Glenn F. Pierce, MD, PhD
Highlights From the 17th Annual Congress of EAHAD

Human liver biopsy analysis reveals lower RNA transcription may contribute to a decline in FVIII levels following AAV5-hFVIII-SQ gene therapy

Presenting Author: Glenn F. Pierce, MD, PhD

A. M. Ismail1, B. Yates1, K. Jayaram1, G. Kenet2,3, J. Mason4, J. Mahlangu5, 6, A. L. Dunn7, S. Shapiro8, 9, M. Wang10, F. Peyvandi11, 12, A. Giermasz13, R. Kazmi14, N. S. Key15, T. M. Robinson1, S. Fong1

  1. BioMarin Pharmaceutical Inc., Novato, USA
  2. Amalia Biron Research Institute of Thrombosis and Hemostasis, Sackler School of Medicine, Tel Aviv, Israel
  3. Sheba Medical Center, Tel Hashomer, Israel
  4. Queensland Haemophilia Centre, Cancer Care Services, Royal Brisbane and Women’s Hospital, University of Queensland, Brisbane, QLD, Australia
  5. Haemophilia Comprehensive Care Centre, Charlotte Maxeke Johannesburg Academic Hospital, South Africa
  6. Department of Molecular Medicine and Haematology, University of Witwatersrand and NHLS, Johannesburg, South Africa
  7. The Division of Hematology, Oncology, and BMT, Nationwide Children’s Hospital and The Ohio State University College of Medicine, Columbus, USA
  8. Oxford Haemophilia and Thrombosis Centre, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, UK
  9. Radcliffe Department of Medicine, Oxford University, Oxford, UK
  10. Hemophilia and Thrombosis Center, University of Colorado School of Medicine, Aurora, USA
  11. Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca’ Granda Ospedale Maggiore Policlinico, Italy
  12. Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
  13. Hemophilia Treatment Center, University of California, Davis, Sacramento, USA
  14. London, University Hospital Southampton and National Institute for Health and Care Research Clinical Research Facility, Southampton, UK
  15. UNC Blood Research Center, University of North Carolina, Chapel Hill, USA

Data Points

Figure 1: Liver Biopsy Samples

This graphic shows the FVIII activity level in the liver following biopsy up to 4.1 years after receiving valoctogene roxaparvovec. FVIII activity level varied across patients, and two patients initially had high FVIII activity, but has since declined to < 3 IU/dL.

Figure 2: Episome Persistence

This figure shows the persistence of the episomal transgene over time in patients who received valoctogene roxaparvovec. The mean circular full-length episomes in the study participants were 3.60 ± 1.99 (range, 1.53–7.82) vg/diploid cell and did not decrease overtime. The circular full-length episomes were positively correlated with FVIII activity (r = 0.61, P = 0.026).

Figure 3: Transgene Expression

These figures show the expression of FVIII-SQ over time related to factor activity. The mean FVIII-SQ RNA transcript levels in participants with FVIII > 3 IU/dL were 78.5 ± 50.9 (range, 7.6–152.9; n = 11) transcripts/ng RNA. Additionally, two participants' FVIII activity declined to < 3 IU/dL, with poor RNA transcript levels observed (0.15 and 1.68 transcripts/ng RNA). Despite this decline, the level of transduction and full-length vector genomes remained similar to those with FVIII > 3 IU/dL (1.95–2.2 vg/diploid cell).

Figure 4:Transcriptional Efficiency

These graphics show the transcriptional efficiency of valoctogene roxaparvovec in patients 138-170 weeks after infusion. Participants with FVIII that declined to < 3 IU/dL (n = 2) had a significantly lower RNA/DNA ratio than participants with FVIII > 3 IU/dL (n = 5) over a similar time period (Welch’s t-test, P = 0.034).


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