Three-year outcomes of valoctocogene roxaparvovec gene therapy for hemophilia A

Bella Madan; Margareth C Ozelo; Priyanka Raheja; Emily Symington; Doris V Quon; Andrew D Leavitt; Steven W Pipe; Gillian Lowe; Gili Kenet; Mark T Reding; Jane Mason; Michael Wang; Annette von Drygalski; Robert Klamroth; Susan Shapiro; Hervé Chambost; Amy L Dunn; Johannes Oldenburg; Sheng-Chieh Chou; Flora Peyvandi; Carolyn M Millar; Dane Osmond; Hua Yu; Ebony Dashiell-Aje; Tara M Robinson; Johnny Mahlangu

doi:10.1016/j.jtha.2024.04.001

Three-year outcomes of valoctocogene roxaparvovec gene therapy for hemophilia A

J Thromb Haemost. 2024 Apr 12:S1538-7836(24)00184-3. doi: 10.1016/j.jtha.2024.04.001. Online ahead of print.

Authors

Bella Madan¹, Margareth C Ozelo², Priyanka Raheja³, Emily Symington⁴, Doris V Quon⁵, Andrew D Leavitt⁶, Steven W Pipe⁷, Gillian Lowe⁸, Gili Kenet⁹, Mark T Reding¹⁰, Jane Mason¹¹, Michael Wang¹², Annette von Drygalski¹³, Robert Klamroth¹⁴, Susan Shapiro¹⁵, Hervé Chambost¹⁶, Amy L Dunn¹⁷, Johannes Oldenburg¹⁸, Sheng-Chieh Chou¹⁹, Flora Peyvandi²⁰, Carolyn M Millar²¹, Dane Osmond²², Hua Yu²², Ebony Dashiell-Aje²², Tara M Robinson²², Johnny Mahlangu²³

Affiliations

¹ Centre for Haemostasis and Thrombosis, Guy's and St Thomas' National Health Service Trust, London, United Kingdom. Electronic address: Bella.Madan@gstt.nhs.uk.
² Hemocentro University of Campinas, Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.
³ Haemophilia Centre, Royal London Hospital, Barts Health National Health Service Trust, London, United Kingdom.
⁴ Haemophilia Centre, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, United Kingdom.
⁵ Orthopaedic Hemophilia Treatment Center, Los Angeles, California, USA.
⁶ Hemophilia Treatment Center, University of California San Francisco, San Francisco, California, USA.
⁷ Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, Michigan, USA.
⁸ West Midlands Adult Haemophilia Comprehensive Care Centre, University Hospitals Birmingham National Health Service Foundation Trust, Birmingham, United Kingdom.
⁹ The National Hemophilia Center and Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel HaShomer, Tel Aviv University, Tel Aviv, Israel.
¹⁰ Center for Bleeding and Clotting Disorders, University of Minnesota, Minneapolis, Minnesota, USA.
¹¹ Queensland Haemophilia Centre, Cancer Care Services, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia; School of Medicine, University of Queensland, Brisbane, Queensland, Australia.
¹² Hemophilia and Thrombosis Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
¹³ Department of Medicine, University of California San Diego, La Jolla, California, USA.
¹⁴ Vascular Medicine and Haemostaseology, Vivantes Klinikum im Friedrichshain, Berlin, Germany; Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Medical Faculty, University of Bonn, Bonn, Germany.
¹⁵ Blood Theme Oxford Biomedical Research Centre, Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom; Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; Oxford National Institute for Health Research Biomedical Research Centre, Oxford, United Kingdom.
¹⁶ AP-HM, Department of Pediatric Hematology Oncology, Children Hospital La Timone & Aix Marseille University, Institut national de la santé et de la recherche médicale, Institut national de la recherche agronomique, Centre recherche en CardioVasculaire et Nutrition, Marseille, France.
¹⁷ The Division of Hematology, Oncology, and Blood and Marrow Transplantation at Nationwide Children's Hospital and Ohio State University College of Medicine, The Ohio State University, Columbus, Ohio, USA.
¹⁸ Institute of Experimental Haematology and Transfusion Medicine and Center for Rare Diseases, University Hospital Bonn, Bonn, Germany.
¹⁹ Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
²⁰ Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico and Fondazione Luigi Villa, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
²¹ Centre for Haematology, Imperial College London, London, United Kingdom; Imperial College Healthcare National Health Service Trust, London, United Kingdom.
²² BioMarin Pharmaceutical Inc, Novato, California, USA.
²³ Hemophilia Comprehensive Care Center, Charlotte Maxeke Johannesburg Academic Hospital, University of the Witwatersrand and National Health Laboratory Service, Johannesburg, South Africa.

PMID: 38614387
DOI: 10.1016/j.jtha.2024.04.001

Abstract

Background: Valoctocogene roxaparvovec transfers a human factor (F)VIII coding sequence into hepatocytes of people with severe hemophilia A to provide bleeding protection.

Objectives: To present 3-year efficacy and safety in the multicenter, open-label, single-arm, phase 3 GENEr8-1 trial.

Methods: GENEr8-1 enrolled 134 adult males with severe hemophilia A who were receiving FVIII prophylaxis. Efficacy endpoints included annualized bleeding rate, annualized FVIII utilization, FVIII activity (chromogenic substrate assay; imputed as 1 IU/dL at baseline and 0 IU/dL after discontinuation), and the Haemophilia-Specific Quality of Life Questionnaire for Adults. Safety was assessed by adverse events (AEs).

Results: At week 156, 131 of 134 participants remained in the study; overall, 17 of 134 resumed prophylaxis. Mean annualized bleeding rate for treated bleeds decreased from 4.8 (SD, 6.5) bleeds/y at baseline to 0.8 (SD, 2.3; P < .0001) bleeds/y after prophylaxis (prophylaxis cessation to last follow-up) and 0.97 (SD, 3.48) bleeds/y during year 3. Annualized FVIII utilization decreased 96.8% from baseline after prophylaxis and 94.2% during year 3. At week 156, mean and median FVIII activity were 18.4 (SD, 30.8) and 8.3 IU/dL, respectively. FVIII activity decrease was lower between years 2 and 3 than between years 1 and 2. At the end of year 3, clinically meaningful improvements in the Haemophilia-Specific Quality of Life Questionnaire for Adults Total Score were observed (mean change from baseline, 6.6; 95% CI, 4.24-8.87; P < .0001). Mild alanine aminotransferase elevations remained the most common AE during year 3 (23.7% of participants). A serious AE of B-cell acute lymphoblastic leukemia was considered unrelated to treatment.

Conclusion: Hemostatic efficacy was maintained, and safety remained unchanged from previous years.

Keywords: adeno-associated virus; clinical trial; gene therapy; health-related quality of life; hemophilia A; phase 3.