Systemic Lupus Erythematosus
Abstract 588. Patients with Active Systemic Lupus Erythematosus (SLE) Treated with Belimumab Improve Health-Related Quality of Life (HRQOL) in a Randomized Controlled Trial (RCT)
Authors: V. Strand1, B. Crawford2, M. Petri3, R. Ramsey-Goldman4, M. Weisman5, S. Lim6, J. T. Merrill7, J. Zhong8, W. Freimuth8, M. Chevrier8, and LBSL02 Study Group. 1Stanford U, Palo Alto, CA; 2MAPI Values/Tufts U, Boston, MA; 3JHU, Balt, MD; 4Northwestern U, Chicago, IL; 5Cedars-Sinai, LA, CA; 6Emory U, Atlanta, GA; 7OMRF, OK City, OK; 8HGS, Rockville, MD
Background: The above 4 abstracts summarize the Phase II trial of Lymphostat B, a humanized monoclonal antibody against the B lymphocyte stimulator (BLyS) protein in SLE. An earlier trial in rheumatoid arthritis had shown efficacy, but not comparable to anti-TNF biologics in RA. BLyS is a B-cell survival factor that allows B cells to undergo the IgM to IgG switch and protects B cells against apoptosis. BLyS levels are elevated in patients with SLE and RA. In SLE, changes in BLyS levels are associated with changes in SLEDAI. In animal models of SLE, reduction in BLyS levels is protective.
Methods: 449 SLE patients with baseline SELENA SLEDAI > 4 were randomized to placebo or 1, 4 or 10 mg/kg of belimumab in a double-blind randomized Phase II trial, and followed for 52 weeks. The primary outcomes were: 1) reduction in SELENA SLEDAI and 2) prolongation in time to flare.
Results: Abstract 535 summarizes the clinical results. All doses were equally effective. In the total population, there was not a statistically significant reduction in SELENA SLEDAI at week 52. In a “seropositive” subgroup (positive ANA or ant-dsDNA), there was a 29% reduction (p=0.044). Time to severe flare was not reduced, but severe flares requiring new therapy were reduced by 30%.
Abstract 2012 extends the results to 76 weeks. Serum IgG decreased 11.9% by week 76. Low C4 improved to 96% at week 76.
Abstract 1985 summarizes biologic effects. At weeks 52 and 76, plasmacytoid and total CD20+ B cells were reduced. Clinical responders had greater reduction in activated B cells (p=0.05) and plasmacytoid cells (p=0.08). Plasma cells increased over baseline. IgG, IgA, IgE, and IgM were reduced. Anti-dsDNA was reduced by 30%.
Abstract 588 summarized the benefit on the physical component score of the SF-36 (p=0.057), and in the seropositive subset (p<0.02).
Conclusion: Lymphostat B was safe and had biologic activity on B cell subsets. Although it failed to reach the primary clinical endpoints, a subset of seropositive SLE patients (71% of the total) did show statistical significance.
Editorial Comment: Multiple B cell approaches are currently being tested in SLE. It is likely that they will differ in efficacy and safety. Belimumab is the first to reach completion of a Phase II trial. It did not reach the primary endpoints of reduction in disease activity or prolongation of time to flare. It was extremely safe. Is there enough of an efficacy “signal” to justify further development?
Human Genome Sciences identified a subset that was “seropositive” (positive ANA or positive anti-dsDNA), that represented 71% of the total. In this subgroup, there was a significant reduction in disease activity and a prolongation of time to flare (24 to 52 weeks). This appears to be an appropriate subset, since a B cell directed therapy in SLE would be expected to be more appropriate in SLE patients actively making autoantibodies. In this subgroup, there was also significant improvement in the physical component score of the SF-36.
The remarkable safety included no increase in serious infections, or laboratory toxicity. Infusion reactions were rare. Only one patient had immunogenicity. A Phase III trial is now planned in seropositive SLE patients, with the primary outcome being reduction in SELENA SLEDAI with no worsening in the physician’s global assessment or BILAG flare.