Real world use of avacopan for ANCA-associated vasculitis. First experiences in Ireland.

Introduction

ANCA-associated vasculitis (AAV) is a necrotising small-vessel vasculitis that leads to systemic inflammation and organ dysfunction and predominantly affects the lungs and kidneys. The 2012 Revised International Chapel Hill Consensus Conference categorises AAV into three primary subtypes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA)¹. Epidemiological studies indicate an incidence of 24.7 per million in Northern Europe and 33 per million in the United States^2,3.

Conventional treatment involves induction and maintenance of immunosuppressive therapy, typically rituximab or cyclophosphamide, in combination with prolonged glucocorticoid administration. However, long-term corticosteroid use is associated with substantial morbidity, including an increased risk of infection, which remains the leading cause of mortality in AAV⁴. Avacopan is a first-in-class selective C5aR antagonist that offers a steroid-sparing alternative for the management of GPA and MPA. Initially approved in Japan in September 2021, avacopan subsequently received regulatory approval in the United States and Europe^5,6.

The ADVOCATE trial, a multinational, phase III, randomised, double-blind, active-controlled study, evaluated avacopan in AAV⁷. The trial demonstrated that avacopan was non-inferior to prednisone in achieving remission at 26 weeks and superior in sustaining remission at 52 weeks, with additional benefits to renal function among patients with active glomerulonephritis. However, further research is needed to determine its long-term role, particularly in patients with advanced kidney disease (estimated glomerular filtration rate [eGFR] <15 mL/min/1.73m²).

This study details the first clinical experience with avacopan in Ireland prior to its reimbursement under a high-tech scheme in July 2024. Currently, avacopan prescriptions are restricted to Nephrologists, Rheumatologists, and Immunologists.

Methods

This report describes all patients in the Republic of Ireland who received avacopan between January 2017 and June 2024. Patients receiving avacopan with AAV were identified through the RITA-Ireland Vasculitis (RIV) Registry and Biobank, and through collaboration with treating physicians. The RIV registry collates clinical data and bio-samples from patients with vasculitis and from disease and healthy controls at a national level with the aim of improving long-term outcomes in patients with rare kidney disease⁸. Central ethical approval was granted by Tallaght University Hospital/St James’s Hospital Joint Research Ethics Committee (reference 2019-08 List 29 (07) on August 30, 2019, and locally by study site. All the participants provided written informed consent. Central storage of anonymised registry data is hosted on the secure password-protected web application REDCap⁹. Data were collected between January 2024 and March 2025 using the patient’s unique RIV identifier.

Eligible patients had a definite diagnosis of GPA or MPA and were administered avacopan. Multiple data points were collected, including demographics, antibody status, organ involvement, number of flares, previous treatment, reason for commencing avacopan, cumulative steroid dose before and during avacopan treatment, and any adverse events. The data collection points are listed in Table 1.

Results

Ten patients (n=10) commenced avacopan therapy through an early access program between December 2017 and June 2024. Five patients were male and five were female, with an average age of 53.7 years (range: 18–69 years). Five patients were MPO-positive and five were PR3-positive. Five patients had newly diagnosed AAV, whereas five had established disease. 90% of the included patients had renal involvement with a mean pre-treatment estimated glomerular filtration rate (eGFR) of 44 mL/min/1.73 m² (range 13-108 mL/min/1.73 m²). EGFR improved in four patients and decreased in three patients following the commencement of avacopan treatment. In those patients whose eGFRs improved, pre-treatment eGFRs were on average 22 mL/min/1.73m² (range 16-27 mL/min/1.73 m²), improving to 32.75 mL/min/1.73 m² following treatment with avacopan. In patients whose eGFRs worsened, pre-treatment eGFRs were on average 73 mL/min/1.73 m² (range 13-108 mL/min/1.73 m²), disimproving to 57 mL/min/1.73 m² following treatment with avacopan. 70% of patients had pulmonary involvement. Other organ system involvement included musculoskeletal (30%); ear, nose, and throat (20%); central nervous system (20%); cutaneous (10%); and abdominal (20%).

The mean follow-up duration following the commencement of avacopan was 41.4 months (range 13 – 87 months). The average BVAS (data collected in 8/10 patients) at the commencement of avacopan treatment was 17.75 (range 0–34). The average duration of avacopan treatment was 12 months (range 4–20 months). The majority of patients (n=8) received rituximab as concurrent therapy with avacopan. On average, patients received 2.285 grams of prednisolone equivalent prior to the commencement of avacopan. Although it is challenging to estimate the prednisolone dose range from the available clinical data, we estimated this as a range of 0–8.125 grams per patient. Two patients relapsed after the discontinuation of avacopan. One patient had low disease activity one month after avacopan discontinuation, which was classified as a minor relapse. This patient had a subsequent relapse five years post-avacopan (major relapse). The second patient experienced a minor relapse 8 months post-avacopan. All relapses after avacopan were treated with oral prednisolone and rituximab. Relapses occurred among the patients with the longest follow-up duration.

Other immunosuppressive agents administered alongside avacopan for AAV treatment in this cohort were rituximab (n=8), cyclophosphamide (n=2), azathioprine (n=1), and mycophenolate mofetil (n=1). One patient underwent a plasma exchange.

Adverse events were observed in three patients in this cohort. Reported adverse events that may be related to avacopan include neutropenia, persistent liver dysfunction, pinpoint maculopapular rash on the legs and lower abdomen, and COVID-19 pneumonia. Overall, avacopan was well-tolerated.

Discussion

To our knowledge, this is the first study on the use of avacopan for the management of AAV in the Irish population. Baseline patient characteristics and treatment outcomes were comparable to those of European cohorts. The Spanish Avacopan early access program (Draibe J et al.) analysed 29 patients with AAV¹⁰. When comparing with the Irish data there was a similar sex distribution (41.4% male (Spain) vs 50% male (Irish)) and a similar age profile (56 years (Spain) vs 53.7 years (Irish)).

Renal involvement was observed in 79.31% of patients in the Spanish early access program compared to 90% of patients in the Irish cohort. Mean eGFRs pre-commencement were lower in the Spanish cohort, 23.2 ± 11.2 mL/min/1.73m² compared to 36.0 ± 29.54 mL/min/1.73m² among patients with renal involvement in the Irish cohort. Comparing with a US cohort of 92 patients with AAV, the mean eGFR among patients with renal involvement (n=71) was 33 ± 26.7mL/min/1.73m²¹¹. There was a predominance of MPO (72.4%, Spain; 72%, USA) in the Spanish and US cohorts. In a multicentre observational study on avacopan for AAV (Zimmerman J et al.), the baseline eGFR was 37 mL/min/.73m² which more closely aligns with Irish data¹². Furthermore, of the 39 patients in Zimmerman’s study, 56% were PR3 positive with the remaining 44% being either MPO-or MPO and anti-GBM positive which closely aligns with the Irish data. Although the overall pre-avacopan eGFR was comparatively high in the Irish cohort, the patients were in the chronic kidney disease (CKD) 3b category, which is consistent with international data. Furthermore, the high standard deviation and small sample size (n=10) in the Irish cohort makes it difficult to draw any meaningful conclusions from these data.

In the ADVOCATE trial, significant improvements in the eGFR were observed in the avacopan arm. Among those with an eGFR < 30 mL/min/1.73m², the mean improvement at week 52 in the avacopan arm was 13.7 mL/min/1.73m² compared to 8.2 mL/min/1.73 m² in the prednisone arm. Among the four patients in the Irish early access program whose eGFR improved following treatment with avacopan, the average pretreatment eGFR was 22 mL/min/1.73m², improving to 32.75 mL/min/1.73m². In this subset of patients, the patient with the longest follow-up had creatinine measured nine times after the commencement of avacopan. Additionally, this patient had the highest baseline creatinine level in this subset. Creatinine trends pre- and post-avacopan are shown in Figure 1. Consistent improvements in eGFR can be observed across other early access programs. In the Spanish early access cohort, eGFR improved from 23.2 mL/min/1.73m² to 38.38 mL/min/1.73m². Similarly, in a USA cohort, the mean eGFR improved from 37 to 51 mL/min1.73m² over a 12-month period.

Figure 1. Creatinine trends pre and post avacopan.

The mean BVAS score in the Irish population was 17.75, which was similar to the mean BVAS score of 16 in the ADVOCATE trial. A similar BVAS was observed in other European studies. The average treatment duration with avacopan in the Irish population was 12 months (range: 4–20 months). Although the treatment duration range is variable, the real-world duration of treatment with avacopan is between 37 – 48 weeks¹³.

The ADVOCATE trial cites liver dysfunction as the most common side effect secondary to avacopan use (5.4% in the avacopan group and 3.7% in the prednisone group) with complete normalisation of liver enzymes after discontinuation of avacopan. One patient in this cohort had deranged liver function tests. Recovery of liver function tests to baseline was slow in this patient; however, it transpired that they had developed sludge and gallstones in the gallbladder with their liver dysfunction fully resolved following successful endoscopic retrograde cholangiopancreatography (ERCP). Avacopan had been discontinued in this patient prior to this, although predominantly due to persistent neutropenia and concerns regarding infection risk. Avacopan was not recommenced and the patient remained in clinical remission.

Conclusion

This study provided the first real-world data on avacopan use in the Republic of Ireland. Avacopan offers an effective alternative to traditional therapies such as corticosteroids. Its targeted mechanism of action, which inhibits the complement system, is a promising option for patients who experience adverse effects from long-term corticosteroid use. Avacopan has demonstrated efficacy as a steroid-sparing agent with a favourable safety profile, reducing reliance on corticosteroids and mitigating their associated toxicities. While remission rates are promising, further follow-up is necessary to evaluate long-term relapse risks.

With avacopan now funded by the Health Service Executive in Ireland, future audits and research should focus on long-term outcomes and cost-effectiveness. These findings support the integration of avacopan into AAV treatment guidelines in Ireland, with the potential to improve AAV clinical outcomes.