Ascending Dose Study of Genome Editing by Zinc Finger Nuclease Therapeutic SB-FIX in Subjects With Severe Hemophilia B
Study Details
Study Description
Brief Summary
The purpose of the study is to evaluate the safety, tolerability and effect on FIX antigen and activity levels of ascending doses of SB-FIX. SB-FIX is an intravenously delivered Zinc Finger Nuclease (ZFN) Therapeutic for genome editing. It inserts a correct copy of the Factor 9 gene into the albumin locus in hepatocytes with the goal of lifelong therapeutic production of the Factor IX clotting factor.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 1 |
Detailed Description
The objective of the study is to provide long term expression of Factor IX in subjects with severe hemophilia B. SB-FIX is a therapeutic for ZFN-mediated genome editing which will be delivered by adeno-associated virus (AAV)-derived vectors. SB-FIX is intended to function by placement of a corrective copy of the Factor IX transgene into the genome of the subject's own hepatocytes, under the control of the highly expressed endogenous albumin locus, and is expected to provide permanent, liver-specific expression of Factor IX for the lifetime of a hemophilia B subject.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Cohort 1 SB-FIX: Low Dose |
Biological: SB-FIX
Single dose of each of the 3 components of SB-FIX: ZFN1, ZFN2 and cDNA Donor.
|
Experimental: Cohort 2 SB-FIX: Medium Dose |
Biological: SB-FIX
Single dose of each of the 3 components of SB-FIX: ZFN1, ZFN2 and cDNA Donor.
|
Experimental: Cohort 3 SB-FIX: High Dose |
Biological: SB-FIX
Single dose of each of the 3 components of SB-FIX: ZFN1, ZFN2 and cDNA Donor.
|
Outcome Measures
Primary Outcome Measures
- Treatment related Adverse Events in subjects who received SB-FIX as assessed by Common Terminology Criteria for Adverse Events (CTCAE) [Up to 36 months after the SB-FIX infusion]
Secondary Outcome Measures
- Change from baseline in FIX antigen and activity levels [up to 36 months after the SB-FIX infusion]
- Change from baseline in use of Factor IX replacement therapy [Baseline and up to 36 months after the SB-FIX infusion]
• Change from baseline in the number of FIX units infused per week
- Change from baseline in frequency and severity of bleeding episodes [Up to 36 months after the SB-FIX infusion]
- Immune response to FIX [Up to 36 months after the SB-FIX infusion]
• Change in neutralizing antibodies to FIX from baseline over time
- Presence and shedding of AAV2/6 vector DNA by PCR in plasma, saliva, urine, stool and semen [Follow up until 2 consecutive measurements are negative of AAV]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Male >18 years of age
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Severe hemophilia B (native circulating FIX activity <1%, with or without cross reactive material)
Exclusion Criteria:
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Presence of neutralizing antibodies
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History of hypersensitivity response or an allergic reaction to FIX or FIX products
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Currently receiving long acting FIX replacement therapy
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FIX mutations known to be associated with FIX inhibitors
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Polymorphisms in the ZFN target region
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Presence of any liver mass on MRI, or elevated alpha-fetoprotein (AFP)
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Any contraindication to the use of corticosteroids for immunosuppression
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Currently receiving antiviral therapy for hepatitis B or C or with history or active hepatitis B or hepatitis C or HIV-1 or HIV1/2 antibody positive.
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Chronic anemia, leukopenia, or thrombocytopenia
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Past medical history of active tuberculosis or significant fungal disease
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Symptomatic cardiovascular disease as a co-morbid condition
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Markers of hepatic inflammation or overt or occult cirrhosis
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History of chronic renal disease or creatinine ≥ 1.5 mg/dL
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Systemic (iv or oral) immunomodulatory agent or steroid use (topical treatment is allowed)
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History of chronic infection or other chronic disorder considered an unacceptable risk
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History of malignancy except for treated basal cell or squamous cell carcinoma
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History of alcohol or substance abuse
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Previously received gene therapy product
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Participation in prior investigational drug or medical device study within the previous 3 months
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History of therapeutic non-adherence
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Any other reason that, in the opinion of the Investigator or Medical Monitor, would render the subject unsuitable for participation in the study
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Georgetown University Medical Center | Washington | District of Columbia | United States | 20007 |
Sponsors and Collaborators
- Sangamo Therapeutics
Investigators
- Study Director: Medical Monitor, Sangamo Therapeutics, Inc.
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- SB-FIX-1501