Safety, pharmacokinetics and pharmacodynamics of atacicept in healthy volunteers.
OBJECTIVE
Atacicept, a recombinant fusion protein, blocks the activity of BLyS (a B-lymphocyte stimulator) and APRIL (a proliferation-inducing ligand) and may be a potential treatment for B-cell-mediated diseases. This study assesses the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of atacicept.


METHODS
In this Phase I study, healthy male volunteers received a single subcutaneous dose of atacicept (2.1, 70, 210 or 630 mg) or placebo and were monitored over 7 weeks for injection-site pain, local tolerability, vital signs, echocardiography, haematology, coagulation, blood chemistry, serum virology, urinalysis and PK/PD markers [lymphocyte cell counts, BLyS-atacicept complex, immunoglobulin G (IgG), IgM].


RESULTS
Atacicept was well tolerated at all doses (n = 23). There were no clinically significant changes in vital signs or laboratory parameters during the study. Treatment-emergent adverse events (AEs) were mainly mild or moderate in severity, and all were transient, resolving without any clinical sequelae. There was no evidence of any relationship between atacicept dose and the incidence of AEs. Local tolerability was good. Serum atacicept peaked 16 h after dosing, and the area under the concentration-time curve increased in an approximately dose-related manner. The 70-, 210- and 630-mg doses of atacicept demonstrated a dose-dependent biological effect on IgM levels, which was apparent up to 210 days post-dose. There were no treatment-related effects on IgG levels or lymphocyte subpopulations.


CONCLUSIONS
These results showed that single subcutaneous doses of atacicept were well tolerated in healthy volunteers, demonstrated non-linear PK and were biologically active, according to IgM levels.
Munafo
Alain
A
Merck Serono S.A., 9 Chemin des Mines, Geneva 1202, Switzerland. alain.munafo@merckserono.net
Priestley
Anthony
A
Nestorov
Ivan
I
Visich
Jennifer
J
Rogge
Mark
M
D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D053264:B-Cell Activating Factor / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000037:antagonists & inhibitors*
D053264:B-Cell Activating Factor; D011993:Recombinant Fusion Proteins; C114631:TNFSF13 protein, human; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; C524618:TACI receptor-IgG Fc fragment fusion protein