SHANGHAI, China—B-cell-directed treatments being tested for systemic lupus erythematosus (SLE) include not only monoclonals that deplete B-cells but also compounds that jam the signals required for B-cell growth and development, according to David Wofsy, MD, chief of rheumatology at the VA Medical Center and also the George A. Zimmerman Distinguished Professor of Rheumatology at the University of California, in San Francisco. He described current work on novel lupus therapies at the 8th International Congress on SLE.1
Dr. Wofsy characterized the work directed at B-cells in the context of mechanisms known to contribute to SLE:
- B-cells that promote autoantibody production
- T-cells that provide help for pathologic immune responses
- cytokines and/or complement components that contribute to tissue damage
Rituximab in phase II/III trials
The B-cell strategies first tested in SLE are designed to produce B-cell depletion. The best known is rituximab (anti-CD20). "Rituximab is already approved for the treatment of RA, and preliminary uncontrolled experience in lupus has raised hopes that it may be effective in SLE as well," Dr. Wofsy said. He stated that rituximab is currently being studied in two large phase II/III trials in lupus patients with and without lupus nephritis. Rituximab and the anti-CD22 epratuzumab are attractive because they produce long-lasting, but reversible B-cell depletion.
Another approach is to interfere with signals required for B-cell proliferation and differentiation, including the anti-BLyS (B lymphocyte stimulator) monoclonal belimumab and the fusion protein atacicept (TACI-Ig, [transmembrane activator and CAMI interactor]-immunoglobulin).
"There are also strategies that focus more narrowly on attempts to inhibit the function of selected B-cells that produce pathogenic autoantibodies [eg, riquent and edratide], as well as strategies designed to block critical interactions between T-cells and B-cells [eg, through the use of abatacept/CTL4Ig]," Dr. Wofsy said.
Belimumab, atacicept show promising early results
BLyS and APRIL (a proliferation-inducing ligand) are bound by receptors on B-cells that are expressed differentially, depending on developmental stage. Dr. Wofsy pointed out that high levels of BLyS in SLE patients correlate positively with levels of anti-dsDNA (anti-double-stranded DNA). SLE patients also have higher levels of APRIL than either healthy controls or patients with RA. Dr. Wofsy described a 52-week phase II, randomized, double-blind, placebo-controlled trial of belimumab in 449 patients with active, but mild SLE.
"This study demonstrated potent biologic effects, including a 54% reduction in circulating B-cell counts, a 70% reduction in activated B-cells, a 10% reduction in serum IgG concentration, and a 30% reduction in anti-dsDNA. Despite these effects, this trial did not meet its primary clinical endpoints in the overall study population. However, subsequent subset analysis suggested possible clinical benefit. It is expected that this issue will be clarified in an upcoming phase III trial," Dr. Wofsy said.
Atacicept was recently tested in a phase Ib, double-blind, placebo-controlled, dose-escalating trial in 49 patients with SLE. "After 4 weekly doses of atacicept, total B-cells declined by 30% to 35% and mature B-cells declined by 50% to 60% relative to baseline. Treatment also reduced IgM levels by 50%, IgA levels by 32%, and IgG levels by 16%. This study was not powered to assess efficacy, which will be done in an upcoming phase II trials," Dr. Wofsy concluded.
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Reference
1. Wofsy D. An update on novel therapies for systemic lupus erythematosus (SLE). Presented at: 8th International Congress on SLE; May 24, 2007; Shanghai, China.