Ascending Dose Study of Genome Editing by Zinc Finger Nuclease Therapeutic SB-FIX in Subjects With Severe Hemophilia B

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I, Open-Label, Ascending Dose Study to Assess the Safety and Tolerability of AAV2/6 Factor IX Gene Therapy Via Zinc Finger Nuclease (ZFN) Mediated Targeted Integration of SB-FIX in Adult Subjects With Severe Hemophilia B

Conditions
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Hemophilia B

Intervention / Treatment
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* Biological: SB-FIX


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male >18 years of age Severe hemophilia B (native circulating FIX activity <1%, with or without cross reactive material) Exclusion Criteria: Presence of neutralizing antibodies History of hypersensitivity response or an allergic reaction to FIX or FIX products Currently receiving long acting FIX replacement therapy FIX mutations known to be associated with FIX inhibitors Polymorphisms in the ZFN target region Presence of any liver mass on MRI, or elevated alpha-fetoprotein (AFP) Any contraindication to the use of corticosteroids for immunosuppression 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. Chronic anemia, leukopenia, or thrombocytopenia Past medical history of active tuberculosis or significant fungal disease Symptomatic cardiovascular disease as a co-morbid condition Markers of hepatic inflammation or overt or occult cirrhosis History of chronic renal disease or creatinine ≥ 1.5 mg/dL Systemic (iv or oral) immunomodulatory agent or steroid use (topical treatment is allowed) History of chronic infection or other chronic disorder considered an unacceptable risk History of malignancy except for treated basal cell or squamous cell carcinoma History of alcohol or substance abuse Previously received gene therapy product Participation in prior investigational drug or medical device study within the previous 3 months History of therapeutic non-adherence Any other reason that, in the opinion of the Investigator or Medical Monitor, would render the subject unsuitable for participation in the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>SB-FIX: Low Dose | Biological: SB-FIX<br>* Single dose of each of the 3 components of SB-FIX: ZFN1, ZFN2 and cDNA Donor.<br>|
| Experimental: Cohort 2<br>SB-FIX: Medium Dose | Biological: SB-FIX<br>* Single dose of each of the 3 components of SB-FIX: ZFN1, ZFN2 and cDNA Donor.<br>|
| Experimental: Cohort 3<br>SB-FIX: High Dose | Biological: SB-FIX<br>* Single dose of each of the 3 components of SB-FIX: ZFN1, ZFN2 and cDNA Donor.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | • Change from baseline in the number of FIX units infused per week | Baseline and up to 36 months after the SB-FIX infusion | 
| Change from baseline in frequency and severity of bleeding episodes |  | Up to 36 months after the SB-FIX infusion | 
| Immune response to FIX | • Change in neutralizing antibodies to FIX from baseline over time | Up to 36 months after the SB-FIX infusion | 
| 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 |