Original Research
Monday, November 13, 2023
01:00 PM–02:30 PM
Abstract
Introduction: The U.S. Food and Drug Administration is conducting research to inform on critical aspects of the use of pharmacodynamic (PD) biomarkers to support the demonstration of biosimilarity, which can streamline development programs by negating the need for comparative clinical studies with efficacy endpoint(s). miRNA profiling (miRomics) has the potential to identify PD biomarkers for PD similarity assessment without relying on clinical efficacy endpoints.
Research Question or Hypothesis: To evaluate the utility of miRomics and an analytical framework for identifying potential circulating PD biomarkers of IFNß-1a and pegIFNß-1a products.
Study Design: A pilot study was conducted using plasma samples from 36 healthy subjects from a placebo-controlled randomized single dose clinical study with IFNß-1a and pegIFNß-1a.
Methods: Using miRNA-sequencing, we measured miRNAs at baseline/pre-treatment in all subjects, and at 9 timepoints, over 6 days in the IFNß-1a group (n=11 [30µg]), and at 11 timepoints, over 13 days in the pegIFNß-1a group (n=11[125µg]) and placebo-specific groups (n=6 each) and identified 108 mature miRNAs (with 10 read/count minimum in 50% of samples). We conducted linear-mixed effect models regressing normalized count changes from baseline with treatment*time interaction. miRNAs with false discovery rate-corrected p-values<0.1 were considered differentially expressed. Analysis was conducted in R (v4.1.2). DIANA-miRPath v3.0 was used for functional characterization of miRNA biomarkers.
Results: We identified 11 and 13 differentially expressed miRNAs over treatment and time by IFNß-1a and pegIFNß-1a, respectively, compared to placebo. hsa-miR-223-3p and hsa-miR-21-5p were common for both products. Importantly, hsa-miR-223-3p regulates Mx1 and STAT1 which are proposed individual candidate PD biomarkers for IFNß-1a and pegIFNß-1a and are also involved in IFNß-1a signaling. Functional analysis of top miRNAs identified 24 overlapping pathways for both products including Hepatitis B and Hippo signaling.
Conclusion: Using miRomics, we identified two plasma miRNAs as potential PD biomarkers of IFN-ß1a biologics for further investigation to support biosimilar development programs.
Presenting Author
Mai Mehanna M.S., Ph.D.U.S. Food and Drug Administration
Authors
Yan Guo M.S.
U.S. FDA
Paula Hyland PH.D
FDA
Esraa Mohamed M.S.
U.S. FDA
Lakshmi Manasa Sakuntala Chekka Pharm.D., Ph.D.
U.S. FDA
Erica Decker BS
U.S Food and Drug Administration
Jeffry Florian PH.D
FDA
Yow-Ming Wang Ph.D.
U.S. FDA
James Weaver PhD
U.S. FDA
Deepti Samarth PH.D
FDA
Sarah Schrieber Pharm.D.
U.S. FDA
David Strauss M.D., Ph.D.
U.S. FDA