This analysis of patients treated with RTX was a prespecified subgroup of the ADVOCATE study, a multicentre, randomised, double-blind, double-dummy, active-controlled trial (NCT02994927).4 Avacopan (30 mg two times per day) or matching placebo was administered for 52 weeks, randomly assigned (1:1) using an interactive web-response system, with the use of a minimisation algorithm, to maintain balance between the treatment groups. Prednisone or a matched placebo was administered on a tapering schedule over 20 weeks (60 mg per day tapered to discontinuation by week 21). Study medication was given within hard gelatin capsules to maintain blinding. Randomisation was performed centrally and stratified according to vasculitis disease status (newly diagnosed or relapsing), ANCA type (anti-proteinase 3 (PR3) positive or anti-myeloperoxidase (MPO) positive) and immunosuppressive therapy (CYC (followed by azathioprine) or RTX with no redosing). The dose of intravenous RTX was 375 mg/m2 of body surface area per week for 4 weeks. The study protocol and any changes made are available online as part of supplementary material of the original ADVOCATE report.4

Patients with GPA or MPA were enrolled in 143 centres across 20 countries. Detailed inclusion and exclusion criteria for each study were previously reported.4 Briefly, eligible patients had newly diagnosed or relapsing GPA or MPA, according to the Chapel Hill Consensus Conference definitions,5 a history of a positive test result for antibodies to either PR3-ANCA or MPO-ANCA, an estimated glomerular filtration rate (eGFR) of at least 15 mL/min/1.73 m2 of body surface area, and at least one major or three non-major items or at least the two renal items of haematuria and proteinuria on the Birmingham Vasculitis Activity Score (BVAS), V.3.6

The key efficacy outcomes were remission at week 26, defined as a BVAS of 0 and no receipt of GCs for AAV 4 weeks before week 26, and sustained remission, defined as remission at week 26 and at week 52 with no receipt of GCs for AAV 4 weeks before week 52 and no relapse between weeks 26 and 52. Relapse was defined as a return of active vasculitis after previous achievement of a BVAS of 0 at any time that involved at least one major BVAS item, at least three minor BVAS items, or one or two minor BVAS items for at least two consecutive trial visits. Exploratory analyses summarised the proportion of patients experiencing a relapse under two conditions: (1) for the first time after achieving remission at week 26, and (2) for the first time after achieving remission (BVAS of 0) at any time for which the Cox proportional model was used to estimate the hazard ratio (HR) of time to relapse.

Additional outcomes in exploratory analyses included the Glucocorticoid Toxicity Index (GTI),7 8 GC use (presented as mg prednisone equivalent), and change from baseline in health-related quality of life (HRQoL), assessed with the Short-Form 36 questionnaire (SF-36) V.29 and the EuroQoL Group 5-Dimensions 5-Level Questionnaire (EQ-5D-5L).10 For both the GTI Cumulative Worsening Score (GTI-CWS) and the GTI Aggregate Improvement Score (GTI-AIS), lower scores indicate lesser severity of toxic effects. In patients with renal disease at baseline on the basis of BVAS, eGFR and urinary albumin to creatinine ratio (UACR) were assessed (in patients with albuminuria (UACR≥10 mg/g)). eGFR for patients with a baseline eGFR less than 30 mL/min/1.73 m² was also analysed. eGFR (in mL/min/1.73 m²) was calculated using the serum creatinine-based formula (Modification of Diet in Renal Disease) for adults,11 the Japanese equation for Japanese adults,12 and the modified Schwartz equation for adolescents.13

Safety outcomes included incidence of adverse events (AEs) and serious AEs (SAEs). Data were collected and coded using the Medical Dictionary for Regulatory Activities (v19.1)14 and graded according to the Common Terminology Criteria for Adverse Events Version 5.0.15

The efficacy and safety analysis sets comprised the intention-to-treat population, which included all randomised patients who received at least one dose of blinded study drug. The summary statistics for the outcome measures of the subgroup analysis were prespecified. No statistical inference or hypothesis testing for the subgroup was conducted.

Data were summarised descriptively by the treatment group. For continuous variables, means, medians, ranges SDs and SEMs were calculated. Frequency counts and percentages were presented for categorical variables.

The proportion of patients achieving disease remission at week 26, sustained disease remission at week 52, and two-sided 95% CIs for the difference in proportions (avacopan minus prednisone taper) were estimated. CIs for group response reproportions were calculated using the Clopper-Pearson method. CIs for the difference in proportions were calculated using the stratified summary score estimate for the common difference in proportions adjusted for randomisation strata (newly diagnosed or relapsed AAV, and anti-PR3 or anti-MPO ANCA). Missing data were imputed as not achieving remission (for week 26) or not achieving sustained remission (for week 52).

For changes from baseline, least squares mean (LS mean) and SEM were calculated from mixed effects models for repeated measures with treatment group, visit and treatment-by-visit interaction as factors and baseline as a covariate. These analyses were exploratory. Patients were considered as repeated measure units over visits. Logarithmic transformations were applied to the UACR data before fitting the model, and 95% CIs were transformed back to the original scale. Percent changes from baseline in UACR were calculated based on ratios of geometric means of visit over baseline. No imputation was performed for missing data. All statistical analyses were performed using Statistical Analysis System (SAS) software (V.9.4 of SAS for Windows, SAS Institute).

Site investigators collected data, and ChemoCentryx (a wholly owned subsidiary of Amgen) sponsored the trial and provided trial medication. Medpace conducted the trial and data analysis with guidance from ChemoCentryx. All authors interpreted the data and collaborated in manuscript preparation with support from professional medical writers funded by Amgen. All authors made the decision to submit the manuscript and attested to the veracity and completeness of data and analyses and to the fidelity of this report.

The results of this subgroup analysis suggest that avacopan with background induction therapy with RTX showed comparable efficacy to a prednisone taper with background RTX in achieving remission at week 26 and a higher rate of sustained remission at week 52. The results regarding efficacy in this current subgroup analysis are similar to those of the full study population, in which avacopan was non-inferior to the prednisone taper for achieving remission at week 26 (72.3% for avacopan vs 70.1% for prednisone) and superior for sustaining remission at week 52 (65.7% for avacopan vs 54.9% for prednisone).4 The data presented here provide evidence for improved treatment options over the current treatment guidelines, which recommend the use of GCs with RTX or CYC. The American College of Rheumatology/Vasculitis Foundation guidelines recommend using RTX with GC as the first-line approach for induction of remission for AAV.16 The Kidney Disease Improving Global Outcomes and the 2022 European Alliance of Associations for Rheumatology (EULAR) recommend the combination of GC with either RTX or CYC, with the EULAR guidelines suggesting consideration of avacopan to reduce GC exposure.17 18

Although the use of RTX has improved treatment options for patients with AAV,19 challenges to maintain remission still exist, including increased risk of infections and hypogammaglobulinaemia with repeat doses of RTX and risk of relapse after cessation of treatment with RTX.20–24 Management of patients with AAV on RTX was particularly challenging during the coronavirus disease (COVID-19) pandemic since RTX is associated with increased severity of COVID-19 infection,25 there is impaired humoral response to vaccination,26 and delays in administration of RTX for maintenance of remission were common.27 Currently, there are no data available on the use of avacopan in patients who have contracted COVID-19, and further research is needed.

The rate of sustained remission at 12 months is low in patients treated with RTX with no maintenance therapy, with one trial estimating it to be less than 50%.28 The rate of sustained remission can be increased by continuing treatment with prednisolone, as in the RITUXVAS trial in which sustained remission at month 12 was achieved by 76% of patients receiving RTX for induction of remission with continued prednisolone at a dose of 5 mg daily for 12 months.29 Sustained remission can also be achieved by repeated doses of RTX; however, more than 40% of patients experience a relapse after the withdrawal of RTX.30–33 For comparison, this subgroup analysis reports relapse rates after remission at any time of 20.2% for the prednisone taper group and 8.7% for the avacopan group at 52 weeks among patients who achieved BVAS of 0 at any time, suggesting that the addition of avacopan reduced the rates of relapse. Consistent with the rates of remission reported in other trials, in the current analysis, patients who received background therapy with RTX without redosing and were randomised to a 20-week prednisone taper had a rate of sustained remission of 56.1% at week 52. In contrast, the rate of sustained remission at week 52 was much higher (71.0%) among patients who received avacopan. These results indicate the benefit of avacopan for the treatment of AAV among patients also receiving RTX induction.

Beyond the efficacy outcomes of remission and relapse rates, other outcomes reported in this study indicate benefits of avacopan with background induction RTX therapy, including trends of renal recovery and improvement in HRQoL outcomes. For context, in the overall ADVOCATE trial, LS mean eGFR increased by 7.3 mL/min/1.73 m2 in the avacopan group and 4.1 mL/min/1.73 m2 in the prednisone taper group at week 52.4 In this subgroup analysis among patients who received RTX, LS mean eGFR increased by 5.8 mL/min/1.73 m2 in the avacopan group and 2.8 mL/min/1.73 m2 in the prednisone taper group at week 52. Patients with baseline eGFR<30 mL/min/1.73 m2 had even higher increases of 8.7 mL/min/1.73 m2 and 6.6 mL/min/1.73 m2, respectively. Other improvements of note were observed in UACR at weeks 2 and 4, SF-36 role physical and vitality domains and PCS at week 26, and SF-36 general health domain and EQ-5D-5L VAS at week 52. HRQoL results described here are similar to those of the overall trial.34

Data from trials in vasculitis showed that treatment-related damage occurs secondary to GCs and that higher levels of damage are independently associated with the duration of use of GCs.35 Two trials for induction of remission in AAV demonstrated that a reduced-dose GC regimen was non-inferior to a high-dose GC regimen.36 37 From a patient’s perspective, the minimal clinically important difference in GTI is reported to be 10 points, and was evaluated at this threshold, as well as 20-point and 30-point thresholds previously used for such analyses.38 The LS mean value for GTI-AIS at weeks 13 and 26 exceeded the 20-point threshold in the prednisone taper group and exceeded the 10-point threshold in the avacopan group, indicating a perceptible difference to patients. For GTI-CWS, the LS mean value for the prednisone taper group exceeded the 30-point threshold at weeks 13 and 26, while in the avacopan group, this threshold was reached at week 26 only. This current subgroup analysis of the ADVOCATE trial demonstrates that among patients treated with RTX induction, use of avacopan, compared with a prednisone taper, can reduce GC toxicity potentially ameliorating the burden of chronic, treatment-related harms for patients, without compromising efficacy.

Among patients treated with RTX, the number of SAEs was 47% higher in the prednisone taper group than in the avacopan group, and there were numerically more infections, serious infections and deaths in the prednisone taper group than in the avacopan group. SAEs of an abnormality on liver-function testing occurred in 2.8% of the patients in the avacopan group and 3.7% of those in the prednisone taper group.

Strengths of this study include involvement of a large cohort of patients with GPA or MPA recruited into a clinical trial with recruitment from 143 centres internationally, with the trial cohort representative of other trial populations in AAV. There was also a rigorous study design and analysis with minimal loss to follow-up. In addition, the results of this report are largely consistent with the overall results of the ADVOCATE trial.

This study has some limitations to consider. Based on the approved treatment at the time of the trial, patients who received RTX did not receive repeat dosing at week 26 in the ADVOCATE trial. However, repeat dosing of RTX is currently the recommended treatment approach.16–18 Thus, the efficacy and safety of avacopan when used alongside RTX for maintenance of remission are unknown. Yet, rates of remission and sustained remission are substantial even without redosing of RTX. In addition, patients with an eGFR of less than 15 mL/min/1.73 m2 and those with alveolar haemorrhage requiring mechanical ventilation were not included in this study, and these findings need to be confirmed in this cohort. Lastly, limited data on the use of avacopan beyond week 52 is available. Longer follow-up is important to better understand the benefits and risks of the adjunctive use of avacopan therapy for AAV.

In conclusion, similar to the overall ADVOCATE trial, the results of the current subgroup analysis suggest that in patients with GPA or MPA receiving background induction therapy with RTX, the addition of avacopan, compared with a prednisone taper, provides a favourable safety profile and achieves similar rates of remission at week 26, higher rates of sustained remission at week 52, improved recovery of renal function, faster reduction in albuminuria and lower GC toxicity.