What is the role of Avacopan (selective complement C5a receptor inhibitor) in treating a patient with a history of ANCA (Antineutrophil Cytoplasmic Antibody)-associated vasculitis, particularly granulomatosis with polyangiitis or microscopic polyangiitis?

Avacopan in ANCA-Associated Vasculitis

Avacopan (30 mg twice daily with food) may be considered for remission induction in granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) when combined with rituximab or cyclophosphamide, specifically as a glucocorticoid-sparing strategy rather than as monotherapy. 1

Primary Indication and Positioning

Avacopan is FDA-approved as adjunctive treatment—not as replacement therapy—for severe active ANCA-associated vasculitis in combination with standard therapy including glucocorticoids. 2 The 2024 EULAR and KDIGO guidelines position avacopan as a glucocorticoid-reduction strategy, not glucocorticoid elimination. 1

Specific Patient Populations Where Avacopan Should Be Prioritized

Consider avacopan preferentially in two high-benefit subgroups: 1

• Patients at high risk for glucocorticoid toxicity (diabetes, osteoporosis, obesity, prior serious infections, psychiatric disease)
• Patients with active glomerulonephritis and rapidly deteriorating kidney function (particularly eGFR 15-50 mL/min/1.73 m²)

The ADVOCATE trial demonstrated that patients with active glomerulonephritis at baseline achieved greater recovery of kidney function with avacopan compared to standard glucocorticoid therapy. 1 Post-hoc analysis showed particularly robust eGFR improvement in patients with baseline eGFR <20 mL/min/1.73 m². 1, 3

Evidence Base and Efficacy

The ADVOCATE trial (n=331) established avacopan's role by demonstrating: 1, 4, 5

• Non-inferiority for remission at week 26: 72.3% with avacopan vs. 70.1% with prednisone (p<0.001 for non-inferiority)
• Superiority for sustained remission at week 52: 65.7% with avacopan vs. 54.9% with prednisone (p=0.007 for superiority)
• Cumulative glucocorticoid dose reduction: 2.3 grams lower over one year in the avacopan group
• Significantly lower glucocorticoid toxicity: Measured by Glucocorticoid Toxicity Index at week 26

The safety profile was comparable between groups, with serious adverse events occurring in 37.3% of avacopan patients versus 39.0% of prednisone patients. 4, 5

Critical Limitations and Exclusions

Do not use avacopan in the following scenarios: 1, 3, 2

• Severe kidney disease requiring dialysis (eGFR <15 mL/min/1.73 m² was excluded from ADVOCATE; no data exist for dialysis-dependent patients despite claims in some sources)
• Alveolar hemorrhage requiring mechanical ventilation (excluded from trials)
• Active serious infections (FDA contraindication)
• Severe hepatic impairment (Child-Pugh Class C—not studied)

Avacopan use beyond 1 year cannot be recommended due to absence of long-term safety and efficacy data. 1 The role in maintenance therapy, refractory disease, and whether it can be discontinued when rituximab is used for maintenance remains unknown. 1

Practical Dosing and Administration

Standard dosing: 30 mg (three 10 mg capsules) twice daily with food. 2 Food increases bioavailability by approximately 72% for AUC, making administration with meals essential. 2

Drug interactions requiring dose adjustment: 2

• Strong CYP3A4 inhibitors (ketoconazole, clarithromycin): Reduce avacopan to 30 mg once daily
• Strong/moderate CYP3A4 inducers (rifampin, phenytoin): Avoid concomitant use
• CYP3A4 substrates: Consider dose reduction of co-administered substrates

Monitoring Requirements

Mandatory monitoring includes: 2

• Hepatic function tests before initiation and as clinically indicated (hepatotoxicity occurred in trials)
• Signs of hepatitis B reactivation (cases occurred in trials; withhold avacopan if reactivation occurs)
• Hypersensitivity reactions including angioedema (observe and manage accordingly)

Algorithmic Approach to Avacopan Use

Step 1: Confirm diagnosis and severity

• Active GPA or MPA with severe disease requiring systemic therapy 1, 2
• Exclude eGFR <15 mL/min/1.73 m² or dialysis dependence 1

Step 2: Assess glucocorticoid risk profile

• High-risk features present (diabetes, osteoporosis, obesity, psychiatric disease, prior serious infections): Strongly consider avacopan 1
• Active glomerulonephritis with eGFR 15-50 mL/min/1.73 m²: Strongly consider avacopan 1

Step 3: Initiate combination therapy

• Avacopan 30 mg twice daily with food 2
• Plus rituximab or cyclophosphamide (followed by azathioprine) 1, 4
• Plus reduced-dose glucocorticoids (not glucocorticoid-free) 1, 2

Step 4: Duration planning

• Plan for 52 weeks of avacopan therapy based on trial data 1, 4
• Do not extend beyond 1 year without additional evidence 1

Common Pitfalls to Avoid

Critical errors in avacopan use: 1, 2

1. Using avacopan as monotherapy or without glucocorticoids entirely—FDA label specifies adjunctive use with glucocorticoids
2. Prescribing for dialysis-dependent patients—no safety or efficacy data exist
3. Failing to administer with food—significantly reduces bioavailability
4. Ignoring drug interactions with CYP3A4 inhibitors/inducers—can lead to toxicity or treatment failure
5. Extending use beyond 1 year—no long-term data support this practice

Comparative Context with Plasma Exchange

While avacopan addresses glucocorticoid reduction, plasma exchange may be considered for patients with serum creatinine >300 μmol/L (>3.4 mg/dL) due to active glomerulonephritis. 1 However, the 2024 guidelines downgraded plasma exchange recommendations based on PEXIVAS trial results showing no mortality benefit and increased infection risk. 1 Avacopan and plasma exchange address different therapeutic goals and are not interchangeable strategies. 1