N Engl J Med 2021 Feb 18
Avacopan for the Treatment of ANCA-Associated Vasculitis.
Abstract
Background
The C5a receptor inhibitor avacopan is being studied for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.
Methods
In this randomized, controlled trial, we assigned patients with ANCA-associated vasculitis in a 1:1 ratio to receive oral avacopan at a dose of 30 mg twice daily or oral prednisone on a tapering schedule. All the patients received either cyclophosphamide (followed by azathioprine) or rituximab. The first primary end point was remission, defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 (on a scale from 0 to 63, with higher scores indicating greater disease activity) at week 26 and no glucocorticoid use in the previous 4 weeks. The second primary end point was sustained remission, defined as remission at both weeks 26 and 52. Both end points were tested for noninferiority (by a margin of 20 percentage points) and for superiority.
Results
A total of 331 patients underwent randomization; 166 were assigned to receive avacopan, and 165 were assigned to receive prednisone. The mean BVAS at baseline was 16 in both groups. Remission at week 26 (the first primary end point) was observed in 120 of 166 patients (72.3%) receiving avacopan and in 115 of 164 patients (70.1%) receiving prednisone (estimated common difference, 3.4 percentage points; 95% confidence interval [CI], -6.0 to 12.8; P<0.001 for noninferiority; P = 0.24 for superiority). Sustained remission at week 52 (the second primary end point) was observed in 109 of 166 patients (65.7%) receiving avacopan and in 90 of 164 patients (54.9%) receiving prednisone (estimated common difference, 12.5 percentage points; 95% CI, 2.6 to 22.3; P<0.001 for noninferiority; P = 0.007 for superiority). Serious adverse events (excluding worsening vasculitis) occurred in 37.3% of the patients receiving avacopan and in 39.0% of those receiving prednisone.
Conclusions
In this trial involving patients with ANCA-associated vasculitis, avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52. All the patients received cyclophosphamide or rituximab. The safety and clinical effects of avacopan beyond 52 weeks were not addressed in the trial. (Funded by ChemoCentryx; ADVOCATE ClinicalTrials.gov number, NCT02994927.).
Related Questions
How would you approach failure of maintenance therapy (Azathioprine) for PR3 positive, c-ANCA positive, pulmonary–renal vasculitis previously induced with cyclophosphamide, with a history of anaphylaxis to rituximab?
This is a challenging clinical situation with several appropriate treatment approaches as follows: Desensitization to rituximab - this would need to be done in the ICU but is effective for patients who are willing to undergo the process for whom other maintenance regimen options are suboptimal. Avac...
How do you determine which patients with ANCA associated vasculitis may be good candidates for reduced dose glucocorticoid tapering?
This is an important question. Currently there are several groups of patients that benefit from reduced dose glucocorticoids: The largest group are patients who are receiving avacopan for remission induction. The ADVOCATE trial demonstrated that avacopan can markedly reduce the dose of glucocorticoi...
What is your approach for steroid dosing for patients with ANCA vasculitis on induction treatment with rituximab, avacopan, and glucocorticoid therapy?
I do not personally have a one-size-fits-all approach. Remember that ADVOCATE had a screening window of up to 2 weeks where many patients got steroids before they were randomized. At the time of randomization, patients had to be on less than 20mg of prednisone which was tapered over 4 weeks.In addit...
How do you approach deciding how long to use Avacopan for ANCA-associated vasculitis?
This is such an interesting question and one that I hope we have more data to guide our management in the future.The ADVOCATE trial used a year of Avacopan, demonstrating that sustained remission was superior in the Avacopan group (66% vs 55%). HOWEVER, the control group received either cytoxan foll...
Would you consider using avacopan in PR3+ mononeuritis multiplex without other systemic involvement?
I would certainly consider using avacopan in AAV mononeuritis multiplex. While we don't know the outcomes of mononeuritis in avacopan-treated patients specifically, ~20% of patients in the ADVOCATE trial (Jayne et al., PMID 33596356) had neuropathy and the outcomes overall suggest a robust response ...
Should the use of avacopan be limited to those patients at increased risk of steroid toxicity given the anticipated high cost of this medication?
Once Avacopan is available for clinical use in the treatment of patients with AAV, providers will need to carefully weigh risks and benefits of the medication while considering other factors including cost.The ADVOCATE trial used a novel glucocorticoid toxicity index that captures common GC-related ...
Are there particular subsets of AAV patients in which avacopan is more effective?
The following answer was jointly drafted by Dr. Peter Merkel and Dr. David Jayne:Patients in the ADVOCATE trial were stratified at entry according to time of diagnosis (new/relapsing), diagnosis (GPA/MPA), ANCA serotype (PR3/MPO), and background immunosuppressive (cyclophosphamide/rituximab) with re...
How should the results of the ADVOCATE trial be applied in AAV patients who receive rituximab induction and maintenance therapy?
The following answer was jointly drafted by Dr. Peter Merkel and Dr. David Jayne:The data from ADVOCATE indicate that patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) treated with avacopan 30 mg twice daily and prednisone placebo were able to achieve remission w...