Transcon PTH, a Sustained Release PTH Analogue for the Treatment of Hypoparathyroidism – Proof-of-Principle in Monkeys and Tptx Rats

Presentation Number: LB SAT 46
Date of Presentation: April 1st, 2017

Kennett Sprogoe*1, Lars Holten-Andersen2, Felix Cleeman2, Joachim Zettler2, Susanne Pihl3 and Vibeke Miller Breinholt2
1Ascendis Pharma A/S, Hellerup, Denmark, 2Ascendis Pharma, 3Ascendis Pharma, Hellerup, Denmark



Neither conventional vitamin D and calcium therapy nor currently available recombinant PTH products control all symptoms of hypoparathyroidism (HP). TransCon PTH is a prodrug releasing unmodified teriparatide, PTH(1-34), via non-enzymatic hydrolysis of the TransCon linker. It is designed to maintain a steady concentration of PTH in the blood stream within the normal range and thereby overcome the fundamental limitation of short-acting PTH molecules.

Design and methods

TransCon PTH was administered at 1 or 5 µg/kg to cynomolgus monkeys (N=3) in a single dose PK/PD study assessing serum calcium levels and urinary calcium excretion.

Using the TPTX rat model of HPP, TransCon PTH was also assessed in a head-to-head comparison with PTH(1-84), both administered as daily subcutaneous injections.

TPTx rats (n = 9/group) were dosed with TransCon PTH (5 or 10 µg/kg/day), PTH (1-84) (70 µg/kg/day) or vehicle for 28 days. A group of sham operated rats were injected with vehicle. Serum calcium (sCa), serum phosporous (sP), and bone turnover markers (P1NP and CTx) were measured and the bone quality assessed by ex vivo pQCT.


Following TransCon PTH administration to cynomolgus monkeys, sCa increased in a dose-dependent manner. At the 1 µg/kg dose, sCa levels remained within the normal range for 96 hours post-dose and a clear trend for decreased urinary calcium levels over the first 24 hours was observed.

In untreated TPTx, sCa was significantly lower (8.3 mg/dL) compared to sham-operated control rats (10.9 mg/dL), whereas sP values were significantly increased in (8.3 mg/dL) compared to sham-operated animals (5.9 mg/dL). Administration of TransCon PTH at 5 and 10 µg/kg/day led to an increase in sCa which normalized by day 6. In contrast PTH(1-84) failed to normalize sCa (7.2 – 8.5 mg/dL). Bone mineral density (BMD) and bone mineral content (BMC) were increased in TPTx controls as seen in HP patients. Treatment with TransCon PTH slightly decreased BMD, BMC and area in parallel with an increase in CTx compared to sham and vehicle-treated TPTx animals. A significant increase in trabecular BMD was observed in animals dosed with PTH(1-84) compared to both control groups (10-22%).


In monkeys, TransCon PTH increased sCa levels in a dose-dependent manner. At a dose maintaining sCa in the normocalcemic range, a concurrent decrease in urinary Ca excretion was observed.

In TPTx rats, TransCon PTH normalized sCa and sP levels following once-daily administration. Following 28 days of TransCon PTH treatment, trabecular and cortical BMD in vertebrae were within normal range, whereas an anabolic effect was observed for PTH(1-84) on trabecular and cortical bone in vertebrae. These studies show TransCon PTH may normalize sCa and sP, while reducing urinary Ca, addressing key unmet medical need in patients with HP.

In conclusion these data support clinical development of TransCon PTH for the treatment of HP.


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