Preclinical development of EXT608, an investigational parathyroid hormone derivative with extended half-life for the treatment of hypoparathyroidism.

Autor:	Hall DB; Extend Biosciences, Inc., Newton, MA 02458, United States., Kostyla CH; Extend Biosciences, Inc., Newton, MA 02458, United States.; Present address: Atalanta Therapeutics, 51 Sleeper St. Boston, MA 02210, United States., Hales LM; Extend Biosciences, Inc., Newton, MA 02458, United States., Soliman TM; Extend Biosciences, Inc., Newton, MA 02458, United States.
Jazyk:	angličtina
Zdroj:	JBMR plus [JBMR Plus] 2024 Apr 18; Vol. 8 (6), pp. ziae045. Date of Electronic Publication: 2024 Apr 18 (Print Publication: 2024).
DOI:	10.1093/jbmrpl/ziae045
Abstrakt:	Hypoparathyroidism, a deficiency of parathyroid hormone (PTH), results in hypocalcemia, hyperphosphatemia, and hypercalciuria. The disease is poorly controlled by calcium and vitamin D supplements or native PTH(1-84) replacement therapy. A version of PTH is being developed using D-VITylation technology, whereby vitamin D is conjugated to a therapeutic peptide, which confers a long plasma half-life by virtue of binding to the abundant vitamin D binding protein (DBP). D-VITylation of PTH caused no reduction in activity at the PTHR1 receptor, and resulted in a plasma elimination half-life of 7-15 h in rats and 24-32 h in cynomolgus monkeys. Analysis of steady-state pharmacokinetics as a function of dose showed flat profiles with smaller peak:trough ratios at low doses, indicative of slower subcutaneous absorption. In thyroparathyroidectomized (TPTx) rats, PTH(1-34)-vitamin D conjugates restored serum calcium and phosphate levels into the normal range over the 24 h dosing period, and increased bone turnover markers and reduced bone mineral density. Urinary calcium was initially elevated, but normalized by the end of treatment on day 27. In healthy monkeys, a single dose of PTH(1-34)-vitamin D conjugates elevated serum calcium levels above the normal range for a period of 24-48 h while simultaneously reducing urinary calcium. Therefore, the lead compound, EXT608, is a promising candidate as a therapeutic that can truly mimic the endogenous activity of PTH and warrants further study in patients with hypoparathyroidism. Competing Interests: D.B.H., L.M.H., and T.M.S. are current employees of Extend Biosciences and hold stock options. C.H.K. is a former employee of Extend Biosciences and holds stock options. (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)
Databáze:	MEDLINE
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