New research, treatments move glomerular disease to center of nephrology care
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Treatment of glomerular disease has a hard endpoint, Brad H. Rovin, MD, FACP, FASN, said — slowing progression of chronic kidney disease by stabilizing or improving eGFR.
New clinical trials and approved drugs to treat glomerular disease have taken center stage in nephrology. These treatments are showing success in reducing proteinuria, which has been significant in some cases. An important deliverable for these treatments, however, is to slow the advancement of chronic kidney disease, Rovin told Healio | Nephrology News & Issues.
“The key outcome for treating all glomerular diseases is to preserve kidney function and keep patients away from the need for dialysis or transplantation,” Rovin, the Lee A. Hebert Professor of Nephrology and medical director of The Ohio State Wexner Medical Center for Clinical Research Management, said. “Often, treatment to preserve kidney function and prolong kidney survival goes hand-in-hand with reduction of proteinuria.
“Each glomerular disease is a bit different,” Rovin said, “and for each, the exact relationship between the reduction of proteinuria and effect size on stabilizing GFR may be different.”
Richard Lafayette, MD, FACP, recently reported results of the Origin phase 2 trial of atacicept (Vera Therapeutics), a new drug to treat immunoglobulin A (IgA) nephropathy that showed a reduction in proteinuria and stabilization of eGFR vs. controls.
“Proteinuria is an excellent signal (surrogate) for kidney protection but the exact relationship between degree of proteinuria reduction and kidney protection – freedom from large loss of kidney function or needing dialysis/transplant, the true gold standard – seems variable study by study and drug by drug,” Lafayette told Healio | Nephrology News & Issues. “Stabilization of eGFR is a more direct measurement of how the kidney is doing, and short-term changes in eGFR (by simple change or by slope) appears to be a better predictor of those hard outcomes, especially by one or two years on new treatment.”
Lafayette and other researchers reported in The Lancet on phase 3 trial results from the NeflgArd study indicating that patients who took budesonide (Tarpeyo, Calliditas Therapeutics) showed “clinically significant improvements in eGFR, potentially delaying the onset of clinical outcomes by 12.8 years compared to current standards of care,” according to a press release. The FDA granted an accelerated approval in August for Tarpeyo for reducing proteinuria in adults with primary IgA nephropathy at risk of rapid disease progression. Calliditas has presented phase 3 trial data to the FDA with a Prescription Drug User Fee Act (PDUFA) date of Dec. 20 for full approval of the drug, according to a company press release.
“The significant eGFR treatment benefit observed across the entire study population provides further evidence that Tarpeyo can be disease-modifying, potentially significantly delaying the need for dialysis or kidney transplantation for patients at risk,” Renee Aguiar-Lucander, CEO of Calliditas said in a press release.
Underdiagnosed
Ali Poyan Mehr, MD, the regional director of the Glomerular Disease Program at Kaiser Permanente Northern California, told Healio | Nephrology News & Issues that glomerular diseases are “vastly underdiagnosed and under-estimated” because of the low number of biopsies performed to verify the cause of end-stage kidney disease.
“Although the primary cause of ESKD is reported via the CMS 2728 form, this form is seen as what it is: an ‘End Stage Renal Disease Medical Evidence Report Medicare Entitlement and/or Patient Registration,’ and not a clinical disease documentation note,” Poyan Mehr said. “Therefore, many question the accuracy of this information, particularly because only a tiny fraction of patients have their diagnosis established via a kidney biopsy. The overwhelming majority are diagnosed based on clinical suspicion, which studies have shown to be often insufficient or wrong.
“At most, we do 60,000 biopsies per year in the U.S.; our diagnostic accuracy and understanding of the true prevalence of glomerular disease is grim,” Poyan Mehr said.
Poyan Mehr said data from the U.S. Renal Data System show that 5%-13% of the Medicare/Medicaid population is being tested for proteinuria, and 50% if they have CKD, “confirming the old wisdom that you won’t diagnose what you don’t test for,” he said.
Poyan Mehr is a founding member of the Glomerular Disease Study & Trial Consortium (GlomCon), an academic research and educational resource for nephrologists. “GlomCon aims to provide medical education, foster research collaboration and support nephrologists in treating glomerular diseases,” he told Healio | Nephrology News & Issues. “It achieves those goals through various programs, including weekly seminars for nephrologists, nephropathologists and trainees, a year-long glomerular disease fellowship that is now in its fourth year and has been hugely successful (more than 550 current and former participants), a funded research consortium for real-world evidence studies, a kidney pathology certificate program and an online network for patients and caregivers to identify experts and clinical trials opportunities close to them,” Poyan Mehr said.
GlomCon also funds GlomCon Physician Scientist, a scholarship program for early career nephrologists and nephropathologists to pursue a research project in glomerular disease. The curriculum for the fellowship includes detailed study and management of common glomerular diseases, such as podocytopathies (minimal change disease and primary FSGS), lupus nephritis and IgA nephropathy, Poyan Mehr said. Eligible applicants include adult and pediatric nephrologists and nephropathologists who have completed their first year of fellowship training.
Rovin also chairs a committee that is reviewing guidelines on glomerular disease released by Kidney Disease: Improving Global Outcomes in 2021. Two of the updated guidelines will be published soon.
“The next steps are reviewing each [glomerular disease] chapter, or each disease, to assess if there is sufficient new information to develop and update, and then we re-engage the original work group to assess the available new evidence, put it into context of the existing evidence, and use this to update and rank guidelines,” Rovin said. “The updated guidelines for [antineutrophilic cytoplasmic antibody] ANCA-associated vasculitis are also completed and awaiting their publication, and the work group for IgA nephropathy is re-engaged and working on these recommendations.”
At ASN Kidney Week, where more than 400 oral presentations and posters related to the management of glomerular diseases were presented, the High-Impact Clinical Trials session included presentations on the use of Filspari (sparsentan, Travere Therapeutics) to treat IgA nephropathy and focal segmental glomerulosclerosis (FSGS).
In the PROTECT3 trial, Rovin presented data showing that for IgAN patients treated with sparsentan the decline in eGFRover 2 years was 3.7 mL/min/1.73 m2 less than the fall in eGFR seen in those treated with irbesartan. Treatment benefits of sparsentan on eGFR slope were consistent across baseline levels of eGFR and proteinuria, “supporting the potential for sparsentan as a foundational treatment option across different stages of disease,” Rovin said during the Kidney Week session.
But similar results for improved eGFR were not seen among patients with FSGS in the phase 2 DUPLEX study supported by Travere.
“The most important results of the study are that it reduced proteinuria significantly compared to the active comparator,” Michelle N. Rheault, MD, professor of the department of pediatrics and director of the division of pediatric nephrology at the University of Minnesota, told Healio | Nephrology News & Issues. “More patients treated with sparsentan achieved partial and complete remission. Although the difference in the GFR slope between groups was not significant, we believe there still may be a clinical benefit for patients to be treated,” Rheault said.
Rovin said lowering of eGFR might take longer in some of patients with glomerular disease.
“For trials such as the one in FSGS, it may be that the reduction in proteinuria takes a longer time to translate into a GFR benefit than the duration of the trial. It may be that certain subsets respond faster or slower,” he said.
Treatment approaches
Jay B. Wish, MD, a professor of clinical medicine at Indiana University School of Medicine and chief medical officer for dialysis at Indiana University Health in Indianapolis, said the strong interest in glomerular disease at ASN Kidney Week is an indicator of more research to come.
“Glomerular disease seems to be the primary focus for treatment innovation in non-dialysis CKD,” Wish told Healio | Nephrology News & Issues. “The innovation is driven by a growing understanding of the pathophysiology of glomerulonephritis, especially the role of the complement system in IgA nephropathy and C3 glomerulopathy, as well as improved identification of autoantibodies in membranous nephropathy, the predisposition to which may be genetic,” Wish, who is also chair of the Editorial Advisory Board for Healio | Nephrology News & Issues, said. “This will lead to more targeted therapies in conditions that were previously thought to be homogeneous.”
“There has been a recent resurgence of investigation into IgAN treatments,” Patrick Gleason, MD, and colleagues wrote in an article recently published in Nephrology, Dialysis and Transplantation. “The menu of available reno-protective medications is rapidly expanding beyond blockade of the renin-angiotensin-aldosterone system to include sodium-glucose cotransporter 2 and endothelin type A receptor antagonism.”
Rovin agreed. “For the first time in many years, we have had several successful clinical trials of novel drugs for kidney diseases. This has been especially true in the [glomerularnephritis] space,” Rovin said.
“Much of this work, for example in the IgA nephropathy studies, has been propelled by the outcome of a public-private partnership of the ASN with the FDA and the Kidney Health Initiative to provide clear regulatory pathway for drug evaluation and approval.”
Gleason and colleagues wrote there is still much work to be done in getting new therapies into the hands of nephrologists to treat the various conditions associated with glomerular diseases.
“It is our opinion that to prevent kidney failure during the lifetime of a patient with IgAN, multi-targeted combination therapies will be required,” they wrote. “Treatment will need to be commenced early, with supportive and disease-modifying therapies used simultaneously.
“To better inform personalized patient management, and to monitor therapeutic response, we are in desperate need of validated biomarkers — this must be the focus of future research,” they wrote.
- References:
- Gleason P, et al. Nephrol Dial Transplant. 2023;doi:10.1093/ndt/gfad146.
- https://www.healio.com/news/nephrology/ 20230804/trial-results-show-decrease-in- proteinuria-stabilized-gfr-with-iga-nephropathy- drug.
- https://www.healio.com/news/nephrology/20231103/video-sparsentan-reduced-proteinuria-in-patients-with-focal-segmental-glomerulosclerosis.
- https://www.healio.com/news/nephrology/ 20231103/video-sparsentan-welltolerated- demonstrated-sustained-antiproteinuria- effects.
- Lafayette R, et al. Lancet. 2023;doi:10.1016/S0140-6736(23)01554-4.
- For more information:
- Richard Lafayette, MD, can be reached at czar@stanford.edu.
- Ali Poyan Mehr, MD, can be reached at poyanmehr@gmail.com.
- Michelle H. Rheault, MD, can be reached at rheau002@umn.edu.
- Brad H. Rovin, MD, FACP, FASN, can be reached at brad.rovin@osumc.edu.
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