Pharmacokinetics of Transcon PTH, a Sustained-Release PTH Prodrug for Hypoparathyroidism, in Rat and Cynomolgus Monkey

Presentation Number: SAT 355
Date of Presentation: April 1st, 2017

Kennett Sprogoe*1, Susanne Pihl2, Caroline Elisabeth Rasmussen3, Lars Holten-Andersen3, Felix Cleeman3 and Vibeke Miller Breinholt3
1Ascendis Pharma A/S, Hellerup, Denmark, 2Ascendis Pharma, Hellerup, Denmark, 3Ascendis Pharma



Natpara (PTH1-84) is approved for subcutaneous injection as an adjunct to vitamin D and calcium in patients with hypoparathyroidism but has not demonstrated the ability to reduce the incidence of hypercalcemia, hypocalcemia, or hypercalciuria relative to conventional therapy. Continuous infusion of teriparatide (PTH1-34) has been shown to be superior to twice daily injections in clinical studies. Thus, a PTH product that provides continuous exposure with daily dosing could represent a major step forward in addressing a large unmet medical need. TransCon PTH is a prodrug releasing unmodified teriparatide via non-enzymatic hydrolysis of the proprietary TransCon Linker for the treatment of hypoparathyroidism.


TransCon PTH has been designed to maintain a normal range, steady concentration of PTH in the blood stream. It is intended to address the fundamental limitation of short-acting PTH molecules by providing infusion-like PTH blood levels.

Design and methods

TransCon PTH was administered to rat and cynomolgus monkeys in single dose studies and in 28-day toxicology studies with daily dosing. The systemic concentrations of TransCon PTH and calcium were assessed at multiple time point following dosing.


TransCon PTH exhibited in both rat and monkey long half-lives providing infusion-like pharmacokinetics. In both species, exposure to TransCon PTH increased in a dose proportional manner. Sex differences in systemic exposure of TransCon PTH and serum calcium were observed in rats, with females exhibiting increased exposures compared to males. No differences between sexes were observed for TransCon PTH or serum calcium in cynomolgus monkeys.


Nonclinical experiments in rats and cynomolgus monkeys demonstrated that TransCon PTH may provide full therapeutic coverage in contrast to available therapies; PTH(1-34) and PTH(1-84) both have half-lives on the order of minutes. The PK characteristics of TransCon PTH after steady state resemble an infusion like profile, suggesting that TransCon PTH can support continuous PTH exposure in hypoparathyroid patients. The substantial extension of PTH half-life may more closely mimic physiological levels of PTH observed in healthy individuals and therefore maintain blood calcium and phosphorous levels while normalizing urinary calcium excretion.


Disclosure: KS: Employee, Ascendis Pharma. SP: Employee, Ascendis Pharma. CER: Employee, Ascendis Pharma. LH: Employee, Ascendis Pharma. FC: Employee, Ascendis Pharma. VMB: Employee, Ascendis Pharma.