BioMarin Pharmaceutical Inc. · NASDAQ:BMRN
BioMarin Pharmaceutical — Technical Presentation (2024)
11 slides from BioMarin Pharmaceutical's technical presentation, Apr 9, 2024
Slide 1: Human liver biopsy analysis reveals lower RNA transcription may contribute to FVIII decline
European Association for Haemophilia and Allied Disorders (EAHAD) 2024 Human liver biopsy analysis reveals SLAM session 6: OR06 lower RNA transcription may contribute to a decline in FVIII levels following AAV5-hFVIII-SQ gene therapy Ashrafali M Ismail, PhD1; Bridget Yates, BS1; Kala Jayaram, MD1; G
Slide 2: Disclosures
Disclosures • Ashrafali M Ismail is a BioMarin Inc. employee and stockholder 2
Slide 3: FVIII activity declines over time following AAV5 gene therapy
FVIII activity declines over time following AAV5 gene therapy • Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is a gene therapy for hemophilia A that uses an AAV5 vector to deliver a B-domain-deleted hFVIII coding sequence controlled by a liver- selective promoter • A single infusion has provided hemo
Slide 4: Aims
Aims • To assess rAAV5-HLP-co-hFVIII-SQ vector transduction efficiency • To characterize and quantify episomal forms of vector DNA • To quantify transgene expression (hFVIII-SQ RNA) and correlate with FVIII activity • To examine liver histopathology FVIII, factor VIII; hFVIII-SQ, B-domain-deleted hu
Slide 5: Sub-study design
Sub-study design • Optional sub-study of the phase 2 trial and the phase 3, single-arm, open-label GENEr8-1/3 trials assessing 6x1013 vg/kg valoctocogene roxaparvovec in adult males with severe hemophilia A (FVIII ≤1 IU/dL) • Biopsy exclusion criteria were any condition, detected via liver ultrasoun
Slide 6: Collection of liver biopsy samples
Collection of liver biopsy samples • Biopsy collection ranged from early post-gene transfer to beyond 4 years • Participants’ FVIII activity level varied • Two participants originally had high FVIII activity, but it had since declined to <3 IU/dL • Three biopsy samples collected at the time of trans
Slide 7: Circular full-length episomes persist through years of post-gene therapy follow-up
Circular full-length episomes persist through 4 years of post-gene therapy follow-up • Circular full-length episomes did not decrease over time – Mean ± SD circular full-length episomes in the study participants were 3.60 ± 1.99 (range, 1.53–7.82) vg/diploid cell • Circular full-length episomes corr
Slide 8: FVIII-SQ RNA expression influences FVIII response
FVIII-SQ RNA expression influences FVIII response • Mean ± SD hFVIII-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 • Two participants’ FVIII activity declined to <3 IU/dL: – Poor RNA transcript levels (0.15 and 1.68 transc
Slide 9: Transcriptional efficiency is significantly lower in those with FVIII <3 IU/dL
Transcriptional efficiency is significantly lower in those with FVIII <3 IU/dL, suggesting transgene silencing may mediate the decline of FVIII expression following AAV5-hFVIII-SQ treatment • Participants with FVIII that declined to <3 IU/dL (n = 2) had a significantly lower RNA/DNA ratio than parti
Slide 10: Conclusions
Conclusions • Follow-up liver biopsy analysis of AAV5-hFVIII-SQ gene therapy suggests efficient hepatocyte transduction occurred • Full-length circular episome levels were persistent and did not decrease over time • FVIII-SQ RNA expression impacts FVIII activity and may contribute to decline in FVII
Slide 11: Acknowledgements
Acknowledgements Thank you to all the trial participants, their families, study-site personnel, and investigators. • Funding for this study was provided by BioMarin Pharmaceutical Inc. • Medical writing and editorial support were provided by Taryn Bosquez-Berger, PhD, of AlphaBioCom, a Red Nucleus c
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