OP-0123-
The Effects of Repeated Doses of Briobacept (BR3-FC) in Patients with Rheumatoid Arthritis
Authors: Shaw, Trapp, Del Giudice, Burnette, Beckman, anand, Cheu, Maciuca, McLean. USA. [Sponsors, Genentech, Biogen-Idec]
Objective:
To evaluate the safety, pharmacokinetic (PK) and pharmacodynamic (PD) properties of repeated doses of Briobacept (BR3-Fc) in patients with RA. Briobacept is a homodimeric fusion glycoprotein consisting of the Fc domain of human IgG1 and 2 copies of the extracellular domain of the human BAFF receptor BR3. B-cell activating factor of the TNF family (BAFF; TNFSF13B) is a survival factor for B cells.
Methods:
35 RA pts on stable regimens of NSAIDs, prednisone <10 mg/day and DMARDs were randomized to a SC injections of one of the following: BR3-Fc 300mg per week (n= 9), 150mg per week (n=8), 300mg every 4 weeks (n=10), or placebo (PLA) (n=8) by for a total of 9 doses over 2 months. Adverse events (AEs), serious AE (SAEs), B-cell markers and other laboratory parameters were monitored. PK has been analyzed to 70 days after randomization, and safety and PD to 364 days.
Results:
The most common adverse events (AEs) were injection reactions (50% placebo, 41% BR3-Fc). Infections (3 in 10 placebo, 5 in 25 BR3-Fc, patients) were distributed approximately evenly between study arms. Two patients experienced a reactivation of Herpes Zoster at the top dose (300 mg) of BR3-Fc. Area-under-curve and peak exposures to BR3-Fc were approximately proportional to the dose administered. The half-life was 10-12 days, and accumulation with repeat dosing was up to 2-fold. CD19+ cells decreased by ~55% and persisted in many patients for > 364 days; there was no dose response. B-cell reductions occurred largely in the CD19+CD27- (naïve) population. An initial increase in the CD19+27+ (memory) cells, and then return to baseline, was observed. Minimal (5-10%) decreases in RF and anti-CCP levels were observed. Clinical data were not presented but the presenter noted that there was no effect of BR3-Ig on number of swollen or tender joints, ESR or CRP.
Conclusion:
Repeated doses of BR3-Fc appear to be generally safe and well tolerated. PK and PD properties were favorable for monthly SC administration.
Editorial Comment:
The numbers treated in this study are too small to make any meaningful conclusions. Yet, it is disturbing that while B cell depletion appears to be effective, no inkling of a clinical response was observed. These data are reminiscent of other trials targeting B cell growth/survival factors which have also been negative, while the B cell depleting antibodies – in contrast - are clearly efficacious. Sorting out the cause of this apparently discrepant result will be interesting. It may be that certain pools of B cells are more important than others, and the different classes of B cell agents target different pools. For now, however, the BR3-Fc agent doesn’t look overly promising from an efficacy standpoint.
