BioMarin Presents Abstract on Vector DNA Transmission Risk at ISTH

The focus of the abstract is the investigational hemophilia A gene therapy, valoctocogene roxaparvovec.

BioMarin recently shared findings from a phase 3 clinical trial (GENEr8-1) evaluating the presence of vector DNA in patients two years after they received a single dose of valoctocogene roxaparvovec, the company’s investigational hemophilia A gene therapy. The results were presented during last month’s International Society on Thrombosis and Haemostasis (ISTH) Congress in London.

Valoctocogene roxaparvovec uses adeno-associated viruses (AAVs) vectors to deliver the DNA genetic codes that illicit the production of the factor VIII (FVIII) in people with hemophilia A. AAVs are meant to deliver the genetic material into living cells to sustain a therapeutic effect without, ideally, causing disease or triggering significant immune responses.

The trial’s focus was biodistribution and vector shedding. The former refers to the spread and persistence of vector DNA within the body after administration of the therapy, including in tissues, body fluids, or organs. While vector shedding is the release of virus-based gene therapy products from the body through various routes such as the blood, saliva, urine, stool, or semen.

Although AAV vectors “pose minimal risk for horizontal transfer or environmental release, comprehensive assessment of vector shedding in secreta and excreta is a necessary safety evaluation,” explained the authors’ presentation at ISTH.

Investigators focused on the 134 patients participating in GENEr8-1, all of whom have received a single dose of valoctocogene roxaparvovec and have been observed for at least two years post treatment. Lab tests of blood, saliva, urine, stool, and semen samples were performed at baseline and throughout the study until three consecutive negative samples could be identified – patients who reached this threshold achieved clearance of vector DNA.

Amongst all participants, the median vector DNA levels peaked within eight days post-administration and steadily decreased thereafter. Whole blood contained the highest levels of vector DNA, followed by saliva, semen, stool, and urine. 100% of patients achieved clearance of vector DNA via three negative urine and saliva samples, while vector DNA levels were undetectable in urine within approximately 12 days and saliva within 32 days. Clearance was also achieved for stool among 84.3% of patients and for semen by 99.2%. Vector DNA levels persisted longer in blood, with clearance achieved by 5.2% of patients by data cutoff.

The findings prompted the authors to urge caution during the six-month post infusion period, with a specific recommendation to mitigate risk of DNA vector transmission.

“Contraception is recommended for men for 6 months following treatment with valoctocogene roxaparvovec,” the authors said, which “is based primarily on time to clearance in semen and plasma of potentially transduction-competent encapsidated vector DNA,” The authors concluded that “the replication-incompetent nature of valoctocogene roxaparvovec and the rapid clearance of encapsidated vector make the risk of transmission to untreated individuals extremely low.”

The full abstract can be accessed on the ISTH website:

Agarwal S, Sandza K, Obrochta K, et al. Blood biodistribution and vector shedding of valoctocogene roxaparvovec in people with severe hemophilia A: results from the phase 3 GENEr8-1 trial. Br J Haematol. Presented at: ISTH 2022 Congress; July 9-13, 2022. Abstract B0210.

Source: Hematology Advisor, July 26, 2022