{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T10:45:35Z","timestamp":1788864335575,"version":"build-2803163510"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2024,4,18]],"date-time":"2024-04-18T00:00:00Z","timestamp":1713398400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R44DK107231"],"award-info":[{"award-number":["R44DK107231"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R44DK107231"],"award-info":[{"award-number":["R44DK107231"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,4,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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\u201315\u00a0h in rats and 24\u201332\u00a0h 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\u00a0h 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\u201348\u00a0h 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.<\/jats:p>","DOI":"10.1093\/jbmrpl\/ziae045","type":"journal-article","created":{"date-parts":[[2024,4,18]],"date-time":"2024-04-18T01:05:46Z","timestamp":1713402346000},"source":"Crossref","is-referenced-by-count":6,"title":["Preclinical development of EXT608, an investigational parathyroid hormone derivative with extended half-life for the treatment of hypoparathyroidism"],"prefix":"10.1093","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5085-8334","authenticated-orcid":false,"given":"Daniel B","family":"Hall","sequence":"first","affiliation":[{"name":"Extend Biosciences, Inc. , Newton, MA 02458 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline H","family":"Kostyla","sequence":"additional","affiliation":[{"name":"Extend Biosciences, 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