Sparsentan Studies and UPCR Reduction in Patients on RAS Inhibitors
Yes, sparsentan was primarily studied in patients already on RAS inhibitors, with clinical trials showing approximately 40-62% reduction in UPCR compared to 4-15% with irbesartan alone in these patients.
Background on Sparsentan
Sparsentan is a novel dual-acting antagonist that blocks both:
- Angiotensin II receptor type 1 (ARB component)
- Endothelin receptor type A (ERA component)
This dual mechanism provides a theoretical advantage over traditional RAS inhibitors alone in reducing proteinuria and slowing kidney disease progression.
Evidence from Clinical Trials
PROTECT Trial (IgA Nephropathy)
The PROTECT trial, a phase 3 randomized controlled study, specifically enrolled patients with IgA nephropathy who were:
- Already on maximized RAS inhibition for at least 12 weeks
- Had persistent proteinuria ≥1.0 g per day despite this treatment 1
Key findings at 110 weeks:
- Sparsentan group: 42.8% reduction in UPCR from baseline
- Irbesartan group: Only 4.4% reduction in UPCR from baseline
- Geometric least-squares mean ratio: 0.60 (40% lower proteinuria with sparsentan)
- Slower eGFR decline with sparsentan (-2.7 vs -3.8 mL/min/1.73m² per year) 1
DUET Trial (FSGS)
The DUET trial studied sparsentan in primary focal segmental glomerulosclerosis (FSGS):
- Designed as a phase 2 randomized controlled trial
- Compared sparsentan (200-800 mg daily) to irbesartan (300 mg daily)
- Primary endpoint was reduction in UPCR at 8 weeks 2
A post-hoc analysis of DUET showed:
- 43% of patients achieved complete remission (UPCR ≤0.3g/g) at least once during follow-up
- Complete remission was associated with significantly slower eGFR decline
- Higher sparsentan doses were associated with greater likelihood of complete remission 3
Real-World Evidence with SGLT2 Inhibitors
Recent real-world data examined sparsentan in patients already on both:
- Maximum tolerated doses of RAS inhibitors
- SGLT2 inhibitors
Results showed:
- 62% median relative reduction in UPCR after 14 weeks
- Baseline median UPCR: 1.5 g/g
- 14-week median UPCR: 0.60 g/g 4
This demonstrates that sparsentan provides additional proteinuria reduction even when added to optimized RAS inhibition plus SGLT2 inhibitors.
Clinical Context and Implications
The evidence clearly shows that sparsentan was specifically studied as an add-on therapy to existing RAS inhibition:
Patient selection: Trials deliberately enrolled patients with persistent proteinuria despite maximized RAS inhibitor therapy
Comparative efficacy:
- Sparsentan: ~40-62% UPCR reduction
- Irbesartan alone: ~4-15% UPCR reduction
Mechanism rationale: Current guidelines recommend maximizing RAS inhibition for proteinuric kidney disease 5, but many patients have residual proteinuria. Sparsentan's dual mechanism provides additional benefit.
Safety considerations: The dual blockade with sparsentan appears well-tolerated, unlike traditional dual RAS blockade (ACEi+ARB) which is not recommended due to adverse effects 5.
Clinical Application
When considering sparsentan for patients with proteinuric kidney disease:
- Ensure patients are already on maximized RAS inhibitor therapy (as in the clinical trials)
- Monitor for expected UPCR reduction of approximately 40-60% beyond what was achieved with RAS inhibitors alone
- Continue to monitor kidney function and electrolytes as would be done with any RAS inhibitor
- Consider the additive benefit even in patients already on SGLT2 inhibitors
The significant additional UPCR reduction with sparsentan suggests it addresses residual risk that persists despite optimal RAS inhibition, potentially offering improved long-term kidney outcomes.