Background: For patients with ANCA-associated vasculitis, both failure to achieve remission and relapse after achieving remission are associated with worse long-term outcomes. Avacopan, an oral selective inhibitor of the C5a receptor, is approved for the treatment of ANCA-associated vasculitis. The phase 3 ADVOCATE study tested daily avacopan as a substitute for a standard oral glucocorticoid taper regimen. At week 26, the avacopan group achieved a remission rate (72.3%) comparable to the prednisone group (70.1%) and superior sustained remission at Week 52 (65.7% avacopan vs. 54.9% prednisone groups, respectively [1]). The median (mean) total glucocorticoid dose from all sources was 400 mg (1349 mg) in the avacopan group versus 2939 mg (3655 mg) in the prednisone group, representing 86% (63%) lower glucocorticoid exposure in the avacopan group. Compared with the prednisone group, the avacopan group showed a reduction in the proportion of patients who relapsed after achieving remission and, among patients who achieved remission, a longer time to relapse (1).

Objectives: To further characterize efficacy, additional post-hoc analyses compared the avacopan and prednisone groups regarding i) failure to achieve remission and ii) relapse after achieving remission.

Methods: ADVOCATE, a phase 3, randomized, double-blind, controlled trial in 330 patients, evaluated the efficacy and safety of avacopan. Patients with ANCA-associated vasculitis (new-onset or relapsing disease) were randomized to receive avacopan 30 mg twice daily, or a standard 20-week oral prednisone taper, plus matching placebos, in addition to background immunosuppressant therapy. For the purpose of these analyses, remission was defined as the first timepoint when a BVAS of 0 was achieved. Relapse was defined as worsening of disease, after having previously achieved remission, that involved one or more major or three or more minor items in the BVAS, or one or two minor items in the BVAS recorded at two consecutive study visits.

Two post-hoc sensitivity analyses of patients in the intent-to-treat population examined: i) the proportion of patients who failed to achieve remission, or achieved remission and subsequently relapsed after achieving that remission, and ii) relapse-free time. For patients who achieved remission, relapse-free time was calculated as the number of days from the initial remission achieved to relapse. For patients who failed to achieve remission, relapse-free time was imputed as one day (remission and relapse on the same day). Patients who did not relapse were censored at the time of the last BVAS assessment.

Results: Baseline characteristics and time to achieve initial remission were similar between groups, and the incidence of BVAS 0 at any point in the study occurred approximately equally in both groups (158 avacopan vs. 157 prednisone). In the first sensitivity analysis, the avacopan group showed a reduction in the proportion of patients who failed to achieve remission, or relapsed after remission, compared with the prednisone group (24 [14.5% vs 40 [24.4%], p=0.011). In the second sensitivity analysis that included all patients in the trial, the hazard ratio of relapse-free time for avacopan vs prednisone was 0.57, 95% CI (0.35, 0.96), p=0.029 (log-rank test) ( Figure 1 ).

Figure 1.

Relapse-free time among patients with ANCA-associated vasculitis in ADVOCATE (intention-to-treat population).

Conclusion: In the phase 3 ADVOCATE study of ANCA-associated vasculitis, more patients in the avacopan group compared to the prednisone group achieved remission, and fewer in the avacopan group relapsed after achieving remission. Patients receiving avacopan had a longer relapse-free time compared to the prednisone group. These post-hoc sensitivity analyses provide additional evidence of the efficacy of avacopan for the treatment of ANCA-associated vasculitis.

REFERENCES:

[1]Jayne D et al., Avacopan for the Treatment of ANCA-Associated Vasculitis. N Engl J Med 2021 384(7):599-609.

Disclosure of Interests: Peter A. Merkel Consultant of: AbbVie, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, CSL Behring, Dynacure, EMDSerono, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, Immagene, InflaRx, Jannsen, Kiniksa, Kyverna, Magenta, MiroBio, Neutrolis, Novartis, Pfizer, Regeneron, Sparrow, Takeda, Talaris.

Royalties: UpToDate., Grant/research support from: AbbVie, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, Eicos, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Sanofi, Takeda, Huibin Yue Shareholder of: ChemoCentryx, Employee of: ChemoCentryx, Emil deGoma Shareholder of: ChemoCentryx, Employee of: ChemoCentryx, Pirow Bekker Shareholder of: ChemoCentryx, Consultant of: ChemoCentryx, David Jayne Paid instructor for: Lecture Fees: Amgen, Vifor, Consultant of: Astra-Zeneca, BMS, Boehringer-Ingelheim, Chemocentryx, GSK, NICE, Novartis, Otsuka, Roche/Genentech, Takeda, UCB & Vifor. Board Member: Aurinia., Grant/research support from: Commercial: GSK, Roche/Genentech; Non-commercial: EU, MRC, NIHR, Versus Arthritis