{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:18:18Z","timestamp":1787019498323,"version":"build-2736575974"},"reference-count":63,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020337","name":"Springworks Therapeutics","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100020337","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Therapeutic Advances in Rare Disease"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:p>Drug development for rare diseases can be long, complex, and costly. Desmoid tumors (DT), a rare type of soft-tissue tumor, are associated with substantial and debilitating burden, including disease-specific symptoms (e.g., pain, impaired mobility), reduce functioning for daily activities, and worsen quality of life for patients with this condition. These tumors can be potentially life-threatening when they invade surrounding tissues, affect vital structures, or interfere with the body\u2019s functions. Until recently, there were no approved treatments specific to DT and little alignment on disease management. However, on November 27, 2023, the US Food and Drug Administration approved nirogacestat, an oral, targeted, and selective gamma secretase inhibitor, indicated for adult patients with progressing DT who require systemic treatment. This development milestone ascribes to nirogacestat the first approval of a gamma secretase inhibitor for human clinical use and the first therapy specifically indicated for treating patients with DT, thus addressing a long-term unmet need in this patient population. In the DeFi phase III trial of nirogacestat in adults with DT (NCT03785964), nirogacestat demonstrated statistically significant and clinically meaningful improvement in progression-free survival, objective response rate, DT-specific symptom burden (including pain), physical functioning, role functioning, and overall quality of life. This review chronicles the clinical development journey of nirogacestat from 2009 to the present day. Motivated to improve patient outcomes\u2014and navigating considerable skepticism and uncertainty\u2014the dedicated efforts of individuals within academic and medical institutions, industry, and patient advocacy groups shepherded nirogacestat through the development process, including those times when development stalled and might otherwise have been abandoned. Nirogacestat\u2019s pathway to becoming a treatment for DT demonstrates how critically important collaboration and coordination are for identifying unique, creative solutions to overcome challenges in rare disease drug development.<\/jats:p>","DOI":"10.1177\/26330040251317546","type":"journal-article","created":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T00:10:01Z","timestamp":1739319001000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":6,"title":["Nirogacestat\u2014the pathway to approval of the first treatment for desmoid tumors, a rare disease"],"prefix":"10.1177","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6906-1627","authenticated-orcid":false,"given":"Shivaani","family":"Kummar","sequence":"first","affiliation":[{"name":"Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nam","family":"Bui","sequence":"additional","affiliation":[{"name":"Stanford University, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wells A.","family":"Messersmith","sequence":"additional","affiliation":[{"name":"University of Colorado School of Medicine, Aurora, CO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanne","family":"Whiting","sequence":"additional","affiliation":[{"name":"The Desmoid Tumor Research Foundation, Woodcliff Lake, NJ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlene","family":"Portnoy","sequence":"additional","affiliation":[{"name":"The Desmoid Tumor Research Foundation, Woodcliff Lake, NJ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Lim","sequence":"additional","affiliation":[{"name":"SpringWorks Therapeutics, Stamford, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. Mary","family":"Smith","sequence":"additional","affiliation":[{"name":"SpringWorks Therapeutics, Stamford, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2025,2,11]]},"reference":[{"key":"bibr1-26330040251317546","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdx323"},{"key":"bibr2-26330040251317546","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2017.06.017"},{"key":"bibr3-26330040251317546","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.32555"},{"key":"bibr4-26330040251317546","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2019.11.013"},{"key":"bibr5-26330040251317546","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2014.11.019"},{"key":"bibr6-26330040251317546","doi-asserted-by":"publisher","DOI":"10.1245\/s10434-013-3197-x"},{"key":"bibr7-26330040251317546","doi-asserted-by":"publisher","DOI":"10.1007\/s12325-023-02592-0"},{"key":"bibr8-26330040251317546","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.34332"},{"key":"bibr9-26330040251317546","doi-asserted-by":"publisher","DOI":"10.1245\/s10434-015-4632-y"},{"key":"bibr10-26330040251317546","unstructured":"Orphanet. 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SpringWorks Therapeutics announces FDA approval of OGSIVEO\u2122 (nirogacestat) as the first and only treatment for adults with desmoid tumors, https:\/\/ir.springworkstx.com\/news-releases\/news-release-details\/springworks-therapeutics-announces-fda-approval-ogsiveotm (2023, accessed 29 November 2023)."},{"key":"bibr14-26330040251317546","unstructured":"US Food & Drug Administration. FDA approves nirogacestat for desmoid tumors, https:\/\/www.fda.gov\/drugs\/resources-information-approved-drugs\/fda-approves-nirogacestat-desmoid-tumors (2023, accessed 12 January 2024)."},{"key":"bibr15-26330040251317546","doi-asserted-by":"publisher","DOI":"10.1080\/14737167.2023.2203915"},{"key":"bibr16-26330040251317546","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.33.5489"},{"key":"bibr17-26330040251317546","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocp.2017.02.012"},{"key":"bibr18-26330040251317546","doi-asserted-by":"publisher","DOI":"10.1097\/00000658-198912000-00012"},{"key":"bibr19-26330040251317546","doi-asserted-by":"publisher","DOI":"10.1007\/BF02053335"},{"key":"bibr20-26330040251317546","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.11937"},{"key":"bibr21-26330040251317546","doi-asserted-by":"publisher","DOI":"10.1016\/0959-8049(92)90445-8"},{"key":"bibr22-26330040251317546","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdq341"},{"key":"bibr23-26330040251317546","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2017.02.001"},{"key":"bibr24-26330040251317546","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2019.37.15_suppl.11052"},{"key":"bibr25-26330040251317546","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(19)30276-1"},{"key":"bibr26-26330040251317546","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.03.6566"},{"key":"bibr27-26330040251317546","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2009.08.016"},{"key":"bibr28-26330040251317546","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.02.1923"},{"key":"bibr29-26330040251317546","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdr051"},{"key":"bibr30-26330040251317546","unstructured":"Congressional Budget Office. 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SpringWorks Therapeutics Receives Breakthrough Therapy Designation for Nirogacestat for the Treatment of Adult Patients with Progressive, Unresectable, Recurrent or Refractory Desmoid Tumors, https:\/\/ir.springworkstx.com\/news-releases\/news-release-details\/springworks-therapeutics-receives-breakthrough-therapy (2019, accessed 12 January 2024)."},{"key":"bibr58-26330040251317546","unstructured":"SpringWorks Therapeutics. 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SpringWorks Therapeutics completes submission of new drug application to the FDA for nirogacestat for the treatment of adults with desmoid tumors, https:\/\/ir.springworkstx.com\/news-releases\/news-release-details\/springworks-therapeutics-completes-submission-new-drug (2022, accessed 28 November 2023)."},{"key":"bibr63-26330040251317546","unstructured":"SpringWorks Therapeutics. SpringWorks Therapeutics Announces FDA Acceptance and Priority Review of New Drug Application for Nirogacestat for the Treatment of Adults with Desmoid Tumors, https:\/\/ir.springworkstx.com\/news-releases\/news-release-details\/springworks-therapeutics-announces-fda-acceptance-and-priority (2024, accessed 12 January 2024)."}],"container-title":["Therapeutic Advances in Rare Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/26330040251317546","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/26330040251317546","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/26330040251317546","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T01:10:41Z","timestamp":1777597841000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/26330040251317546"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1]]},"references-count":63,"alternative-id":["10.1177\/26330040251317546"],"URL":"https:\/\/doi.org\/10.1177\/26330040251317546","relation":{},"ISSN":["2633-0040","2633-0040"],"issn-type":[{"value":"2633-0040","type":"print"},{"value":"2633-0040","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1]]},"article-number":"26330040251317546"}}