ESPE Abstracts (2016) 86 RFC8.2

Pharmacokinetic Modelling Predicts Native hGH Levels Following Administration of a Sustained-Release Prodrug, TransCon hGH, to Children with GHD

Kennett Sprogøea, Michael Beckertb, Eva Dam Christoffersenb, David Gilfoyleb & Thomas Weggec

aAscendis Pharma Inc., Palo Alto, USA; bAscendis Pharma A/S, Hellerup, Denmark; cAscendis Pharma GmbH, Heidelberg, Germany

Background: TransCon Growth Hormone is a once-weekly sustained-release prodrug of recombinant human growth hormone (hGH, somatropin). Based on the inert TransCon prodrug technology unmodified hGH is released with a Cmax and AUC comparable to daily therapy. TransCon hGH leverages the known pharmacology of daily hGH and is being developed for the treatment of growth hormone deficiency (GHD).

Objective and hypotheses: Both hGH levels and resulting IGF-I levels should be maintained at safe and efficacious levels as observed for daily hGH. A PK model was used to predict serum levels of unmodified hGH released from the TransCon hGH prodrug.

Method: The PK model was constructed using first-order kinetics for hGH release from the TransCon prodrug, absorption from the injection site and elimination of hGH and prodrug, respectively. Values for absorption and elimination of unmodified hGH were obtained from the literature and the model used to predict unmodified hGH released from the TransCon prodrug in a Phase 2 study in children with GHD (NCT01947907, n=53).

Results: In children with GHD serum concentration of unmodified hGH was predicted to be 13 ng/mL following administration of 0.21 mg/kg per week, correlating well with the observed 13 ng/mL in GHD children. Daily hGH at 0.03 mg/kg per day (0.21 mg/kg per week) resulted in a Cmax of 17 ng/mL, demonstrating that weekly TransCon hGH and daily hGH has comparable maximal serum levels of free hGH.

Conclusion: The PK model provided excellent prediction of unmodified hGH levels following TransCon hGH administration to children with GHD. Clinical studies in children and adults with GHD have demonstrated that TransCon hGH has comparable safety and efficacy to daily hGH when administered at the same cumulative weekly dose. TransCon hGH has the potential to offer patients requiring growth hormone therapy a sustained-release alternative to daily injections, designed to maintain the same safe and efficacious growth hormone levels in the body as daily hGH.

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