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

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

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.

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.

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