Evaluation of the immunogenicity of the dabigatran reversal agent idarucizumab during Phase I studies

Abstract

Aims: Idarucizumab, a humanized monoclonal anti-dabigatran antibody fragment, is effective in emergency reversal of dabigatran anticoagulation. Pre-existing and treatment-emergent anti-idarucizumab antibodies (antidrug antibodies; ADA) may affect the safety and efficacy of idarucizumab. This analysis characterized the pre-existing and treatment-emergent ADA and assessed their impact on the pharmacokinetics and pharmacodynamics (PK/PD) of idarucizumab.

Methods: Data were pooled from three Phase I, randomized, double-blind idarucizumab studies in healthy Caucasian subjects; elderly, renally impaired subjects; and healthy Japanese subjects. In plasma sampled before and after idarucizumab dosing, ADA were detected and titrated using a validated electrochemiluminescence method. ADA epitope specificities were examined using idarucizumab and two structurally related molecules. Idarucizumab PK/PD data were compared for subjects with and without pre-existing ADA.

Results: Pre-existing ADA were found in 33 out of 283 individuals (11.7%), seven of whom had intermittent ADA. Titres of pre-existing and treatment-emergent ADA were low, estimated equivalent to <0.3% of circulating idarucizumab after a 5 g dose. Pre-existing ADA had no impact on dose-normalized idarucizumab maximum plasma levels and exposure and, although data were limited, no impact on the reversal of dabigatran-induced anticoagulation by idarucizumab. Treatment-emergent ADA were detected in 20 individuals (19 out of 224 treated [8.5%]; 1 out of 59 received placebo [1.7%]) and were transient in ten. The majority had specificity primarily toward the C-terminus of idarucizumab. There were no adverse events indicative of immunogenic reactions.

Conclusion: Pre-existing and treatment-emergent ADA were present at extremely low levels relative to the idarucizumab dosage under evaluation. The PK/PD of idarucizumab appeared to be unaffected by the presence of pre-existing ADA.

Trial registration: ClinicalTrials.gov NCT01688830 NCT01955720 NCT02028780.

Keywords: antibodies; anticoagulants; coagulation; immunology; pharmacokinetics.

Figure 1

Pre‐existing anti‐idarucizumab responses in plasma from treatment‐naïve individuals from the three Phase I studies evaluated. (A) blocking of ADA assay responses by idarucizumab, (B) blocking of ADA assay responses with molecule 2 (a Fab with constant regions C_H1 and C_L identical to those in idarucizumab, but with different variable regions), and (C) lack of blocking of ADA assay response by molecule 1 (a full‐length IgG1 molecule containing two idarucizumab Fab fragments). ADA, antidrug antibody; RLU, relative luminescence units

Figure 2

Comparison of (A) dose‐normalized maximum plasma concentrations (C _max) of idarucizumab for all subjects with normal renal function who received a single 5‐min idarucizumab infusion and (B) dose‐normalized area under the plasma idarucizumab concentration–time curve (AUC_0–∞) values for all subjects with normal renal function with and without pre‐existing anti‐idarucizumab antibodies; pooled data from the three Phase I studies. ADA, antidrug antibodies; AUC, area under the curve; C _max, maximum plasma concentration; P5, P10, P90 and P95, 5th, 10th, 90th and 95th centiles

Figure 3

Comparison of (A) mean diluted thrombin time assay and (B) ecarin clotting time assay results after anticoagulation with dabigatran followed by infusion of 5 g idarucizumab with and without pre‐existing anti‐idarucizumab antibodies in volunteers.^{a  a}The figure includes all subjects who received a total dose of 5 g idarucizumab: n = 6, middle‐aged; n = 8, elderly; n = 6, mild renal impairment; n = 6, moderate renal impairment; n = 9, healthy Japanese volunteers. ADA, antidrug antibodies; ULN, upper limit of normal