Avacopan May Be Effective Option to Steroids for AAV, Phase 3 Trial Finds

Use of avacopan can increase remission rates and improve kidney function in people with ANCA-associated vasculitis (AAV), while limiting the toxicity associated with standard steroid therapy, according to results from a Phase 3 clinical trial.

Top-line data from the ADVOCATE trial, which opened on March 15, 2017, and concluded on Nov. 1, 2019, were announced by the company shortly after it ended.

Now, its findings have undergone a peer review and are presented in the study “Avacopan for the Treatment of ANCA-Associated Vasculitis,” published in The New England Journal of Medicine.

“The results of the ADVOCATE trial are transformational and demonstrate the potential of avacopan to offer a substantial change in the treatment paradigm for ANCA-associated vasculitis,” Peter A. Merkel, MD, a study co-author and professor at the University of Pennsylvania, said in a press release.

Avacopan is a potential oral treatment that works by blocking the activity of the complement system, a group of immune proteins in the blood that normally help to fight infections. These proteins, however, can contribute to autoimmune disorders like AAV.

ADVOCATE (NCT02994927) was designed to investigate avacopan in people with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), the two most common AAV subtypes.

It enrolled 331 patients, who were randomized to treatment with either avacopan (30 mg twice daily) or to a standard treatment regime with the steroid prednisone. All participants were also given other standard immune-suppressing medications — rituximab or cyclophosphamide, followed by azathioprine.

The study’s goal was to determine whether avacopan could effectively replace conventional steroid therapy, which is often associated with side effects. ADVOCATE was sponsored by ChemoCentryx, which is developing the investigational medicine.

“Current treatment for ANCA-associated vasculitis consists of combining months of daily glucocorticoids (steroids such as prednisone) with other immunosuppressive medications,” Merkel said. “Use of prednisone is associated with significant side-effects, including infections, diabetes mellitus, weight gain, and other problems.”

After 26 weeks, the number of patients in remission — as assessed by a score of 0 on the Birmingham Vasculitis Activity Score, and no steroid therapy during the previous four or more weeks — was similar in both the avacopan and prednisone groups (72.3% and 70.1%).

While avacopan was at least as good as prednisone at inducing remission, additional data showed that significantly more people in the avacopan group were still in remission after 52 weeks (65.7% vs. 54.9%).

“Avacopan was noninferior but not superior to tapered prednisone with respect to remission at week 26 and was superior to prednisone with respect to sustained remission at week 52,” the researchers concluded.

Likewise, significantly fewer patients on avacopan experienced a relapse one year after remission (10.1%) than did those on prednisone (21%), representing a 54% reduction in relapse risk.

While kidney function — assessed using the estimated glomerular filtration rate (eGFR) — was not significantly different for avacopan and prednisolone in the overall population (7.3 vs. 4.1 mL/min/1.73²), avacopan significantly increased kidney function in a group of patients who entered the trial with severe kidney disease (13.7 vs. 8.2 mL/min/1.73²).

“The ADVOCATE trial clearly demonstrates avacopan’s ability to improve kidney function, measured by eGFR, in ANCA-associated vasculitis,” said David Jayne, MD, of Addenbrooke’s Hospital in Cambridge and another study co-author. “This is a significant advantage over other treatment options that often come with added toxicities and will likely lead to reduced risk of kidney failure over the longer term.”

Quality of life measurements — such as the Short Form 36 (SF-36), and the EuroQoL Group 5-Dimensions 5-Level Questionnaire (EQ-5D-5L) — generally followed a similar trend to the remission data, with avacopan tending to outperform prednisone after 52 weeks.

Scores on the Glucocorticoid Toxicity Index (a measure of steroid-associated toxicity) were lower among avacopan-treated patients than those given prednisone — consistent with more steroids being used in the prednisone group.

Safety trial data were generally positive. Nearly all (over 98% in both groups) participants reported at least one adverse event. In the avacopan group, 70 people experienced 116 serious adverse events; in the prednisone group, 74 experienced 166 adverse events. Worsening of vasculitis was the most common serious adverse event.

Six people died during the trial — two in the avacopan group, one due to worsening of vasculitis and one to pneumonia, and four in the prednisone group (causes were generalized fungal infection, infectious pleural effusion, and acute myocardial infarction; one death was marked as unknown cause).

Serious infections occurred in 13.3% of avacopan group patients, and 15.2% of those in the prednisone group. Serious abnormalities on liver function tests occurred in 5.4% of the avacopan group, and 3.7% of the prednisone group.

Collectively, the findings suggest that avacopan could replace conventional steroid therapy for the treatment of AAV, the study’s researchers wrote.

“The ability of avacopan to replace prednisone and help patients achieve sustained remission is a significant and exciting advance for the treatment of patients with ANCA-associated vasculitis,” Merkel said.

The study’s authors, however, also favored further trials of  avacopan in treating patients.

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 this year.