AVACOPAN

A clinical compound targeting complement 5a Receptor (C5aR). It is potent and selective, however, displays reduced activity on C5aR from most model species, including mice, rats, and rabbits. For PD studies, transgenic human C5aR is required.

Avacopan (CCX168) is a selective antagonist of the human complement 5a receptor (C5aR1 or CD88) and competitively inhibits the interaction between the receptor and the anaphylatoxin C5a, a terminal component of the complement cascade. By specific and selective inhibition of C5aR1, this compound reduces the pro-inflammatory effects of C5a, including neutrophil activation, migration, and adherence to sites of small blood vessel inflammation, vascular endothelial cell retraction and permeability. Avacopan displays ~10,000-fold or greater selectivity for hC5aR relative to most other chemotactic receptors, and 6,700-fold for CCR5 and 8,000-fold for CCR10. Avacopan has been also evaluated against a panel of 55 unrelated receptors and membrane-associated proteins: at 10 µM (~5.8 µg/mL) Avacopan showed weak activity on the human Adenosine A2a (42% inhibition) and A3 receptors (33% inhibition), as well as on the sodium channel (site 2). The weak activity of Avacopan was observed at exposures >16,000-fold the clinical Cmax (unbound) for Avacopan of 0.349 ng/mL. The FDA has approved Tavneos (Avacopan) in 2021 as an adjunctive treatment for adults with severe active ANCA-associated vasculitis, specifically granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), the two main types of ANCA-associated vasculitis (AAV) - alongside standard therapy. In 2022 the EMA (European Medicines Agency) has also approved Tavneos as an add-on therapy for adults with severe GPA or MPA.