What is the role of Avacopan (complement 5a receptor inhibitor) in treating a patient with a history of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA)?

Avacopan for GPA/MPA Treatment

Avacopan (30 mg twice daily) may be considered as an adjunctive glucocorticoid-sparing agent in combination with rituximab or cyclophosphamide for remission induction in GPA or MPA, particularly for patients at high risk of glucocorticoid toxicity or those with active glomerulonephritis requiring better renal recovery. 1

FDA-Approved Indication

• Avacopan is FDA-approved as an adjunctive treatment for severe active ANCA-associated vasculitis (GPA and MPA) in combination with standard therapy including glucocorticoids 2
• Critical caveat: Avacopan does not eliminate glucocorticoid use entirely 2

Evidence-Based Positioning

Primary Role: Glucocorticoid Reduction Strategy

• The ADVOCATE trial (331 patients) demonstrated non-inferiority to standard prednisone taper for achieving remission at 26 weeks (72.3% vs 70.1%) and superiority for sustained remission at 52 weeks (65.7% vs 54.9%) 1, 3
• Avacopan reduced cumulative glucocorticoid exposure by 2.3 grams over one year compared to standard prednisone taper 1
• Glucocorticoid toxicity scores were significantly lower at both 26 and 52 weeks with avacopan 1, 3

Specific Patient Populations with Enhanced Benefit

Prioritize avacopan use in: 1

• Patients with active glomerulonephritis and rapidly deteriorating kidney function - demonstrated superior renal recovery compared to glucocorticoids alone 1
• Patients at high risk for glucocorticoid-related complications, including:
  • Pre-existing diabetes mellitus
  • Severe osteoporosis
  • History of serious infections
  • Psychiatric conditions exacerbated by steroids
  • Uncontrolled hypertension

Safety Profile

• Serious adverse events were comparable between avacopan (10.2%) and prednisone (14.0%) groups 3
• Infection rates were not different between groups 1
• Monitor hepatic function before initiation and during therapy - hepatotoxicity has been reported 2
• Screen for hepatitis B virus - reactivation cases occurred in clinical trials 2

Dosing and Administration

• Standard dose: 30 mg (three 10 mg capsules) twice daily with food 2
• Drug interactions requiring dose adjustment: 2
  • Strong CYP3A4 inhibitors: reduce to 30 mg once daily
  • Avoid strong/moderate CYP3A4 inducers
  • Consider dose reduction of co-administered CYP3A4 substrates

Critical Limitations and Gaps in Evidence

• No data support use beyond 12 months - longer-term use cannot be recommended 1
• No data for patients with GFR <15 mL/min/1.73 m² 1
• No data for refractory disease 1
• Unknown whether avacopan can be discontinued when rituximab is used for maintenance 1

Practical Implementation Algorithm

Step 1: Assess disease severity and patient risk factors 1

• Severe/organ-threatening disease → Standard induction with rituximab or cyclophosphamide + glucocorticoids

Step 2: Identify glucocorticoid-sparing candidates 1

• Active glomerulonephritis with declining renal function
• High risk for glucocorticoid toxicity
• History of poor glucocorticoid tolerance

Step 3: If avacopan is selected 1, 2

• Initiate 30 mg twice daily with food
• Continue standard immunosuppression (rituximab or cyclophosphamide)
• Use reduced glucocorticoid regimen (not eliminated)
• Monitor liver function tests regularly
• Screen for hepatitis B before initiation

Step 4: Duration of therapy 1

• Continue for up to 12 months during induction/early maintenance phase
• Transition to standard maintenance therapy (rituximab, azathioprine, or methotrexate) after 12 months

Common Pitfalls to Avoid

• Do not use avacopan as monotherapy - it must be combined with standard immunosuppression 2
• Do not completely eliminate glucocorticoids - some glucocorticoid exposure remains necessary 2
• Do not continue beyond 12 months without additional evidence - safety and efficacy data are limited to one year 1
• Do not use in active serious infections - avoid initiation during active infection 2