Clinical trial NCT02695160: Ascending Dose Study of Genome Editing by Zinc Finger Nuclease Therapeutic SB-FIX in Subjects With Severe Hemophilia B
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Hemophilia B
Lead sponsor: Sangamo Therapeutics
Sponsor class: INDUSTRY
First posted: 2016-03-01
Enrollment: 1
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With Treatment Related Adverse Events in Subjects Who Received SB-FIX as Assessed by Common Terminology Criteria for Adverse Events (CTCAE)
timeFrame: Up to 36 months after the SB-FIX infusion
Secondary outcomes:
measure: 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
timeFrame: From screening through to week 28 after SB-FIX infusion
measure: Use of Factor IX Replacement Therapy
timeFrame: From baseline through 36 months after the SB-FIX infusion
measure: Frequency and Severity of Bleeding Episodes
timeFrame: From baseline through 36 months after the SB-FIX infusion
measure: Immune Response to FIX
timeFrame: Change from baseline through 28 weeks after the SB-FIX infusion
measure: Presence of Shedding of AAV2/6 Vector DNA (in Copies/10 µL) by PCR in Plasma
timeFrame: From baseline through week 20 after SB-FIX infusion
measure: Presence and Shedding of AAV2/6 Vector DNA (in Copies/100ng) by PCR in Saliva, Stool and Semen
timeFrame: From baseline through week 20 after SB-FIX infusion
measure: Presence and Shedding of AAV2/6 Vector DNA (in Copies/250 µL) by PCR in Urine
timeFrame: From baseline through week 12 after SB-FIX infusion
Other outcomes:
Locations:
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
Study officials:
affiliation: Sangamo Therapeutics, Inc.
name: Medical Monitor
role: STUDY_DIRECTOR
References: