Systemic Lupus Erythematosus
Abstract 499: Trial of Atacicept in Patients with Systemic Lupus Erythematosus (SLE)
Authors: Maria Dall'Era1, Eliza Chakravarty2, Mark Genovese2, Daniel Wallace3, Arthur Kavanaugh4, Kenneth Kalunian4, Patricia Dhar5, Claudia Pena-Rossi6, David Wofsy1, Serono and ZymoGenetics Atacicept Study Group. 1University of California, San Francisco, CA; 2Stanford University, Palo Alto, CA; 3Cedars-Sinai Medical Center, Los Angeles, CA; 4University of California, San Diego, CA; 5Wayne State University, Detroit, MI; 6Serono, Geneva, Switzerland
Background: Several new biologics being tested in SLE are directed against B cells. One approach is to delete B cells, as with rituximab. Other approaches include targeting the most active B cells, those which rely on the survival factor B Lymphocyte stimulator protein (BLyS). This clinical trial examined atacicept, a TACI-IG fusion protein that inhibits B cell stimulation by binding to BLyS and to APRIL. BLyS, but not APRIL, can be targeted by anti-BLyS antibodies. Which approach is best?
Methods: This phase 1b clinical trial enrolled 49 SLE patients in a dose escalating trial. Six dosing cohorts, each containing 6 patients treated with atacicept and 2 treated with placebo, were studied. The first 4 cohorts received a single subcutaneous dose (0.3, 1, 3 or 9 mg/kg). Cohorts 5 and 6 received 4 weekly doses of 1 mg/kg or 3 mg/kg.
Results: Biologic activity was demonstrated by reduction in immunoglobulin levels, total and mature B cells, especially in cohorts 5 and 6 that received multiple doses. In the highest dose group there was a 50% decrease in median IgM levels (16% IgG, 32% IgA). Total B cells decreased by 30-35% and mature B cells by 50-60% in cohorts 5 and 6 throughout the 9 week follow-up. Two patients with low complement normalized in the multiple dose cohorts.
In terms of clinical activity, two of three atacicept patients with SLEDAI > 6 improved to 0. There were mild injection site reactions. There were no differences in infection. Protective levels of anti-tetanus antibodies were maintained.
Conclusion: The authors concluded that biologic activity was demonstrated and that further studies were warranted.
Editorial Comment: This Phase Ib trial shows biologic efficacy but had insufficient numbers of moderate SLE (defined here as SLEDAI > 6) to show clinical efficacy convincingly. Overall, safety was excellent. As with Lymphostat B (anti-BLyS but no effect on APRIL), the safety of this general approach has been remarkable. This early trial suggests – but does not prove – that its onset may be faster than Lymphostat B. However, larger trails of greater numbers of sicker SLE patients are needed to ascertain whether targeting BLyS and APRIL will be faster or more efficacious than targeting BLyS alone.