The risk of transmission of potentially transduction-competent encapsidated vector DNA from valoctocogene roxaparvovec gene therapy for severe hemophilia A is very low, but contraception is recommended for 6 months after infusion due to persistence in plasma and semen, according to the results of an analysis of a phase 3 study presented at the ISTH 2022 Congress.

Valoctocogene roxaparvovec is a gene therapy that delivers a B-domain-deleted FVII coding sequence to hepatocytes, resulting in expression of FVIII. This sequence is contained within a recombinant adeno-associated virus (AAV) that is replication incompetent.

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,” the authors said in their presentation.

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The aim of this study was to evaluate the biodistribution and shedding of the vector during a 2-year period after valoctocogene roxaparvovec administration in the phase 3 GENEr8-1 study.

The multicenter, open-label phase 3 GENEr8-1 trial randomly assigned adult men with severe hemophilia A with no history of inhibitors to receive a single infusion of valoctocogene roxaparvovec or placebo. Testing of blood, saliva, urine, stool, and semen quantitative polymerase chain reaction (qPCR) for biodistribution and vector shedding was performed at baseline and throughout the study until there were 3 consecutive negative samples. Whole blood and peripheral blood mononuclear cells were used to evaluate the contiguity of vector genomes.

Of the 134 men who received valoctocogene roxaparvovec, the median vector DNA levels peaked within 8 days after administration and steadily decreased thereafter. Whole blood contained the highest levels of vector DNA, followed by saliva, semen, stool, and urine.

There were 100% of patients who achieved clearance of vector DNA, defined as 3 consecutive negative samples, in urine and saliva. 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.

Encapsidated vector DNA was more rapidly cleared than vector DNA, with complete clearance achieved in blood and semen achieved by 100% and 98.5% of patients within 12 weeks.

“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.”

Disclosures: This study was supported by BioMarin Pharmaceuticals. All of the study authors are employees and stockholders of BioMarin Pharmaceuticals Inc.


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.