Objective To evaluate the clinical relevance of antidrug antibodies (ADAs) measured using a drug-tolerant assay in a post hoc analysis of the Trough Concentration (TC) Adapted Infliximab Treatment (TAXIT) randomised controlled trial.
Design ADA in serum samples (n=221) of 76 patients enrolled in TAXIT, who presented with an infliximab TC <3 µg/mL at screening, were reanalysed after optimisation and at the end of the study using a drug-tolerant ADA assay. Patients underwent dose escalation to achieve therapeutic TCs between 3 µg/mL and 7 µg/mL prior to randomisation. Patients were grouped into quartiles (Q1–4) according to ADA concentration at screening.
Results Using a drug-tolerant assay, the immunogenicity detection rate increased from 21% (drug-sensitive assay) to 63% at screening, from 0% to 51% after optimisation and from 3% to 42% at the end of TAXIT. Patients in ADA Q4 required a higher cumulative infliximab dose (2390 (880–2998) mg) to achieve target TCs, resulting in a higher drug cost (€10 712 (4120–13 596)) compared with ADA-negative patients (€2060 (1648–3296)) and patients in ADA Q1/Q2 (€2060 (1648–4120)/€2060 (1751–3296), p<0.001). However, all but one patient belonging to ADA Q4 were also ADA-positive using a drug-sensitive assay.
Conclusions Upon dose intensification, low concentration ADAs, not detectable using a drug-sensitive assay, disappear in more than half of the patients over time and are clinically non-relevant. In contrast, high concentration ADAs which are typically also detected in a drug-sensitive assay, persist over time and necessitate a higher cumulative dose and drug cost. In the latter group, proactive drug switching may be more cost-efficient.
Clinical Trials Register 2011-002061-38; Post-results.
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Contributors TVS designed the study, performed research, interpreted data, implemented statistical analyses and drafted the manuscript. NVC designed the study, interpreted data and critically revised the manuscript. GVA and MF interpreted data and critically revised the manuscript. SV helped with the acquisition and interpretation of data and critically revised the manuscript. AG designed the study, coordinated the experiments, interpreted data and critically revised the manuscript for intellectual content. All authors read and approved the final version of the manuscript.
Funding This study was financially supported in part by C2 grant C22/15/025 from the KU Leuven and TBM grant T003716N of the Research Foundation-Flanders (FWO), Belgium.
Competing interests TVS is a PhD fellow of Flanders Innovation and Entrepreneurship (VLAIO, Flanders). GVA, MF and SV are senior clinical researchers of the FWO. NVC received consultancy fees from Boehringer Ingelheim, Pfizer, UCB and Takeda. GVA received financial support for research from Abbott and Ferring Pharmaceuticals, lecture fees from Janssen, MSD and Abbott, and consultancy fees from PDL BioPharma, UCB Pharma, Sanofi-Aventis, Abbott, Abbvie, Ferring, Novartis, Biogen Idec, Janssen Biologics, NovoNordisk, Zealand Pharma A/S, Millenium/Takeda, Shire, Novartis and Bristol Mayer Squibb. MF received financial support for research from Takeda, lecture fees from MSD, Janssen, Abbvie, Boehringer-Ingelheim, Ferring, Chiesi, Tillotts, Zeria and Mitsubishi Tanabe, and consultancy fees from MSD, Janssen, Abbvie, Boehringer-Ingelheim and Ferring. SV received grant support from MSD, Abbvie and Takeda, lecture fees from Abbvie, MSD, Ferring Pharmaceuticals, Takeda, Hospira and consultancy fees from Abbvie, Takeda, Pfizer, Ferring Pharmaceuticals, Shire Pharmaceuticals Group, MSD, Hospira, Mundipharma, Celgene, Galapagos, Genentech/Roche. AG has served as a speaker for MSD, Janssen Biologicals, Pfizer, Takeda and Abbvie, as consultant for UCB and has received Investigator Initiated Research Grants from Pfizer.
Provenance and peer review Not commissioned; externally peer reviewed.
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