• Margareth C Ozelo, Johnny Mahlangu, K John Pasi, Adam Giermasz, Andrew D Leavitt, Michael Laffan, Emily Symington, Doris V Quon, Jiaan-Der Wang, Kathelijne Peerlinck, Steven W Pipe, Bella Madan, Nigel S Key, Glenn F Pierce, Brian O'Mahony, Radoslaw Kaczmarek, Joshua Henshaw, Adebayo Lawal, Kala Jayaram, Mei Huang, Xinqun Yang, Wing Y Wong, Benjamin Kim, and GENEr8-1 Trial Group.
• From Hemocentro UNICAMP, Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, Brazil (M.C.O.); the Hemophilia Comprehensive Care Center, Charlotte Maxeke Johannesburg Academic Hospital, University of the Witwatersrand and NHLS, Johannesburg (J.M.); Barts and the London School of Medicine and Dentistry (K.J.P.), the Centre for Haematology, Imperial College London (M.L.), and Guy's and St. Thomas' NHS Foundation Trust (B.M.), London, and Cambridge University Hospitals NHS Foundation Trust, Cambridge (E.S.) - all in the United Kingdom; the Hemophilia Treatment Center, University of California, Davis, Sacramento (A.G.), the University of California, San Francisco, San Francisco (A.D.L.), the Orthopedic Hemophilia Treatment Center, Los Angeles (D.V.Q.), independent consultant, La Jolla (G.F.P.), and BioMarin Pharmaceutical, Novato (J.H., A.L., K.J., M.H., X.Y., W.Y.W., B.K.) - all in California; the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); the Department of Vascular Medicine and Hemostasis and Hemophilia Center, University Hospitals Leuven, Leuven, Belgium (K.P.); the Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor (S.W.P.); the UNC Blood Research Center, University of North Carolina, Chapel Hill (N.S.K.); the Irish Haemophilia Society and Trinity College, Dublin (B.O.); the Department of Pediatrics, Indiana University School of Medicine, IUPUI-Wells Center for Pediatric Research, Indianapolis (R.K.); and the Laboratory of Glycobiology, Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland (R.K.).
• N. Engl. J. Med. 2022 Mar 17; 386 (11): 101310251013-1025.

BackgroundValoctocogene roxaparvovec (AAV5-hFVIII-SQ) is an adeno-associated virus 5 (AAV5)-based gene-therapy vector containing a coagulation factor VIII complementary DNA driven by a liver-selective promoter. The efficacy and safety of the therapy were previously evaluated in men with severe hemophilia A in a phase 1-2 dose-escalation study.MethodsWe conducted an open-label, single-group, multicenter, phase 3 study to evaluate the efficacy and safety of valoctocogene roxaparvovec in men with severe hemophilia A, defined as a factor VIII level of 1 IU per deciliter or lower. Participants who were at least 18 years of age and did not have preexisting anti-AAV5 antibodies or a history of development of factor VIII inhibitors and who had been receiving prophylaxis with factor VIII concentrate received a single infusion of 6×1013 vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in factor VIII activity (measured with a chromogenic substrate assay) during weeks 49 through 52 after infusion. Secondary end points included the change in annualized factor VIII concentrate use and bleeding rates. Safety was assessed as adverse events and laboratory test results.ResultsOverall, 134 participants received an infusion and completed more than 51 weeks of follow-up. Among the 132 human immunodeficiency virus-negative participants, the mean factor VIII activity level at weeks 49 through 52 had increased by 41.9 IU per deciliter (95% confidence interval [CI], 34.1 to 49.7; P<0.001; median change, 22.9 IU per deciliter; interquartile range, 10.9 to 61.3). Among the 112 participants enrolled from a prospective noninterventional study, the mean annualized rates of factor VIII concentrate use and treated bleeding after week 4 had decreased after infusion by 98.6% and 83.8%, respectively (P<0.001 for both comparisons). All the participants had at least one adverse event; 22 of 134 (16.4%) reported serious adverse events. Elevations in alanine aminotransferase levels occurred in 115 of 134 participants (85.8%) and were managed with immune suppressants. The other most common adverse events were headache (38.1%), nausea (37.3%), and elevations in aspartate aminotransferase levels (35.1%). No development of factor VIII inhibitors or thrombosis occurred in any of the participants.ConclusionsIn patients with severe hemophilia A, valoctocogene roxaparvovec treatment provided endogenous factor VIII production and significantly reduced bleeding and factor VIII concentrate use relative to factor VIII prophylaxis. (Funded by BioMarin Pharmaceutical; GENEr8-1 ClinicalTrials.gov number, NCT03370913.).Copyright © 2022 Massachusetts Medical Society.

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