Abatacept fails to show benefit for non-severe GPA in clinical trial
Researchers note difficulty of assessing disease activity with few biomarkers
The selective immunosuppressive medication abatacept failed to significantly prevent treatment failure relative to a placebo in people with relapsing, non-severe granulomatosis with polyangiitis (GPA) taking part in a Phase 3 clinical trial, new data show.
In addition to failing to meet this main goal of the study — called ABROGATE (NCT02108860) and spanning 20 locations in North America and Europe — the therapy was also not superior to the placebo at all other secondary goals, including reduction of relapse rates and severity, and increases in periods without standard glucocorticoid treatment.
The scientists noted that it can be difficult to capture and evaluate non-severe disease symptoms in GPA, which may have contributed to the negative results.
“This experience provides further evidence of the need to continue the investigation of clinical, laboratory, and imaging biomarkers as well as patient-reported outcomes to better assess non-severe disease activity in GPA in conjunction with the pursuit of novel treatment options,” the team wrote.
The findings were detailed in “A randomized, double-blind, placebo-controlled trial of abatacept for the treatment of relapsing, non-severe, granulomatosis with polyangiitis,” a study published in Arthritis & Rheumatology, which serves as the official journal of the American College of Rheumatology. The work was funded by Bristol-Myers Squibb, the company that markets abatacept under the brand name Orencia for its approved indications.
GPA is a common type of ANCA-associated vasculitis — a group of conditions in which abnormal immune attacks drive inflammation and damage to the body’s small blood vessels. Among people with this disease type, symptoms typically affect the respiratory tract and kidneys.
Immunosuppressive treatments, particularly glucocorticoids, are used to reduce disease activity and push GPA into remission, but relapses are still common.
Although relapse symptoms often aren’t severe or life-threatening, they can still substantially impact a person’s quality of life. Adding to that, continued use of glucocorticoids can come with serious side effects, data have shown.
“For this reason, there is a great unmet need to provide safe and effective management options for non-severe disease relapses in GPA that allow sparing of glucocorticoids,” the researchers wrote.
Earlier clinical trial had suggested benefits of abatacept for GPA
Abatacept is designed to suppress the activity of T-cells, a class of immune cells that are central to the inflammatory attacks that cause GPA symptoms. Essentially, it aims to block certain protein interactions needed for T-cell activation.
The therapy is approved in the U.S. under the brand name Orencia for certain types of arthritis and to lower the risk of serious complications after a stem cell transplant. It also had shown promise for treating non-severe GPA.
In an earlier Phase 1/2 clinical trial (NCT00468208), 20 people with relapsing, non-severe GPA were treated with 10 mg/kg of abatacept, administered directly into the bloodstream. The therapy was found to be generally safe and to help most of the participants achieve disease remission and stop glucocorticoid treatment.
This prompted the launch of the Phase 3 ABROGATE trial, which enrolled 65 people with GPA, ages 15 and older, who had experienced a non-severe disease relapse within a month of being screened.
The trial’s participants were randomly assigned to receive weekly subcutaneous, or under-the-skin, injections of either abatacept (125 mg) or a placebo, in addition to the glucocorticoid prednisone and standard immunosuppressive treatments. Prednisone was tapered off over three months.
Treatment was continued for a year after the last participant was enrolled, but was stopped early if a severe relapse or disease worsening occurred. Participants who experienced a non-severe relapse or disease worsening, or hadn’t achieved remission by month six, were eligible to receive abatacept for up to a year along with steroid tapering.
No differences seen for patients given therapy vs. placebo
The main study goal was to evaluate abatacept’s ability to reduce the rate of treatment failure during the study’s placebo-controlled part. This was defined as a relapse, disease worsening, or failure to achieve a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis of 0 or 1 — reflecting no or minimal active disease — by six months.
The results showed that a lower proportion of patients on abatacept experienced treatment failure relative to those on the placebo (64.7% vs. 74.2%), but this difference failed to reach statistical significance, and therefore, the study’s main goal was not attained.
Most treatment failures in either group were due to relapses consisting of predominately non-severe symptoms.
There also were no significant differences between the two groups in terms of the study’s secondary goals, such as relapse severity, time to achieve remission, time spent free of glucocorticoids, quality of life, and prevention of disease- and treatment-related damage.
The findings from this trial were contrary to the positive impressions seen in the [Phase 1/2] study which was the basis for conducting this new trial.
Rates and frequency of adverse events were also generally comparable between the abatacept and placebo groups.
Overall, “the findings from this trial were contrary to the positive impressions seen in the [Phase 1/2] study which was the basis for conducting this new trial,” the researchers wrote.
However, the team noted that the underlying hypotheses here should still be further studied.
“Although the current findings do not support the use of abatacept in GPA, these findings should not deter exploration of the role of T-cells and T-cell activation in the [disease mechanisms] of GPA and investigation of novel therapies for which there is a supportive safety and efficacy rationale,” the researchers wrote.
The team also noted the challenges of assessing symptoms among those with non-severe disease — which, they theorized may have played a role in the trial’s failure.
“In conducting this trial, much was learned about the challenges of conducting a randomized trial in patients with GPA with non-severe disease,” the scientists wrote.
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