A combination of belimumab plus standard maintenance treatment is no better than standard of care alone at delaying relapse in ANCA-associated vasculitis (AAV) patients in remission, a Phase 3 clinical trial shows.
Findings were recently published in the journal Arthritis and Rheumatology, in the study, “Efficacy and Safety of Belimumab and Azathioprine for Maintenance of Remission in ANCA‐Associated Vasculitis: A Randomized Controlled Study.”
AAV, a condition characterized by small vessel inflammation, is caused by the production of abnormal autoantibodies — called anti-neutrophil cytoplasmic antibodies (ANCAs) — that target the patients’ own immune cells.
AAV is normally treated in two phases. First, patients receive Rituxan or cyclophosphamide to induce disease remission. Then, a maintenance treatment with low-dose glucocorticoids in combination with either azathioprine, methotrexate, mycophenolate mophetil, or Rituxan is given to prevent the disease from returning.
“Despite use of the above therapies, relapse is a major clinical problem in AAV,” the investigators said.
Belimumab — marketed as Benlysta by GlaxoSmithKline for some lupus patients — is an antibody that binds the B lymphocyte stimulator (BLyS), a protein that stimulates B-cells to develop into antibody-producing cells.
BLyS seems to participate in AAV development, which led researchers to test if adding belimumab to standard maintenance treatment with azathioprine and low-dose glucocorticoids could help delay relapse in AAV patients.
The Phase 3 BREVAS trial (NCT01663623) included 105 patients in remission from 15 countries in Europe, Central and North America, and Australia.
Patients had either granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) — two AAV subtypes — and were randomly assigned belimumab or a placebo, given in combination with azathioprine — or methotrexate in case of intolerance — plus low-dose glucocorticoids.
The trial’s main goal was to determine the time to first relapse, defined as having a Birmingham Vasculitis Activity Score (BVAS) — a measure of disease activity — of six or higher, a predefined BVAS major item, or the receipt of medications not allowed by study protocol.
A secondary measure was the time to a major relapse, deemed as a predefined BVAS major item only.
In total, 15.4% of patients in the placebo arm and 11.3% of those receiving belimumab experienced a vasculitis relapse during the study. Although the median time to first vasculitis relapse was 105 days for those on placebo and 251 days for those receiving belimumab, the results did not reach statistical significance.
A limited number of patients experienced a major relapse, which did not allow the researchers to determine belimumab’s benefits over a placebo for this objective.
Interestingly, while relapses in the placebo group were evenly distributed across different induction treatments — Rituxan and cyclophosphamide — and types of ANCAs — PR3 or MPO — all relapses in the belimumab group occurred in patients who had received cyclophosphamide induction treatment and produced PR3-ANCAs.
These findings suggest that patients taking Rituxan as an induction treatment might benefit from belimumab maintenance, likely because Rituxan increases the levels of BLyS in these patients.
“This finding in a small subgroup of patients warrants further investigation and is consistent with data from preclinical models and case studies suggesting that dual B-cell–targeted immunotherapy (B-cell depletion [i.e., rituximab] + BLyS blockade [i.e., belimumab]) may be more efficacious than either therapy prescribed alone,” the researchers wrote.
More patients receiving belimumab experienced an adverse event than those on placebo — 92.5% versus 82.7% — but serious adverse events were similar across the two groups of patients.
“The addition of belimumab to azathioprine and low dose glucocorticoids for the maintenance of remission in AAV did not reduce the risk of … vasculitis relapse,” the investigators concluded. “However, patients with rituximab-induced remission who were subsequently treated with belimumab exhibited no vasculitis relapses. This observation warrants further investigation.”