Bridging the Gap Between Preclinical and Clinical Evaluation of Therapeutic Candidates

Session 2

Use of Translational Biomarkers in Drug Development

Margaret A. Read, Ph.D.
Infinity Pharmaceuticals, Cambridge, MA

The proteasome inhibitor, bortezomib (VelcadeTM), posed particular challenges in development due to the drug being rapidly removed from the vascular compartment. While distributed widely to tissues, the blood levels of the drug quickly approach limits of detection. Thus, correlating plasma concentration of the drug with the degree of proteasome inhibition was difficult. A pharmacodynamic (PD) assay was developed that provided a reliable measure of 20S proteasome activity in whole blood and tissues. The sensitive and reproducible assay allows for measurement of bortezomib pharmacodynamics and reflects its target activity. The assay has been used preclinically and in clinical studies to guide dose escalation, determine the maximum-tolerated dose of the drug, and to characterize the pharmacodynamics of 20S proteasome inhibition when bortezomib is administered in combination with other agents. The rapid approval of bortezomib set the stage for evaluation of novel agents that impact protein homeostasis, including the heat shock protein 90 (Hsp90) inhibitor, IPI-504. IPI-504 is the chemical reduction product of 17-AAG and is highly water soluble. IPI-504 is currently in Phase I clinical trials for GIST and NSCLC. Multiple PD markers have been used in preclinical and clinical evaluation of this agent, including Hsp70 induction in peripheral blood leukocytes and tissue, kinetics of specific client protein degradation, and PET imaging of tumors. The utility of these assays in preclinical and clinical investigation of IPI-504 will be discussed.

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