New Oral Agent Shows Clinical Activity in Rare C3 Glomerulopathy


The investigational drug avacopan, an oral inhibitor of complement activation, showed meaningful clinical activity in the treatment of C3 glomerulopathy, indicates the largest study ever done in this rare kidney disease.

In a group of 52 participants, there was a “clear trend” in favor of those treated with active therapy, with a mean reduction in biopsy-based disease activity score, the primary endpoint, of 0.2% with avacopan versus a 20.6% increase with placebo, reported Andrew Bomback, MD, MPH, at the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) 2021 Virtual Congress.

The difference between the two groups did not quite reach statistical significance (P = .64) because there was considerable variability in baseline levels of inflammation as well as variable responses to the drug, explained Bomback, associate professor of medicine, Columbia University Irving Medical Center, New York City, in an email to Medscape Medical News.

However, changes in secondary outcomes between the two groups were statistically significant at 6 months, he noted, and the tolerability and safety of avacopan did not differ from placebo.

“Right now, there is no standard of care, although there has been limited success slowing the disease down using a combination of steroids and mycophenolate mofetil, a regimen used to treat lupus nephritis,” Bomback noted.

“So we believe these are important results from a large study in C3 glomerulopathy, and we hope this is the first of many complement inhibitors that will show benefit in patients with this disease,” he said during a virtual press briefing.

C3 glomerulopathy is a rare disease in which the deposition of C3 protein causes severe inflammation of the glomeruli, which can lead to end-stage kidney disease (ESKD). C3 glomerulopathy has, to date, been treated by lowering blood pressure and proteinuria and with nonspecific immunosuppression.

Asked to comment on the findings, session chair Danilo Fliser, MD, of Saarland University Medical Centre, Homburg, Germany, noted that, so far, no specific treatment has been available for C3 glomerulopathy.

“The results presented by Bomback and colleagues were exciting: during a 6-month treatment period, eGFR significantly improved with avacopan therapy in contrast to the placebo treatment arm,” he told Medscape Medical News in an email.

Moreover, proteinuria and indirect markers of disease chronicity decreased, and no safety concerns were raised, he added. “Taken together, these study results are encouraging and will hopefully be confirmed in the real-world clinical setting,” Fliser observed.

ERA-EDTA President Markus Ketteler, MD, concurred. “Treatment with avacopan now shows that this compound is effective to suppress glomerular infiltration, which is thought to mediate progressive renal damage in C3 glomerulopathy,” he told Medscape Medical News in an email.

“So these are very promising data,” he said, adding that another benefit of being able to use avacopan is that it will spare patients glucocorticoid-associated side effects, “and this still not infrequently used treatment could be dispensed with or significantly dose-reduced in the future.”

Slow Down Inflammation and Scarring to Prevent ESKD

In the new ACCOLADE study, researchers examined whether the inflammatory C5a receptor can be selectively blocked with avacopan; this targeted immune intervention would likely be less toxic than general immunosuppression.

Patients were randomized to 30 mg of orally administered avacopan twice daily (n = 28) or placebo (n = 29) for 26 weeks. The mean duration of disease prior to enrolment was about 4 years, and although patients generally had preserved renal function at study entry, they had high levels of proteinuria, at about 3.5 grams/day.

The primary outcome — the C3HI “disease activity score” — was used to measure changes in histology over time by means of repeat kidney biopsies (with higher values indicating severe disease).

Secondary endpoints were the histologic disease chronicity score (degree of fibrosis), glomerular filtration rate (eGFR), and proteinuria (urinary protein to creatinine ratio).

“When you look at the group randomized to placebo, there was an increase in activity on their biopsy which is a surrogate for inflammation, suggesting that the disease is becoming more pronounced over the course of 6 months,” Bomback explained.

The same change in activity was not seen in patients randomized to avacopan, he added.

Patients randomized to placebo also had a significantly higher degree of scarring progression — a 57.5% change from baseline — compared with the active treatment group, which had a 31.7% change from baseline (P = .04), the lower score reflecting less progression to fibrosis for patients taking avacopan.

As Bomback explained, a recent validation study found that the score, which reflects scarring, is a stronger predictor of progression to ESKD than the activity or inflammation score, “so we believe that this is an important result, that we see less chronicity on the biopsy when patients are randomized to the active drug,” he emphasized.

Changes in eGFR were also statistically significant. In the avacopan group, eGFR increased by, on average, 4.8% compared with an average decrease of 5.9% in the placebo group (P = .022). “This significance was equal to or even more pronounced in the subgroup of patients who entered the study with impaired kidney function, with an eGFR of less than 60 mL/min/1.73m2 (P = .01),” Bomback added.

Lastly, mean levels of proteinuria were also significantly lower among patients treated with avacopan compared with placebo (P < .05).

“If you don’t slow down inflammation and scarring, patients will eventually develop irreversible kidney damage leading to ESKD,” Bomback noted. 

C3 Glomerulopathy Can Reoccur Following Kidney Transplantation

However, alternative complement pathways remain hyperactive following kidney transplantation, Bomback noted. While most of the patients in the study were nontransplant patients, the disease did recur in the kidney following transplantation in two patients, one in each treatment group.

“This is important,” Bomback said, “because the natural history of the disease is that it progresses to ESKD on average at about 10 years, and if patients do undergo transplantation, the disease also invariably will recur in the transplanted kidney, so therapies are needed both for the native disease and the transplant disease,” he emphasized.

He added that the more selectively nephrologists can target the causal disease mechanisms in the immune system, the less the immune system as a whole is suppressed, which should yield not only more effective, but less toxic, therapies.

Avacopan was recently given the thumbs up by the US Food and Drug Administration’s Arthritis Advisory Committee, which voted 10-8 on May 6 to recommend approval of the drug for two subtypes of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis — granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) — a rare and serious autoimmune condition.

Accolade was funded by the Office of Orphan Products Development. Bomback has reported receiving consulting or advisory board honorarium from Achillion/Alexion, Catalyst, ChemoCentryx, Novartis, and Visterra. Fliser has reported receiving financial support from Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Otsuka, Roche, and FMC-VIFOR.

ERA-EDTA 2021 Virtual Congress. Abstract 2478. Presented June 6, 2021.

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