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

Status

Terminated

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02695160

Enrollment

Registered

2016-03-01

Start date

2016-11-15

Completion date

2021-04-19

Last updated

2024-07-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hemophilia B

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.

Interventions

BIOLOGICALSB-FIX

Single dose of each of the 3 components of SB-FIX: ZFN1, ZFN2 and cDNA Donor.

Study design

Allocation

NON_RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

MALE

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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.
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.
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.
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.
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.
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.
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.

Countries

United States

Participant flow

Participants by arm

Arm	Count
High Dose 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.	1
Total	1

Baseline characteristics

Characteristic	High Dose
Age, Continuous	60 years STANDARD_DEVIATION 0
Height	173 cm
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	0 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	1 Participants
Sex: Female, Male Female	0 Participants
Sex: Female, Male Male	1 Participants
Weight	74.7 kg

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 1
other Total, other adverse events	1 / 1
serious Total, serious adverse events	0 / 1

Outcome results

Primary

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

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

Time frame: Up to 36 months after the SB-FIX infusion