.kint.2023.11.003

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Sunny ME, Santhosh C. US FDA approves Sweden-based Calliditas’ kidney disease drug. Reuters. December 21, 2023. https://www.reuters.com/business/healthcare-pharmaceuticals/us-fda-approves-sweden-based-calliditas-kidney-disease-drug-2023-12-20/

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    • Search Google Scholar
    • Export Citation
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