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

Primary Purpose

Hemophilia B

Status

Terminated

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

SB-FIX

About this trial

This is an interventional treatment trial for Hemophilia B

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept 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

Sites / Locations

Georgetown University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Cohort 1

Cohort 2

Cohort 3

Arm Description

SB-FIX: Low Dose

SB-FIX: Medium Dose

SB-FIX: High Dose

Outcomes

Primary Outcome Measures

Treatment related Adverse Events in subjects who received SB-FIX as assessed by Common Terminology Criteria for Adverse Events (CTCAE)

Secondary Outcome Measures

Change from baseline in FIX antigen and activity levels

Change from baseline in use of Factor IX replacement therapy

• Change from baseline in the number of FIX units infused per week

Change from baseline in frequency and severity of bleeding episodes

Immune response to FIX

• Change in neutralizing antibodies to FIX from baseline over time

Presence and shedding of AAV2/6 vector DNA by PCR in plasma, saliva, urine, stool and semen

Full Information

NCT ID

NCT02695160

First Posted

February 24, 2016

Last Updated

March 8, 2022

Sponsor

Sangamo Therapeutics

1. Study Identification

Unique Protocol Identification Number

NCT02695160

Brief Title

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

2. Study Status

Record Verification Date

March 2022

Overall Recruitment Status

Terminated

Study Start Date

November 15, 2016 (Actual)

Primary Completion Date

April 19, 2021 (Actual)

Study Completion Date

April 19, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Sangamo Therapeutics

4. Oversight

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hemophilia B

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

1 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cohort 1

Arm Type

Experimental

Arm Description

SB-FIX: Low Dose

Arm Title

Cohort 2

Arm Type

Experimental

Arm Description

SB-FIX: Medium Dose

Arm Title

Cohort 3

Arm Type

Experimental

Arm Description

SB-FIX: High Dose

Intervention Type

Biological

Intervention Name(s)

SB-FIX

Intervention Description

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

Primary Outcome Measure Information:

Title

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

Secondary Outcome Measure Information:

Title

Change from baseline in FIX antigen and activity levels

Time Frame

up to 36 months after the SB-FIX infusion

Title

Change from baseline in use of Factor IX replacement therapy

Description

• Change from baseline in the number of FIX units infused per week

Time Frame

Baseline and up to 36 months after the SB-FIX infusion

Title

Change from baseline in frequency and severity of bleeding episodes

Time Frame

Up to 36 months after the SB-FIX infusion

Title

Immune response to FIX

Description

• Change in neutralizing antibodies to FIX from baseline over time

Time Frame

Up to 36 months after the SB-FIX infusion

Title

Presence and shedding of AAV2/6 vector DNA by PCR in plasma, saliva, urine, stool and semen

Time Frame

Follow up until 2 consecutive measurements are negative of AAV

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Medical Monitor

Organizational Affiliation

Sangamo Therapeutics, Inc.

Official's Role

Study Director

Facility Information:

Facility Name

Georgetown University Medical Center

City

Washington

State/Province

District of Columbia

ZIP/Postal Code

20007

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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