{"id":4757,"date":"2025-07-22T08:34:09","date_gmt":"2025-07-22T08:34:09","guid":{"rendered":"https:\/\/medical.biomarin.com\/en-us\/?page_id=4757"},"modified":"2026-01-07T19:45:25","modified_gmt":"2026-01-07T19:45:25","slug":"liver-health","status":"publish","type":"page","link":"https:\/\/medical.biomarin.com\/en-us\/hemophilia-a\/valoctocogene-roxaparvovec-safety\/liver-health\/","title":{"rendered":"Liver health"},"content":{"rendered":"<div id=\"acf-block-645511272e5db\" class=\"hero hero-no-overlay hero-small-title\">\n            <div class=\"hero-background-image hero-background-image-desktop\" style=\"background-image: url(https:\/\/medical.biomarin.com\/en-us\/wp-content\/uploads\/sites\/2\/2025\/10\/Program-banner-drop.png?v=1.20);\"><\/div>\n\t    <div class=\"hero-background-image hero-background-image-mobile\" style=\"background-image: url(https:\/\/medical.biomarin.com\/en-us\/wp-content\/uploads\/sites\/2\/2025\/10\/Program-banner-drop-Mobile.png?v=1.20);\"><\/div>\n    \t<div class=\"overlay\"><\/div>\n\t<div class=\"wrapper\">\n\t\t<div class=\"inner-wrapper\">\n\t\t\t<div class=\"hero-content\">\n\t\t\t    \t\t\t        <ul class=\"breadcrumb\">\n\t\t\t            \t\t\t                                                                        <li><a href=\"https:\/\/medical.biomarin.com\/en-us\/hemophilia-a\/\">Hemophilia A<\/a><\/li>\n                            \t\t\t                                                                        <li><a href=\"https:\/\/medical.biomarin.com\/en-us\/hemophilia-a\/valoctocogene-roxaparvovec-safety\/\">Valoctocogene roxaparvovec safety<\/a><\/li>\n                            \t\t\t                                                                        <li>Liver health<\/li>\n                            \t\t\t            \t\t\t        <\/ul>\n\t\t\t    \t\t\t\t\t\t\t\t\t\t\t\t    <h1>Liver Health\n<\/h1>\n\t\t\t\t\t\t\t\t\t\t\t\t\n                <p class=\"inline-buttons\">\n                                                        <\/p>\n\t\t\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t<\/div>\n<\/div>\n\n\n<div id=\"acf-block-645512ae5ba05\" class=\"block wrapped-content bg-band bg-band-primary block-zero-top block-tight-bottom\">\n    <div class=\"wrapper\">\n        <div class=\"inner-wrapper\">\n                \n<div id=\"acf-block-645512ae5bb64\" class=\"block-wysiwyg\">\n            <h2>State of Knowledge Summary<\/h2>\n<ul>\n<li>Alanine aminotransferase (ALT) elevations are a known adverse event of adeno-associated virus (AAV) gene therapy.<sup>1-3<\/sup><\/li>\n<li>Following valoctocogene roxaparvovec administration, the majority of patients experienced transient ALT elevations; some of which were temporally associated with a decrease in expression of the factor VIII (FVIII) transgene protein.<sup>4,5<\/sup> The mechanism of these reactions is not yet fully understood.<\/li>\n<li>ALT elevations (Grade 1-3) were generally rapidly responsive to corticosteroid treatment (or alternative immunosuppressants) with no symptoms or sequelae suggestive of clinically significant hepatocellular injury or liver dysfunction.<sup>4,5,7<\/sup><\/li>\n<li>Histopathological examination of liver biopsy samples retrieved up to 4 years after vector administration reveal no evidence of drug-induced liver injury.<sup>8<\/sup><\/li>\n<\/ul>\n    <\/div>\n        <\/div>\n    <\/div>\n<\/div>\n\n<div id=\"acf-block-64871308b3868\" class=\"block wrapped-content\">\n    <div class=\"wrapper\">\n        <div class=\"inner-wrapper\">\n                \n<div id=\"acf-block-64871308b39a5\" class=\"block-wysiwyg\">\n            <h2>Additional Information<\/h2>\n<h3>ALT Elevations<\/h3>\n<p><strong>Study 270-201<\/strong><\/p>\n<ul>\n<li>ALT elevations were reported in 6 (85.7%) of 7 patients in the 6 x 10<sup>13<\/sup> vg\/kg cohort of Study 270-201.<sup>4<\/sup> All were characterized as mild, nonserious, and transient; none were accompanied by cholestatic markers (alkaline phosphatase and bilirubin); and none met the criteria for Hy&#x2019;s law.<sup>9<\/sup><\/li>\n<li>In Study 270-201, &#x3B3;-glutamyltransferase enzyme levels were monitored as a sensitive indicator of hepatotoxicity and no safety signals emerged.<sup>9<\/sup><\/li>\n<\/ul>\n<p><strong>GENEr8-1 (Study 270-301)&#xA0;<\/strong><\/p>\n<ul>\n<li>Most patients in GENEr8-1 experienced ALT elevations meeting adverse event criteria.<sup>5<\/sup><\/li>\n<li>In GENEr8-1, adverse events of ALT elevation were initially defined as elevation &#x2265;1.5x upper limit of normal (ULN) for directly enrolled patients.<sup>6<\/sup> This was later amended to also include elevations greater than the ULN when ALT was also &gt;2x baseline. For patients rolling over from Study 270-902, the definition was further expanded so that ALT greater than the ULN or &ge;1.5x baseline qualified as an AE. Events meeting the threshold valid at the time of event are reported here as adverse events.<\/li>\n<li>No Grade 4 or higher ALT elevations occurred in GENEr8-1.<sup>5,6,10-12<\/sup><\/li>\n<\/ul>\n    <\/div>\n\n<figure id=\"acf-block-64871308b3b55\">\n    <div class=\"image image-rounded image-align-left\">\n                    <img decoding=\"async\" class=\"\" src=\"https:\/\/medical.biomarin.com\/en-us\/wp-content\/uploads\/sites\/2\/2025\/11\/ALT-Elevations-Table-Nov_2025.jpg?v=1.20\" alt=\"Image of ALT Elevations-Table\"\/>            <\/div>\n    <\/figure>\n        <\/div>\n    <\/div>\n<\/div>\n\n<div id=\"acf-block-64871e656cacf\" class=\"block wrapped-content\">\n    <div class=\"wrapper\">\n        <div class=\"inner-wrapper\">\n                \n<div id=\"acf-block-64871e656cc19\" class=\"block-wysiwyg\">\n            <h3>Liver Biopsies<\/h3>\n<ul>\n<li>No clinically relevant hepatic issues were detected on histopathological examination of liver biopsy samples from all 5 recipients of valoctocogene roxaparvovec who agreed to participate in the liver biopsy sub-study of Study 270-201.<sup>8<\/sup><\/li>\n<li>There was no evidence of dysplasia, architectural distortion, fibrosis, or chronic inflammation, and no endoplasmic reticulum stress was detected in hepatocytes expressing hFVIII-SQ protein.<sup>8<\/sup><\/li>\n<li>Mild steatosis was observed in 4 of 5 patients but was considered to be representative of the expected high prevalence within normal male populations in developed countries.<sup>8<\/sup><\/li>\n<\/ul>\n    <\/div>\n\n<div id=\"acf-block-6487242f65614\" class=\"block-wysiwyg\">\n    <\/div>\n\n<figure id=\"acf-block-64871e656cdc9\">\n    <div class=\"image image-rounded image-align-left\">\n                    <img decoding=\"async\" class=\"\" src=\"https:\/\/medical.biomarin.com\/en-us\/wp-content\/uploads\/sites\/2\/2025\/07\/LIVER-BIOPSIES-TABLE.svg\" alt=\"Table outlining liver biopsies\"\/>            <\/div>\n    <\/figure>\n        <\/div>\n    <\/div>\n<\/div>\n\n<div id=\"acf-block-64873a42bd9a4\" class=\"block next-previous\">\n    <div class=\"wrapper\">\n\t\t<div class=\"inner-wrapper\">\n            <div class=\"link link-prev\">\n                                    <p><a class=\"button button-text button-arrow button-arrow-left\" href=\"https:\/\/medical.biomarin.com\/en-us\/valoctocogene-roxaparvovec-safety\/\" target=\"_self\">Valoctocogene roxaparvovec safety<\/a><\/p>\n                            <\/div>\n            <div class=\"link link-next\">\n                                    <p><a class=\"button button-text button-arrow\" href=\"https:\/\/medical.biomarin.com\/en-us\/valoctocogene-roxaparvovec-safety\/malignancy-vector-integration\/\" target=\"_self\">Malignancy (vector integration)<\/a><\/p>\n                            <\/div>\n\t\t<\/div>\n\t<\/div>\n<\/div>\n\n<div id=\"acf-block-6487179ccbcfc\" class=\"block references\">\n    <div class=\"wrapper\">\n\t\t<div class=\"inner-wrapper\">\n\t\t    \t\t\t    <h4>References:\n<\/h4>\n\t\t\t\t\t\t                <ol>\n                                                                                                                        <li><span>Monahan PE, Negrier C, Tarantino M, et al. Emerging Immunogenicity and Genotoxicity Considerations of Adeno-Associated Virus Vector Gene Therapy for Hemophilia. J Clin Med. 2021;10(11).\n<\/span><\/li>\n                                                                                                                                                <li><span>Batty P, Lillicrap D. Hemophilia Gene Therapy: Approaching the First Licensed Product. Hemasphere. 2021;5(3):e540.\n<\/span><\/li>\n                                                                                                                                                <li><span>Miesbach W, Foster GR, Peyvandi F. Liver-related aspects of gene therapy for hemophilia: need for collaborations with hepatologists. J Thromb Haemost. 2023;21(2):200-203.\n<\/span><\/li>\n                                                                                                                                                <li><span>Rangarajan S, Walsh L, Lester W, et al. AAV5-Factor VIII Gene Transfer in Severe Hemophilia A. N Engl J Med. 2017;377(26):2519-2530.\n<\/span><\/li>\n                                                                                                                                                <li><span>Ozelo MC, Mahlangu J, Pasi KJ, et al. Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A. N Engl J Med. 2022;386(11):1013-1025.\n<\/span><\/li>\n                                                                                                                                                <li><span>Mahlangu J, Kaczmarek R, von Drygalski A, et al. Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A. N Engl J Med. 2023;388(8):694-705.\n<\/span><\/li>\n                                                                                                                                                <li><span>Mahlangu J, von Drygalski A, Shapiro S, et al. Efficacy and safety of valoctocogene roxaparvovec gene transfer for severe hemophilia A: Results from the GENEr8-1 three-year analysis [presentation]. Presented at the Society of Thrombosis and Hemostasis Research (GTH) Annual Meeting. February 21-24, 2023; Frankfurt, Germany.\n<\/span><\/li>\n                                                                                                                                                <li><span>Fong S, Yates B, Sihn CR, et al. Interindividual variability in transgene mRNA and protein production following adeno-associated virus gene therapy for hemophilia A. Nat Med. 2022;28(4):789-797.\n<\/span><\/li>\n                                                                                                                                                <li><span>Pasi KJ, Rangarajan S, Mitchell N, et al. Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A. <em>N Engl J Med. <\/em>2020;382(1):29-40.\n<\/span><\/li>\n                                                                                                                                                <li><span>Madan B, Ozelo MC, Raheja P, et al. Three-year outcomes of valoctocogene roxaparvovec gene therapy for hemophilia A. <em>J Thromb Haemost. <\/em>2024;22(7):1880-1893.\n<\/span><\/li>\n                                                                                                                                                <li><span>Leavitt AD, Mahlangu J, Raheja P, et al. Efficacy, safety, and quality of life 4 years after valoctocogene roxaparvovec gene transfer for severe hemophilia A in the phase 3 GENEr8-1 trial. <em>Res Pract Thromb Haemost.<\/em> 2024;8(8):102615.\n<\/span><\/li>\n                                                                                                                                                <li><span>Leavitt AD, Mahlangu J, Raheja P, et al. Final GENEr8-1 results confirm enduring efficacy, safety, and quality of life improvements 5 years after valoctocogene roxaparvovec gene transfer [poster]. Presented at the International Society on Thrombosis and Haemostasis (ISTH) Congress. June 21-25, 2025; Washington, D.C.\n<\/span><\/li>\n                                                                                                                                                <li><span><span style=\"color: #242424;font-family: 'Aptos Narrow', Calibri, 'sans-serif', 'Mongolian Baiti', 'Microsoft Yi Baiti', 'Javanese Text', 'Yu Gothic';font-size: 14.6667px\">Symington E, Rangarajan S, Lester W, et al. Valoctocogene roxaparvovec gene therapy provides durable haemostatic control for up to 7 years for haemophilia A. Haemophilia. 2024;30(5):1138-1147.<\/span>\n<\/span><\/li>\n                                                            <\/ol>\n\t\t\t\t\t<\/div>\n\t<\/div>\n<\/div>","protected":false},"excerpt":{"rendered":"","protected":false},"author":2,"featured_media":0,"parent":4754,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_acf_changed":false,"inline_featured_image":false,"footnotes":""},"class_list":["post-4757","page","type-page","status-publish","hentry"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.1.1 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Liver health | BioMarin Medical<\/title>\n<meta name=\"description\" content=\"Learn more about liver health\" \/>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/medical.biomarin.com\/en-us\/hemophilia-a\/valoctocogene-roxaparvovec-safety\/liver-health\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Liver health | BioMarin Medical\" \/>\n<meta property=\"og:description\" content=\"Learn more about liver health\" \/>\n<meta property=\"og:url\" content=\"https:\/\/medical.biomarin.com\/en-us\/hemophilia-a\/valoctocogene-roxaparvovec-safety\/liver-health\/\" \/>\n<meta property=\"og:site_name\" content=\"BioMarin Medical\" \/>\n<meta property=\"article:modified_time\" content=\"2026-01-07T19:45:25+00:00\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\/\/schema.org\",\"@graph\":[{\"@type\":\"WebPage\",\"@id\":\"https:\/\/medical.biomarin.com\/en-us\/hemophilia-a\/valoctocogene-roxaparvovec-safety\/liver-health\/\",\"url\":\"https:\/\/medical.biomarin.com\/en-us\/hemophilia-a\/valoctocogene-roxaparvovec-safety\/liver-health\/\",\"name\":\"Liver health | BioMarin Medical\",\"isPartOf\":{\"@id\":\"https:\/\/medical.biomarin.com\/en-us\/#website\"},\"datePublished\":\"2025-07-22T08:34:09+00:00\",\"dateModified\":\"2026-01-07T19:45:25+00:00\",\"description\":\"Learn more about liver health\",\"breadcrumb\":{\"@id\":\"https:\/\/medical.biomarin.com\/en-us\/hemophilia-a\/valoctocogene-roxaparvovec-safety\/liver-health\/#breadcrumb\"},\"inLanguage\":\"en-US\",\"potentialAction\":[{\"@type\":\"ReadAction\",\"target\":[\"https:\/\/medical.biomarin.com\/en-us\/hemophilia-a\/valoctocogene-roxaparvovec-safety\/liver-health\/\"]}]},{\"@type\":\"BreadcrumbList\",\"@id\":\"https:\/\/medical.biomarin.com\/en-us\/hemophilia-a\/valoctocogene-roxaparvovec-safety\/liver-health\/#breadcrumb\",\"itemListElement\":[{\"@type\":\"ListItem\",\"position\":1,\"name\":\"Home\",\"item\":\"https:\/\/medical.biomarin.com\/en-us\/\"},{\"@type\":\"ListItem\",\"position\":2,\"name\":\"Hemophilia A\",\"item\":\"https:\/\/medical.biomarin.com\/en-us\/hemophilia-a\/\"},{\"@type\":\"ListItem\",\"position\":3,\"name\":\"Valoctocogene roxaparvovec safety\",\"item\":\"https:\/\/medical.biomarin.com\/en-us\/hemophilia-a\/valoctocogene-roxaparvovec-safety\/\"},{\"@type\":\"ListItem\",\"position\":4,\"name\":\"Liver health\"}]},{\"@type\":\"WebSite\",\"@id\":\"https:\/\/medical.biomarin.com\/en-us\/#website\",\"url\":\"https:\/\/medical.biomarin.com\/en-us\/\",\"name\":\"BioMarin Medical\",\"description\":\"\",\"potentialAction\":[{\"@type\":\"SearchAction\",\"target\":{\"@type\":\"EntryPoint\",\"urlTemplate\":\"https:\/\/medical.biomarin.com\/en-us\/?s={search_term_string}\"},\"query-input\":{\"@type\":\"PropertyValueSpecification\",\"valueRequired\":true,\"valueName\":\"search_term_string\"}}],\"inLanguage\":\"en-US\"}]}<\/script>\n<!-- \/ Yoast SEO plugin. -->","yoast_head_json":{"title":"Liver health | BioMarin Medical","description":"Learn more about liver health","robots":{"index":"index","follow":"follow","max-snippet":"max-snippet:-1","max-image-preview":"max-image-preview:large","max-video-preview":"max-video-preview:-1"},"canonical":"https:\/\/medical.biomarin.com\/en-us\/hemophilia-a\/valoctocogene-roxaparvovec-safety\/liver-health\/","og_locale":"en_US","og_type":"article","og_title":"Liver health | BioMarin Medical","og_description":"Learn more about liver health","og_url":"https:\/\/medical.biomarin.com\/en-us\/hemophilia-a\/valoctocogene-roxaparvovec-safety\/liver-health\/","og_site_name":"BioMarin Medical","article_modified_time":"2026-01-07T19:45:25+00:00","twitter_card":"summary_large_image","schema":{"@context":"https:\/\/schema.org","@graph":[{"@type":"WebPage","@id":"https:\/\/medical.biomarin.com\/en-us\/hemophilia-a\/valoctocogene-roxaparvovec-safety\/liver-health\/","url":"https:\/\/medical.biomarin.com\/en-us\/hemophilia-a\/valoctocogene-roxaparvovec-safety\/liver-health\/","name":"Liver health | BioMarin Medical","isPartOf":{"@id":"https:\/\/medical.biomarin.com\/en-us\/#website"},"datePublished":"2025-07-22T08:34:09+00:00","dateModified":"2026-01-07T19:45:25+00:00","description":"Learn more about liver health","breadcrumb":{"@id":"https:\/\/medical.biomarin.com\/en-us\/hemophilia-a\/valoctocogene-roxaparvovec-safety\/liver-health\/#breadcrumb"},"inLanguage":"en-US","potentialAction":[{"@type":"ReadAction","target":["https:\/\/medical.biomarin.com\/en-us\/hemophilia-a\/valoctocogene-roxaparvovec-safety\/liver-health\/"]}]},{"@type":"BreadcrumbList","@id":"https:\/\/medical.biomarin.com\/en-us\/hemophilia-a\/valoctocogene-roxaparvovec-safety\/liver-health\/#breadcrumb","itemListElement":[{"@type":"ListItem","position":1,"name":"Home","item":"https:\/\/medical.biomarin.com\/en-us\/"},{"@type":"ListItem","position":2,"name":"Hemophilia A","item":"https:\/\/medical.biomarin.com\/en-us\/hemophilia-a\/"},{"@type":"ListItem","position":3,"name":"Valoctocogene roxaparvovec safety","item":"https:\/\/medical.biomarin.com\/en-us\/hemophilia-a\/valoctocogene-roxaparvovec-safety\/"},{"@type":"ListItem","position":4,"name":"Liver health"}]},{"@type":"WebSite","@id":"https:\/\/medical.biomarin.com\/en-us\/#website","url":"https:\/\/medical.biomarin.com\/en-us\/","name":"BioMarin Medical","description":"","potentialAction":[{"@type":"SearchAction","target":{"@type":"EntryPoint","urlTemplate":"https:\/\/medical.biomarin.com\/en-us\/?s={search_term_string}"},"query-input":{"@type":"PropertyValueSpecification","valueRequired":true,"valueName":"search_term_string"}}],"inLanguage":"en-US"}]}},"_links":{"self":[{"href":"https:\/\/medical.biomarin.com\/en-us\/wp-json\/wp\/v2\/pages\/4757","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/medical.biomarin.com\/en-us\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/medical.biomarin.com\/en-us\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/medical.biomarin.com\/en-us\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/medical.biomarin.com\/en-us\/wp-json\/wp\/v2\/comments?post=4757"}],"version-history":[{"count":7,"href":"https:\/\/medical.biomarin.com\/en-us\/wp-json\/wp\/v2\/pages\/4757\/revisions"}],"predecessor-version":[{"id":6279,"href":"https:\/\/medical.biomarin.com\/en-us\/wp-json\/wp\/v2\/pages\/4757\/revisions\/6279"}],"up":[{"embeddable":true,"href":"https:\/\/medical.biomarin.com\/en-us\/wp-json\/wp\/v2\/pages\/4754"}],"wp:attachment":[{"href":"https:\/\/medical.biomarin.com\/en-us\/wp-json\/wp\/v2\/media?parent=4757"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}