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Expert perspective in IgAN

CE / CME

An Expert’s Perspective: Where We Are and What Lies Ahead in Treating IgAN

Nurses: 0.25 Nursing contact hour

Physicians: maximum of 0.25 AMA PRA Category 1 Credit™

Physician Assistants/Physician Associates: 0.25 AAPA Category 1 CME credit

ABIM MOC: maximum of 0.25 Medical Knowledge MOC point

Released: January 25, 2024

Expiration: January 24, 2025

CME/CE Information

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Key Takeaways
  • The treatment landscape for immunoglobulin A nephropathy (IgAN) is evolving as several novel therapies could potentially become standard of care.
  • In December 2023, the oral glucocorticoid budesonide was FDA-approved for the treatment of IgAN and in February 2023 the dual endothelin angiotensin receptor antagonist  sparsentan was granted accelerated approval. 
  • Patients, healthcare professionals, advocacy groups, payors, and manufacturers must strive for equitable access to care and to the fruits of scientific progress.

We are in an unprecedented era of innovation in the treatment of patients with immunoglobulin A nephropathy (IgAN). Just a few years ago, recommended therapies were limited to renin–angiotensin system inhibitors and glucocorticoids, with the latter at the center of considerable debate regarding their usefulness. A large and well-conducted clinical trial (TESTING) has since provided the best data yet that characterizes the benefits and risks of methylprednisolone (a systemic glucocorticoid) in patients at high risk of declining kidney function. Further, we have witnessed the development of a new class of agents—sodium-glucose cotransporter (SGLT2) inhibitors—that dramatically attenuate the progression of chronic kidney disease, with additional benefits confirmed specifically for IgAN.

Novel and Approved Agents
In less than 3 years, the FDA granted accelerated approval to 2 agents (budesonide and sparsentan) to reduce proteinuria in adults with IgAN who are at risk of disease progression. In December 2023, the FDA granted full approval to budesonide—the first in this area.

What’s Ahead in the Pipeline
There are now more than a dozen phase II and/or III clinical trials that are studying novel therapies with various (and potentially complementary) mechanisms of action for treating IgAN. Among these studies, a few broad drug classes bear mentioning. Endothelin receptor antagonists show reliable, class-wide reductions in proteinuria, fibrosis, and inflammation across several agents like sparsentan, atrasentan, and zibotentan. These agents could become standard-of-care additions to maintenance therapy for IgAN, although whether the FDA will grant sparsentan full approval remains to be seen. 

Next, there are several agents currently being evaluated in advanced studies that target B-cell activation via blockade of APRIL (proliferation-inducing ligand), with or without blockade of BAFF (B-cell activating factor). Preliminary data look promising, but close attention will need to be paid to their safety profile (particularly infection risk) and treatment durability. Finally, multiple agents that target the complement system are in active development. These agents and their mechanisms of action are much more heterogenous, and we should consider them individually rather than as a monolithic “class.” This was highlighted in 2023 by 2 nearly simultaneous announcements of contrasting phase III outcomes: narsoplimab (a lectin pathway-targeting agent) was not found to be statistically better than placebo at reducing proteinuria, whereas iptacopan (a complement factor B inhibitor) resulted in a significant reduction in proteinuria.

Although progress is welcomed by both healthcare professionals and patients alike, it carries a fresh set of challenges for us to face:

  • We do not yet have a clear, consensus-driven treatment algorithm for IgAN that incorporates this new knowledge and incoming novel therapies. Current clinical trials will not directly address this need because they largely avoid active control arms. Treating IgAN will only become more complicated as any new agents enter the landscape, so we must be prepared for academic debates.
  • The use of chronic, long-term maintenance therapies (dubbed “supportive care”) will need to continually be refined and redefined. The clearest example of this is the addition of SGLT2 inhibitors, and the potential of endothelin receptor antagonists and mineralocorticoid receptor blockers like finerenone (which ameliorates diabetic kidney disease), being added to the treatment cocktail. How should each of these agents be prioritized? How much “supportive care” is required before attempting more aggressive therapies like immunomodulators? These questions must be answered to optimize patient outcomes.
  • As supportive care becomes more comprehensive and effective and baseline expectations regarding disease progression improve, clinical trials of new agents will become increasingly difficult to power and fully enroll. Of course, if this means that patients are doing better, it is a good thing. One could even argue that this would define success. But for a disease with a lengthy course, where progression to end-stage kidney disease in middle-aged patients is still expected for many, we may unintentionally impede the development of better or potentially curative agents for IgAN.
  • Cost and access questions must also be considered, particularly among health systems with limited budgets. This will require collaboration between patients, healthcare professionals, advocacy groups, payers, and manufacturers with the hope that all are striving for equitable access to the fruits of scientific progress. 

I am fond of reminding folks that although these are difficult challenges, they are fundamentally “good” problems to have. Compared to the previous era of research scarcity in IgAN therapeutics, patients now have more options, comprising both approved and experimental therapies, that are available to them (particularly for those eager to participate in clinical trials). The future brims with opportunity, and there is much more work—good work—still ahead.

Your Thoughts
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