{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T17:36:07Z","timestamp":1794072967959,"version":"4.8.0"},"reference-count":37,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T00:00:00Z","timestamp":1734912000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016469","name":"Takeda Pharmaceuticals International","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016469","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Haemophilia"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>Haemophilia A is an X\u2010linked bleeding disorder resulting from a deficiency of factor VIII (FVIII). To date, multiple gene therapies have entered clinical trials with the goal of providing durable haemostatic protection from a single dose. TAK 754 (BAX 888) is an investigational AAV8\u2010based gene therapy containing a FVIII transgene. Reduction in CpG motifs was performed to reduce immunogenicity based on prior observations. Here, we describe the results of the first two cohorts treated with TAK 754.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>To report clinical and translational results of the TAK\u2010754 phase 1\/2 AAV gene therapy study for the treatment of haemophilia A.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A phase 1\/2 single arm open\u2010label dose escalation study of TAK\u2010754 was performed in participants with severe haemophilia A (NCT03370172). Participants were monitored for safety events, endogenous FVIII activity and bleeding rates. Glucocorticoids were implemented to preserve transgene expression. A transcriptomics analysis was performed to evaluate immunogenicity along with additional post\u2010hoc analyses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Four participants were dosed in two cohorts. Infusion of TAK 754 was well\u2010tolerated. All participants developed mild transient transaminase elevation and subsequent loss of FVIII expression within the first 12 months of treatment despite use of glucocorticoids. Transcriptomic analysis did not demonstrate significant changes in immunogenicity signals in peripheral blood. One serious adverse event of hypophosphatemia occurred in the second cohort without obvious risk factors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Sustained FVIII expression remains a challenge in haemophilia A AAV gene therapy trials. Mechanisms of transgene expression loss require further study as clinical studies enter long term follow\u2010up periods.<\/jats:p><\/jats:sec>","DOI":"10.1111\/hae.15121","type":"journal-article","created":{"date-parts":[[2024,12,24]],"date-time":"2024-12-24T07:59:00Z","timestamp":1735027140000},"page":"108-117","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["A phase 1\/2 safety and efficacy study of TAK\u2010754 gene therapy: The challenge of achieving durable factor VIII expression in haemophilia A clinical trials"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3365-7757","authenticated-orcid":false,"given":"John","family":"Chapin","sequence":"first","affiliation":[{"name":"Rare Genetics and Hematology Therapeutic Area Unit Takeda Development Center of the Americas  Cambridge USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3296-4288","authenticated-orcid":false,"given":"Maria Teresa","family":"\u00c1lvarez Rom\u00e1n","sequence":"additional","affiliation":[{"name":"Hospital Universitario La Paz Universidad Aut\u00f3noma de Madrid  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mila","family":"Ayash\u2010Rashkovsky","sequence":"additional","affiliation":[{"name":"Clinical Sciences Rare Disease Therapeutic Area Unit Takeda Development Center of the Americas  Cambridge USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorothee","family":"Diogo","sequence":"additional","affiliation":[{"name":"Human Genetics Preclinical and Translational Sciences Takeda Development Center of the Americas  Cambridge USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon","family":"Kenniston","sequence":"additional","affiliation":[{"name":"Hematology Pathway Head Rare Genetics and Hematology Drug Discovery Unit Takeda Development Center of the Americas  Cambridge USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco\u2010Jose","family":"Lopez\u2010Jaime","sequence":"additional","affiliation":[{"name":"Unidad de Hemostasia y Trombosis Hospital Universitario Regional de M\u00e1laga  Malaga Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Maggiore","sequence":"additional","affiliation":[{"name":"Hemato\u2010Oncology Medical and Scientific Services IQVIA  Durham USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda\u2010Eva","family":"Mingot\u2010Castellano","sequence":"additional","affiliation":[{"name":"Hospital Universitario Virgen del Rocio Instituto de Biomedicina de Sevilla  Seville Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kavitha","family":"Rajavel","sequence":"additional","affiliation":[{"name":"Clinical Sciences Rare Disease Therapeutic Area Unit Takeda Development Center of the Americas  Cambridge USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoine","family":"Rauch","sequence":"additional","affiliation":[{"name":"H\u00e9mostase Clinique\u2010Transfusion Institut C\u0153ur Poumon CHRU Lille  Lille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Susen","sequence":"additional","affiliation":[{"name":"H\u00e9mostase Clinique\u2010Transfusion Institut C\u0153ur Poumon CHRU Lille  Lille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcin","family":"von Grotthuss","sequence":"additional","affiliation":[{"name":"Machine Learning, Computational Biology Takeda Development Center of the Americas  Cambridge USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt","family":"Wagoner","sequence":"additional","affiliation":[{"name":"Head of Investigative Toxicology Drug Safety Research &amp; 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