Avacopan outperforms prednisone for ANCA-associated vasculitis remission at 1 year
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Avacopan is superior to prednisone taper in preventing relapse in patients with antineutrophil cytoplasmic antibody-associated vasculitis at 1 year, and is at least as effective as steroids in controlling the disease at 6 months, according to data.
“High-dose steroids are currently necessary to control the severe inflammation of vasculitis, but their toxicity is a major problem for patients, and they are not always effective,” David R.W. Jayne, MD, FMedSci, of Addenbrooke's Hospital and the University of Cambridge, in the United Kingdom, told Healio Rheumatology. “Complement inhibition with avacopan is a real opportunity to replace steroids with a safer drug that also appears more effective in controlling the disease.”
To compare avacopan (CCX168, ChemoCentryx) with a tapering schedule of prednisone among patients with ANCA-associated vasculitis who were being simultaneously treated with immunosuppressive drugs, Jayne and colleagues conducted the ADVOCATE study, a phase 3, randomized controlled trial. A total of 331 participants with ANCA-associated vasculitis were assigned 1:1 to receive 30 mg of oral avacopan twice daily or oral prednisone on a tapering schedule. All participants also received either cyclophosphamide, followed by azathioprine, or rituximab (Rituxan, Genentech).
The researchers used two primary endpoints. The first was remission, defined as a Birmingham Vasculitis Activity Score (BVAS) of 0, at week 26 with no glucocorticoid use in the previous 4 weeks. The second primary endpoint was sustained remission, defined as remission at both weeks 26 and 52. Both endpoints were analyzed for noninferiority and superiority.
According to the researchers, who published their findings in the New England Journal of Medicine, the mean BVAS at baseline was 16 in both the avacopan and prednisone groups. Week 26 remission was observed in 72.3% of participants treated with avacopan, and in 70.1% of those in the prednisone group (estimated common difference = 3.4 percentage points; 95% CI, –6 to 12.8). Sustained remission at week 52 was later observed in 65.7% of the avacopan group, and in 54.9% of those who received prednisone (estimated common difference = 12.5 percentage points; 95% CI, 2.6-22.3).
Regarding safety, 37.3% of participants treated with avacopan demonstrated serious adverse events, excluding worsening vasculitis, compared with 39% in the prednisone group.
“The ADVOCATE study demonstrated that avacopan was at least as effective in controlling disease at 6 months as steroids — with all patients receiving an immune suppressive as well — but between 6 and 12 months, and following tapering of steroids, the avacopan group did better through prevention of relapse,” Jayne said. “Secondary endpoints also showed superiority for avacopan with respect to recovery of renal function for those with kidney involvement, in recovery of quality of life, and in fewer side-effects.”
“Avacopan will offer patients and their physicians an alternative to steroid and the potential for better overall disease control,” he added. “This is likely to have long-term benefits for patients in terms of reduced risk of end stage renal failure, reduced risk of steroid induced damage such as osteoporosis and cataracts, and a reduced number of relapse events.”
Perspective
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David A. McLain, MD, MACR, FACP, FRCP
A revolution in medicine occurred with the use of cortisone in rheumatology beginning in the 1950s. With the subsequent appearance of severe side effects associated with long-term steroids, rheumatologists dreamed of “a drug that works like a corticosteroid but without corticosteroid side effects”. Even though no such drug has been developed to date, the use of corticosteroids has decreased over the years.
In rheumatoid arthritis, we are now using effective DMARDs (with the use of methotrexate starting in the 1980s), TNF inhibitor biologics (starting in 1998), other biologics, and more recently, JAK inhibitors. There are fewer and fewer patients with RA on prednisone now than 30 years ago. There are few, if any, patients having solumedrol infusions in the ER or hospital for RA or lupus as there were in the past.
For lupus, we now have belimumab, rituximab, and recently, voclosporin, to obviate the need for steroids. In the distant past, when we envisioned a substitute for prednisone that would have fewer adverse events, we thought it might be a prednisone analog. We never envisioned drugs with a specific site of action like avacopan, a C5A receptor antagonist. This precision is producing drugs with excellent efficacy and less toxicity. The future is often different than we envisioned it.
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