Biomarin Pharmaceutical Inc. · NASDAQ:BMRN
Biomarin Pharmaceutical — ISTH 2025
14 slides from Biomarin Pharmaceutical's conference presentation, Jun 24, 2025
Slide 1: Mechanisms of AAV Vector Persistence Following Infant Gene Therapy in the Severe Hemophilia A Dog Model
Mechanisms of AAV Vector Persistence Following Infant Gene Therapy in the Severe Hemophilia A Dog Model Paul Batty, Bridget Yates, A.M. Ismail, Laura L. Swystun, Alexandre Menard, Aomei Mo, Lori Harpell, Abbey Pender, Andrew Winterborn, Sandra Salcido, Alyssa Gonzalez, Chan Kyu Kim, Sebastian Brenna
Slide 2: Conflict of Interest Disclosure – Paul Batty
Conflict of Interest Disclosure – Paul Batty • Grant / Research Support: BioMarin • Receipt of honoraria or consultation fees: BioMarin, Octapharma, Pfizer, Novo Nordisk, CSL Behring & INME • Participation in a company sponsored speaker's bureau: n/a • Stock or shareholder: n/a • Spouse/partner: n/a
Slide 3: Canine Hemophilia A
Canine Hemophilia A Similar Genotype • Intron-22 inversion like F8 mutation1 Similar Clinical Phenotype • Spontaneous bleeding events • Treated with recombinant canine FVIII • Inhibitor-prone c. 25% incidence Long-term follow-up >10 years2 (1) Hough C. et al. Thromb Haemost. 2002; 87(4):659-65. (2)
Slide 4: Study Rationale and Aims
Study Rationale and Aims Background: • Adeno-associated viral (AAV) gene therapy is approved for adults with severe hemophilia • Treatment during childhood might prevent the long-term effects of joint bleeding and improve quality of life Aims: To evaluate the safety and efficacy of AAV-canine FVIII
Slide 5: Study Outline
Study Outline Peripheral infusion of AAV5-cFVIIIco • Epigenomic data - 2 months of age in • Treatment age: neonatal (2-weeks, N=2), dogs equivalent to 9 months in humans1 infant (2-months, N=3) • Integration site analysis by target • Target dose: 2e14 vg/kg (2e14 – 9.8e14 vg) enrichment sequencing (
Slide 6: Stable FVIII expression in dogs despite increased liver volumes
Stable FVIII expression in dogs treated at 2-months despite increased liver volumes Liver Volume (MRI) FVIII:C CSA 2-weeks 500 UNO21 Liver volume (mL) 400 BRI21 2-weeks 300 BUX21 200 CAM21 RYE21 100 -20 0 20 40 60 Weeks post-AAV-cFVIII
Slide 7: No bleeds occurred during follow-up for dogs
No bleeds occurred during follow-up for dogs treated at 2-months Whole-blood clot time (WBCT) Bleeding Events 2-weeks 2-weeks 15 WBCT untreated hemophilia A dogs UNO21 UNO21 BRI21 WBCT (minutes) BRI21 10 2-months BUX21 BUX21 2-months 5 CAM21 CAM21 RYE21 Normal RYE21 0 Range 0 20 40 60 80 100 Weeks p
Slide 8: Histopathological evaluation of liver biopsies was normal
Histopathological evaluation of liver biopsies was normal Dogs treated at 2-weeks Dogs treated at 2-months UNO21 BRI21 BUX21 CAM21 RYE21 Samples obtained at 12-month liver biopsy No evidence of chronic inflammation or tumor
Slide 9: Stable circular full-length vector genomes were observed in dogs
Stable circular full-length vector genomes were observed in dogs treated at 2-months Circular full-length FVIII RNA correlates with FVIII expression (3, 6, and 12 months post-AAV-cFVIII) vector genomes cFVIII-SQ transcripts (normalized to B2M) 0.005 2-weeks 4 r= 0.88 Circular full-length vector UNO2
Slide 10: AAV integration was seen at low frequencies in all samples
AAV integration was seen at low frequencies in all samples Integrated vector Concatameric versus integrated sequencing reads 100 90 2-weeks 80 Vector-Vector Frequency (%) 70 (Concatameric) Reads 60 Vector-Genome (Integrated) Reads 50 Episomal or integrated 40 2-months Vector-Vector concatemerized ve
Slide 11: AAV integration was seen at low frequencies in all samples
AAV integration was seen at low frequencies in all samples Estimated unique integration sites IS location – in-gene vs intergenic Unique Insertion Sites (n) 1500 Estimated unique #IS/1000 cells 2-weeks 8 UNO21 BRI21 Upstream 1000 6 In-Gene 2-months Downstream 4 500 Unannotated BUX21 CAM21 2 RYE21 0
Slide 12: Top Common Integration Sites (CIS)
Top 5 Common Integration Sites (CIS) Rank Count Chromosome Locus Dimension (nt) Gene(s) Top 1 20 13 63203367 93074 AFP, ALB 1, 2 Top 2 16 13 33380817 1027 MIR30D 1 Top 3 14 1 122221447 231317 MIR578 1 Top 4 13 X 124891115 9853 CLIC2 1 Top 5 5 8 69727858 98019 MIR410 1 CIS identified in Queen’s Unive
Slide 13: Conclusions
Conclusions Dogs treated at 2-weeks • Low (<3%) FVIII:C, improved WBCT • Stable FVIII expression despite liver expansion Dogs treated at 2-months • Normalized bleeding phenotype • Stable full-length circular vector genome levels • Low rates of vector integration Integration analysis • No evidence of
Slide 14: Acknowledgements
Acknowledgements pab7@queensu.ca & paul.batty@ucl.ac.uk • Hemophilia colony dogs @paulbatty.bsky.social @paul_batty1 • Queen’s University • David Lillicrap • Alex Menard • Lori Harpell • Aomei Mo • Abbey Pender • BioMarin • Sylvia Fong • Britta Handyside • Mohamed Ismail Ashrafali • Bridget Yates