Evaluating the Utility of Proteomics for the Identification of Circulating Pharmacodynamic Biomarkers of IFNβ‐1a Biologics

Abstract

Proteomics has the potential to identify pharmacodynamic (PD) biomarkers for similarity assessment of proposed biosimilars without relying on clinical efficacy end points. In this study, with 36 healthy participants randomized to therapeutic doses of interferon-beta 1a products (IFNβ-1a) or pegylated-IFNβ-1a (pegIFNβ-1a) approved to treat multiple sclerosis or placebo, we evaluated the utility of a proteomic assay that profiles > 7,000 plasma proteins. IFNβ-1a and pegIFNβ-1a resulted in 248 and 528 differentially expressed protein analytes, respectively, between treatment and placebo groups over the time course. Thirty-one proteins were prioritized based on a maximal fold change ≥ 2 from baseline, baseline adjusted area under the effect curve (AUEC) and overlap between the 2 products. Of these, the majority had a significant AUEC compared with placebo in response to either product; 8 proteins showed > 4-fold maximal change from baseline. We identified previously reported candidates, beta-2microglobulin and interferon-induced GTP-binding protein (Mx1) with ~ 50% coefficient of variation (CV) for AUEC, and many new candidates (including I-TAC, C1QC, and IP-10) with CVs ranging from 26%-129%. Upstream regulator analysis of differentially expressed proteins predicted activation of IFNβ1 signaling as well as other cytokine, enzyme, and transcription signaling networks by both products. Although independent replication is required to confirm present results, our study demonstrates the utility of proteomics for the identification of individual and composite candidate PD biomarkers that may be leveraged to support clinical pharmacology studies for biosimilar approvals, especially when biologics have complex mechanisms of action or do not have previously characterized PD biomarkers.

New science, drug regulation, and emergent public health issues: The work of FDA’s division of applied regulatory science

“…This included conducting three clinical studies ( 58 – 60 ) to define best practices on characterizing PD biomarkers for different classes of drugs and to develop general considerations applicable to all types of biomarkers for biological products. These studies included assessments to evaluate uses of proteomic and transcriptomic analysis of human plasma to identify novel biomarkers for biosimilar development ( 61 ). A joint FDA/Duke Margolis Workshop ( 62 ) discussed initial findings and facilitated a broader discussion on use of PD biomarkers for biosimilar development.…”

“…A joint FDA/Duke Margolis Workshop ( 62 ) discussed initial findings and facilitated a broader discussion on use of PD biomarkers for biosimilar development. Additional details will be reported in the January 2023 themed issue on Innovations in Biosimilars in the journal Clinical Pharmacology and Therapeutics ( 61 , 63 ).…”

“… Many of division of applied regulatory science (DARS’) current initiatives will inform the agency’s thinking on the use of pharmacodynamic (PD) biomarkers to demonstrate biosimilarity that may streamline or negate the need for comparative clinical studies ( 56 , 57 ). This includes conducting applied clinical research ( 58 – 60 ) to fill information gaps, inform best practices, and evaluate novel omics methodologies ( 61 ). DARS also developed an evidentiary framework, the draft version of which was presented at a DARS-led public workshop ( 62 ).…”

Pharmacodynamic Biomarkers Evidentiary Considerations for Biosimilar Development and Approval

“…In addition to characterizing the values and variability of standard PD metrics and model parameters of prespecified biomarkers, these studies aim to contextualize the utility of omics technologies to identify and characterize biomarkers that could be used for a PD similarity assessment. The three primary results papers and a separate proteomics analysis are reported separately in this journal 13–15 …”

“…The three primary results papers and a separate proteomics analysis are reported separately in this journal. 13 , 14 , 15 …”