{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T16:25:37Z","timestamp":1793291137592,"version":"4.5.0"},"reference-count":20,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T00:00:00Z","timestamp":1665446400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T00:00:00Z","timestamp":1665446400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pituitary"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Many patients with Cushing\u2019s disease (CD) require long-term medical therapy to control their hypercortisolism. In the core phase of a Phase II study (LINC 2; NCT01331239), osilodrostat normalized mean urinary free cortisol (mUFC) in 78.9% of patients with CD. Here, we report long-term efficacy and safety data for osilodrostat following completion of an optional extension to LINC 2.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Adult patients with CD were enrolled in a 22-week prospective Phase II study. Patients with mUFC\u2009\u2264\u2009upper limit of normal (ULN) or receiving clinical benefit at week 22 could enter the optional extension. The proportion of complete (mUFC\u2009\u2264\u2009ULN) or partial (mUFC\u2009&gt;\u2009ULN but\u2009\u2265\u200950% decrease from baseline) mUFC responders was assessed over time.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Sixteen of 19 enrolled patients entered the extension. Median (range) osilodrostat exposure from baseline to study end was 5.4\u00a0years (0.04\u20136.7); median (range) average dose was 10.6\u00a0mg\/day (1.1\u201347.9). Overall response rate (complete and partial mUFC responders) was consistently\u2009\u2265\u200950%. Sustained control of most cardiovascular-related parameters was observed during the extension. The long-term safety profile was consistent with that reported during the core phase. Testosterone levels (females) decreased towards baseline levels during long-term follow-up, with no new or worsening cases of hirsutism during the extension.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In the longest prospective study of a steroidogenesis inhibitor to date, osilodrostat provided sustained reductions in mUFC for up to 6.7\u00a0years of treatment, with no new safety signals emerging during the extension. These findings support osilodrostat as an effective long-term treatment for patients with CD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11102-022-01280-6","type":"journal-article","created":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T07:03:38Z","timestamp":1665471818000},"page":"959-970","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Long-term efficacy and safety of osilodrostat in Cushing\u2019s disease: final results from a Phase II study with an optional extension phase (LINC 2)"],"prefix":"10.1007","volume":"25","author":[{"given":"Maria","family":"Fleseriu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beverly M. K.","family":"Biller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9r\u00f4me","family":"Bertherat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques","family":"Young","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betul","family":"Hatipoglu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Arnaldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"O\u2019Connell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Izquierdo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto M.","family":"Pedroncelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosario","family":"Pivonello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,10,11]]},"reference":[{"key":"1280_CR1","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1016\/S2213-8587(21)00235-7","volume":"9","author":"M Fleseriu","year":"2021","unstructured":"Fleseriu M, Auchus R, Bancos I et al (2021) Consensus on diagnosis and management of Cushing\u2019s disease: a guideline update. Lancet Diabetes Endocrinol 9:847\u2013875","journal-title":"Lancet Diabetes Endocrinol"},{"key":"1280_CR2","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1016\/S0140-6736(14)61375-1","volume":"386","author":"A Lacroix","year":"2015","unstructured":"Lacroix A, Feelders RA, Stratakis CA, Nieman LK (2015) Cushing\u2019s syndrome. Lancet 386:913\u2013927","journal-title":"Lancet"},{"key":"1280_CR3","doi-asserted-by":"publisher","first-page":"648","DOI":"10.3389\/fendo.2020.00648","volume":"11","author":"R Pivonello","year":"2020","unstructured":"Pivonello R, Ferrigno R, De Martino MC et al (2020) Medical treatment of Cushing\u2019s disease: an overview of the current and recent clinical trials. 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Eur J Endocrinol 187:531\u2013541","journal-title":"Eur J Endocrinol"}],"container-title":["Pituitary"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11102-022-01280-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11102-022-01280-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11102-022-01280-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,19]],"date-time":"2022-11-19T16:37:34Z","timestamp":1668875854000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11102-022-01280-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,11]]},"references-count":20,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["1280"],"URL":"https:\/\/doi.org\/10.1007\/s11102-022-01280-6","relation":{},"ISSN":["1386-341X","1573-7403"],"issn-type":[{"value":"1386-341X","type":"print"},{"value":"1573-7403","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,11]]},"assertion":[{"value":"23 September 2022","order":1,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 October 2022","order":2,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"MF has received research support to Oregon Health & Science University as a principal investigator from Novartis, Recordati and Xeris (Strongbridge), has performed occasional scientific consultancy for Novartis, Recordati, HRA Pharma, Sparrow and Xeris (Strongbridge) and is on the Editorial Board of <i>Pituitary<\/i>. BMKB has served as the PI of research grants to Massachusetts General Hospital from Novartis, Millendo and Strongbridge and received occasional consulting honoraria from Crinetics, HRA Pharma, Novartis, Recordati, Sparrow and Strongbridge. JB has research contracts with Novartis, Pfizer, and HRA Pharma and has received consulting fees from HRA Pharma, Novartis, Corcept, and Recordati. JY has research contracts with Ipsen, Novartis, and Recordati, has taken part in conferences and symposia for Ipsen, Novartis, and Recordati, and is a member of the Board of Experts for Ipsen, Novartis, and Recordati. BH and GA have no conflicts of interest to declare. POC and MI are employees of Novartis. POC has shares in Novartis. AMP is an employee of Recordati. RP has received research support to Universit\u00e0 Federico II di Napoli as a principal investigator for clinical trials from Novartis Pharma,\u00a0Recordati,\u00a0Strongbridge Biopharma, Corcept Therapeutics, HRA Pharma,\u00a0Shire, Takeda, Neurocrine Biosciences, Camurus AB, and Pfizer, has received research support to Universit\u00e0 Federico II di Napoli from Pfizer, Ipsen, Novartis Pharma, Strongbridge Biopharma, Merk Serono, and Ibsa,\u00a0and received occasional consulting honoraria from Novartis Pharma, Recordati, Strongbridge Biopharma, HRA Pharma,\u00a0Crinetics Pharmaceuticals, Corcept Therapeutics, Pfizer, and Bresmed Health Solutions.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Patients provided written informed consent to participate in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Patients provided written informed consent for their data to be published anonymously.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}},{"value":"The study was conducted in accordance with the Declaration of Helsinki, with an independent ethics committee\/institutional review board at each site approving the study protocol.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}