Considerations for Use of Pharmacodynamic Biomarkers to Support Biosimilar Development - (I) A Randomized Trial with...

Area of Science:

• Biopharmaceutical development
• Pharmacodynamics and pharmacokinetics
• Biomarker analysis

Background:

• US FDA guidance allows biosimilar development using pharmacokinetic (PK) and pharmacodynamic (PD) data instead of clinical efficacy studies.
• There is a need for more PD comparability studies in biosimilar development to address planning and analysis uncertainties.

Purpose of the Study:

• To evaluate approaches for planning PD comparability studies.
• To inform best practices for data analysis in biosimilar development.
• To apply emerging technologies in biomarker characterization for biosimilars.

Main Methods:

• A randomized, double-blinded, placebo-controlled clinical study in 72 healthy participants.
• Administration of placebo or varying doses of PCSK9 inhibitors (alirocumab, evolocumab).
• Evaluation of biomarkers: low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB), assessing maximum change from baseline (ΔPDmax) and area under the effect curve (AUEC).

Main Results:

• Lower coefficient of variation for LDL-C compared to apoB at therapeutic doses.
• Modeling and simulation confirmed dose-response relationships and sensitivity of therapeutic doses.
• Similar dose-response curves for both biomarkers, with ΔPDmax plateauing at lower doses than AUEC.

Conclusions:

• Pilot study data can effectively inform appropriate dosing and data analysis strategies for PK/PD similarity studies.
• The study provides a framework for designing robust PD comparability studies for biosimilars.
• Emerging technologies and statistical approaches can enhance biomarker characterization in biosimilar evaluations.