Avacopan for the treatment of ANCA-associated vasculitis: an update

ABSTRACT

Introduction

Glucocorticoids (GC) have been part of the standard treatment of anti-neutrophil cytoplasm autoantibodies (ANCA)-associated vasculitides (AAV) for more than 60 years. Various therapeutic advances have occurred over the past 2 decades and led to a significant reduction of GC exposure, but most patients still have to suffer from complications of GC, including infections, metabolic abnormalities, and cardiovascular morbidity. In 2007, activation of the complement pathway was demonstrated to play a role in the pathogenesis of AAV. Avacopan, an oral competitive inhibitor of the C5a receptor (C5aR1, CD88), was then developed, with an additional aim to decrease the use of GC.

Areas covered

In this article, we briefly summarize the rationale for targeting the complement pathway in AAV, and review relevant findings from pre-clinical, phase I, II, and III studies, subsequent and more recent case reports and series on the efficacy and safety of avacopan.

Expert opinion

Based on the results of these studies, avacopan was approved in most countries since late 2021, as an adjunctive induction treatment for patients with AAV. Several newer questions now are pending answers, including as to how avacopan should be used in real-world practice, beyond how it was given in the original clinical trials.

KEYWORDS:

• ANCA
• avacopan
• complement
• glucocorticoids
• vasculitis

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Correction

Article highlights

• Avacopan is an oral small molecule that blocks the binding of C5a to its receptor (C5aR1).

• Avacopan was shown to be safe and effective in patients with severe granulomatosis with polyangiitis and microscopic polyangiitis, based on the results of the CLEAR, CLASSIC, and ADVOCATE studies.

• Based on these studies, avacopan has been approved by the FDA in October 2021, and in several other countries now, as an adjunctive treatment of adult patients with severe, active granulomatosis with polyangiitis and microscopic polyangiitis, in combination with standard therapy.

• Avacopan can help reduce glucocorticoid exposure and toxicity in patients with granulomatosis with polyangiitis and microscopic polyangiitis and may have further benefit in terms of renal recovery.

• More studies are needed now to determine how to best use of avacopan in clinical practice, including on its optimal duration, role during maintenance therapy, and for the treatment of most severe or refractory forms of granulomatosis with polyangiitis and microscopic polyangiitis.

Acknowledgments

We thank Amgen for factual review of the avacopan information in this paper.

Declaration of interest

C Pagnoux reports receiving in the past 2 years fees for serving on advisory boards from ChemoCentryx, GlaxoSmithKline, Astra-Zeneca, and Hoffman-LaRoche; he also reports lecture fees and research/educational grant support from Hoffman-LaRoche, Pfizer, and GlaxoSmithKline. J Cohen Tervaert reports serving as the chair of the IDMC for InflaRx; he also reports lecture fees from Sanofi, Medexus, GlaxoSmithKline, and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose. Amgen provided a scientific accuracy review of the avacopan information at the request of the journal editor. Amgen provided no editorial, writing, or financial support.

Additional information

Funding

This paper was not funded.