Abstract
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.
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Acknowledgements
We would like to than Mauro Bertolino of Merck Serono for his valuable assistance in data analysis. This trial was sponsored by Merck Serono S.A. (Geneva, Switzerland), which is developing atacicept in various indications in collaboration with Zymogenetics, Inc. (Seattle, Wash., USA). The procedures in this study complied with the current laws of the country in which they were performed (UK).
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Munafo, A., Priestley, A., Nestorov, I. et al. Safety, pharmacokinetics and pharmacodynamics of atacicept in healthy volunteers. Eur J Clin Pharmacol 63, 647–656 (2007). https://doi.org/10.1007/s00228-007-0311-7
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DOI: https://doi.org/10.1007/s00228-007-0311-7