Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus: results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating trial.
OBJECTIVE
To assess the safety and tolerability of atacicept in patients with systemic lupus erythematosus (SLE) and the biologic effect of atacicept on B lymphocyte and immunoglobulin levels. Atacicept is a TACI-Ig fusion protein that inhibits B cell stimulation by binding to B lymphocyte stimulator and a proliferation-inducing ligand.


METHODS
This phase Ib, double-blind, placebo-controlled, dose-escalating trial comprised 6 cohorts of patients treated with atacicept or placebo in a 3:1 ratio of active drug to placebo (n = 8 per group; n = 7 in cohort 5). Cohorts 1-4 received a single subcutaneous dose of placebo or either 0.3 mg/kg, 1 mg/kg, 3 mg/kg, or 9 mg/kg of atacicept. Cohorts 5 and 6 received weekly doses of placebo or either 1 mg/kg or 3 mg/kg of atacicept for 4 weeks. Patients were followed up for 6 weeks (cohorts 1-4) or 9 weeks (cohorts 5 and 6). Patients with mild-to-moderate SLE were enrolled.


RESULTS
Biologic activity of atacicept was demonstrated by dose-dependent reductions in immunoglobulin levels and in mature and total B cell numbers. This effect was most pronounced in the repeated-dose cohorts and was sustained throughout the followup period. There were no changes in the numbers of T cells, natural killer cells, or monocytes. Mild injection-site reactions occurred more frequently among the atacicept group than the placebo group. There were no differences in the frequency or type of adverse events and no severe or serious adverse events in patients treated with atacicept.


CONCLUSIONS
Atacicept administered subcutaneously was well tolerated and demonstrated biologic activity consistent with the proposed mechanism of action.
Dall'Era
Maria
M
Division of Rheumatology, University of California-San Francisco. 533 Parnassus Avenue, San Francisco, CA 94143, USA. maria.dallera@ucsf.edu
Chakravarty
Eliza
E
Wallace
Daniel
D
Genovese
Mark
M
Weisman
Michael
M
Kavanaugh
Arthur
A
Kalunian
Kenneth
K
Dhar
Patricia
P
Vincent
Emmanuelle
E
Pena-Rossi
Claudia
C
Wofsy
David
D
D000328:Adult; D000888:Antibodies, Anti-Idiotypic / Q000097:blood; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D003176:Complement C3; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D007075:Immunoglobulin M / Q000097:blood*; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012330:RNA, Double-Stranded / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
D000888:Antibodies, Anti-Idiotypic; D003176:Complement C3; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D012330:RNA, Double-Stranded; D011993:Recombinant Fusion Proteins; C524618:TACI receptor-IgG Fc fragment fusion protein