What is the role of Sparsentan in treating kidney diseases, such as Focal Segmental Glomerulosclerosis (FSGS) and Immunoglobulin A (IgA) nephropathy?

Role of Sparsentan in Treating Kidney Diseases

Sparsentan is a novel dual endothelin and angiotensin II receptor antagonist indicated to slow kidney function decline in adults with primary immunoglobulin A nephropathy (IgAN) who are at risk for disease progression, but is not yet established in the treatment of focal segmental glomerulosclerosis (FSGS). 1

IgA Nephropathy Treatment

Current Treatment Paradigm

The cornerstone of IgA nephropathy management has traditionally been:

1. Optimized supportive care:

   • ACE inhibitors or ARBs for all patients with proteinuria >0.5 g/day 2
   • Blood pressure targets <130/80 mmHg (proteinuria <1 g/day) or <125/75 mmHg (proteinuria ≥1 g/day) 2
   • Dietary sodium restriction (<2.0 g/day), weight normalization, smoking cessation 3

2. Additional therapies for persistent proteinuria:

   • Corticosteroids may be considered for patients with persistent proteinuria ≥1 g/day despite optimized supportive care and eGFR ≥30 ml/min/1.73 m² 2
   • Fish oil supplementation may be considered 2

Sparsentan's Position in IgAN Treatment

Sparsentan represents a significant advancement in IgAN treatment as:

1. First non-immunosuppressive therapy specifically approved for IgAN 1, 4

   • FDA-approved to slow kidney function decline in adults with primary IgAN at risk for disease progression

2. Mechanism of action:

   • Dual endothelin and angiotensin II receptor antagonist 1
   • Provides both hemodynamic and anti-inflammatory properties without immunosuppression 5

3. Clinical evidence:

   • In the PROTECT trial, sparsentan demonstrated:
     • 41% greater reduction in proteinuria compared to irbesartan at 36 weeks (49.8% vs 15.1% reduction) 6
     • Slower rate of eGFR decline over 110 weeks (-2.7 vs -3.8 mL/min/1.73m² per year) 7
     • Maintained 40% lower proteinuria than irbesartan at 110 weeks 7
     • Composite kidney failure endpoint (40% eGFR reduction, end-stage kidney disease, or death) was reached by 9% of sparsentan patients vs 13% of irbesartan patients 7

4. Safety profile:

   • Similar adverse event profile to irbesartan 7, 6
   • Most common adverse reactions (≥5%): hyperkalemia, hypotension, peripheral edema, dizziness, anemia, and acute kidney injury 1
   • Carries boxed warnings for hepatotoxicity and embryo-fetal toxicity 1

Focal Segmental Glomerulosclerosis (FSGS) Treatment

Current FSGS Treatment Approach

According to KDIGO guidelines, FSGS treatment includes:

1. First-line therapy: High-dose glucocorticoids (Grade 1D) 3

   • Oral prednisone 1 mg/kg/day for up to 16 weeks
   • Total duration of 6 months (high-dose period plus taper)

2. Second-line therapy: Calcineurin inhibitors (CNIs) for glucocorticoid-resistant or intolerant patients (Grade 1C) 3

   • Cyclosporine 3-5 mg/kg/day or tacrolimus 0.05-0.1 mg/kg/day
   • Total duration of 12 months

Sparsentan's Potential Role in FSGS

While sparsentan has shown promise in FSGS treatment, it is not yet FDA-approved for this indication:

• In the DUET study, sparsentan reduced proteinuria by 44.8% compared to 18.5% with irbesartan at 8 weeks in FSGS patients 8
• Further long-term data on renal function and safety in FSGS are still needed

Clinical Implementation

When to Consider Sparsentan for IgAN

Sparsentan should be considered for:

• Adults with biopsy-proven primary IgAN
• Patients with persistent proteinuria despite maximized RAS inhibition
• Patients at risk for disease progression

Dosing and Administration 1

1. Prior to initiation:

   • Discontinue all RAAS inhibitors and endothelin receptor antagonists
   • Perform pregnancy testing (contraindicated in pregnancy)
   • Measure liver aminotransferases and total bilirubin

2. Dosing regimen:

   • Initial dose: 200 mg orally once daily
   • After 14 days: Increase to 400 mg once daily as tolerated
   • Take with water before morning or evening meal

3. Monitoring:

   • ALT and AST monthly for 12 months, then every 3 months
   • Monitor for hypotension, acute kidney injury, hyperkalemia, and fluid retention

Important Precautions

1. Boxed warnings 1:

   • Hepatotoxicity: Monitor liver function tests regularly
   • Embryo-fetal toxicity: Contraindicated in pregnancy; effective contraception required

2. Drug interactions 1:

   • Avoid concomitant use with ARBs, ERAs, or aliskiren (contraindicated)
   • Avoid strong CYP3A inhibitors or inducers
   • Avoid antacids within 2 hours before or after use
   • Monitor for hyperkalemia with potassium-sparing agents

Conclusion for Clinical Practice

Sparsentan represents an important advancement in IgAN treatment as the first non-immunosuppressive therapy specifically approved to slow kidney function decline. Its dual mechanism targeting both endothelin and angiotensin II receptors provides greater proteinuria reduction and kidney function preservation compared to traditional ARB therapy alone.

For FSGS, current guidelines still recommend glucocorticoids as first-line therapy followed by CNIs, with sparsentan potentially offering a future treatment option pending further clinical evidence and regulatory approval.