
From the Chair
IgA nephropathy (IgAN) is at the forefront of newer treatments for glomerular disease. Therapeutic strategies like sparsentan and targeted-release budesonide are already approved, while therapies targeting complement and B-cell survival factors are being actively investigated.
In two recent articles, one a review in the Journal of the American Society of Nephrology (JASN)1 and the other a review in the Clinical Journal of the American Society of Nephrology (CJASN),2 the treatment of IgAN is the focus. In the JASN article by El Karoui et al, both current and evolving treatment strategies are discussed. In the CJASN article by Cheung et al, strategies targeting B-cell survival factors—a proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF)—are reviewed.
The El Karoui review in JASN points out that because IgAN involves several hits (summarized in the Table), targeting one factor is likely to be of limited value. It also emphasizes the importance of selecting patients at high risk by trying to predict which patients are likely to progress and identifying patients with active as opposed to chronic disease.
El Karoui et al review four therapeutic approaches that should be considered in the management of IgAN: renin-angiotensin-aldosterone blockade, sodium-glucose cotransporter-2 (SGLT2) inhibition therapy, endothelin receptor antagonism, and broad-acting immunosuppression (corticosteroids and/or mycophenolate mofetil).
Among current therapies, the “new kid on the block” is sparsentan, a selective endothelin type A receptor and angiotensin II subtype 1 receptor antagonist. It has generated tremendous excitement because it significantly reduces proteinuria, which led to its conditional accelerated approval from the US Food and Drug Administration (FDA). However, the excitement has become somewhat muted due to its modest effects on stabilizing kidney function. This latter issue may slow down or impact its full approval from the FDA.
Budesonide, a corticosteroid, is likely to become a first-line steroid therapy for IgAN. Like sparsentan, budesonide has received accelerated approval from the FDA. Budesonide appears to work by delayed release in the gastrointestinal tract so that it targets the cells in Peyer’s patch in the distal ileum and proximal colon that produce IgA and Gd-IgA1. The delayed release is a result of packaging budesonide in a pH-sensitive starch capsule. The other advantage of budesonide is that, although it is a corticosteroid, only a fraction is absorbed systemically. The results of the Effect of Nefecon in Patients With Primary IgA Nephropathy at Risk of Developing End-stage Renal Disease (NEFIGAN) trial and the phase 3 Efficacy and Safety of Nefecon in Patients With Primary IgA Nephropathy (NefIgArd) study of high-risk patients with IgAN were very promising in terms of both proteinuria reduction and stabilization of kidney function.
Therefore, in addition to supportive therapies (eg, renin-angiotensin inhibition and SGLT2 inhibition), both sparsentan and targeted-release budesonide should be considered, especially for high-risk IgAN patients.
Several emerging therapies are either in phase 2 or phase 3 trials, including agents that target complement and those homing in on B-cell factors APRIL and BAFF.
Anticomplement agents under development include avacopan, an oral C5a receptor inhibitor; iptacopan, which impacts the alternative pathway; and narsoplimab, which targets the lectin pathway. Anti-APRIL agents include sibeprenlimab (VIS649) and the anti-APRIL/BAFF targeting therapy zigakibart (BION-1301) and atacicept. These novel compounds are promising because they reduce proteinuria and appear to slow kidney disease progression.
In summary, IgAN is on the cusp of a transformational change in its treatment. In addition to sparsentan and targeted-release budesonide, specific treatments that inhibit complement pathways and B-cell survival are on the horizon.
References
- El Karoui K, Fervenza FC, De Vriese AS. Treatment of IgA nephropathy: a rapidly evolving field. J Am Soc Nephrol. 2024;35(1):103-116. doi:10.1681/ASN.0000000000000242
- Cheung CK, Rajasekaran A, Barratt J, Rizk DV. An update on the current state of management and clinical trials for IgA nephropathy. J Clin Med. 2021;10(11):2493. doi:10.3390/jcm10112493