OC 20.1 - Bleeding, FVIII activity, and safety 3 years after gene transfer with valoctocogene roxaparvovec: Results from GENEr8-1

Sunday, June 25, 2023

14:45 – 15:00 ET

Room: 517

Session Available As: Live-Stream and On-Demand

Presenting Author(s)

Johnny Mahlangu, MD (he/him/his)

Professor and Director
Haemophilia Comprehensive Care Centre, Charlotte Maxeke Johannesburg Academic Hospital, University of the Witwatersrand and National Health Laboratory Service, Johannesburg, South Africa
Johannesburg, Gauteng, South Africa

Co-Author(s)

Annette von Drygalski, MD

Director, Hemophilia & Thrombosis Treatment Center
University of California San Diego
La Jolla, California, United States
Susan Shapiro, MD, PhD (she/her/hers)

Consultant Hematologist
Oxford University Hospitals National Health Service Foundation Trust, Oxford, UK
Oxford, England, United Kingdom
Sheng-Chieh Chou, MD. (he/him/his)

Hematologist
Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital
Taipei, Taipei, Taiwan (Republic of China)
Margareth C. Ozelo, MD, PhD (she/her/hers)

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

Director
The National Hemophilia Center, and Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Tel Aviv University, Tel Aviv, Israel
Yehud-Monosson, HaMerkaz, Israel
Flora Peyvandi, MD, PhD (she/her/hers)

Director
IRCCS Ca' Granda Maggiore Hospital Foundation, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milano, Italy; Università degli Studi di Milano, Department of Pathophysiology and Transplantation, Milano, Italy
Milano, Lombardia, Italy
Bella Madan, MD FRCP FRCPath

Consultant Haematologist
Guy's & St. Thomas’ NHS Foundation Trust, London, UK
London, England, United Kingdom
Michael A. Laffan, MD

Professor
Centre for Haematology, Imperial College London, London, UK
London, England, United Kingdom
AD

Amy L. Dunn

Director
Oncology and Bone Marrow Transplant, Nationwide Children's Hospital and The Ohio State University College of Medicine, OH, USA
Ohio, Ohio, United States
JM

Jane Mason

Consultant Haematologist and Director
Queensland Haemophilia Centre, Cancer Care Services, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia
Brisbane, Queensland, Australia
Doris V. Quon, MD, PhD (she/her/hers)

Medical Director, Orthopaedic Hemophilia Treatment Center
Luskin Orthopaedic Institute for Children
Los Angeles, California, United States
AL

Andrew D. Leavitt

Professor and Medical Director
Adult Hemophilia Treatment Center, University of California San Francisco, San Francisco, CA, USA
San Francisco, California, United States
Johannes Oldenburg, MD (he/him/his)

Professor, Chairman and Director
University Clinic Bonn AöR, Institute of Experimental Haematology and Transfusion Medicine, Bonn, Germany
Bonn, Nordrhein-Westfalen, Germany
HC

Hervé Chambost

Professor and Head of the Comprehensive Care Centre for Congenital Bleeding Disorders
AP-HM, Department of Pediatric Hematology Oncology, Children Hospital La Timone & Aix Marseille University, INSERM, INRA, C2VN, Marseille, France
Marseille, Provence-Alpes-Cote d'Azur, France
MR

Mark T. Reding

Professor and Director
Center for Bleeding and Clotting Disorders, University of Minnesota, Minneapolis, MN, USA
Minneapolis, Minnesota, United States
KJ

Kala Jayaram

Executive Medical Director, Pharmacovigilance
BioMarin Pharmaceutical Inc., Novato, CA, USA
Novato, California, United States
HY

Hua Yu

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

Tara M. Robinson

Medical Director, Clinical Science
BioMarin Pharmaceutical Inc., Novato, CA, USA
Novato, California, United States
Steven W. Pipe, MD

Professor of Pediatrics and Pathology
University of Michigan, Ann Arbor, MI, USA
Ann Arbor, Michigan, United States

Background: Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) provides endogenous factor VIII (FVIII) production to prevent bleeding in people with severe hemophilia A.

Aims: Evaluate outcomes 3 years after receiving valoctocogene roxaparvovec.

Methods: The open-label, multicenter phase 3 GENEr8-1 trial (NCT03370913) evaluated 6E13 vg/kg valoctocogene roxaparvovec in 134 adult men with severe hemophilia A (FVIII ≤1 IU/dL) without inhibitors. Bleeds and FVIII use were self-reported after regular prophylaxis ended (scheduled for week [W] 4) through data cutoff. Comparisons to baseline on FVIII prophylaxis were performed in 112 HIV-negative participants enrolling from a non-interventional study (rollover population). FVIII activity per chromogenic assay and quality of life (QOL) per Haemo-QOL-A were assessed in 132 HIV-negative participants (modified intent-to-treat [mITT] population). Safety was assessed in all participants.

Results: Median follow-up was 162 weeks (N=134); 131 participants completed W156. Over 3 years in 112 rollover participants, mean annualized treated bleeding rate was 0.8 bleeds/year, mean annualized rate of all bleeds was 1.3 bleeds/year, and mean FVIII utilization was 125 IU/kg/year (Table). During year 3, 73.2% of 110 rollover participants had zero treated bleeds and 61.6% had no bleeds (excluding surgeries/procedures). At W156, mean and median FVIII were 18.8 and 8.4 IU/dL (mITT, N=132; Figure); 11.4%, 56.1%, and 32.6% of mITT participants had FVIII activity ≥40 IU/dL, ≥5 and < 40 IU/dL, and < 5 IU/dL, respectively. Overall, 10/132 (7.6%) participants resumed prophylaxis. Mean Haemo-QOL-A Total Score improvement from baseline to W156 was 6.6 (n=122; P < 0.0001), exceeding the anchor-based clinically important difference (5.5). No new safety signals emerged. Since the previous data cut, 34/134 participants (25.4%) had alanine aminotransferase (ALT) elevation, mostly Grade 1, but none initiated immunosuppressants. Overall, 106/134 (79.1%) used corticosteroids for ALT elevation for median 33 weeks.

Conclusion(s): Valoctocogene roxaparvovec provided robust hemostatic efficacy relative to FVIII prophylaxis for 3 years, with QOL improvement and stable safety.

Learning Objectives:

Upon completion, participants will be able to describe the GENEr8 1 study design and endpoints
Describe the impact of valoctocogene roxaparvovex gene therapy infusion in bleeding rates and FVIII level
Describe the safety profile of valoctocogene roxaparvovex gene therapy infusion in haemophilia A participants in the GENEr8 study