First WHO International Reference Standard Established for Etanercept

Jackie Syrop

Several biosimilar etanercept products are now approved in the United States and in Europe, and several more “intended copy” versions are approved in poorly regulated countries. Availability of an international reference standard would allow qualification of assays for determining biological activity of intended copies or biosimilars.

Etanercept, a recombinant human tumor necrosis factor (TNF)—receptor Fc fusion protein, is an effective treatment for adults with rheumatoid arthritis, anklylosing spondylitis, psoriatic arthritis, or plaque psoriasis, and for children with juvenile idiopathic arthritis and plaque psoriasis. Patent expiration for the reference product (Enbrel) in Europe and intense development of etanercept biosimilars worldwide triggered the need for the development of an international reference standard to allow the determination of biological activity.

Several biosimilar etanercept products are now approved in the United States and in Europe, and several more “intended copy” versions of etanercept are approved in poorly regulated countries. Availability of an international reference standard (IS) would allow qualification of assays for determining biological activity of intended copies or biosimilars, enabling market availability of etanercept products with similar biological activities and ensuring patient access to products that are consistent in quality and efficacy.

Meenu Wadhwa, PhD, and colleagues sought to select a suitable standard and assign a unitage for in vitro biological activity. The researchers evaluated, in collaboration with the European Pharmacopeia, 3 candidate etanercept preparations for their suitability to serve as an IS for bioactivity of etanercept in a multicenter, international study comprising 28 laboratories from 15 countries. Their report is published in the August 2017 issue of the Journal of Immunological Methods.

The study had 2 goals: first, to assess the suitability of candidate preparations of etanercept to serve as the first IS for the bioassay of human etanercept by assaying their biological activity in a range of routine, in-house bioassays, and second, to assess the relative activity of the candidate preparations in different assays in current use and determine, if possible, concentrations of etanercept required to neutralize specific amounts of tumor necrosis factor-alpha.

The 3 preparations (coded as 13/192, 13/204, and 13/260) were tested for neutralization activity against the third TNF-alpha IS in different in vitro cell-based assays. Regardless of the assay and the amount of TNF-alpha IS used, potency estimates for the different preparations were very similar, the authors found. Results indicated that the candidate coded 13/204 was stable and suitable to serve as an IS for the biological activity of etanercept. Therefore, preparation 13/204 was established by the World Health Organization (WHO) Expert Committee on Biological Standardization in 2015 as WHO’s first IS for etanercept with an assigned in vitro bioactivity of 10,000 IU per ampule.

This first-in-class IS is available from the National Institute for Biological Standards and Control and also as a biological reference preparation from the European Directorate for the Quality of Medicines and Healthcare. It is intended to control the performance of biological assays for etanercept and to support the establishment of in-house bioassay standards, the researchers said. They stress that it is not intended for describing the labelling or dosage of etanercept therapeutic products or for use as a comparator (reference product) for biosimilarity determination.