Abstract

Traditionally, in First in Human
clinical trials the primary/secondary endpoints are concerned with safety. By
expanding these studies to include exploratory biomarkers it is possible to
gain added value, as such biomarkers can indicate efficacy and confirm mode of
action of the therapeutic. Incorporating this information from an early stage can
assist in go/no-go decisions and can greatly increase the likelihood of
success. We show here how we currently use this strategy to monitor biomarkers
in a translation manner using LPS-induced immune responses as an example. In
vitro assays using human whole blood and PBMCs are routinely used to screen
test compounds and determine their influence at the gene and protein level,
using qPCR, nanostring and luminex platforms. This can be followed by in vivo
pharmacology PD models (small rodent LPS challenge) to further refine the
compound selection and develop suitable readouts such as Multiplex cytokine
analysis. When a candidate compound then progresses to First In Human clinical
trials, we can support the inclusion of exploratory biomarkers using ‘uplifted’
Good Clinical Laboratory Practice (GCLP) level assay validation, to ensure
reliable clinical data. At this stage, a more focussed panel of cytokines can
be selected and measured either directly in plasma or secondary to ex vivo
stimulation. In addition, the use of flow cytometry and ELISPOT support
investigations of T cell modulating therapies. Such a strategy provides early
indications on whether a therapeutic is hitting it’s expected target in man.