Avacopan Shows Superiority Over Steroids to Treat AAV in Phase 3 ADVOCATE Trial
Avacopan (CCX168) can effectively improve remission rates, kidney function, and overall quality of life of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), compared with standard therapy with steroids, according to top-line results from a pivotal Phase 3 clinical trial.
ChemoCentryx and its collaborator, Vifor Fresenius Medical Care Renal Pharma, are now preparing to make regulatory submissions for full marketing approval of avacopan in both Europe and the United States in 2020.
The pivotal ADVOCATE trial (NCT02994927) met both of its primary objectives: remission at week 26 and sustained remission at 52 weeks, as determined by a score of zero in the Birmingham Vasculitis Activity Score (BVAS) and being off glucocorticoid therapy for at least the previous four weeks.
Approximately 72.3% of avacopan-treated participants achieved disease remission at 26 weeks, compared with 70.1% of participants treated with standard glucocorticoid therapy.
This positive clinical response was sustained through 52 weeks in 65.7% of the avacopan-treated participants and in 54.9% in the glucocorticoid-treated group.
These long-term clinical data demonstrate that avacopan may be an alternative treatment for AAV that can lead to similar or even better outcomes than available standard-of-care steroid-based therapies — and can do so with lower toxicity.
“This is the transformational result that clinicians and patients all over the world had been hoping for,” David Jayne, MD, director of the Vasculitis and Lupus Clinic at Addenbrooke’s Hospital, in Cambridge, said in a press release. “The ADVOCATE trial demonstrated clearly that avacopan effectively brought patients into a state of remission for their acute vasculitis symptoms and kept them there for the entire period of this study. Importantly, avacopan did this in the absence of the traditional sustained daily steroid therapy that is the current standard of care.”
The Phase 3 trial enrolled 331 patients with acute AAV who were randomly assigned to take either avacopan or prednisone. Patients in both groups also took Rituxan (rituximab) or cyclophosphamide, followed by azathioprine.
The benefits of avacopan therapy extended beyond its impact on AAV activity, with significant improvements in kidney function in patients with renal disease.
Patients on avacopan experienced significant improvements in estimated glomerular filtration rate (eGFR) from the start of the study to 26 weeks of 5.8 mL/min/1.732 and to 52 weeks of 7.3 mL/min/1.732 compared with 2.8 mL/min/1.732 and 4 mL/min/1.732 reported in the group on standard therapy at the same time points.
Patients’ health-related quality of life also improved with avacopan therapy with significantly better outcomes on the EuroQOL-5D-5L assessment tool.
Evaluation of glucocorticoid-related toxicity — a major side effect associated with long-term use of AAV standard therapy — showed that patients treated with avacopan had significantly lower glucocorticoid toxicity index scores.
“The notable and significant improvements in quality of life, the reductions in overall glucocorticoid toxicities and especially the improvements in renal function with avacopan therapy when compared to the steroid-containing standard of care are remarkable,” Jayne said. “These each have direct impacts on the lives of ANCA vasculitis patients, with the renal function improvement having long-term implications on patient survival and kidney failure risk.”
Avacopan also showed an acceptable safety profile. Fewer patients reported serious adverse events in the avacopan group than in the standard-of-care group (42% vs. 45%, respectively).
The most common serious side effects reported during the trial were related to underlying AAV manifestations, and their frequency was similar to previously published AAV trials.
Fewer cases of serious infections were reported among those treated with avacopan than in the group treated with prednisone.
Researchers are still conducting additional analyses of the full clinical and safety data, and expanded results are expected to be announced in the upcoming weeks.
“These results exceed our expectations,” said Thomas J. Schall, PhD, president and CEO of ChemoCentryx. “Today we mark the dawn of a new and historic period in the lives of ANCA vasculitis patients. This day we have for the first time demonstrated that a highly targeted therapy aimed at the very center of the ANCA disease process is superior to the traditional approach of broad immune suppression therapy; a therapy which the present findings may make obsolete.”
Avacopan is an investigational oral inhibitor of the complement C5a receptor, and works by preventing the overactivation of the C5a complement protein. This protein is part of the complement system — a set of more than 30 blood proteins that form part of the body’s immune defenses — that is thought to be involved in the overactivation of the immune system in AAV.
ChemoCentryx holds full rights over avacopan in the U.S. and Vifor Fresenius Medical Care Renal Pharma has an exclusive license to commercialize avacopan outside the U.S.