Pipeline for Remission of Proteinuria in IgA Nephropathy is Encouraging

Presenters: Tingting Li, MD, MSc, FASN, Washington University, St. Louis, MO; Jonathan Barratt, MBChB, PhD, University of Leicester, United Kingdom; Richard A. Lafayette, MD, Stanford University Medical Center, Stanford, CA

Li T, Barratt J, Lafayette RA. IgA nephropathy: the role of the renal endothelin system and other therapeutic implications. Educational Symposium presented at American Society of Nephrology Kidney Week 2022, November 3, 2022, 12:45 pm – 1:45 pm.

Summary: Experts address the clinical implications of proteinuria in IgA nephropathy and discuss emerging treatment options.

Supportive care and blood pressure control with renin-angiotensin-aldosterone system (RAAS) inhibitors have been mainstays in the management of IgA nephropathy. Disease-specific treatments have been elusive with an incomplete understanding of disease mechanisms, said Tingting Li, MD, MSc, FASN, from Washington University, St. Louis, MO.

“We knew IgA nephropathy was an immune-mediated kidney disease; therefore, many of us used glucocorticoids and immunosuppressive therapies to try to slow or prevent progression of kidney disease in our high-risk patients,” she said, adding that their efficacy is questionable and associated toxicities are often unacceptable.

The treatment landscape is evolving, starting with the recent accelerated approval by the US Food and Drug Administration of targeted-release budesonide for the treatment of proteinuria in adults with primary IgA nephropathy at risk of rapid disease progression. New agents in the pipeline for the treatment of IgA nephropathy include sparsentan, atrasentan, and iptacopan.

The lifetime risk of kidney failure with IgA nephropathy is significant, said Jonathan Barratt, PhD, from University of Leicester, UK. Proteinuria is the strongest single prognostic factor in IgA nephropathy and is used to define high-risk populations. Each incremental increase greater than 1 g/day in proteinuria is associated with a 10- to 25-fold more rapid rate of decline in renal function compared with increases of less than 1 g/day.1

“A high risk of progression is currently defined as proteinuria greater than 1 g/day despite at least 90 days of supportive care,” he said. This level can be used as a marker for the need for additional therapy. “For me, it means enrollment into a clinical trial,” Prof. Barratt added.

Sustained proteinuria is associated with poor clinical outcomes, and an early change in proteinuria is a reliable marker of response to treatment. “If I see a reduction in proteinuria, I can be confident that it will translate into kidney function protection in the future for my patient with IgA nephropathy,” he said. The goal of treatment is to reduce proteinuria to as low a level as possible. Current guidelines call for less than 1 g/day; Prof. Barratt predicted that this recommendation will probably be revised lower because it reflects the risk of kidney failure only over the following 5 to 10 years rather than lifetime risk.

Maximizing RAAS inhibition is the best available conservative therapy for IgA nephropathy, and sodium-glucose cotransporter 2 (SGLT-2) inhibitors are likely to have additive benefit, said Richard A. Lafayette, MD, Stanford University Medical Center, Stanford, CA. Steroids may be beneficial in populations at high risk of progressive chronic kidney disease (CKD) despite maximal supportive care, but adverse events are concerning. “The risk/benefit ratio [with steroids] seems to be razor thin,” he said. Steroid use is strongly associated with serious infections with no benefit on kidney function.

A randomized clinical trial of patients with IgA nephropathy and persistent proteinuria greater than 1 g/day compared a 6- to 9-month course of oral methylprednisolone with placebo. Methylprednisolone significantly reduced the risk of a composite outcome of a decline in kidney function, kidney failure requiring dialysis or transplant, or death due to kidney disease.2 Almost 11% of patients had serious adverse events, but a reduced-dose protocol of methylprednisolone lowered this risk.

Endothelin is a potent vasoconstrictor and evidence is abundant that endothelin is upregulated in CKD. “Endothelin receptor antagonists look highly promising to be antiproteinuric and hopefully will prove to maintain kidney function,” Dr. Lafayette said.

In patients with type 2 diabetes and CKD, the endothelin A receptor antagonist atrasentan reduced the risk of adverse renal end points compared with placebo in a multicenter study.3 Based on these results, “going to younger healthier patients makes sense,” he said.

Interim results from an ongoing phase 3 study showed a mean reduction in proteinuria of 49.8% from baseline to 36 weeks in patients randomized to sparsentan, a dual endothelin angiotensin receptor antagonist, compared with a reduction of 15.1% in patients randomized to irbesartan (P < 0.0001).4 Study completion is expected in March 2023.

Newer anti-inflammatory therapies (ie, targeted budesonide, anticomplement therapies, anti B-cell therapies, and others) deserve further evaluation, said Dr. Lafayette.

Targeted-release budesonide demonstrated clinically significant improvements in urinary protein-to-creatinine and estimated glomerular filtration rate compared with placebo in the multicenter randomized double-blind NeflgArd trial in patients with primary IgA nephropathy at risk of progressing to kidney failure.5

Combinations with RAAS inhibitors may be the future of treatment in IgA nephropathy, he said.

References

  1. Reich HN, Troyanov S, Scholey DC. Remission of proteinuria improves prognosis in IgA nephropathy. J Am Soc Nephrol 2007;18:3177-3183. doi: 10.1681/ASN.2007050526
  2. Lv J, Wong MG, Hladunewich MA, 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
  3. Heerspink HJL, Parving H-H, Andress DL, et al. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial. Lancet 2019;393:1937-1947. doi: 10.1016/S0140-6736(19)30772-X
  4. Travere Therapeutics press release. Travere Therapeutics announces positive topline interim results from the ongoing phase 3 PROTECT study of sparsentan in IgA nephropathy, August 16, 2021. https://ir.travere.com/news-releases/news-release-details/travere-therapeutics-announces-positive-topline-interim-results
  5. Barratt J, Lafayette R, Kristensen J, et al. Results from part A of the multi-center, double-blind, randomized, placebo-controlled NeflgArd trial evaluated targeted-release formulation of budesonide for the treatment of primary immunoglobulin A nephropathy published online ahead of print 2022 Oct. 18]. Kidney Int 2022. doi: 10.1016/j.kint.2022.09.017

Disclosures

Support was provided by an educational grant from Travere Therapeutics, Inc.

Dr. Li reports consultant fees from ChemoCentryx, GlaxoSmithKline, Reata Pharmaceuticals, and Travere Therapeutics, and research funding from Aurinia Pharmaceuticals, Genentech, and Omeros Corporation.

Dr. Barratt reports consultant fees from Alnylam Pharmaceuticals, Astellas Pharma, BioCryst Pharmaceuticals, Calliditas Therapeutics, Chinook Therapeutics, Dimerix Limited, Novartis, Omeros Corporation Travere Therapeutics, Vera Therapeutics, and Visterra; and research funding from Argenx, Calliditas Therapeutics, Chinook Therapeutics, Galapagos, GlaxoSmithKline, Novartis, Omeros Corporation, Travere Therapeutics, and Visterra.

Dr. Lafayette reports consultant fees from Alexion, Aurinia Pharmaceuticals, Calliditas Therapeutics, Chinook Therapeutics, Novartis, Omeros Corporation, Otsuka, Travere Therapeutics, Vera Therapeutics, and Visterra; and research funding from Apellis, Calliditas Therapeutics, ChemoCentryx, Chinook Therapeutics, National Institutes of Health, Omeros Corporation, Otsuka, Pfizer, Roche, Travere Therapeutics, and Vera Therapeutics.

Link to session: https://www.asn-online.org/education/kidneyweek/2022/program-session-details.aspx?sessId=439549

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