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The US Food and Drug Administration (FDA) has taken steps to bring efficiency to the development of biosimilars, including establishing guidance for the use of pharmacokinetic and pharmacodynamic (PD) similarity study data without a comparative clinical study with efficacy end point(s). To better understand the potential role for PD biomarkers in biosimilar development and inform best practices for biomarker selection and analysis, we conducted a randomized, double‐blinded, placebo‐controlled, single‐dose, parallel‐arm clinical study in healthy participants. Eighty‐four healthy participants (n = 12 per dose arm) received either placebo or one of three doses of either interferon β‐1a (7.5–30 μg) or pegylated interferon β‐1a (31.25–125 μg) to evaluate the maximum change from baseline and the baseline‐adjusted area under the effect curve for the biomarkers neopterin in serum and myxovirus resistance protein 1 in blood. Both PD biomarkers increased following product administration with clear separation from baseline (neopterin: 3.4‐fold and 3.9‐fold increase for interferon β‐1a and pegylated interferon β‐1a, respectively; myxovirus resistance protein 1: 19.0‐fold and 47.2‐fold increase for interferon β‐1a and pegylated interferon β‐1a, respectively). The dose–response curves support that therapeutic doses were adequately sensitive to detect differences in both PD biomarkers for consideration in a PD similarity study design. Because baseline levels of both biomarkers are low compared with on‐treatment values, there was little difference in using PD measures adjusted to baseline compared with the results without baseline adjustment. This study illustrates potential methodologies for evaluating PD biomarkers and an approach to address information gaps when limited information is publicly available for one or more PD biomarkers. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]