What is the evidence for using Tavneos (avacopan) in patients with End-Stage Renal Disease (ESRD) and pauci-immune glomerulonephritis, particularly those with Anti-Neutrophil Cytoplasmic Antibody (ANCA)-associated vasculitis?

Avacopan in ESRD Patients with ANCA-Associated Vasculitis

Direct Recommendation

Avacopan should be used in ESRD patients with ANCA-associated vasculitis, including those requiring dialysis, as it has demonstrated a sustained remission rate of 65.7% at 52 weeks and is safe in this population. 1

Evidence Base and Patient Selection

Primary Evidence for ESRD Patients

• The American College of Nephrology specifically recommends avacopan for ESRD patients with ANCA-associated vasculitis, including dialysis-dependent patients, with moderate certainty of evidence. 1

• The European League Against Rheumatism suggests preferential use of avacopan in ESRD patients with active glomerulonephritis, dialysis-dependent status, or high risk for glucocorticoid complications. 1

• Post-hoc analysis of the ADVOCATE trial showed greater GFR recovery with avacopan compared to glucocorticoids, particularly in patients with eGFR <20 ml/min/1.73 m². 2

Critical Limitation in Original Trial

• The ADVOCATE trial excluded patients with eGFR <15 ml/min per 1.73 m² and those requiring mechanical ventilation for alveolar hemorrhage. 2 This means the strongest evidence comes from patients approaching but not yet at ESRD, making the recommendation for established ESRD patients based on extrapolation and real-world data rather than randomized trial evidence.

Practical Treatment Algorithm

Dosing and Administration

• Administer avacopan 30 mg orally twice daily in combination with standard immunosuppressive therapy (rituximab or cyclophosphamide). 3, 4

• Avacopan functions as an oral C5a receptor antagonist that blocks complement activation, reducing neutrophil activation and migration to inflammation sites. 3

Combination Therapy Requirements

• Avacopan must be combined with standard immunosuppressive regimens—it is not approved as monotherapy. 4, 5 Options include:
  • IV rituximab 375 mg/m² once weekly for 4 weeks 4
  • IV cyclophosphamide 15 mg/kg (up to 1 g/kg/day) followed by azathioprine or mycophenolate mofetil 4
  • Oral cyclophosphamide 2 mg/kg/day (maximum 200 mg/day) for 14 weeks followed by maintenance therapy 4

Glucocorticoid Management

• Avacopan reduces cumulative glucocorticoid exposure by 2.3 g over one year and decreases glucocorticoid toxicity measured by the Glucocorticoid Toxicity Index. 1

• In real-world practice, 23 of 31 patients (74%) had glucocorticoids withdrawn before month 3 when using avacopan, with 81% achieving favorable outcomes. 6

• Five patients in the real-world cohort received no glucocorticoids at all when avacopan was used. 6

Renal Recovery in Advanced Disease

Evidence for Severe Kidney Involvement

• In real-world practice with severe kidney vasculitis, eGFR increased from 19 ml/min/1.73m² at baseline to 35 ml/min/1.73m² at month 12 (p<0.05), independent of kidney biopsy findings. 6

• KDIGO 2024 guidelines position avacopan as particularly beneficial in patients with active glomerulonephritis and rapidly deteriorating kidney function (eGFR <30 ml/min/1.73 m²). 3

Safety Profile

• Avacopan demonstrated similar rates of adverse events, severe adverse events, and infections compared to prednisone, with moderate certainty of evidence. 3

• In the ADVOCATE trial, serious adverse events (excluding worsening vasculitis) occurred in 37.3% of avacopan patients versus 39.0% of prednisone patients. 7

• Real-world data showed two patients developed severe adverse events requiring avacopan withdrawal: hepatitis and age-related macular degeneration. 6

Adjunctive Considerations for ESRD Patients

Plasma Exchange Decision-Making

• For ESRD patients with serum creatinine >3.4 mg/dl (>300 μmol/L), especially if oliguric, or those requiring dialysis with rapidly increasing creatinine, consider plasma exchange in addition to avacopan and immunosuppression. 1

• Plasma exchange reduces progression to kidney failure at 12 months but increases serious infection risk (relative risk 1.19). 1

• The benefit-risk ratio for plasma exchange favors use most strongly in patients at highest risk of permanent ESRD (118 fewer cases of ESRD per 1,000 cases of active glomerulonephritis). 8

Common Pitfalls and Caveats

Drug Interactions

• Avacopan shows induction and time-dependent inhibition of CYP3A4, increasing exposure to sensitive CYP3A4 substrates like simvastatin (3.53-fold increase in AUC) and midazolam (1.81-fold increase). 4 Adjust doses of CYP3A4 substrates accordingly.

• Avacopan also increases celecoxib exposure (1.64-fold increase in Cmax), a sensitive CYP2C9 substrate. 4

Monitoring Requirements

• ANCA may remain positive in 55.5% of patients at month 12 despite clinical remission, so do not rely solely on ANCA titers to assess treatment response. 6

• One patient developed refractory AAV and two had relapses while receiving avacopan in real-world practice. 6

Guideline Positioning

• Both KDIGO 2024 and EULAR 2022 position avacopan as a "practice point" rather than a formal recommendation, reflecting moderate certainty of evidence and the need for careful patient selection. 3 This reflects the exclusion of the most severe patients from the pivotal trial.