Original Research
Monday, November 13, 2023
01:00 PM–02:30 PM
Abstract
Introduction: Proteomics has the potential to identify pharmacodynamic (PD) biomarkers for biosimilarity assessment without relying on clinical efficacy endpoints. Interferon beta-1a (IFNß-1a) biologics are a class of biologics with limited well characterized PD biomarkers. Our previous proteomics study using plasma samples from a placebo-controlled single-dose randomized clinical study identified 249 and 530 potential candidates that were differentially expressed in response to therapeutic/high doses of IFNß-1a (30 µg) and pegIFNß-1a (125 µg), respectively.
Research Question or Hypothesis: To independently replicate previous candidates at a lower dose and characterize them using FDA guidelines for PD biomarkers for biosimilars.
Study Design: New proteomics data (SOMAscan® v4.1) was generated for longitudinal plasma samples from 48 healthy subjects (12 each) from intermediate and low dose groups of IFNß-1a (15 µg or 7.5 µg) and pegIFNß-1a (62.5 µg or 31.25 µg) from the same clinical study.
Methods: Previously identified candidates were tested for differential expression with IFNß-1a (15 µg) and pegIFNß-1a (62.5 µg), compared to previously published placebo data using ANOVA on linear-mixed effect models, regressing protein changes with treatment*time interaction. Candidates with Bonferroni-corrected p-value<0.05 were considered replicated. We further prioritized candidates based on magnitude of response, significant baseline adjusted area under the effect curve (AUEC) and a monotonic dose-response relationship using high, intermediate, and low doses and placebo data. Analysis was conducted in R (v4.1.2).
Results: Of the previously identified candidates, 166 and 325 were replicated for IFNß-1a (15 µg) and pegIFNß-1a (62.5 µg) respectively, of which 59 IFNß-1a and 113 pegIFNß-1a candidates were prioritized as PD biomarkers. Most candidates followed Emax dose-response models. Several PD biomarkers such as I-TAC, C1QT1, LAG3, and MCP-2, MX-1 were identified. I-TAC showed the largest magnitude of response and LAG-3 showed the least variance in AUEC among those identified.
Conclusion: We replicated and characterized several PD biomarkers for IFN-ß1a biologics with potential utility in biosimilar development programs.
Presenting Author
Lakshmi Manasa Sakuntala Chekka Pharm.D., Ph.D.U.S. FDA
Authors
Yan Guo M.S.
U.S. FDA
Paula Hyland PH.D
FDA
Esraa Mohamed M.S.
U.S. FDA
Jeffry Florian PH.D
FDA
Yow-Ming Wang Ph.D.
U.S. FDA
William Wheeler M.S.
Information Management Services
Deepti Samarth PH.D
FDA
Sarah Schrieber Pharm.D.
U.S. FDA
David Strauss M.D., Ph.D.
U.S. FDA