Efficacy and Safety of Valoctocogene Roxaparvovec Adeno-associated Virus Gene Transfer for Severe Hemophilia A: Results from the Phase 3 GENEr8-1 Trial

M.C Ozelo¹, J. Mahlangu², KJ. Pasi³, A. Giermasz⁴, A.D Leavitt⁵, M. Laffan⁶, E. Symington⁷, D.V Quon⁸, J.-D. Wang⁹, K. Peerlinck¹⁰, S. Pipe¹¹, B. Madan¹², N.S Key¹³, G.F Pierce¹⁴, B. O’Mahony^15,16, R. Kaczmarek^17,18, A. Lawal¹⁹, M. Huang¹⁹, W.Y. Wong¹⁹, B. Kim¹⁹, GENEr8-1 Trial Group

¹Hemocentro UNICAMP, Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, Brazil, ²Hemophilia Comprehensive Care Center, Charlotte Maxeke Johannesburg Academic Hospital, University of the Witwatersrand and NHLS, Johannesburg, South Africa, ³Barts and the London School of Medicine and Dentistry, London, United Kingdom, ⁴Hemophilia Treatment Center, University of California Davis, Sacramento, United States, ⁵University of California, San Francisco, United States, ⁶Centre for Haematology, Imperial College London, London, United Kingdom, ⁷Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom, ⁸Orthopaedic Hemophilia Treatment Center, Los Angeles, United States, ⁹Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan, Province of China, ¹⁰Department of Vascular Medicine and Haemostasis and Haemophilia Centre, University Hospitals Leuven, Leuven, Belgium, ¹¹Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, United States, ¹²Guy's & St. Thomas’ NHS Foundation Trust, London, United Kingdom, ¹³UNC Blood Research Center, University of North Carolina, Chapel Hill, United States, ¹⁴Independent Consultant, La Jolla, United States, ¹⁵Irish Haemophilia Society, Dublin, Ireland, ¹⁶Trinity College, Dublin, Ireland, ¹⁷Department of Pediatrics, Indiana University School of Medicine, IUPUI-Wells Center for Pediatric Research, Indianapolis, United States, ¹⁸Laboratory of Glycobiology, Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland, ¹⁹BioMarin Pharmaceutical Inc., Novato, United States

Abstract Number: OC 26.1

Meeting: ISTH 2021 Congress

Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia Gene Therapy

Background: Valoctocogene roxaparvovec transfers a factor VIII (FVIII-SQ) gene to hepatocytes using an adeno-associated virus vector, enabling endogenous FVIII production in individuals with congenital hemophilia A.

Aims: To assess efficacy and safety of valoctocogene roxaparvovec for severe hemophilia A.

Methods: A phase 3, single-arm, open-label trial (GENEr8-1, NCT03370913) enrolled adult men with severe hemophilia A (FVIII ≤1 IU/dL) on FVIII prophylaxis negative for FVIII inhibitors. Participants received a single 6×10¹³ vg/kg valoctocogene roxaparvovec infusion. Primary endpoint was change from baseline in median FVIII activity (chromogenic assay) during weeks 49–52 in HIV-negative participants. Secondary endpoints were change from baseline in annualized treated bleed and FVIII infusion rates for participants rolling over from a noninterventional study. Adverse events (AEs) were monitored.

Results: Overall, 134 participants (median [range] age, 30 [18, 70] years) were dosed and completed 49–52 weeks. In 132 HIV-negative participants, chromogenic FVIII activity increased by a mean (95% CI)/median of 41.9 (34.1–49.7)/22.9 IU/dL at weeks 49–52 (Figure 1).

Mean and median FVIII activity per chromogenic substrate assay in 4- and 6-week intervals
In 112 rollover participants, mean annualized bleeding and FVIII infusion rates decreased after week 4 by 84% and 99%, respectively, from baseline (Figure 2).

Mean and median annualized bleeding rate and annualized FVIII infusion rate at baseline and after week 4

After week 4, 89/112 (79.5%) participants experienced 0 treated bleeds vs 36/112 (32.1%) at baseline; 2/134 (1.5%) resumed prophylaxis. All 134 participants reported an AE; 22 (16.4%) reported serious AEs. Alanine aminotransferase elevations occurred in 115/134 (86%) participants; of these, 106 and 39 received corticosteroids and/or other immunosuppressants, respectively, per protocol, and 95.6% of events resolved. Other common AEs (≥30%) were headache (38%), nausea (37%), and aspartate aminotransferase elevation (35%). No participants developed FVIII inhibitors or thromboembolism. Additional data will be presented at ISTH.

Conclusions: In the largest-to-date hemophilia gene therapy trial, valoctocogene roxaparvovec yielded meaningful endogenous FVIII expression in participants with severe hemophilia A, resulting in significant decreases in bleeding and FVIII infusion.

To cite this abstract in AMA style:

C Ozelo M, Mahlangu J, Pasi K, Giermasz A, D Leavitt A, Laffan M, Symington E, V Quon D, Wang J-, Peerlinck K, Pipe S, Madan B, S Key N, F Pierce G, O’Mahony B, Kaczmarek R, Lawal A, Huang M, Wong WY, Kim B, GENEr8-1 Trial Group . Efficacy and Safety of Valoctocogene Roxaparvovec Adeno-associated Virus Gene Transfer for Severe Hemophilia A: Results from the Phase 3 GENEr8-1 Trial [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/efficacy-and-safety-of-valoctocogene-roxaparvovec-adeno-associated-virus-gene-transfer-for-severe-hemophilia-a-results-from-the-phase-3-gener8-1-trial/. Accessed November 30, 2023.

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