BioMarin Pharmaceutical Inc. · NASDAQ:BMRN
BioMarin Pharmaceutical — Technical Presentation (2024)
22 slides from BioMarin Pharmaceutical's technical presentation, Apr 9, 2024
Slide 1: Immunoadsorption Plasmapheresis for the Removal of Plasma Immunoglobulins to Enable Repeat Dosing
Immunoadsorption Plasmapheresis for the Removal of Plasma Immunoglobulins to Enable Repeat Rose Administration with an AAV5 Gene Therapy Vector. Brian R Long1, M Benjamin Hock1, Charles A O’Neill1, Jeremy Arens1, Theresa Seitel1, Lucy Crockett1, Francis Relouzat2, Claire-Maëlle Fovet2, Nathalie Dere
Slide 2: Disclosures
Internal use Disclosures Brian Long is an employee and stockholder of BioMarin Pharmaceutical Inc 2
Slide 3: Executive summary
Executive summary • The presence of pre-existing anti-AAV antibodies may limit the efficacy of AAV- delivered gene therapy • Most clinical trials exclude patients with pre-existing immunity to AAV • Depletion of anti-AAV antibodies by IAP is a strategy that could allow successful vector administrati
Slide 4: Neutralizing and/or binding antibodies impact the efficacy of AAV-vectored gene therapy
Neutralizing and/or binding antibodies impact the efficacy of AAV-vectored gene therapy • Due to a reduction in the efficacy of AAV-gene therapy, patients who test positive for AAV5 TAb and AAV NAb antibodies are ineligible for treatment1-4 AAV, adeno-associated virus; AAV NAb, AAV neutralizing anti
Slide 5: We have defined global seroprevalence of AAV by serotype
We have defined global seroprevalence of AAV by serotype BMN 270-901 Global Seroprevalence Study (N = 540) AAV5 exhibits the lowest seroprevalence Pre-existing titers range widely over 5 logs, globally (~30%) with AAV5 having the lowest mean and smallest range AAV antibody titer Global hemophilia A
Slide 6: Rationale
Rationale • Develop strategies that enable patients with pre-existing antibodies to be considered for treatment and those with treatment-induced antibodies to be considered for additional AAV treatment Aims: Investigate the applicability of immunoadsorption plasmapheresis to deplete both pre- existi
Slide 7: Plasmapheresis: a routine medical procedure with an excellent safety profile
Plasmapheresis: a routine medical procedure with an excellent safety profile • Plasmapheresis: removes and returns or exchanges blood plasma from and to the blood circulation • IAP separates plasma from blood cells, selectively removes antibodies by ex vivo immunoadsorption, and returns antibody-dep
Slide 8: Experimental outline
Experimental outline • Animals were sensitized with a single IV dose of AAV5-bCG at 6x1013 vg/kg • Multiple rounds of IAP were performed over multiple days as tolerated by each animal; at minimum, 1 day with 4 rounds of IAP • Following IAP procedure, animals were administered repeat (challenge) dose
Slide 9: Multiple rounds of IAP over multiple days enabled up to 99% reduction of anti-AAV5 TAb titers
Multiple rounds of IAP over multiple days enabled up to 99% reduction of anti-AAV5 TAb titers Anti-AAV5 TAb titer Results from one NHP example AAV5, adeno-associated virus serotype 5; anti-AAV5 TAb, anti-AAV5 total binding antibodies; bCG, beta subunit of cynomolgus chorionic gonadotropin; IAP, 9 im
Slide 10: Percent reduction in AAV5 TAb titer is dependent on number of days and runs
Percent reduction in AAV5 TAb titer is dependent on number of days and number of runs per day of successful IAP • Number of days and runs achieved for each subject varied based on the health of each animal following each run AAV5, adeno-associated virus serotype 5; AAV5 TAb, anti-AAV5 total binding
Slide 11: Mean reduction of 98.5% in antibody titers and successful second transduction (liver DNA/RNA)
Mean reduction of 98.5% in AAV-induced antibody titers and successful second transduction achieved after 2 days of IAP in NHPs • Liver hFIX vector DNA and RNA: – Liver samples collected ~8 weeks following challenge dose and assessed via ddPCR Liver hFIX DNA Liver hFIX RNA 1.6x107 1.3x106 6.8x106 Liv
Slide 12: Mean reduction of 98.5% in antibody titers and successful second transduction (plasma hFIX)
Mean reduction of 98.5% in AAV-induced antibody titers and successful second transduction achieved after 2 days of IAP in NHPs • Plasma hFIX protein concentration: – Peak hFIX expression and AUC are shown from day 0 through 4 weeks post challenge dose Peak hFIX plasma protein AUC hFIX plasma protein
Slide 13: A 98% decrease would reduce TAb titers in all patients below cut-point
A 98% decrease would reduce TAb titers in all patients from BMN270-901 to below cut-point, assuming IAP was equally effective in patients 1000 AAV5 TAb titer at baseline AAV5 TAb titer 100 MRD 10 AAV5 TAb titer with 98% reduction 1 Participants ordered by AAV5 TAb titer (ascending) 13 AAV5, AAV sero
Slide 14: Summary: plasmapheresis is likely to reduce TAb titers and make liver transduction achievable
Internal use Summary: plasmapheresis is likely to reduce TAb titers and make liver transduction achievable • Pre-existing immunity to AAV is postulated to arise from prior exposure to wild-type infection and could prevent patients who test positive from being considered for gene therapy treatment •
Slide 15: Acknowledgments
Internal use Acknowledgments • 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 company, and funded by BioMarin Pharmaceutical Inc. 15
Slide 16: Thank You Questions?
Internal use Thank You Questions? 16
Slide 17: In patients, pre-existing AAV5 antibody titers span logs
In patients, pre-existing AAV5 antibody titers span 3 logs, suggesting patients may require different numbers of IAP cycles to achieve transduction AAV5 TAb titer category High (>1000) Mid (100 to <1000) Low (<100) 1000 3.2% AAV5 TAb titer 31.4% 97% addressable after 2 days (4 cycles) of IAP 100 65.
Slide 18: Pre-existing AAV antibodies postulated to arise from prior AAV and adenovirus exposure
Pre-existing AAV antibodies postulated to arise from prior AAV and adenovirus exposure • AAV belongs to the parvovirus family and is dependent on co-infection with other large DNA viruses, mainly adenoviruses, to replicate • Antibodies are produced during recovery from virus-mediated infection • Rou
Slide 19: Pre-existing antibody titers are lower and more manageable than treatment-emergent titers
Pre-existing antibody titers are lower and more manageable than treatment-emergent titers in patients with hemophilia A AAV5 TAb titer 19 AAV5, adeno-associated virus serotype 5; AAV5 TAb, anti-AAV5 total binding antibodies; ITT, intention to treat; MRD, minimum required dilution.
Slide 20: Depletion of IgG correlates with declining TAb titer in NHPs
Depletion of IgG correlates with declining TAb titer in NHPs • Potential “real-time” point-of-care dosing surrogate to extrapolate the reduction in AAV5 TAb AAV5 TAb titer and plasma IgG AAV5 TAb titer and plasma IgG AAV5 TAb titer and plasma IgG (NHP1) (NHP2) (NHP4) 0.45 0.35 0.45 y = 3x10-6x − 0.0
Slide 21: Plasma volumes of IAP per day resulted in 83% decrease in AAV5 TAb titer after 1 day
Data collected over several experiments showed that 2 plasma volumes of IAP per day resulted in an 83% decrease in AAV5 TAb titer after 1 day and a 95% reduction in AAV5 TAb titer after 2 days AAV5 TAb titer Pre-IAP Day 1 Day 2 Day 3 Day 4 AAV5, adeno-associated virus serotype 5; AAV5 TAb, anti-AAV5
Slide 22: Vector genome DNA and RNA well correlated with peak hFIX in NHPs
Vector genome DNA and RNA well correlated with peak hFIX in NHPs Peak Peak FIX vs hFIX vsvg DNA(vg) DNA PeakhFIX Peak FIX vs vsvg RNA(vg) RNA vg DNA DNA (vg)vs vsvgRNA RNA(vg) 2×10 7 R2=0.9669 400,000 400000 R2=0.8712 400,000 400000 R2=0.8955 (cp/µg) (cp/µg) 2 = 0.9669 R2 = 0.8712 2 = 0.8955 (cp/µg)
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