AAV Vector Shedding Data in Clinical Trials

Vector shedding is the release of virus-based gene therapy products from the patient through one or all of the following routes: excreta (feces), secreta (urine, saliva, nasopharyngeal fluids, etc.), and skin (pustule, sores, wounds)1

vectshed1.svg

AAV vectors are the most extensively investigated viral vectors for use in gene therapy to date1

Currently, data are available on vector shedding following treatment with three AAV-based gene therapies that have received regulatory approval2–7

AAV Vector Shedding Associated with Voretigene Neparvovec-rzyl

Indication:

Voretigene neparvovec-rzyl is an AAV-based gene therapy indicated for the treatment of patients with confirmed bi-allelic RPE65 mutation-associated retinal dystrophy2

Administration:

Voretigene neparvovec-rzyl is administered by subretinal injection to each eye on separate days within a close interval2

After treatment with voretigene neparvovec-rzyl, levels of vector shedding were found to be low, transient, and localized to tear samples from injected eye, though there were also positive peripheral blood samples2,3

In a Phase 3 study, voretigene neparvovec-rzyl vector DNA sequences were detected in tear samples in 45% of patients, most of which were negative after Day 1 post-injection3

 

Vector DNA sequences were detected in serum in 10% of patients, up to Day 3 following each injection3

 

 

Vector DNA was not detected in any whole blood samples3

 

AAV Vector Shedding Associated with Alipogene Tiparvovec

Indication:

Alipogene tiparvovec is an AAV-based gene therapy that was indicated for the treatment of adult patients with familial lipoprotein lipase deficiency and suffering from severe or multiple pancreatitis attacks*4

Administration:

Alipogene tiparvovec was administered as a one-time series of intramuscular injections in the legs4

After administration of alipogene tiparvovec, highest vector DNA concentrations were detected in serum, with clearance by one to two logs per week4

 

Vector DNA was detectable for up to 12 weeks in saliva, up to 10 weeks in urine, and up to 26 weeks in semen4

The concomitant administration of immunosuppressants may have caused longer persistence of virus DNA in serum and longer shedding in saliva, urine, and semen4

High levels of vector DNA were observed up to 12 months in the injected leg muscle, but not the non-injected muscle4

In an open-label trial, peak levels of alipogene tiparvovec vector DNA were detected 24 hours after administration in serum, saliva, and urine. In semen, vector levels were first measured at Week 15

In an open-label trial, peak levels of alipogene tiparvovec vector DNA were detected 24 hours after administration in serum, saliva, and urine. In semen, vector levels were first measured at Week 15

AAV Vector Shedding Associated with Onasemnogene Abeparvovec-xioi

Indication:

Onasemnogene abeparvovec-xioi is an AAV-vector-based gene therapy indicated for the treatment of pediatric patients less than 2 years of age with SMA with bi-allelic mutations in the SMN1 gene7

Administration:

Onasemnogene abeparvovec-xioi is administered as a single-dose intravenous infusion7

After administration of onasemnogene abeparvovec-xioi, temporary vector shedding was observed with vector DNA detected in saliva, urine, and stool7

In saliva, vector DNA concentration was low on Day 1 after infusion and declined to undetectable levels within 3 weeks7

In urine, vector DNA concentration was very low on Day 1 after infusion and declined to undetectable levels within 1 to 2 weeks7

In stool, vector DNA concentration was much higher than in saliva or urine for 1 to 2 weeks after infusion and declined to undetectable levels by 1 to 2 months after infusion7

Handling Recommendations for Voretigene Neparvovec-rzyl

Precautionary handling recommendations are included in prescribing information for voretigene neparvovec-rzyl in both the US and EU2,8

Personal Protection8

Recommendation to wear gloves for dressing changes and waste disposal

Especially relevant in case of underlying pregnancy, breastfeeding, and immunodeficiency of caregivers

Waste Material2,8

Handle waste material generated from dressings, tears, and nasal secretions appropriately

Waste material should be stored in sealed bags prior to disposal

The US and EU product labels have differing guidelines on how long these precautions should be followed; the US recommends 7 days post-treatment, while the EU recommends 14 days

Patient Donations8

Patients treated with voretigene neparvovec-rzyl should not donate blood, organs, tissues, and cells for transplantation

Handling Recommendations for Onasemnogene Abeparvovec-xioi

Precautionary handling recommendations are included in prescribing information for onasemnogene abeparvovec-xioi7

Proper hand hygiene is advised when in contact with patient body waste7

Proper handling of patient feces is recommended7

Procedures include sealing disposal diapers in disposable trash bags and then discarding into regular trash7

All precautions should be followed for 1 month after onasemnogene abeparvovec-xioi infusion7

PABSC-VectorShed-Slide21 2

Summary / Module Recap

Vector shedding is the release of gene therapy from the patient through one or all of the following routes: excreta (feces), secreta (urine, saliva, nasopharyngeal fluids, etc.), and skin (pustule, sores, wounds)9

The safety concern associated with vector shedding is extremely low for replication-deficient viral vectors but is a potential concern for replication-competent viral vectors9,10

Most viral-based gene therapy products are replication deficient and hence are incapable of multiplying in humans; they are shed to a lower extent than replication competent vectors and in a form that is incapable of establishing an infection9

However, data collected from patients in clinical gene therapy trials have demonstrated that shedding of viral vectors occurs in practice11

For viral-based products that have the potential to cause disease in humans, appropriate precautionary measures should be taken to minimize the risk of transmission of the viral-based product from the patient to other individuals9

References

        1. Naso MF, et al. BioDrugs 2017;31(4):317–334;
        2. Luxturna™ [package insert]. 2017. Available at: http://sparktx.com/LUXTURNA_US_Prescribing_Information.pdf. Accessed September 10, 2019;
        3. Spark Therapeutics. Press release. October 12, 2017. Available at: https://www.fda.gov/media/108385/download. Accessed September 10, 2019;
        4. Glybera [summary of product characteristics – medicinal product no longer authorized]. 2017. Available at: https://www.ema.europa.eu/en/documents/product-information/glybera-epar-product-information_en.pdf. Accessed September 10, 2019;
        5. Gaudet D, et al. Gene Ther 2013;20(4):361–369;
        6. U.S. FDA. News release. May 24, 2019. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease. Accessed September 10, 2019;
        7. Zolgensma® [package insert]. 2019. Available at: https://www.avexis.com/content/pdf/prescribing_information.pdf. Accessed September 10, 2019;
        8. Luxturna™ [summary of product characteristics]. 2019. Available at: https://www.ema.europa.eu/en/documents/product-information/luxturna-epar-product-information_en.pdf. Accessed September 10, 2019;
        9. U.S. Food and Drug Administration. Design and analysis of shedding studies for virus or bacteria-based gene therapy and oncolytic products. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/design-and-analysis-shedding-studies-virus-or-bacteria-based-gene-therapy-and-oncolytic-products. Accessed September 10, 2019;
        10. van den Akker E, et al. Curr Gene Ther 2013;13:395–412;
        11. Husain SR, et al. Cancer Gene Ther 2015;22(12):554–563.