Written By: Kaitlin Lima, Michael Lopker, Yoon Qiu, Julia Sun; Northwestern University

Based on: Jayne et al. NEJM.2021;384:599-609 (NEJM link)

Topic Overview

The ANCA-associated vasculitides are life-threatening autoimmune diseases with significant morbidity and mortality from both organ damage and treatment related toxicity. The alternative complement pathway has been implicated in the pathogenesis of ANCA-associated vasculitis, which culminates in production of C5a. Avacopan is an oral small molecule C5a-receptor antagonist that selectively blocks the effect of C5a, including blocking neutrophil chemoattraction and activation. Avacopan protects against development of glomerulonephritis after exposure to antimyeloperoxidase antibodies in mouse models, and Phase II trials in humans showed safety compared to standard of care.

The ADVOCATE trial¹ was a phase 3 randomized controlled trial of 331 MPO or PR3 positive patients with new or relapsing disease in which patients received either avacopan 30 mg twice a day (n=166) OR corticosteroids (n=165) on a tapering schedule in addition to rituximab or cyclophosphamide at the investigators’ discretion. Avacopan was found to be noninferior to prednisone for remission at week 26 (defined as Birmingham Vasculitis Activity Score (BVAS)=0 and no corticosteroid use in the previous four weeks) with 72.3% in avacopan group vs 70.1% in prednisone group. Avacopan had superior sustained remission at week 52 (65.7% vs 54.9%). There was a trend towards higher eGFR and decreased albuminuria in the avacopan group, which mirrors other studies in mice² and humans^3,4. Serious adverse events were similar in the two groups.

Implications for Patients, Providers, & Researchers

Current implications: The ADVOCATE trial has made the previously unthinkable possible: inducing disease remission in ANCA-vasculitis without glucocorticoids. With the use of Avacopan in ANCA-vasculitis, patients with new or relapsing active disease, the amount of glucocorticoid use was significantly reduced with superior results at week 52. This resulted in fewer glucocorticoid-related side effects (as demonstrated by significantly lower Glucocorticoid Toxicity Index) while not compromising ability to achieve remission.

Future implications: The success of the ADVOCATE trial opens the door to the evaluation of other complement-directed treatments for ANCA-vasculitis. A monoclonal antibody (IFX-1) to C5a is in stage 2 clinical trials and there are case reports suggesting efficacy using eculizumab in refractory ANCA-vasculitis.

Will Avacopan Win its First Round Match-up?

In what is best represented as a #2 ADVOCATE vs #15 PEXIVAS matchup, PEXIVAS is the clear underdog. This negative trial won’t have nearly the impact of ADVOCATE, as knowing when NOT to use plasma exchange in a small subset of ANCA-associated vasculitis will clearly impact fewer patients. It did have an important secondary finding: that reduced-dose steroid regimens are non-inferior to standard regimens. While a reduced-dose regimen is a substantial step forward in reducing morbidity, a complete steroid sparing regimen is a giant leap. PEXIVAS is also not unique in this finding.

Could Avacopan Win it All?

Avacopan has a “blood blood” chance at making it to the final showdown – rheumatologists have been craving steroid-free treatment options for our most challenging diseases and this trial does not disappoint. If ADVOCATE can overcome the group of death second round matchup against SLE therapeutics, its path to the championship game is almost assured. Avacopan compared to prednisone was superior for sustained remission at week 52, had lower glucocorticoid toxicity, and a trend higher eGFR and decreased albuminuria with similar adverse events. While questions remain including durability and the use of avacopan for minor relapses, the prospect of almost completely eliminating steroids from the treatment regimen of this life-threatening condition represents a likely paradigm shift for the field of rheumatology.

Reference(s)

1. Jayne et al. NEJM. 2021;384:599-609
2. Xiao et al. J Am Soc Nephrol. 2014;25:225-231.
3. Jayne et al. J Am Soc Nephrol. 2017;28:2756-2767.
4. Merkel et al. ACR Open Rheumatol 2020;2:662-671.

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