Presentation Details
| Safety and efficacy of valoctocogene roxaparvovec gene transfer for severe hemophilia A: an update from 4 years after treatment Andrew D Leavitt1, Johnny Mahlangu2, Emily Symington3, Doris V Quon4, Adam Giermasz5, Nigel S Key6, Steven W Pipe7, Bella Madan8, Sheng-Chieh Chou9, Robert Klamroth10, 11, Jane Mason12, Flora Peyvandi13, 14, Hua Yu15, Tara M Robinson15, Margareth C Ozelo16. 1Adult Hemophilia Treatment Center, University of California San Francisco, San Francisco, CA, USA.2Hemophilia Comprehensive Care Center, Charlotte Maxeke Johannesburg Academic Hospital, University of the Witwatersrand and NHLS, Johannesburg, South Africa.3Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.4Orthopaedic Hemophilia Treatment Center, Los Angeles, CA, USA.5Hemophilia Treatment Center, University of California Davis, Sacramento, CA, USA.6UNC Blood Research Center, University of North Carolina, Chapel Hill, NC, USA.7Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, MI, USA.8Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom.9Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.10Vascular Medicine and Haemostaseology, Vivantes Klinikum im Friedrichshain, Berlin, Germany.11Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Medical Faculty, University of Bonn, Bonn, Germany.12Queensland Haemophilia Centre, Cancer Care Services, Royal Brisbane and Women’s Hospital, Brisbane and University of Queensland, Brisbane, Australia.13Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Milan, Italy.14Università degli Studi di Milano, Department of Pathophysiology and Transplantation, Milan, Italy.15BioMarin Pharmaceutical Inc., Novato, CA, USA.16Hemocentro UNICAMP, Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, Brazil |
Abstract
Background: Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is a gene transfer therapy for severe hemophilia A (HA) that prevents bleeding by enabling endogenous factor VIII (FVIII) production. Objectives: To evaluate the efficacy and safety of valoctocogene roxaparvovec during year (Y)4 post-treatment. Methods: GENEr8-1 is an open-label, multicenter, phase 3 trial (NCT03370913) that enrolled 134 adult men with severe HA (FVIII ≤1 IU/dL) without FVIII inhibitors. Participants received a single infusion of 6x1013 vg/kg valoctocogene roxaparvovec (intention-to-treat [ITT] population). Bleeding episodes and exogenous FVIII use were self-reported after cessation of regular FVIII prophylaxis, which was scheduled for week (W)4 post-infusion. The primary analysis population for FVIII use and bleeding rate was the rollover population, which included 112 human immunodeficiency virus (HIV)-negative participants who enrolled from a prospective, non-interventional study using FVIII prophylaxis (270-902). FVIII activity (per chromogenic substrate assay [CSA] and one-stage assay [OSA]) and the Haemophilia-Specific Quality of Life Questionnaire for Adults (Haemo-QOL-A) were assessed in the modified ITT (mITT) population, which included the 132 HIV-negative participants. Safety and corticosteroid use were assessed in the ITT population. Return to prophylaxis was defined as “usual FVIII prophylaxis” administered at least once per week for ≥4 consecutive weeks or ≥2 emicizumab injections within 31 days. Alanine aminotransferase (ALT) elevation was defined as ALT >upper limit of normal or ALT ≥1.5x baseline. Results: Overall, 118/134 ITT participants completed 208 weeks or more of follow-up (1 participant discontinued during Y4 due to death unrelated to treatment). Mean and median mITT FVIII per CSA were 16.1 and 6.7 IU/dL, respectively (27.1 and 13.5 IU/dL per OSA, respectively; Figure 1), in line with W156. During Y4, the mean annualized rate of treated bleeds was 0.9 (standard deviation [SD], 2.3) bleeds/y in the rollover population, an 81.3% reduction from baseline and consistent with previous data cuts (Figure 2); 81/110 (73.6%) participants had no treated bleeds during Y4. Similar to previous years, mean annualized FVIII infusion rate decreased 92.2% from baseline to W208 (mean, 10.6 infusions/y; median, 0.0 infusions/y). Health-related quality of life, as measured by mean Haemo-QOL-A Total Score at W208, improved 6.2 points from baseline (95% confidence interval, 3.9–8.4; P <0.0001), the fourth consecutive year at which the change exceeded the anchor-based clinically important difference of 5.5. Of the 24/134 participants who resumed prophylaxis with either FVIII or emicizumab, 11 did so during Y4. During Y4, 106/131 (80.9%) participants experienced an adverse event (AE), 10/131 (7.6%) experienced a treatment-related AE, 13/131 (9.9%) experienced a serious AE, and none experienced a treatment-related serious AE; no AEs led to study discontinuation in Y4. The most common AE during Y4 was ALT elevation, which occurred in 56/131 (42.7%) ITT participants (mostly grade 1–2; 1/131 [0.8%] participant experienced an ALT elevation grade ≥3). No participants initiated immunosuppressants for ALT elevation during Y4. Conclusions: After 4 years of follow-up, valoctocogene roxaparvovec continues to provide long-term FVIII expression, bleed control, and improvements in health-related quality of life for participants with severe HA, consistent with earlier time points. Importantly, no new safety signals emerged.
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