Characterization of Proteomic Pharmacodynamic Biomarkers of IFNβ-1a Biologics to Inform Potential Utility in Biosimilar Development.

Abstract

Pharmacodynamic (PD) biomarkers can support biosimilarity assessment, potentially reducing the need for comparative clinical efficacy studies. This study aimed to characterize previously identified proteomic PD biomarker candidates for Interferon beta-1a (IFNβ-1a, n = 248) and pegylated IFNβ-1a (pegIFNβ-1a, n = 528) biologics at therapeutic doses, to further evaluate the utility of proteomics in biosimilar development. Here, we reproduced the results at lower doses and characterized PD responses across multiple doses using criteria for justifying PD biomarker use in biosimilar development. We analyzed candidate proteins from longitudinal proteomics data (SomaScan™ Assay v4.1) from 48 healthy subjects administered intermediate or low doses of IFNβ-1a (15, 7.5 μg) or pegIFNβ-1a (62.5, 31.25 μg) in an FDA-sponsored study, alongside previously published therapeutic dose and placebo data. EDTA plasma samples were collected at 0, 0.125, 0.33, 0.67, 1.33, 2, 3, 4, 5, 6 days and at 9, 13 days additionally for pegIFNβ-1a. Prioritization criteria included significant differential expression at the intermediate dose vs. placebo, ≥20% response difference from placebo, significant baseline-adjusted area under the effect curve (AUEC) and a monotonic dose-response relationship across all doses. Among the candidates, 165 and 323 were differentially expressed at intermediate doses of IFNβ-1a and pegIFNβ-1a respectively. Nine PD biomarkers, including C-X-C motif chemokine 11 (I-TAC), Lymphocyte activation gene 3 protein (LAG3), and Granulins (GRN), were prioritized as common to both biologics. Most candidates followed the E_max dose-response model. I-TAC showed the strongest response, and LAG-3 showed the least variability in AUEC. Our study identified several suitable plasma PD biomarkers for IFNβ-1a and pegIFNβ-1a biologics with potential utility in biosimilar development programs.