OC 30.2 - Efficacy and safety of valoctocogene roxaparvovec 4 years after gene transfer in GENEr8-1

Monday, June 24, 2024

09:45 – 10:00 ICT

Room: Plenary Hall

Presenting Author(s)

Andrew D. Leavitt, MD

Professor and Medical Director
Adult Hemophilia Treatment Center, University of California San Francisco
San Francisco, California, United States

Co-Author(s)

Johnny Mahlangu, MBBCh, MMed

Head of Department and Principal Haematologist
Department of Molecular Medicine and Haematology, University of the Witwatersrand, National Health Laboratory Service, and Charlotte Maxeke Johannesburg Academic Hospital
Johannesburg, Gauteng, South Africa
Priyanka Raheja

Consultant Haematologist
Barts Health NHS Trust
London, England, United Kingdom
ES

Emily Symington

Consultant Haematologist
Cambridge University Hospitals NHS Foundation Trust
Cambridge, England, United Kingdom
Doris V. Quon

Medical Director
Orthopaedic Hemophilia Treatment Center at Orthopaedic Institute for Children Los Angeles
Los Angeles, California, United States
AG

Adam Giermasz

Associate Professor of Medicine
Division of Hematology/Oncology, Hemophilia Treatment Center, University of California Davis
Sacramento, California, United States
GK

Gili Kenet

CONSULTANT PAEDIATRIC HAEMATOLOGIST
National Hemophilia Center Sheba Medical center, Tel Hashomer & Amalia Biron Research Institute of Thrombosis & Hemostasis, Tel Aviv University, Israel,
Tel Aviv, Tel Aviv, Israel
Gillian Lowe

Consultant Haematologist
West Midlands Adult Haemophilia Comprehensive Care Centre, University Hospitals Birmingham NHS Foundation Trust
Birmingham, England, United Kingdom
NK

Nigel S. Key

Professor
Division of Hematology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Chapel Hill, North Carolina, United States
Carolyn M. Millar, MD PhD

Consultant Haematologist
Imperial College Healthcare NHS Trust & Imperial College London
London, England, United Kingdom
Steven W. Pipe, MD

Professor of Pediatrics and Pathology
University of Michigan
Ann Arbor, Michigan, United States
Bella Madan, MD FRCP FRCPath

Consultant Haematologist
Guy's & St. Thomas' NHS Foundation Trust
London, England, United Kingdom
Sheng-Chieh Chou, MD.

Hematologist
Department of Internal Medicine, National Taiwan University Hospital
Taipei, Taipei, Taiwan (Republic of China)
Robert Klamroth, MD

Head of Department
Vivantes Klinikum, Friedrichshain, Berlin, Germany
Berlin, Berlin, Germany
JM

Jane Mason

Consultant Haematologist and Director
Queensland Haemophilia Centre, Cancer Care Services, Royal Brisbane and Women’s Hospital
Brisbane, Queensland, Australia
HC

Hervé Chambost

Professor and Head
AP-HM, Department of Pediatric Hematology Oncology, Children Hospital La Timone & Aix Marseille University, INSERM, INRA, C2VN
Marseille, Provence-Alpes-Cote d'Azur, France
Flora Peyvandi, MD, PhD

Full Professor
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Università degli Studi di Milano, Department of Pathophysiology and Transplantation
Milan, Lombardia, Italy
HY

Hua Yu

Director of Biostatistics
BioMarin Pharmaceutical Inc.
Novato, California, United States
TR

Tara M. Robinson

Senior Medical Director
BioMarin Pharmaceuticals Inc.
Novato, California, United States
Margareth C. Ozelo, MD, PhD

Professor
Hemocentro UNICAMP, Department of Internal Medicine, School of Medical Sciences, University of Campinas
Campinas, Sao Paulo, Brazil

Background: Valoctocogene roxaparvovec (AAV5-hFVIII-SQ), a gene transfer therapy for severe hemophilia A, enables endogenous factor VIII (FVIII) production to prevent bleeding.

Aims: Evaluate efficacy and safety outcomes 4 years post-valoctocogene roxaparvovec treatment.

Methods: In the open-label, multicenter, phase 3 GENEr8-1 trial (NCT03370913), 134 adult men with severe hemophilia A (FVIII ≤1 IU/dL) without FVIII inhibitors received 6E13 vg/kg valoctocogene roxaparvovec (intention-to-treat [ITT] population). Bleeds and FVIII use were self-reported after regular prophylaxis cessation (scheduled week [W]4). The rollover population, which included 112 HIV-negative participants who enrolled from a non-interventional study, was used for comparisons with baseline FVIII use and bleeding rate. Chromogenic (CSA) and one-stage assay (OSA) FVIII activity was assessed in 132 HIV-negative participants (modified ITT [mITT] population). Safety was assessed in the ITT population.

Results: In the ITT population, 118/134 participants completed W208; 24/134 participants resumed prophylaxis. In the rollover population, mean annualized treated bleeding rate was 0.8 bleeds/y, mean annualized bleeding rate for all bleeds was 1.3 bleeds/y, and mean annualized FVIII infusion rate was 6.1 infusions/y over 4 years (Table). During year 4, 81/110 (73.6%) participants had 0 treated bleeds and 68/110 (61.8%) participants had 0 bleeds regardless of treatment. At W208, mean CSA and OSA FVIII activity was 16.1 and 27.1 IU/dL, respectively, in the mITT population (18.0 and 25.5 IU/dL at W260 for the mITT subgroup dosed ≥5 years prior; Figure); 10/130 (7.7%), 68/130 (52.3%), 18/130 (13.8%), and 34/130 (26.2%) participants had CSA FVIII activity ≥40, ≥5 to < 40, ≥3 to < 5, and < 3 IU/dL, respectively. During year 4, the most common adverse event was alanine aminotransferase (ALT) elevation (56/131 participants; ALT >upper limit of normal or ≥1.5x baseline); no participants initiated immunosuppressants for ALT elevation.

Conclusion(s): Bleed control and FVIII expression were maintained 4 years post-valoctocogene roxaparvovec treatment. No new safety signals emerged.