ESPE Abstracts (2018) 89 P-P2-218

The Rationale and Design of TransCon GH

Kennett Sprogøea, Michael Beckerta, Eva Mortensenb, David B Karpfb & Jonathan A Leffb

aAscendis Pharma A/S, Copenhagen, Denmark; bAscendis Pharm Inc., Palo Alto, CA, USA

Background: The fundamental challenge of developing a long-acting growth hormone (LAGH) is to create a more convenient growth hormone (GH) dosing profile while retaining the excellent safety, efficacy, and tolerability of daily GH. With GH receptors on virtually all cells, replacement therapy should achieve the same tissue distribution and effects of daily (and endogenous) GH while maintaining levels of GH and resulting IGF1 within the physiologic range.

Methods: To create a LAGH that extends the GH half-life thereby allowing less frequent dosing, two basic approaches have been followed: (a) combine unmodified GH with a prolongation technology (a depot, crystal, or prodrug) or (b) modify GH in such a way (protein enlargement or albumin binding) that the GH analogue has a longer half-life. We reviewed the nearly 20 LAGHs that have reached various stages of clinical development and analyzed why a product delivering unmodified GH combined with an inert prolongation technology may be an appropriate and potentially optimal design for a successful LAGH.

Results: To date, only two LAGHs have gained the approval of either the Food and Drug Administration (FDA) or the European Medicines Agency (EMA); both released unmodified GH, thus presumably replicating distribution and pharmacological actions of daily GH. Other technologies have been applied to create LAGHs, including modifying GH (for example, protein enlargement or albumin binding) such that the resulting analogues possess a longer half-life. TransCon GH is a LAGH prodrug in which GH is transiently bound to an inert carrier. It was designed to achieve the same safety, efficacy, and tolerability as daily GH but with more convenient weekly dosing. In phase 2 trials of children and adults with growth hormone deficiency (GHD), similar safety, efficacy and tolerability to daily GH was shown as well as GH and IGF1 levels within the physiologic range.

Conclusion: The only LAGHs that have succeeded in providing both accelerated height velocity as well as corrected increased truncal metabolism have been (besides daily GH) depot formulations, which release unmodified GH. Therefore, a viable LAGH would likely have to maintain the same tissue distribution as native GH, ie, a candidate based on unmodified GH.

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