Oral Avacopan Improves Kidney Function and Delays Relapse, Trial Reports

Avacopan is superior to prednisone at improving kidney health in people with ANCA-associated vasculitis (AAV) and poor kidney function, and in extending time until a disease relapse, new data from a Phase 3 trial show.

These findings were recently shared at ACR Convergence 2020, the virtual annual meeting of the American College of Rheumatology. Peter Merkel, MD, with the Hospital of the University of Pennsylvania gave the presentation,”The Effect on Renal Function of the Complement C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis.”

Avacopan, developed by ChemoCentryx, is an orally administered small molecule that works to inhibit the C5a protein, one of the most potent pro-inflammatory proteins of the complement system.

The complement system is a part of the immune system that normally helps fight infections, but it can contribute to autoimmune disorders like AAV. By blocking C5a, avacopan is expected to ease the inflammation and blood vessel damage caused by this disease.

Avacopan is under approval review by regulatory authorities in the U.S. and European Union as a potential treatment for AAV patients, with decisions expected in the second half of next year.

These submissions were supported by data from the ADVOCATE Phase 3 trial (NCT02994927), which assessed the safety and efficacy of avacopan, compared with the corticosteroid prednisone, in adults with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), the two most common AAV subtypes.

In the trial, 330 patients were randomly assigned to either avacopan (30 mg twice daily) or prednisone for about one year, while continuing with standard of care treatment — rituximab or cyclophosphamide, followed by azathioprine.

ChemoCentryx reported top-line trial data last year, showing that avacopan was as good as prednisone at inducing clinical remission within the first six months of treatment (72.3% vs. 70.1%), and superior to prednisone at sustaining remission at least until the one-year mark (65.7% vs. 54.9%).

The recent presentation demonstrated that among patients who relapsed after going into remission, those taking avacopan had a longer span of time (about 54% longer) before a relapse than those using prednisone.

These benefits were observed across several patient subgroups, regardless of ANCA type, AAV subtype, disease stage, sex, and choice of standard treatment.

Among patients with kidney disease at the time of treatment initiation, avacopan also outperformed prednisone at improving kidney function — as measured by changes in estimated Glomerular Filtration Rate (eGFR) and the ratio of albumin to creatine in urine.

Glomeruli are structures in the kidneys used to filter waste products from the blood. eGFR refers to the amount of blood filtered by the glomeruli per minute. As kidney function declines due to damage or disease, eGFR decreases and waste products begin to build in the blood.

In ADVOCATE, eGFR values increased significantly more in patients on avacopan than in those receiving prednisone (7.3 vs. 4.1 mL/min/1.73 m²). Notably, the greatest benefit was observed among patient who entered the trial with poor kidney function — those whose eGFR values were below 30 mL/min/1.73 m² at its start.

Avacopan-treated patients also showed faster declines in albuminuria. A healthy kidney prevents essential proteins like albumin from being excreted in urine, so the presence of albumin in urine (albuminuria) is a measure of kidney damage.

Albuminuria declined by 40% in four weeks among patients taking avacopan, and showed no change in those using prednisone. After one year, however, the two treatments showed similar reductions in albuminuria.

Liver function also increased more in avacopan-treated patients than in those on prednisone (5.4% vs. 3.7%).

Overall, avacopan was generally safe and well tolerated. A total of 116 treatment-related side effects and 25 serious infections were reported in avacopan-treated patients, and 166 side effects and 31 serious infections in those on prednisone. Serious adverse events involving white blood cell count decreases occurred in 2.5% of patients taking avacopan and 4.9% of those taking prednisone.

“These findings suggest the potential for better long-term outcomes with avacopan for patients with renal disease than current standard of care treatment and provide intriguing insights into subclinical renal disease activity in ANCA-associated vasculitis,” the investigators wrote in the abstract.