EP-028 - EVALUATING THE UTILITY OF PROTEOMICS FOR THE IDENTIFICATION OF CIRCULATING PHARMACODYNAMIC BIOMARKERS OF IFNΒ-1A BIOLOGICS.
Wednesday, March 22, 2023
12:00 AM EDT
L. Chekka1, D. Samarth2, B. Rosenzweig2, E. Mohamed2, Y. Guo2, W. Wheeler2, J. Weaver2, S. Schrieber2, J. Florian2, Y. Wang2, D. Strauss2, P. Hyland2; 1Koniag Government Services, Silver Spring, MD, United States, 2US Food and Drug Administration, Silver Spring, MD, United States.
Principal Investigator Koniag Government Services Fairfax, Virginia, United States
Background: Proteomics has the potential to identify pharmacodynamic (PD) biomarkers for similarity assessment of proposed biosimilars without relying on clinical efficacy endpoints. Here, we aimed to evaluate the utility of proteomics for identifying PD biomarkers for interferon beta-1a biologics.
Methods: Plasma from 36 healthy subjects randomized to therapeutic doses of IFNβ-1a (n=12 [30µg IM]), pegylated IFNβ-1a (pegIFNβ-1a, n=12 [125µg SC]) and placebo(n=6 each) was profiled for 7288 analytes at baseline/pre-treatment and at 9 timepoints, over 6 days in the IFNβ-1a group, and at 11 timepoints, over 13 days in the pegIFNβ-1a and placebo-specific groups, using the SOMAscan® assay v4.1 (SomaLogic). We identified differentially expressed proteins (DEPs) using linear-mixed effect models and ANOVA, as analytes with treatment*time interaction p-values < 6.8x10E-6 (Bonferroni (BF) adjusted p< 0.05). We further prioritized signals based on biological relevance, maximal fold change ≥2 from baseline, and a significant difference (t-test BF adjusted p< 0.05)) in baseline adjusted area under the effect curve from placebo, with both products. Analysis was conducted in R (v4.1.2).
Results: We identified 248 and 528 DEPs by IFNβ-1a and pegIFNβ-1a respectively, of which, 31 analytes were prioritized. Previously reported PD biomarkers such as B2M, Mx1, IP-10, and IL-1RA and potential new candidates (e.g., I-TAC, C1QC, LAG3, and FGL1) were identified. Upstream regulator analysis of DEPs predicted activation of IFNB1 signaling as well as other cytokine, enzyme and transcription signaling networks by both products.
Conclusion: Using proteomics, we identified several plasma proteins as potential PD biomarkers of IFN-β1a biologics for further investigation to support biosimilar development programs.
Hyland PL, Chekka LMS, Samarth DP, Rosenzweig BA, Decker E, Mohamed EG, Guo Y, Matta MK, Sun Q, Wheeler W, Sanabria C, Weaver JL, Schrieber SJ, Florian J, Wang YM, Strauss DG. Evaluating the Utility of Proteomics for the Identification of Circulating Pharmacodynamic Biomarkers of IFNβ-1a biologics. Clin Pharmacol Ther. 2022 Oct 29. doi: 10.1002/cpt.2778. Epub ahead of print. PMID: 36308070.
