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

Phase 1

Terminated

Conditions: Hemophilia B

Interventions: Biological: SB-FIX

Registration Number: NCT02695160

Lead Sponsor: Sangamo Therapeutics

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.

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: Male

Target Recruitment: 1

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Cohort 2	SB-FIX	SB-FIX: Medium Dose
Cohort 1	SB-FIX	SB-FIX: Low Dose
Cohort 3	SB-FIX	SB-FIX: High Dose

Primary Outcome Measures

Name	Time	Method
Number of Participants With 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	Number of Participants with Treatment Related Adverse Events in Subjects Who Received SB-FIX as Assessed by Common Terminology Criteria for Adverse Events (CTCAE).

Secondary Outcome Measures

Name	Time	Method
Presence and Shedding of AAV2/6 Vector DNA (in Copies/100ng) by PCR in Saliva, Stool and Semen	From baseline through week 20 after SB-FIX infusion	Subject data were collected at baseline and post infusion. Two laboratory tests were run for each sample type: AAV2/6-ZFN 42906 and AAV2/6-hF9. The presence of AAV2/6 vector DNA in saliva and stool was measured in number of copies/100 ng of sample DNA.
Change From Baseline in Factor 9 Antigen Levels Measured in IU/mL and Factor 9 Activity Levels Measured in IU/mL at Week 28 After SB-FIX Infusion	From screening through to week 28 after SB-FIX infusion	FIX antigen levels measured in IU/mL using Enzyme-Linked Immunosorbent Assay (ELISA). FIX activity levels measured in IU/mL using One-Stage Clot.
Frequency and Severity of Bleeding Episodes	From baseline through 36 months after the SB-FIX infusion	The number and severity of bleeding events were collected from 3 weeks post-SB-FIX treatment, and for 120 weeks thereafter.
Presence of Shedding of AAV2/6 Vector DNA (in Copies/10 µL) by PCR in Plasma	From baseline through week 20 after SB-FIX infusion	Two laboratory tests were run: AAV2/6-ZFN 42906 and AAV2/6-hF9. Presence in plasma was measured in number of copies/10 µL of whole plasma.
Use of Factor IX Replacement Therapy	From baseline through 36 months after the SB-FIX infusion	Participants received a single intravenous infusion of SB-FIX which is formed of 3 components (ZFN1, ZFN2, and cDNA donor) in 200mL of diluent adjusted to 0.25% human serum albumin on day 0 over a period of 2-8 hours.
Immune Response to FIX	Change from baseline through 28 weeks after the SB-FIX infusion	Neutralizing antibodies to FIX measured by FIX inhibitor levels using Nijmegen-Bethesda assays.
Presence and Shedding of AAV2/6 Vector DNA (in Copies/250 µL) by PCR in Urine	From baseline through week 12 after SB-FIX infusion	Two laboratory tests were run: AAV2/6-ZFN 42906 and AAV2/6-hF9. Its presence in urine was measured in number of copies/250 µL of whole urine.