Avacopan for the Treatment of ANCA-Associated Vasculitis

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.)

Effect of Disease Activity at Three and Six Months After Diagnosis on Long-Term Outcomes in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: The treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) aims to suppress disease activity and prevent subsequent disease flare. This study sought to explore the association of early disease control with long-term outcomes to validate early disease control as an end point for future clinical trials in AAV. METHODS: Data from 4 European Vasculitis Society inception clinical trials in AAV (1995-2002) and subsequent data on long-term outcomes from the trial data registry were studied. Clinical parameters in patients with AAV at baseline and at 3 and 6 months after diagnosis were assessed to study the long-term risk of death and end-stage renal failure (ESRF). At 6 months, outcomes were defined based on a disease status of either sustained remission (remission by 3 months, sustained to 6 months), late remission (remission after 3 months and by 6 months), relapsing disease (remission by 3 months but relapse by 6 months), or refractory disease (no remission by 6 months). RESULTS: Of the 354 patients with AAV who were followed up for a median of 5.7 years, 46 (13%) developed ESRF, 66 (18.6%) died, and 89 (25.1%) had either died or developed ESRF. At 6 months, predictors of the composite end point of death or ESRF were as follows: age (hazard ratio [HR] 1.02, 95% confidence interval [95% CI] 1-1.05; P = 0.012), estimated glomerular filtration rate (HR 0.94, 95% CI 0.92-0.95; P < 0.001), and disease status at 6 months (late remission, HR 2.94, 95% CI 1.1-7.85 [P = 0.031]; relapsing disease, HR 8.21, 95% CI 2.73-24.65 [P < 0.001]; refractory disease, HR 4.89, 95% CI 1.96-12.18 [P = 0.001]). Similar results were observed when these analyses were performed separately for death and for ESRF. CONCLUSION: The results of this study suggest that disease status at 3 and 6 months following the diagnosis of AAV may be predictive of the long-term risk of mortality and ESRF, and therefore these may be valid end points for induction trials in AAV. The current findings need to be validated in a larger data set

Avacopan for the Treatment of ANCA-Associated Vasculitis.

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.)

C5a receptor inhibitor avacopan in immunoglobulin A nephropathy - an open-label pilot study

Background Improvement of proteinuria as a marker for disease activity is associated with a better renal outcome in immunoglobulin A nephropathy (IgAN). Complement is an effector pathway in IgA-mediated kidney injury. Avacopan, a selective C5a receptor inhibitor, has previously shown efficacy in anti-neutrophil cytoplasmic antibody-associated vasculitis. The aim of this study was to evaluate the safety and efficacy of avacopan in patients with IgAN with persistent proteinuria despite a maximally tolerated dose of renin-angiotensin-aldosterone system blockade. The efficacy evaluation was based on the change in proteinuria. Methods This open-label pilot trial enrolled adult patients with biopsy-proven IgAN, urinary protein:creatinine ratio (UPCR) &amp;gt;1 g/g creatinine and an estimated glomerular filtration rate (eGFR) &amp;gt;60 mL/min/1.73 m(2) or &amp;gt;45 mL/min/1.73 m(2) if eGFR has not declined &amp;gt;10 mL/min/1.73 m(2) over the previous 24 weeks. If the UPCR remained at &amp;gt;1 g/g creatinine after an 8-week run-in period, patients started avacopan 30 mg twice daily. The primary efficacy endpoint was the change in the slope of the UPCR from the 8-week run-in period to the slope in the 12-week avacopan dosing period. Results A total of 10 of 15 screened patients entered the run-in period. Seven patients with a UPCR &amp;gt;1 g/g creatinine received avacopan. Six of seven patients had numerical improvement in the UPCR during the avacopan treatment period, three of whom had a numerical improvement of similar to 50% at week 12. At week 24, five of seven patients still showed numerical improvement in the UPCR compared with baseline. The urinary monocyte chemoattractant protein-1:creatinine ratio decreased numerically 30% by week 8, possibly reflecting the anti-inflammatory activity of avacopan. Avacopan was well tolerated. There was one serious adverse event of unstable angina, which was deemed to be unrelated to avacopan. Conclusions This short-term pilot study showed an improvement in the slope of the UPCR, with similar to 50% improvement in three of seven patients with IgAN. Longer avacopan treatment duration may be indicated for maximal benefit