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

Abstract

AimsIdarucizumab, 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.MethodsData 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.ResultsPre‐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.ConclusionPre‐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.

Safety, pharmacokinetics and pharmacodynamics of idarucizumab, a specific dabigatran reversal agent in healthy Japanese volunteers: a randomized study

“…Any effect of treatment‐emergent ADA on idarucizumab PK/PD could only occur if high titer ADA are present at the time of a subsequent dose of idarucizumab. It has been estimated that at the highest titer observed in the present study, a titer of 40, the amount of ADA circulating is equivalent (on a molar basis) to <0.1% of a 5 g dose of idarucizumab 26. It is likely that the ADA titer would need to be many times higher than 40 to have an effect on PK/PD of a subsequent dose of idarucizumab.…”

Rationale and design of a phase III safety trial of idarucizumab in children receiving dabigatran etexilate for venous thromboembolism

“…Nevertheless, the use of a biologic agent may be a potential risk factor for immunogenicity in the form of ADA production 44. A pooled analysis of data from three phase 1 studies found that pre‐existing and treatment‐emergent antidrug antibodies were present at low levels and had no impact on the PK/PD of idarucizumab in adults 45. However, testing the immunogenic potential of a biologic agent is suggested in the regulatory guidance and is included in this study as a secondary endpoint 46…”

Pharmacokinetics of idarucizumab and its target dabigatran in patients requiring urgent reversal of the anticoagulant effect of dabigatran

“…Samples to determine the presence of ADAs against idarucizumab were taken at baseline (before administration), on days 30 and 90 after idarucizumab administration. ADAs were detected in human plasma samples by a validated bridging electrochemiluminescence method (Covance Laboratories Inc., Chantilly, Virginia), as described elsewhere . The specificities of the ADA for different idarucizumab epitopes were assessed in a competitive‐format electrochemiluminescence assay.…”

“…Consequently, total exposure to idarucizumab increased up to 84% . In phase I studies, based on antidrug antibody (ADA) detection, there was a modest immunogenic effect of idarucizumab with no detectable effect of pre‐existing ADA on the PK of idarucizumab or its pharmacologic effect …”