Sparsentan Limits eGFR Reduction Regardless of IgAN Patient Proteinuria Levels

Sparsentan (FILSPARI) provided significant positive benefit to kidney function preservation relative to irbesartan in patients with immunoglobulin A nephropathy (IgAN) over 2 years, according to phase 3 data.¹

In findings from the PROTECT trial presented at the National Kidney Foundation 2024 Spring Clinical Meeting (SCM) in Long Beach, CA, this week, a team of Travere Therapeutics-supported investigators reported new 110-week data suggesting the non-immunosuppressive dual endothelin / angiotensin receptor agonist fared better than its comparator agent in absolute change in estimated glomerular filtration rate (eGFR) among patients with IgAN. The findings, supplemented by a consistent safety profile, support a long-term care strategy with sparsentan.

Led by Brad Rovin, MD, professor of internal medicine and a nephrologist with The Ohio State University Wexner Medical Center, investigators sought to compare the efficacy and safety of sparsentan to active control irbesartan among patients with IgAN over 2-year outcomes. The preliminary findings of the PROTECT trial published last year showed sparsentan significantly reduced proteinuria versus irbesartan at 36 weeks (-49.8% vs -15.1%, respectively; P <.0001). The team additionally observed significant and sustained proteinuria reduction over 110 weeks in treated patients, with an associated 40% relative reduction in levels among patients on sparsentan compared to irbesartan at that time.²

The investigators analyzed the randomized, double-blind, parallel-group analysis for outcomes with 400 mg daily sparsentan versus maximum-label 300 mg daily irbesartan in adults with biopsy-indicated IgAN who faced risk to progression to kidney failure despite treatment with ACE inhibitors and/or ARBs. Eligible patients additionally had urine protein excretion (UPE) of ≥1.0 g/d, and eGFR ≥30 mL/min/1.73 m².

The observed outcomes of the PROTECT analysis included complete remission of proteinuria (CR) as per UPE <0.3 m2, absolute change in eGFR, rate of eGFR change, and blood pressure in treated patients.¹

Rovin and colleagues observed that patients with IgAN receiving sparsentan were nearly 3-fold more likely to achieve CR (31%) compared to patients receiving irbesartan (11%) by week 110 (relative risk, 2.5; 95% CI, 1.6 – 4.1). There was also a 3.7 mL/min/1.73 m² (95% CI, 1.5 – 6.0) positive difference in mean eGFR change from baseline among the treatment arm (-5.8) versus control (-9.5).

What’s more, patients with baseline urine protein-to-creatinine ratio (UPCR) ≥1.25 treated with sparsentan reported significantly improved change in eGFR reduction versus the same patients on irbesartan.

“Fewer sparsentan-treated patients progressed to composite kidney failure endpoints of confirmed 40% or 50% eGFR reduction, end-stage kidney disease, or death vs irbesartan,” investigators wrote. “Patients initiated immunosuppressive therapy sooner and more frequently with irbesartan versus sparsentan. Improved eGFR slope suggests that sparsentan could delay the need for dialysis or kidney transplant.”

Investigators additionally observed consistent tolerability and safety outcomes similar to irbesartan with sparsentan. No body weight increases nor drug-induced liver injury were reported; 75 (37%) patients receiving sparsentan reported a serious treatment-emergent adverse event (TEAE), though 42 were cases of COVID-19 while 6 were chronic kidney disease. Another 21 (10%) of sparsentan patients discontinued therapy due to TEAEs; 1 patient receiving irbesartan experienced TEAEs leading to death.

Rovin and colleagues concluded sparsentan provided sustained proteinuria reduction and an apparent benefit in eGFR in patients with IgAN over 110 weeks, regardless of baseline proteinuria levels.

“Patients with IgAN treated with sparsentan over 2 years had one of the slowest annual rates of kidney function decline seen in phase 3 IgAN clinical trials,” the team wrote. “Sparsentan is well tolerated, with a consistent safety profile comparable to irbesartan.”

References

1. ^{Sparsentan (SPAR) Shows Clinically Meaningful Treatment Effects vs Irbesartan (IRB) in Patients With IgA Nephropathy (IgAN) in the Phase 3 PROTECT Trial. Poster presented at: National Kidney Foundation 2024 Spring Clinical Meeting (SCM). Long Beach, CA. May 14 – 18, 2024.}
2. ^{Campbell P. PROTECT: Sparsentan Outperforms Irbesartan in IgA Nephropathy. HCPLive. Published November 3, 2023. https://www.hcplive.com/view/protect-sparsentan-outperforms-irbesartan-in-iga-nephropathy}