TARGET ENGAGEMENT EVALUATION
Background
Client developed an inhibitor of PI3Kδ and was looking to establish a target engagement assay.
Prototrial Strategy
Analytical Strategy
PI3Kδ is required by Basophils for IgE-dependent degranulation. We established a flow cytometry assay to quantify Basophil degranulation (CD63, CD123, HLA-DR) in the presence of IgE, fMLP (PI3Kδ-independent inducer of degranulation) and DMSO (drug vehicle). In an in vitro setting the assay demonstrated the ability of the inhibitor to prevent Basophil degranulation in a dose-dependent manner. The assay also demonstrated inter-individual variability in IgE sensitivity and consequently the ability of a PI3Kδ inhibitor to block this.
Outcomes
The biomarker was successfully used in two healthy volunteer clinical trials. A threshold of 10% Basophil degranulation in response to IgE was established for subject inclusion into the study. The level of subject recruitment was seasonally affected with a greater number of subjects being eligible during Spring.
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