#2256 Safety and effectiveness of avacopan beyond 52 weeks: experience to date in the Early Access Program (EAP)
Authors: Alberici Federico , Salvarani Carlo , Morales Enrique , Maxime Samson , Obergfell Achim , Popov Tamara 
Published: May 2024

Abstract

Background and Aims
ANCA-associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), is characterized by a high burden of organ damage, as well as increased mortality [1]. Both the disease itself and the immunosuppression required for its management contribute significantly to poor prognosis [2]. Avacopan is a first-in-class C5aR1 antagonist that demonstrated efficacy and safety over 52 weeks in patients with GPA or MPA, and was associated with a significantly lower requirement of glucocorticoids for disease management [3]. Significant data on long-term avacopan use in the context of real-life settings are sparse. Here, we describe experience with avacopan in 59 patients with GPA or MPA treated beyond 52 weeks within an ongoing Early Access Program (EAP).

Method
Patients with newly diagnosed or relapsing severe, active GPA or MPA were treated in the EAP. Safety data, including lack of effect and other events (i.e., relapse or worsening of disease) in these patients were recorded in a CSL Vifor safety database from Feb 2019 – Dec 2023. We performed analysis of these data for patients treated beyond 52 weeks.

Results
237 patients received ≥ 1 dose of avacopan with a median overall treatment duration of 7 months (range 1-45) at the time of this analysis. 43 of 237 patients had at least one adverse event (AE) reported (18.1%) with a median of 2 (range 1-11) AEs per patient; 19/237 (8.0%) patients experienced a serious AE (SAE). Most of the reported AEs belonged to the System Organ Classes (SOC) of infections and infestations, and gastrointestinal disorders, with COVID-19 being the most frequently-reported event. At the time of this analysis, 59 patients continued treatment beyond 52 weeks, with a median overall duration of treatment of 16 months (range 13-45). Within this group, 12 of 59 patients experienced at least one AE (20.3%) with a total of 46 AEs. 9/ 12 patients reported AEs during the first 52 weeks treatment, while in 3 patients the date of AE occurrence was not available (Table 1). The results in these 59 patients are summarized below. 6 patients experienced at least one SAE (7 SAEs in total). As in the overall EAP population, most of the reported AEs belonged to the SOC of gastrointestinal disorders, followed by infections and infestations, with COVID-19 being the most common AE occurring in 3 patients. 18 AEs were assessed as related to avacopan, with 3 events in 2 patients being classified as serious (deep vein thrombosis [DVT] in one patient, lower urinary tract symptoms and JC polyomavirus test positive in the second). The patient experiencing DVT temporary discontinued avacopan. In the patient who developed lower urinary tract symptoms with active replication of JC virus (1.728.405 copies/mL), avacopan was permanently withdrawn. According to the reporter, the concomitant use of prednisone, rituximab and denosumab could have contributed to these events. Three patients experienced events implying worsening of underlying disease. These events occurred within the first 52 weeks of treatment. The first patient experienced a vasculitis flare 6 months following avacopan initiation that coincided with an unintended dose reduction to 20 mg BID due to a product supply issue. The second patient experienced a worsening of known GPA related mononeuritis multiplex, possibly induced by concomitant treatment with isoniazid and a likely result of pharmacological interaction between rifampicin and avacopan. The third patient experienced an increase of creatinine, proteinuria and microhematuria in the context of avacopan withdrawal due to other events.

Conclusion
These results confirm that avacopan has a manageable safety profile with the potential to be effective beyond 52 weeks in sustaining disease control. Limitations of this analysis include potential underreporting, incomplete data and no control group.