The fusion protein briobacept (BR3-Fc; Biogen Idec/Genentech Inc) may broaden treatment options dominated by rituximab (Rituxan®) for B-cell targeted therapy in rheumatoid arthritis (RA). Early data reported at the 2008 EULAR meeting show that briobacept can be given repeatedly to selectively reduce levels of certain B-cell subgroups.1
The new drug targets B-cell activating factor of the TNF family (BAFF; TNFSF13B), which is a survival factor for B-cells. Briobacept is a homodimeric fusion glycoprotein that links the Fc domain of human immunoglobulin (Ig) and the residues from the extracellular domain of human BAFF receptor BR3. The trial, reported by Marianne Shaw, MD, and colleagues followed earlier work showing that single subcutaneous (SC) doses of up to 3 mg/kg and intravenous doses of up to 10 mg/kg were generally safe and reduced peripheral blood CD19+ B-cell counts in a dose-dependent manner. ?
Dr. Shaw, at the Altoona Center for Clinical Research in Duncansville, Penn, reported on behalf of a research team that included investigators from Biogen Idec, Cambridge, Mass, and Genentech, South San Francisco, Calif.
The goal of this study was to examine the safety, pharmacokinetic, and pharmacodynamic properties of three fixed XC doses of briobacept. The researchers randomized 35 RA patients on stable regimens of NSAIDs, prednisone <10 mg/day, and disease-modifying antirheumatic drugs to briobacept 300 mg SC/week (n = 9), 150 mg/week (n = 8), 300 mg/4 weeks (n = 10), or placebo (n = 8)
Dr. Shaw reported 144 adverse events (AEs) in 27 patients up to 70 days of follow-up, but said that these did not correlate with briobacept dose level. There were two serious AEs: one in the placebo group and one in the treatment group.
The most common AEs were injection reactions, which occurred in 50% of placebo patients and in 41% of briobacept-treated patients. Grade 2 injection site reactions occurred only in patients receiving briobacept, but infections were distributed evenly between study arms. There were two herpes zoster exacerbations in the patients receiving briobacept 300 mg. Briobacept half-life was estimated to be 10.2 to12.1 days. ?
“CD19+ cell levels were reduced by a median of ~ 55%, and, despite the different exposures, [the levels] did not differ among the three dosing regimens. In many subjects the B-cell reductions persisted at least until day 364. B-cell reductions were largely limited to the CD19+CD27- (naïve) population (60%-70% at day 203), while the CD19+CD27+ (memory) cells increased approximately twofold during dosing and gradually returned to baseline levels. In this small sample, there were no significant changes in total or specific Ig levels or in RA disease activity,” Dr. Shaw reported.
The investigators concluded that repeat dosing of briobacept was generally safe and well tolerated and that pharmacokinetic data suggested that monthly SC administration would be adequate. “A robust and long-lived pharmacodynamic effect was produced, suggesting that regimens using relatively infrequent dosing may be possible with BAFF antagonists,” Dr. Shaw said.
Reference
1. Shaw M, Trapp R, Del Giudice J, et al. The effects of repeated doses of briobacept (BR3-FC) in patients with rheumatoid arthritis. Presented at: EULAR 2008; June 11-14, 2008; Paris, France. Presentation OP-0123.
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