PROTECT: Sparsentan Outperforms Irbesartan in IgA Nephropathy

Patients with IgA nephropathy could achieve greater reductions in proteinuria and decrease risk for adverse kidney outcomes with use of sparsentan rather than irbesartan, according to results of the PROTECT trial.

Presented at the American Society of Nephrology Kidney Week 2023, results of the trial provide evidence suggesting use of sparsentan was associated with a more significant antiproteinuric effect at 110 weeks, with this benefit confirmed by chronic and total eGFR slope, relative to use of irbesartan in patients with IgA nephropathy.¹

“The totality of data from the PROTECT study demonstrates FILSPARI is effective, safe and has an important place in the IgAN treatment landscape as a long-term foundational therapy,” said steering committee member Brad Rovin, MD, medical director of the Center for Clinical Research Management and director of the Division for Nephrology at Ohio State University.²

An autoimmune disease characterized by inflammation and kidney damage, recent estimates indicate the US prevalence of IgA nephropathy is approximately 329.0 per 1,000,000 persons. A dual endothelin type A and angiotensin II type 1 receptor antagonist, sparsentan has been shown to reduce proteinuria in clinical trials and, as a result, has received accelerated approval for reducing proteinuria in adults with primary IgA nephropathy in February 2023. The agent being evaluated in the treatment of other forms of glomerular disease, including the phase 3 DUPLEX trial in focal segmental glomerulosclerosis, which was also presented at Kidney Week 2023.^3,4,5

Funded by Travere Therapeutics, the PROTECT trial is billed as being among the largest interventional studies to date in IgA nephropathy and the only head-to-head trial for the disease. Conducted across 134 sites in 18 countries, the randomized, multicenter, double-blind, parallel-arm, active-controlled clinical trial was designed to compare the effects of 400 mg of sparsentan, compared to 300 mg of irbesartan, in 404 patients aged 18 years and older with IgA nephropathy and persistent proteinuria despite receiving at least 50% of max label dose and maximally tolerated ACE or ARB therapy.^1,2

The trial was designed with a 36-week prespecified, primary analysis, which assessed mean reduction in proteinuria. The 36-week interim analysis suggested mean reductions of 49.8% and 15.1% were observed for randomized to sparsentan and irbesartan, respectively (P <.0001).¹

The trial was also designed to assess eGFR total and chronic slope as confirmatory secondary endpoints. Highlighted results from the 2-year eGFR analysis are highlighted below.¹

Chronic 2-year slope (Weeks 6 to 110):

With sparsentan −2.7 mL/min/1.73m2 per year

With irbesartan: −3.8 mL/min/1.73m2 per year

Difference: 1.1 mL/min/1.73m2 per year (95% CI, 0.1 to 2.1; P=.037)

Total 2-year slope (Day 1 to Week 110):

With sparsentan: −2.9 mL/min/1.73m2 per year

With irbesartan: −3.9 mL/min/1.73m2 per year

Difference: 1.0 mL/min/1.73m2 per year (95% CI, −0.03 to 1.94; P=.058).

In a press release, Travere Therapeutics noted the absolute overall change in eGFR from baseline to the end of the study for the sparsentan arm was -5.8 mL/min/1.73m2 compared to -9.5 mL/min/1.73m2 for the irbesartan arm, which translates to a difference of 3.7 mL/min/1.73m2 at 2 years. Further analysis of a composite of kidney failure, which included confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality, suggested such an event occurred among 9% of the sparsentan group and 13% of the irbesartan group (Relative Risk 0.7; 95% CI, 0.4 to 1.2). Travere Therapeutics has expressed plans to use the PROTECT trial as the basis for an sNDA submission for traditional approval of sparsentan.^1,2

“We’re proud to have set the bar very high in delivering clinically meaningful data from two of the most rigorous Phase 3 clinical trials to date in IgAN and FSGS and to now share these two-year data in prestigious peer-reviewed journals and at ASN Kidney Week,” said Jula Inrig, MD, chief medical officer of Travere Therapeutics.² “These data from PROTECT suggest that FILSPARI has the potential to significantly delay time to kidney failure, which based on recently published data is projected to be an additional eight years versus being treated with standard of care.”

References:

1. Rovin BH, Barratt J, Heerspink HJ. Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial. The Lancet. Published online November 3, 2023. doi:10.1016/S0140-6736(23)02302-4
2. Travere Therapeutics, Inc. Travere Therapeutics announces late-breaking data from phase 3 studies of Sparsentan in Igan and FSGS published in the Lancet and the NEJM respectively and presented at the American Society of Nephrology (ASN) Kidney Week 2023. Travere Therapeutics, Inc. November 3, 2023. Accessed November 3, 2023. https://ir.travere.com/news-releases/news-release-details/travere-therapeutics-announces-late-breaking-data-phase-3.
3. IGA nephropathy - NIDDK. National Institute of Diabetes and Digestive and Kidney Diseases. Accessed November 3, 2023. https://www.niddk.nih.gov/health-information/kidney-disease/iga-nephropathy.
4. Lerma EV, Bensink ME, Thakker KM, et al. Impact of Proteinuria and Kidney Function Decline on Health Care Costs and Resource Utilization in Adults With IgA Nephropathy in the United States: A Retrospective Analysis. Kidney Med. 2023;5(9):100693. Published 2023 Jun 25. doi:10.1016/j.xkme.2023.100693
5. Campbell P. Sparsentan use could lower risk of kidney failure, death in FSGS. HCP Live. November 3, 2023. Accessed November 3, 2023. https://www.hcplive.com/view/sparsentan-use-could-lower-risk-of-kidney-failure-death-in-fsgs.