There is increasing interest in the use of biomarkers in clinical drug development, with much of the 21st Century
Cures Act focused on encouraging this approach. Ideally, biomarkers could provide and acute and objective
read out of drug mechanism of action (pharmacodynamic biomarkers), or prediction of later clinical benefit or
harm (surrogate outcome measure). However, very few biomarkers have been validated for routine use in
drug development. This is due to the need to fulfill stringent yet reasonable requirements at multiple levels,
including defining specific context of use, showing that a specific biomarker is fit for purpose (in a context of
use), and demonstrating assay validity for assessments of the biomarker (precision, sensitivity, reliability).
Glucocorticoids (prednisolone and deflazacort) are among the most extensively prescribed drugs, with about
90 million prescriptions per year in the US. They show potent anti-inflammatory efficacy, but also extensive
safety concerns with long-term use in chronic inflammatory states, particularly in pediatrics. Stunting of growth
is seen with both prednisone and deflazacort treatment, and is one of the chief complaints of patients and
families regarding side effects of these drugs. While stunting of growth is a clear safety concern of importance
to patients and families, it is challenging to accurately assess in clinical trials due to the large variance in
growth rates of different children. Here, we propose research focused on building an evidentiary package on
the use of circulating GHBP (growth hormone binding protein) as a surrogate biomarker anticipating later
stunting of growth as a safety concern of drug treatment. ReveraGen Biopharma is a privately owned small
business based in Rockville, MD. In published pre-clinical studies in mouse models of human chronic
inflammatory states, we demonstrated that glucocorticoid-induced growth stunting could be assessed after a 6-
week prednisolone regimen and that this in vivo assay is sufficient to compare different treatments in terms of
their ability to cause stunted growth. Furthermore, in our recently published pharmacodynamic biomarker
studies of anti-inflammatories in children we found the extracellular domain of human growth hormone receptor
(growth hormone binding protein; GHBP) to be at high levels in the sera of glucocorticoid-treated children. In
unpublished data in the mdx model of DMD, we found prednisolone to result in increased GHBP in serum. As
GHBP is considered inhibitory to hGH/GHR signaling, we hypothesize that steroid-induced GHBP may be a
biomarker predictive of later growth stunting.
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