What are the alternatives to Tavneos (avacopan) for treating granulomatosis with polyangiitis?

Alternatives to Tavneos (Avacopan) for Granulomatosis with Polyangiitis

For induction therapy in GPA, use rituximab (375 mg/m² IV weekly for 4 weeks) or cyclophosphamide (oral 2 mg/kg/day or IV 15 mg/kg every 2 weeks initially), both combined with glucocorticoids—these are the established first-line alternatives to avacopan. 1

Induction Therapy Options

Rituximab (Preferred in Most Cases)

• Rituximab 375 mg/m² IV weekly for 4 weeks combined with glucocorticoids is the primary alternative, particularly for patients with relapsing disease, those of childbearing age, or when cyclophosphamide poses specific risks 1, 2
• Rituximab demonstrated non-inferiority to cyclophosphamide in randomized trials (RAVE and RITUXVAS) for severe disease, with potentially superior efficacy in relapsing cases 1, 3
• Rituximab is particularly preferred over cyclophosphamide in patients with PR3-ANCA positivity and history of relapse 2, 4
• The drug causes no fertility concerns, unlike cyclophosphamide which causes ovarian failure and male infertility 2, 4

Cyclophosphamide (Alternative First-Line)

• Oral cyclophosphamide 2 mg/kg/day for 3-6 months or IV 15 mg/kg at weeks 0,2,4,7,10,13 combined with glucocorticoids remains an effective alternative 1
• Dose reductions required: age >60 years (1.5 mg/kg/day oral or 12.5 mg/kg IV), age >70 years (1.0 mg/kg/day oral or 10 mg/kg IV), and GFR <30 ml/min/1.73 m² 1
• Cyclophosphamide is preferred for severe GN with serum creatinine >4 mg/dl (>354 μmol/l), though combination with rituximab can be considered 1
• Cumulative doses above 36 g are associated with malignancy risk 1

Glucocorticoid Tapering Protocol

• Use the PEXIVAS reduced-dose regimen: start with weight-based dosing (50-75 mg prednisone equivalent daily), taper to 5 mg daily by week 20-22, continue 5 mg through week 52 1
• This reduced-dose approach showed equivalent efficacy to standard high-dose protocols with less toxicity 1

Maintenance Therapy Alternatives

Rituximab Maintenance (Preferred)

• Rituximab 500 mg IV every 6 months for 18 months to 4 years after achieving remission is the preferred maintenance strategy 1, 2, 4
• The MAINRITSAN trial showed rituximab resulted in major relapses in only 3 patients versus 17 with azathioprine (hazard ratio 6.61, p=0.002) 2
• Following rituximab induction, most patients should receive maintenance therapy, though some experts suggest MPO-AAV patients with low relapse risk and complete remission might be monitored without maintenance 1

Azathioprine (Alternative Maintenance)

• Azathioprine 1.5-2 mg/kg/day combined with low-dose glucocorticoids is an acceptable alternative when rituximab is unavailable or contraindicated 1
• Azathioprine is preferred when baseline IgG is low (<300 mg/dl) or rituximab availability is limited 1
• Continue for 1 year after diagnosis, then decrease by 25 mg every 3 months 1

Other Maintenance Options

• Mycophenolate mofetil 2000 mg/day (divided doses) can be used for patients intolerant of azathioprine, though it has lower efficacy 1
• Methotrexate is an option for non-severe disease in patients with GFR >60 ml/min/1.73 m², but should not be used below this threshold 1
• Leflunomide can be considered in GPA patients with intolerance to rituximab, azathioprine, and methotrexate 1

Key Clinical Considerations

When to Choose Rituximab Over Cyclophosphamide

• Relapsing disease (rituximab superior) 1, 2
• Women of childbearing potential 1, 2
• PR3-ANCA positivity (higher relapse risk) 1
• Previous cyclophosphamide exposure with moderate cumulative dose 1
• Patient preference to avoid fertility risks 2, 4

When to Choose Cyclophosphamide

• Severe GN with serum creatinine >4 mg/dl 1
• Diffuse alveolar hemorrhage with hypoxemia 1
• Rapidly increasing creatinine or dialysis requirement 1
• Limited rituximab availability 1

Adjunctive Therapies

• Consider plasma exchange for patients with serum creatinine >3.4 mg/dl (>300 mmol/l), dialysis requirement, or diffuse alveolar hemorrhage with hypoxemia 1
• Plasma exchange combined with cyclophosphamide and IV immunoglobulin can be used in truly refractory cases 1
• Pneumocystis jirovecii prophylaxis with trimethoprim-sulfamethoxazole is mandatory during rituximab therapy 2, 4

Common Pitfalls to Avoid

• Do not use ANCA titers alone to guide treatment changes—use structured clinical assessment instead 1, 2
• Do not use methotrexate in patients with GFR <60 ml/min/1.73 m² 1
• Do not withhold cyclophosphamide from elderly patients solely based on age, but adjust dosing appropriately 1
• Monitor immunoglobulin levels every 6 months during rituximab therapy, as hypogammaglobulinemia occurs in 27-58% of patients 2

Refractory Disease Management

• For patients refractory to initial therapy after 4 weeks or with <50% reduction in disease activity after 6 weeks, switch from cyclophosphamide to rituximab or vice versa 2
• Combination of rituximab with low-dose cyclophosphamide (2 IV pulses) can be considered for severe renal involvement 1, 5