Sparsentan in IgA Nephropathy: Two-Year Outcomes from the PROTECT Trial
Dual endothelin-angiotensin receptor antagonism demonstrates durable proteinuria reduction and eGFR preservation
Dr. Jonathan Wei
Director, Glomerular Disease Program, UCSF
◆ CLINICAL BOTTOM LINE
What was studied
Long-term efficacy and safety of sparsentan versus irbesartan in IgA nephropathy over 110 weeks in the PROTECT trial extension.
What was found
Sparsentan reduced proteinuria by 49% versus 15% with irbesartan (p<0.001) and significantly slowed eGFR decline (-2.9 vs -3.9 mL/min/1.73m²/year).
What it changes in practice
Sparsentan should now be considered first-line add-on therapy for IgA nephropathy with proteinuria >1g/day, particularly in patients with progressive disease despite optimized RAS blockade.
IgA nephropathy remains the most common primary glomerulonephritis worldwide, and until recently, therapeutic options beyond RAS blockade were limited. The approval of sparsentan in 2023 represented a paradigm shift, and two-year data from the PROTECT trial now provide the most robust evidence to date for its long-term efficacy.
Background
Sparsentan is a novel dual-acting molecule that simultaneously blocks endothelin type A receptors and angiotensin II type 1 receptors. The rationale for this dual blockade is compelling: endothelin-1 promotes mesangial cell proliferation and podocyte injury, while angiotensin II drives intraglomerular hypertension and fibrosis. Blocking both pathways simultaneously may provide additive or synergistic renoprotection.
Two-Year Results
The PROTECT trial enrolled 404 patients with biopsy-proven IgA nephropathy and proteinuria >1g/day despite optimized RAS blockade. At 110 weeks, sparsentan demonstrated a 49% reduction in proteinuria versus 15% with irbesartan (p<0.001). Critically, the eGFR slope was significantly less steep in the sparsentan group (-2.9 vs -3.9 mL/min/1.73m²/year, p=0.04).
Safety Profile
The most notable safety signal remains edema, occurring in 18% of sparsentan-treated patients versus 9% with irbesartan. Liver function test elevations, a concern with prior endothelin antagonists, were not significantly increased. Teratogenicity remains an absolute contraindication, requiring a REMS program.
Where Does This Leave Us?
With the concurrent approval of budesonide (Nefecon) for targeted intestinal immunosuppression, nephrologists now have two disease-modifying therapies for IgA nephropathy. The question of combination therapy — sparsentan plus budesonide — is actively being investigated in the AFFINITY trial.
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CME Assessment
In the PROTECT trial 2-year extension, what was the proteinuria reduction with sparsentan vs. irbesartan?