{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T23:32:08Z","timestamp":1784849528300,"version":"3.55.0"},"reference-count":44,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T00:00:00Z","timestamp":1707091200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008484","name":"BioMarin Pharmaceutical","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008484","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Haemophilia"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>Valoctocogene roxaparvovec uses an adeno\u2010associated virus serotype 5 (AAV5) vector to transfer a factor VIII (FVIII) coding sequence to individuals with severe haemophilia A, providing bleeding protection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>To assess safety and efficacy of valoctocogene roxaparvovec 5\u20126\u00a0years post\u2010treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In a phase 1\/2 trial, adult male participants with severe haemophilia A (FVIII \u22641\u00a0IU\/dL) without FVIII inhibitors or anti\u2010AAV5 antibodies received valoctocogene roxaparvovec and were followed for 6 (6\u00a0\u00d7\u00a010<jats:sup>13<\/jats:sup> vg\/kg; <jats:italic>n<\/jats:italic>\u00a0=\u00a07) and 5 (4\u00a0\u00d7\u00a010<jats:sup>13<\/jats:sup> vg\/kg; <jats:italic>n<\/jats:italic>\u00a0=\u00a06) years. Safety, including investigation of potential associations between a malignancy and gene therapy, and efficacy are reported.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>No new treatment\u2010related safety signals emerged. During year 6, a participant in the 6\u00a0\u00d7\u00a010<jats:sup>13<\/jats:sup>\u00a0vg\/kg cohort was diagnosed with grade 2 parotid gland acinar cell carcinoma; definitive treatment was uncomplicated parotidectomy with lymph node dissection. Target enrichment sequencing of tumour and adjacent healthy tissue revealed low vector integration (8.25\u00a0\u00d7\u00a010<jats:sup>\u22125<\/jats:sup> per diploid cell). Integrations were not elevated in tumour samples, no insertions appeared to drive tumorigenesis, and no clonal expansion of integration\u2010containing cells occurred. During all follow\u2010ups, &gt;90% decreases from baseline in annualised treated bleeds and FVIII infusion rates were maintained. At the end of years 6 and 5, mean FVIII activity (chromogenic assay) was 9.8\u00a0IU\/dL (median, 5.6\u00a0IU\/dL) and 7.6\u00a0IU\/dL (median, 7.1\u00a0IU\/dL) for the 6\u00a0\u00d7\u00a010<jats:sup>13<\/jats:sup> and 4\u00a0\u00d7\u00a010<jats:sup>13<\/jats:sup> vg\/kg cohorts, respectively, representing proportionally smaller year\u2010over\u2010year declines than earlier timepoints.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Valoctocogene roxaparvovec safety and efficacy profiles remain largely unchanged; genomic investigations showed no association with a parotid tumour.<\/jats:p><\/jats:sec>","DOI":"10.1111\/hae.14936","type":"journal-article","created":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T07:01:24Z","timestamp":1707289284000},"page":"320-330","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Long\u2010term safety and efficacy outcomes of valoctocogene roxaparvovec gene transfer up to 6\u00a0years post\u2010treatment"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2529-8168","authenticated-orcid":false,"given":"Emily","family":"Symington","sequence":"first","affiliation":[{"name":"Cambridge University Hospitals NHS Foundation Trust  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Savita","family":"Rangarajan","sequence":"additional","affiliation":[{"name":"Faculty of Medicine University of Southampton  Southampton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8790-7112","authenticated-orcid":false,"given":"Will","family":"Lester","sequence":"additional","affiliation":[{"name":"University Hospitals Birmingham NHS Foundation Trust  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bella","family":"Madan","sequence":"additional","affiliation":[{"name":"Guy's and St Thomas\u2019 NHS Foundation Trust  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3310-328X","authenticated-orcid":false,"given":"Glenn F.","family":"Pierce","sequence":"additional","affiliation":[{"name":"Independent Consultant  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priyanka","family":"Raheja","sequence":"additional","affiliation":[{"name":"Haemophilia Centre Royal London Hospital Barts Health NHS Trust  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tara M.","family":"Robinson","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical Inc.  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Novato California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wing Yen","family":"Wong","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical Inc.  Novato California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8268-3268","authenticated-orcid":false,"given":"Michael","family":"Laffan","sequence":"additional","affiliation":[{"name":"Centre for Haematology Imperial College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,2,5]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.14046"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.13449"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.24220"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1803550"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020009217"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10245959"},{"key":"e_1_2_11_8_1","first-page":"1687","article-title":"Patient and parent preferences for characteristics of prophylactic treatment in hemophilia","volume":"9","author":"Furlan R","year":"2015","journal-title":"Patient Prefer Adherence"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.14304"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40271-019-00395-6"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2017.12.009"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01751-0"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1708483"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1908490"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.14391"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2113708"},{"key":"e_1_2_11_17_1","volume-title":"First gene therapy for adults with severe hemophilia A, BioMarin's ROCTAVIAN\u2122 (valoctocogene roxaparvovec), approved by European Commission (EC) [press release]","year":"2022"},{"key":"e_1_2_11_18_1","volume-title":"FDA Approves BioMarin's Gene Therapy for a Genetic Bleeding Disorder [press release]","year":"2023"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2211075"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1015"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbx111"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2022.11.001"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2211075"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.4015"},{"issue":"1","key":"e_1_2_11_25_1","first-page":"550","article-title":"Frequency, location and nature of AAV vector insertions after long\u2010term follow up of FVIII transgene delivery in a hemophilia A dog model","volume":"4","author":"Batty P","year":"2020","journal-title":"Res Pract Thomb Haemost"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/d41573-021-00017-7"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/d41573-021-00164-x"},{"key":"e_1_2_11_28_1","unstructured":"Novartis.Novartis shares Zolgensma long\u2010term data demonstrating sustained durability up to 7.5 years post\u2010dosing; 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