Endocrine Abstracts

Background: Hypoparathyroidism (HP), a condition of parathyroid hormone (PTH) deficiency, leads to abnormal calcium metabolism. Standard of care (SOC), ie, large amounts of calcium and active vitamin D, leads to hypercalciuria and increased calcium x phosphate. Daily Natpara, PTH(1-84), injections reduced calcium and active vitamin D doses but not 24-hour urinary calcium (uCa) excretion or incidence of hypo- and hypercalcemia due to its 3-hour half-life (Natpara label). NIH studies of PTH(1-34) in children and adults with HP have shown that a single subcutaneous (SC) injection is superior to SOC, twice daily injections are superior to once daily, and continuous SC infusion normalizes serum calcium (sCa), serum phosphate (sP), and uCa. Ascendis Pharma is developing TransCon PTH, an inactive prodrug of PTH(1-34) for the treatment of HP. In its prodrug form, PTH(1-34) is transiently bound to the TransCon carrier via the TransCon linker. Through autohydrolysis at physiological temperature and pH, unmodified PTH(1-34) is released, providing free PTH at steady state with an infusion-like profile in the physiological range over 24 h.

Methods: This phase 1, randomized, placebo-controlled, single and multiple ascending dose (SAD and MAD) trial evaluated safety, tolerability, pharmacodynamics (PD), and pharmacokinetics (PK) of TransCon PTH in up to 170 healthy adults. Cohorts consisted of 10 subjects (8 active, 2 placebo) and received 7 SAD (3.5, 12, 32, 48, 72, 100, or 124 μg) or up to 9 MAD (3.5, 7.0, 12, 16, 20, 24, 32, 40, and 48 μg) for 10 days. The primary PD endpoints included sCa, uCa, sP, and PTH(1-84). The primary PK endpoint was free PTH.

Results: The completed SAD and MAD cohorts showed TransCon PTH was well-tolerated without DLTs. The PK showed dose-dependent increases in exposure, with T_1/2 of approximately 60 h. Single injections up to 100 μg showed dose-dependent increases in albumin-adjusted sCa (up to 11.0 mg/dl at 100 μg) sustained for ≥72 h and associated with reductions in PTH(1-84) but without change in fractional excretion of Ca (FECa). The trial is ongoing; 7 SAD cohorts and several MAD cohorts, including relevant phase 3 doses, will be presented.

Conclusion: TransCon PTH is being developed for HP as a once-daily SC injection. Interim data supports a normal range infusion-like PTH profile, with a PTH T_1/2 of approximately 60 h and sustained increases in sCa without change in FECa, potentially addressing limitations of available HP therapies.