An exploratory dose-escalating study investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of intravenous atacicept in patients with systemic lupus erythematosus.
Atacicept, a recombinant fusion protein containing the extracellular, ligand-binding portion of the transmembrane activator and calcium modulator and cyclophilin-ligand interactor receptor, and the Fc portion of human immunoglobulin (Ig) G, is designed to block the activity of B-lymphocyte stimulator and a proliferation-inducing ligand, and may have utility as a treatment for B-cell-mediated diseases, such as systemic lupus erythematosus (SLE). This Phase Ib study investigated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of intravenous (i.v.) atacicept in patients with mild-to-moderate SLE. Patients (n = 24) were randomised (5:1) to receive atacicept (single dose: 3, 9 or 18 mg/kg; or multiple dose: 2 x 9 mg/kg) or matching placebo. Patients were followed for 6 weeks after dosing (9 weeks in the 2 x 9 mg/kg cohort). Local tolerability of atacicept was comparable with that of placebo, with only mild injection-site reactions reported with atacicept. Atacicept i.v. was generally well tolerated, both systemically and locally, in patients with mild-to-moderate SLE. Atacicept displayed non-linear PK, which was predictable across doses and between single and repeat doses. The biological activity of atacicept was demonstrated by its marked effect in reducing B-cells and Ig levels in patients with SLE. This supports the utility of this therapeutic approach in the treatment of autoimmune diseases, such as SLE.
Pena-Rossi
C
C
Merck Serono S.A., Geneva, Switzerland. claudia.penarossi@merckserono.net
Nasonov
E
E
Stanislav
M
M
Yakusevich
V
V
Ershova
O
O
Lomareva
N
N
Saunders
H
H
Hill
J
J
Nestorov
I
I
D000328:Adult; D000368:Aged; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D007275:Injections, Intravenous; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D012426:Russia; D016896:Treatment Outcome; D055815:Young Adult
D011993:Recombinant Fusion Proteins; C524618:TACI receptor-IgG Fc fragment fusion protein