BioMarin Pharmaceutical Inc. · NASDAQ:BMRN
BioMarin Pharmaceutical — Technical Presentation (March 2024)
13 slides from BioMarin Pharmaceutical's technical presentation, Mar 1, 2024
Slide 1: Disclosure – conflict of interest
Internal use Disclosure – conflict of interest ü I have the following potential conflict(s) of interest to report • Name of commercial company: BioMarin Pharmaceutical Inc. • Stock shareholder: BioMarin Pharmaceutical In. 1 01.03.24
Slide 2: Early changes in liver transcriptomic profiles following AAV gene therapy in hemophilia A dog model
Internal use Early changes in liver transcriptomic profiles following adeno-associated viral gene therapy in the severe hemophilia A dog model Presenter: Simon Harris Ismail AM, Batty P, Mo A, Yates B, Harpell L, Menard A, Pender A, Khattak NA, L Razon, Winterborn A, Fong S, and Lillicrap D
Slide 3: Disclosures
Internal use Disclosures • Ismail AM, Yates B, Khattak NA, L Razon, and Fong S are employees and shareholders of BioMarin Pharmaceutical Inc. • Batty P has received research support from, and acted in an advisory role for, BioMarin Pharmaceutical Inc. • Lillicrap D has received research support rom
Slide 4: Background
Internal use Background • Recombinant adeno-associated virus vector (rAAV)-mediated gene transfer is a promising therapeutic approach for genetic disorders such as hemophilia A, a recessive X-linked disorder characterized by excessive bleeding due to deficient or dysfunctional clotting factor VIII (
Slide 5: Aim
Internal use Aim To investigate liver gene expression profiles before and after AAV5-hybrid liver promoter (HLP)-canine-BDD-cFVIII administration in a severe hemophilia A dog model 5 01.03.24
Slide 6: Methods
Internal use Methods Study Design • Nine dogs received a single infusion of 1 of 3 AAV5-HLP-cFVIII vectors at doses Study timeline and test constructs ranging from 6x1013 to 2x1014 vg/kg Peripheral • A liver magnetic resonance image IV infusion cFVIII (MRI) was taken at baseline and HLP A1 A2 A3 B-d
Slide 7: Methods
Internal use Methods Assays • Liver cFVIII DNA and RNA levels were measured using droplet digital PCR (QX ONE, QX200; Bio-Rad, Hercules, CA) • cFVIII activity was measured using an in-house one-stage FVIII assay using pooled canine plasma as a standard • The cellular immune response in peripheral bl
Slide 8: Results: Liver cFVIII expression
Internal use Results Transgene expression in liver biopsies at 3 months post-dose. Liver cFVIII expression A) Vector DNA, B) cFVIII RNA, C) Correlation of vector DNA and RNA, D) Correlation between vector DNA and cFVIII activity in plasma • Levels of vector genomes were A) B) cFVIII vgDNA copies/dip
Slide 9: Results: Immune Responses
Internal use Results Immune Responses • No significant cellular immune responses were observed in peripheral blood mononuclear cells (PBMCs) after gene transfer Cellular immune responses over time HLP-co-SQ-cFVIII, HLP-nco-SQ-cFVIII, 1500 6x1013 vg/kg 4000 8.2x1013 vg/kg CAN 3000 BRO SFUs/1x106 PBMC
Slide 10: Results: Transcriptomics
Internal use Results Transcriptomics • Several gene sets were enriched in the liver at 3 months compared to baseline in the data pooled across all samples • Genes related to signaling receptor activity and cytokine receptor activity, growth factor activity and vascular endothelial growth factor rece
Slide 11: Results: ALT elevations
Internal use Results ALT elevations • One dog experienced 2 ALT elevations Episodes of transaminitis and transient loss of • First elevation directly followed a FVIII expression in a dog treated with 6x1013 planned liver biopsy, and was therefore HLP-co-V3-cFVIII likely to be related to the procedur
Slide 12: Conclusions
Internal use Conclusions • Transcriptomic profiling of canine liver samples indicated that mild activation of B cells, dendritic cells, NK-cell and T-cells with an inflammatory cytokine responses occurred in the liver of AAV5-HLP-cFVIII treated dogs 3 months post gene transfer • We are using both hu
Slide 13: Acknowledgements
Internal use Acknowledgements • Medical writing support was provided by M Amin Ghane, PhD, of AlphaBioCom, a Red Nucleus company, and funded by BioMarin Pharmaceutical Inc. 13 01.03.24
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