LB 01.3 - Relationship between transgene-produced FVIII and bleeding rates 2 years after gene transfer with valoctocogene roxaparvovec: Results from GENEr8-1

Sunday, July 10, 2022

3:15 PM – 3:30 PM

Location: ICC Auditorium

Presentation Format: In-Person

Presenting Author(s)

JM

Johnny Mahlangu, MD

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)

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
Sheng-Chieh Chou, MD.

Hematologist
Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital
Taipei, Taipei, Taiwan (Republic of China)
AD

Amy L. Dunn

Doctor
Nationwide Children's Hospital Division of Haematology, Oncology and Bone Marrow Transplant and The Ohio State University College of Medicine, Columbus, OH, USA
Columbus, Ohio, United States
Annette von Drygalski, MD

Director, Hemophilia & Thrombosis Treatment Center
University of California San Diego
La Jolla, California, United States
RK

Radoslaw Kaczmarek

Postdoctoral Research Associate and Assistant Professor
Indiana University School of Medicine, IUPUI-Wells Center for Pediatric Research, and Hirszfeld Institute of Immunology and Experimental Therapy
Indianapolis, Indiana, United States
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
Michael A. Laffan, MD

Professor
Centre for Haematology, Imperial College London, London, UK
London, England, United Kingdom
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
Bella Madan, MD FRCP FRCPath

Consultant Haematologist
Guy's & St. Thomas’ NHS Foundation Trust, London, UK
London, England, United Kingdom
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
Johannes Oldenburg

Professor, Chairman and Director
University Clinic Bonn AöR, Institute of Experimental Haematology and Transfusion Medicine, Bonn, Germany
Bonn, Nordrhein-Westfalen, Germany
Margareth C. Ozelo, MD, PhD

Professor
Hemocentro UNICAMP, Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
Campinas, Sao Paulo, Brazil
Flora Peyvandi, MD, PhD

Professor of Internal Medicine; Director of the Angelo Bianchi Bonomi Hemophilia & Thrombosis Center
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
Milan, Lombardia, Italy
DQ

Doris V. Quon

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

Mark T. Reding

Professor and Director
Center for Bleeding and Clotting Disorders, University of Minnesota, Minneapolis, MN, USA
Minneapolis, Minnesota, United States
Susan Shapiro, MD, PhD

Consultant Hematologist
Oxford University Hospitals National Health Service Foundation Trust, Oxford, UK
Oxford, England, United Kingdom
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) gene transfer reduced bleeding through endogenous factor VIII (FVIII) production over 2 years in people with severe hemophilia A. The relationship between transgene-produced FVIII activity levels and bleed frequency is not well characterized.

Aims: To assess the relationship between endogenous, transgene-derived FVIII activity and bleeding using phase 3 trial data.

Methods: The open-label, multicenter phase 3 trial GENEr8-1 (NCT03370913) evaluated efficacy and safety of 6x10¹³ vg/kg valoctocogene roxaparvovec in adult men with severe hemophilia A (FVIII ≤1 IU/dL) without inhibitors or anti-AAV5 antibodies. Bleeds and FVIII treatment were self-reported and counted from the end of regular prophylaxis (scheduled for week 4) to data cutoff. Follow-up was divided into 4- or 6-week intervals, where the number of treated joint bleeds was paired with median FVIII activity. Baseline comparisons used the rollover population (112 participants enrolling from a noninterventional study). A negative binomial regression model predicting annualized joint bleeding rate and 95% confidence interval (CI) for given FVIII activity was built using data from all 134 participants.

Results: Median follow-up was 110.9 weeks (n = 134). Overall, 83 (61.9%) participants reported 450 bleeds; 39 (29.1%) participants reported 268 treated bleeds. Of treated bleeds, 56.0% were joint bleeds. In the rollover population, the proportion of participants with no bleeds, regardless of treatment, increased during each year (Table). Using data from 134 participants, the negative binomial model predicted increasing bleeds with decreasing FVIII; 1.4 (95% CI, 0.9–2.2) and 1.0 (95% CI, 0.7–1.5) treated joint bleeds/year were predicted with FVIII of 5 IU/dL per one-stage and chromogenic assay, respectively (Figure).

Conclusion(s): Estimates of treated joint bleeding rates per FVIII activity, particularly using the one-stage assay, align with those using epidemiological data in people with hemophilia A on standard therapy, suggesting transgene-derived FVIII provides similar protection as native or exogenous FVIII.