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Transgene-produced and recombinant FVIII-SQ showed comparable specific activity (international units per milligram) in the CS assay, demonstrating that the diverging activities arise in the OS assay. Higher OS activity for transgene-produced FVIII-SQ was observed across various assay kits and clinical laboratories, suggesting that intrinsic molecular features are potential root causes. Further experiments in 2 participants showed that transgene-produced FVIII-SQ accelerated early factor Xa and thrombin formation, which may explain the higher OS activity based on a kinetic bias between OS and CS assay readout times. Despite the faster onset of coagulation, global thrombin levels were unaffected. A correlation with joint bleeds suggested that both OS and CS assay remained clinically meaningful to distinguish hemophilic from nonhemophilic FVIII activity levels. During clinical development, the CS activity was chosen as a surrogate end point to conservatively assess hemostatic efficacy and enable comparison with recombinant FVIII-SQ products. Relevant trials are registered on clinicaltrials.gov as #NCT02576795 and #NCT03370913 and, respectively, on EudraCT (European Union Drug Regulating Authorities Clinical Trials Database; https:\/\/eudract.ema.europa.eu) as #2014-003880-38 and #2017-003215-19.<\/jats:p>","DOI":"10.1182\/blood.2020005683","type":"journal-article","created":{"date-parts":[[2020,9,11]],"date-time":"2020-09-11T19:48:22Z","timestamp":1599853702000},"page":"2524-2534","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":74,"title":["Activity of transgene-produced B-domain\u2013deleted factor VIII in human plasma following AAV5 gene therapy"],"prefix":"10.1182","volume":"136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3452-0138","authenticated-orcid":false,"given":"Steffen","family":"Rosen","sequence":"first","affiliation":[{"name":"Rossix AB, M\u00f6lndal, Sweden;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Tiefenbacher","sequence":"additional","affiliation":[{"name":"Colorado Coagulation, Laboratory Corporation of America Holdings, Englewood, CO;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Robinson","sequence":"additional","affiliation":[{"name":"Colorado Coagulation, Laboratory Corporation of America Holdings, Englewood, CO;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Huang","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical Inc, Novato, CA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaydeep","family":"Srimani","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical Inc, Novato, CA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donnie","family":"Mackenzie","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical Inc, Novato, CA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terri","family":"Christianson","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical Inc, Novato, CA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3394-2099","authenticated-orcid":false,"given":"K. 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