Background The assessment of immunogenicity is mandatory during the comparability exercise of biosimilar candidate drugs, as even small structural differences can potentially elicit antidrug antibodies (ADA) and affect efficacy and safety.
Objectives To review the incidence of ADA and neutralizing ADA (nADA) in confirmatory clinical trials of biosimilar drugs approved for the treatment of inflammatory rheumatic conditions in the European and North-American markets; to review the type of assays used for this purpose; to compare the incidence of ADA with historical data from reference biotechnological drugs.
Methods We performed a literature search in the Medline database and hand searched EULAR and ACR meeting abstracts to identify phase I and III confirmatory clinical trials of biosimilar drugs for the treatment of rheumatic conditions approved in the European and North-American markets. Open-label extensions involving biological switch were not included. All outcomes regarding immunogenicity were extracted (ADA, nADA and type of immunogenicity assays).
Results We screened 255 articles by title and abstract and 7 publications fulfilled our inclusion criteria. Three meeting abstracts were also included. Six studies assessed infliximab biosimilars (CT-P13 and SB2), three studies assessed etanercept biosimilars (SB4 and GP2015) and one study assessed an adalimumab biosimilar (ABP 501). All but two concerned phase III trials and seven were performed on rheumatoid arthritis patients. All biosimilars had comparable immunogenicity profiles in respect to their reference drugs, except for the etanercept biosimilar SB4, which presented significantly less ADA when compared to reference etanercept (0.7% vs 13.1% at 24 weeks and 1.0% vs 13.2% at 52 weeks, p<0.001 for both). As expected, infliximab had the highest incidence of ADA; the proportion of ADA in studies of infliximab and adalimumab was higher when compared to historical data. Only 4 studies reported nADA, which were highest in the infliximab biosimilar CT-P13 54-week study in ankylosing spondylitis patients. Electrochemiluminescence immunoassay was the preferred method to measure ADA. Table 1 summarizes the main findings in the included studies.
Conclusions Currently approved biosimilars for the treatment of rheumatic diseases have comparable immunogenicity profiles in respect to their reference drugs. The discrepancy in ADA between SB4 and reference etanercept did not correlate with efficacy or safety and did not preclude biosimilarity, according to the regulatory agencies. The higher proportion of ADA compared to historical data may be explained by the greater sensitivity of current immunogenicity assays, such as electrochemiluminescence.
Disclosure of Interest None declared