Abstract 1316: Novel Combined response endpoint and systemic lupus erythematosus (SLE) Flare Index (SFI) demonstrate belimumab (fully human monoclonal antibody to BLyS) improves or stabilizes SLE disease activity and reduces flare rate over 2.5 years of therapy.
Michelle Petri
Authors:
M. Petri, R. Furie, E. Ginzler, DJ Wallace, W. Stohl, V. Strand, A. Weinstein, J. Mckay, J Zhong, V Fernandez, W Friemuth, LBSL02/99 Study Group.
Background:
BLyS, or B lymphocyte stimulator protein, is a survival factor for B lymphocytes. It interacts with genes that prevent B cell apoptosis. It is elevated in SLE, and levels predict SLEDAI (disease activity). In a Phase II trial, an anti-BLyS monoclonal did not meet the primary endpoints of decrease in disease activity or prolongation of time to flare. A subset – almost ¾ of patients in the trial – with evidence of B cell activity by high ANA or anti-dsDNA, did show efficacy.
Methods:
The Phase II data were used to develop an outcome measure, the “combined response endpoint” to use in the current Phase III trials. This endpoint requires a > 4 point reduction in the SELENA SLEDAI, but also requires proof of “no worsening” by no BILAG A (severe) or two B (moderate) flares and no 10% worsening on the Physician’s Global Assessment.
Results:
When applied post hoc to the Phase 2 trial, the combined response endpoint would have been statistically significant at 52 weeks. More actively treated patients than placebo met the improvement criteria: 26% of placebo “lost” on the worsening criteria as opposed to 7% of the active arms. The extensions of the Phase II demonstrate continued improvement with plateau at about 76 weeks, as well as reduction in autoantibodies (some reverting to normal) and reduction in hypergammaglobulinemia. The serious infection rate was 5.9% with all active vs 3.6% with placebo.
Conclusion:
The 2.5 year follow-up data indicate sustained improvement in the seropositive group both clinically and serologically. The combined endpoint appeared to function well in that the seropositive group showed both more improvement and less worsening.
Editorial Comment:
Because of the number of “negative” SLE trials, it is important for the academic and pharmaceutical industry work together to develop outcome measures. This outcome measure – the “combined response” utilizes the strengths of several existing instruments – SLEDAI, BILAG, PGA – in a way that meets the goals of the FDA draft guidance document for clinical trials in SLE. It now must be proven to work in the Phase III trials that are underway.
Fascinating new data on autoantibodies also emerged from this trial. SLE patients with anti-RNP (or other ENA) do respond to anti-BLyS therapy (other data indicate that B cell depletion does not work as well in this group). There also appears to be a temporal order in reduction of autoantibodies with anti-BLyS therapy, with anti-DNA reductions seen earliest.
