AB0321 A Totality-of-The-Evidence Approach To The Development of GP2015, A Proposed Etanercept Biosimilar

BackgroundAssessment of biosimilarity uses the “totality-of-the-evidence” concept, whereby a complete data package, comprising physicochemical, biological, nonclinical and clinical data, is used to evaluate and confirm biosimilarity between a proposed biosimilar and an approved originator (reference) product. A stepwise approach, using comparative analytical characterisation to inform next steps, is recommended. The totality-of-evidence derived from these data should demonstrate that the active substance of a biosimilar and its originator are essentially the same.ObjectivesTo describe the development of a proposed etanercept biosimilar (GP2015).MethodsTo define the development target, multiple batches of the originator were characterised over time to understand quality attributes relating to protein structure, function, and amino acid modifications. An iterative, target-directed development process was used to design and produce a potential biosimilar product (GP2015) that fell within the variability range of the originator. Biosimilarity between GP2015 and the originator was confirmed at analytical, functional, nonclinical, pharmacokinetic (PK) and clinical levels using a stepwise approach. Biochemical attributes and functional properties were assessed using a comprehensive and sensitive state-of-the-art panel of analytical tools. Bioequivalence between GP2015 and the originator was assessed in vivo and in four PK studies in healthy volunteers. To confirm there were no clinically meaningful differences between GP2015 and the originator, a study of efficacy, safety and immunogenicity was performed in patients with moderate-to-severe chronic plaque-type psoriasis. This confirmative study assessed the Psoriasis Area and Severity Index response rate at Week 12 and at long-term timepoints.ResultsGP2015 was developed at the same dosage and strength as the originator. Multiple orthogonal analytical methods showed high similarity between GP2015 and the originator. The amino acid sequence was confirmed to be identical and protein folding was indistinguishable. Other attributes, such as glycosylation and product-related impurities, were highly-comparable with the originator. In vitro assays reflecting mechanisms of action and pharmacological properties showed GP2015 and the originator had similar bioactivity. PK bioequivalence between GP2015 and the originator was established in nonclinical and human studies. The study in patients with psoriasis confirmed similar e