Building an evidentiary case for circulating GHBP as a biomarker for drug-associated stunting of growth

There is increasing interest in the use of biomarkers in clinical drug developmentwith much of thest Century
Cures Act focused on encouraging this approachIdeallybiomarkers could provide and acute and objective
read out of drug mechanism of actionpharmacodynamic biomarkersor prediction of later clinical benefit or
harmsurrogate outcome measureHoweververy few biomarkers have been validated for routine use in
drug developmentThis is due to the need to fulfill stringent yet reasonable requirements at multiple levelsincluding defining specific context of useshowing that a specific biomarker is fit for purposein a context of
useand demonstrating assay validity for assessments of the biomarkerprecisionsensitivityreliabilityGlucocorticoidsprednisolone and deflazacortare among the most extensively prescribed drugswith aboutmillion prescriptions per year in the USThey show potent anti inflammatory efficacybut also extensive
safety concerns with long term use in chronic inflammatory statesparticularly in pediatricsStunting of growth
is seen with both prednisone and deflazacort treatmentand is one of the chief complaints of patients and
families regarding side effects of these drugsWhile stunting of growth is a clear safety concern of importance
to patients and familiesit is challenging to accurately assess in clinical trials due to the large variance in
growth rates of different childrenHerewe propose research focused on building an evidentiary package on
the use of circulating GHBPgrowth hormone binding proteinas a surrogate biomarker anticipating later
stunting of growth as a safety concern of drug treatmentReveraGen Biopharma is a privately owned small
business based in RockvilleMDIn published pre clinical studies in mouse models of human chronic
inflammatory stateswe demonstrated that glucocorticoid induced growth stunting could be assessed after aweek prednisolone regimen and that this in vivo assay is sufficient to compare different treatments in terms of
their ability to cause stunted growthFurthermorein our recently published pharmacodynamic biomarker
studies of anti inflammatories in children we found the extracellular domain of human growth hormone receptorgrowth hormone binding proteinGHBPto be at high levels in the sera of glucocorticoid treated childrenIn
unpublished data in the mdx model of DMDwe found prednisolone to result in increased GHBP in serumAs
GHBP is considered inhibitory to hGH GHR signalingwe hypothesize that steroid induced GHBP may be a
biomarker predictive of later growth stunting!Stunting of growth is seen with glucocorticoid treatmentand is one of the chief complaints of patients and
families regarding side effects of these drugsHoweverit is challenging to accurately assess growth stunting
in clinical trials due to the large variance in growth rates in different childrenThe goal of the proposed STTR
research is to build an evidentiary case for GHBP as afit for purposebiomarker for monitoring of druginduced stunting of growth