PWII-002 - EVALUATING THE UTILITY OF PROTEOMICS FOR IDENTIFICATION OF CIRCULATING PHARMACODYNAMIC BIOMARKERS FOR BIOSIMILARITY - USING PCSK-9 INHIBITOR BIOLOGICS AS A CASE STUDY

L. Chekka¹, D. Samarth¹, E. Mohamed¹, Y. Guo¹, W. Wheeler², S. Schrieber¹, J. Florian¹, Y. Wang³, D. Strauss¹, P. Hyland¹; ¹U.S. Food and Drug Administration, ²IMS Inc, ³U.S. Food and Drug Administration, Silver Spring, United States.

Background: Pharmacodynamic (PD) biomarkers may be used for biosimilarity assessment of proposed biosimilars without relying on costly and time-consuming clinical efficacy studies. Here, we assessed the utility of plasma proteomics for the identification of PD biomarkers for two proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, alirocumab and evolocumab, a class of biologics used to lower low-density lipoprotein (LDL)-cholesterol.

Methods: Plasma samples from 24 healthy subjects (8 in each arm) randomized to single dose of alirocumab (100 µg subcutaneous), evolocumab (140 µg subcutaneous) or placebo from an FDA clinical study were profiled for 7288 analytes at 11 time points (including baseline), over 84 days, using the SOMAscan® assay v4.1 (SomaLogic). Differentially expressed proteins were identified using linear-mixed effect models and ANOVA, as analytes with p-value < 6.86xE-6 (Bonferroni adjusted alpha) for treatment*time interaction. Candidate PD biomarker responses (log2 expression ratio from baseline) were correlated with LDL-C levels, a previously used PD biomarker in clinical studies for PCSK9 inhibitor approvals.

Results: We identified three proteins, PCSK9, centrosomal protein 20 (CEP20) and origin recognition complex subunit 6 (ORC6) to be differentially expressed in response to alirocumab and five proteins, PCSK9, CEP20, ORC6, platelet-activating factor acetylhydrolase (PAFAH) and c-type lectin domain family 4 member G (CLC4G) in response to evolocumab. PAFAH and CLC4G were nominally associated with alirocumab (p-value=2.25E-5 and 3.62E-5 respectively). PCSK9 protein, which is the target engagement biomarker was upregulated, while the other biomarker candidates were downregulated, in response to both biologics. Among these biomarker candidates, PAFAH showed the strongest correlation with LDL-C (Pearson’s correlation coefficient=0.77, p-value= 6.9E-31).

Conclusion: Using proteomics, we identified new plasma proteins as potential PD biomarkers of PCSK9 inhibitors. Future investigations will focus on evaluating dose-response relationships and variability in response of these candidates. This approach may be used for identifying PD biomarkers for biologics with complex mechanisms of action and limited well characterized PD biomarkers.