PB0210 - Blood Biodistribution and Vector Shedding of Valoctocogene Roxaparvovec in People with Severe Hemophilia A: Results from the Phase 3 GENEr8-1 Trial

Sunday, July 10, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Presenting Author(s)

SA

Suresh Agarwal

Director, Clinical Pharmacology
BioMarin Pharmaceuticals Inc.
Novato, California, United States

Co-Author(s)

KO

Kristin Obrochta

Sr Scientist, Translational Sciences
BioMarin Pharmaceutical Inc.
Novato, California, United States
MV

Monica Vora

Research Associate, Translational Sciences
BioMarin Pharmaceutical Inc.
Novato, California, United States
AB

Alisa Bowen

Research Associate, Translational Sciences
BioMarin Pharmaceutical Inc.
Novato, California, United States
BB

Brenna Bunch

Research Associate, Translational Sciences
BioMarin Pharmaceutical Inc.
Novato, California, United States
JH

Jennifer Holcomb

Sr Research Associate, Translational Sciences
BioMarin Pharmaceutical Inc.
Novato, California, United States
DG

David Guo

Sr Research Associate, Translational Sciences
BioMarin Pharmaceutical Inc.
Novato, California, United States
TR

Tara M. Robinson

Medical Director, Clinical Science
BioMarin Pharmaceutical Inc., Novato, CA, USA
Novato, California, United States
KJ

Kala Jayaram

Executive Medical Director, Pharmacovigilance
BioMarin Pharmaceutical Inc., Novato, CA, USA
Novato, California, United States
CR

Chris B. Russell

Staff Scientist, Translational Sciences
BioMarin Pharmaceutical Inc.
Novato, California, United States
CV

Christian Vettermann

Principal Scientist, Translational Sciences
BioMarin Pharmaceutical Inc.
Novato, California, United States
JH

Joshua Henshaw

Executive Director, Clinical Pharmacology
BioMarin Pharmaceuticals Inc.
Novato, California, United States

Background: Valoctocogene roxaparvovec is a recombinant adeno-associated virus serotype 5 (AAV5) gene therapy vector that enables steady, endogenous factor VIII expression in people with severe hemophilia A.

Aims: To characterize vector DNA biodistribution and shedding following valoctocogene roxaparvovec administration.

Methods: Adult AAV5-negative men (N=134) with severe hemophilia A received a single 6E13 vg/kg valoctocogene roxaparvovec infusion in the phase 3 GENEr8-1 trial (NCT03370913). Informed consent and all relevant ethics approvals were obtained. Total vector DNA was quantified in blood, saliva, stool, semen, and urine with a validated quantitative (q)PCR assay. Encapsidated vector DNA was measured in plasma and semen with an immunoprecipitation-coupled qPCR assay. The contiguity of vector genomes was measured in whole blood, plasma, peripheral blood mononuclear cells (PBMCs), and red blood cells (RBCs) using a drop-phase droplet-digital (dd)PCR assay. Vector genome inverted terminal repeat (ITR) fusions were measured in whole blood and PBMCs using ddPCR and primers directed outward from the 5’ and 3’ ends of the linear vector genome.

Results: Median peak vector DNA levels were observed 1–8 days after dosing and were highest in blood followed by saliva, semen, stool, and urine; concentrations then declined steadily. Encapsidated vector DNA was cleared more rapidly than total vector DNA, with maximum time to clearance ≤12 weeks in both plasma and semen. Vector genomes transitioned from initial non-contiguous forms into full-length forms over time; fraction of ITR fusions, indicating formulation of circularized episomes, steadily increased. Full data from 2 years of follow-up will be shared at ISTH 2022 Congress.

Conclusion(s): Vector DNA and vector capsids were steadily cleared from the blood and shedding matrices of people with severe hemophilia A treated with valoctocogene roxaparvovec. The replication-incompetent nature of valoctocogene roxaparvovec and the rapid clearance of encapsidated vector make the risk of transmission to untreated individuals extremely low.