What is the role of Avocopan (Avacopan) in the treatment of Anti-Neutrophil Cytoplasmic Antibodies (ANCA)-associated vasculitis?

Avacopan for ANCA-Associated Vasculitis

Avacopan (30 mg twice daily) should be used as an alternative to glucocorticoids during induction therapy for ANCA-associated vasculitis, particularly in patients at high risk for glucocorticoid toxicity or those with lower GFR who may benefit from enhanced renal recovery. 1

Role in Induction Therapy

Avacopan functions as an oral C5a receptor antagonist that blocks complement activation, reducing neutrophil activation and migration to sites of inflammation. 2, 3 The drug is administered at 30 mg twice daily and must be combined with standard immunosuppressive therapy (rituximab or cyclophosphamide)—it is not approved as monotherapy. 1, 4

Evidence Base

The ADVOCATE trial demonstrated that avacopan was:

• Non-inferior to prednisone for achieving remission at week 26 (72.3% vs 70.1%) 1, 5
• Superior to prednisone for sustained remission at week 52 (65.7% vs 54.9%, p=0.007) 1, 5
• Associated with 2.3 g lower cumulative glucocorticoid exposure over one year 1
• Linked to reduced glucocorticoid toxicity measured by the Glucocorticoid Toxicity Index 1

The certainty of evidence for sustained remission and severe adverse events is moderate, though evidence for infections and discontinuation due to adverse events is low. 1

Optimal Patient Selection

Prioritize avacopan in patients with:

• Active glomerulonephritis with rapidly deteriorating kidney function (particularly eGFR <30 ml/min/1.73 m²), where post-hoc analysis showed greater GFR recovery compared to glucocorticoids 1
• High risk for glucocorticoid-related complications, including diabetes, osteoporosis, psychiatric disorders, or obesity 1
• Lower baseline GFR, where patients demonstrated earlier reduction in albuminuria and improved kidney function 1

Important Exclusions from Trial Data

The ADVOCATE trial excluded patients with:

• eGFR <15 ml/min/1.73 m² 1
• Alveolar hemorrhage requiring mechanical ventilation 1
• Most severe end-organ manifestations 1

Clinical caveat: Use caution when extrapolating to these excluded populations, as safety and efficacy data are lacking. 1

Duration and Monitoring

• Approved duration: Up to 52 weeks based on ADVOCATE trial data 1, 5
• No data beyond 1 year: Longer-term use cannot be recommended at this time 1
• Maintenance therapy: There are no data supporting avacopan for maintenance beyond induction; switch to standard maintenance therapy (rituximab or azathioprine with low-dose glucocorticoids) after induction 1

The patient case referenced in the evidence completed 1 year of avacopan appropriately and should transition to rituximab maintenance therapy. 6

Safety Profile

Avacopan demonstrated:

• Similar rates of adverse events, severe adverse events, and infections compared to prednisone 1, 5
• No increase in serious adverse events (37.3% vs 39.0% with prednisone) 5
• Well-tolerated when added to standard-of-care therapy 7

Integration with Standard Therapy

Combination Requirements

Avacopan must be combined with either:

• Rituximab: 375 mg/m² weekly × 4 weeks 1
• Cyclophosphamide: Oral 2 mg/kg/day or IV 15 mg/kg at specified intervals 1

Glucocorticoid Strategy

When using avacopan:

• Can replace the standard glucocorticoid taper entirely 1
• Some clinicians still use pulse IV methylprednisolone (1-3 g) for severe presentations initially 1
• The ADVOCATE trial achieved complete glucocorticoid withdrawal by week 21 5

Practical Limitations

Critical gaps in evidence:

• No data for refractory disease 1
• Unknown whether avacopan can be stopped when rituximab is given for maintenance 1
• Limited data in non-Japanese populations with PR3-ANCA (LoVAS trial was predominantly MPO-ANCA) 1
• No head-to-head comparison with reduced-dose glucocorticoid regimens from PEXIVAS or LoVAS trials 1

Guideline Positioning

Both KDIGO 2024 and EULAR 2022 guidelines position avacopan as a practice point rather than a formal recommendation, reflecting moderate certainty of evidence and the need for careful patient selection. 1 The Work Group specifically chose practice point designation due to methodological concerns in one supporting trial (CLASSIC had high dropout rates and changed primary outcomes). 1