Since the initial description of immunoglobulin A nephropathy (IgAN), significant advances have been made in our understanding of the disease pathogenesis (1). These advances have spurred exciting, new research targeting the various steps in this autoimmune process. But the relatively slow kidney function decline in most IgAN patients has made the implementation of clinical trials with hard outcomes (such as a 50% reduction in estimated glomerular filtration rate [eGFR], kidney failure, or death) quite challenging. In 2016, a partnership between ASN and the US Food and Drug Administration (FDA) identified proteinuria as a surrogate marker of disease progression and response to therapeutic interventions (2). Subsequently, the IgAN community witnessed a renewed interest from the pharmaceutical industry in the treatment of this rare disease and a proliferation of clinical trials (Figure 1). In 2021, the updated Kidney Disease: Improving Global Outcomes (KDIGO) guidelines prioritized clinical trial participation in the hierarchy of disease management strategies (3). Review of all ongoing trials is beyond the scope of this article; it is worth mentioning a few studies that have already yielded exciting results.
The landscape of clinical trials in IgA nephropathy over the past 3 decades
Citation: Kidney News 14, 12
The TESTING trial reevaluated the benefit of systemic steroid treatment (4). Use of a lower dose of prednisolone along with antibiotic prophylaxis resulted in favorable kidney outcomes while mitigating serious adverse events.
The phase 3 NefIgArd trial tested the efficacy of localized steroids at the intestinal mucosal surface where the disease is thought to originate (5). The study showed a 27% relative reduction in proteinuria compared with placebo at 9 months, earning targeted-release budesonide conditional approval by the FDA and recently by the European Medicines Agency.
Another phase 3 trial, PROTECT (6), evaluated the efficacy of sparsentan (a combined angiotensin receptor blocker [irbesartan] and endothelin receptor antagonist) compared with irbesartan alone. The interim results favored sparsentan with a 49.8% mean reduction of proteinuria from baseline versus 15.1%. These positive outcomes are being considered by the FDA for conditional approval.
The DAPA-CKD trial included 270 patients with IgAN in whom dapagliflozin (sodium-glucose cotransporter 2 inhibitor [SGLT2]) reduced the primary end point of a ≥50% decline in eGFR, kidney failure, or kidney/cardiovascular death by 71% (7). The EMPA-KIDNEY study results recently published supported further the benefit of SGLT2 inhibitor use in patients with non-diabetic kidney disease including IgAN. (8)
Many other ongoing trials in earlier stages of clinical development are investigating the safety and tolerability of novel therapies targeting B cells (thought to be responsible for the production of the galactose-deficient IgA1 autoantigen and its autoantibody), as well as the alternative, lectin and terminal complement pathways (9). The rapidly changing treatment landscape in IgAN has energized the nephrology community. Experience gained from current studies will undoubtedly serve as a road map for treating other rare glomerular diseases. Therefore, IgAN patients and their providers have the unique opportunity but also a tremendous responsibility to engage and deliver timely and successful clinical trials.
References
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Rajasekaran A, et al. IgA nephropathy: An interesting autoimmune kidney disease. Am J Med Sci 2021; 361:176–194. doi: 10.1016/j.amjms.2020.10.003
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Thompson A, et al. Proteinuria reduction as a surrogate end point in trials of IgA nephropathy. Clin J Am Soc Nephrol 2019; 14:469–481. doi: 10.2215/CJN.08600718
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Rovin BH, et al. Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases. Kidney Int 2021; 100:753–779. doi: 10.1016/j.kint.2021.05.015
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Lv J, et al. Effect of oral methylprednisolone on decline in kidney function or kidney failure in patients with IgA nephropathy: The TESTING randomized clinical trial. JAMA 2022; 327:1888–1898. doi: 10.1001/jama.2022.5368
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Barratt J, et al. Results from part A of the multi-center, double-blind, randomized, placebo-controlled NefIgArd trial evaluated targeted-release formulation of budesonide for the treatment of primary immunoglobulin A nephropathy. Kidney Int [published online ahead of print October 19, 2022]. https://www.sciencedirect.com/science/article/pii/S0085253822008365
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Wong M, et al. MO209: Baseline characteristics of adults enrolled in the ongoing phase 3 randomized, double-blind, active-control trial of sparsentan for the treatment of immunoglobulin A nephropathy (PROTECT). Nephrol Dial Transplant 2022; 37 (Suppl. 3):i142–i144. https://academic.oup.com/ndt/article/37/Supplement_3/gfac067.008/6578479?login=false
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Wheeler DC, et al. A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy. Kidney Int 2021; 100:215–224. doi: 10.1016/j.kint.2021.03.033
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EMPA-KIDNEY Collaborative Group; Herrington WG, et al. Empagliflozin in patients with chronic kidney disease. N Engl J Med, published online ahead of print November 4, 2022. doi: 10.1056/NEJMoa2204233
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Cheung CK, et al. An update on the current state of management and clinical trials for IgA nephropathy. J Clin Med 2021; 10:2493. doi: 10.3390/jcm10112493