Background Atacicept is a recombinant TACI/IgG1-Fc fusion protein that binds and antagonizes the biological activity of the B lymphocyte stimulating factor (BLyS) and a proliferation inducing ligand (APRIL). BLyS and APRIL appear to play a role in the pathogenesis of systemic lupus erythematosus (SLE).
Objectives Objectives of this study was to investigate the systemic and local safety and tolerability, the pharmacokinetics (PK), and pharmacodynamics (PD) in healthy Japanese and Caucasian subjects of both sexes following a single subcutaneous injection of atacicept administered as 25, 75 or 150 mg liquid formulation.
Methods This was a double-blind, placebo-controlled, single-dose, parallel-group trial in healthy Japanese and 1:1 matched Caucasian subjects. The safety, PK, and PD parameters (e.g. immunoglobulins, immune-cell counts) were evaluated up to 42 days post-dosing.
Results (I) Safety: There were no serious treatment-emergent adverse events (TEAEs) nor treatment-related injection site reactions. Most TEAEs (∼90%) were mild in intensity. The most frequently reported TEAEs considered related to the IMP were upper respiratory tract infection, nasopharyngitis as well as headache. All TEAEs had resolved at the time of end-of-trial. Overall, there was no relevant difference in drug related TEAEs between Japanese and Caucasian subjects. (II) Non-compartmental PK Analysis: Time to maximum serum concentration (tmax) was 20-60 hours (median) across both ethnic groups. A statistical comparison of AUC0–t and Cmax between Caucasian and Japanese subjects across all dose levels based on an ANCOVA with body weight adjustment demonstrated comparable exposure of Japanese and Caucasian subjects with a JAP/CAU ratio of 107.2% (for AUC0–t) and 95.7% (for Cmax). A decrease in dose-normalized AUC0–t (AUC0–t/Dose) was observed with an increasing dose indicating non-linear PK over the dose range examined. (III) Population PK Analysis: A semi-mechanistic non-linear PK model was fitted to the PK profiles of the current study. Using a Quasi-Steady-State approximation of the target-mediated drug disposition model with constant Rtot (total target concentration) a good fit to the observed PK profiles was shown, indicating a dependence of some PK parameters (apparent clearance and volume of distribution of the central compartment) on body weight. (IV) PD parameters: Single doses of SC atacicept 25, 75 and 150 mg, respectively, had no apparent effect on IgG levels. A slight transient decrease in IgM and IgA was observed in both ethnicities in the 75 and 150 mg dose groups. Slight changes in total and subsets of B-cells were associated with single-dose atacicept administration in both ethnicities with no apparent dose dependency.
Conclusions After single doses of SC atacicept 25 mg, 75 mg, and 150 mg, there were no clinically meaningful differences between the safety profile of Japanese and Caucasian subjects. Ethnic comparability in PK parameters was demonstrated when considering body weight differences between Japanese and Caucasian subjects. A decrease in dose-normalized AUC0-t (AUC0-t/Dose) was observed with increasing dose. Safety and biomarker data were consistent with a previous healthy volunteer trial.
Disclosure of Interest D. Willen Employee of: Merck KGaA, M. Golob Employee of: Merck KGaA, P. Wolna Employee of: Merck KGaA, O. Papasouliotis Employee of: Merck Serono, W. Uhl Employee of: Merck KGaA, Ö. Yalkinoglu Employee of: Merck KGaA