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Ascending Dose Study of Genome Editing by the Zinc Finger Nuclease (ZFN) Therapeutic SB-913 in Subjects With MPS II

Primary Purpose

Mucopolysaccharidosis II, MPS II

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
SB-913
Sponsored by
Sangamo Therapeutics
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Mucopolysaccharidosis II focused on measuring MPS ll, Mucopolysaccharidosis II, Hunter syndrome, Gene Editing, Gene therapy, Zinc Finger, ZFN, SB-913, Rare, Genetic, DNA, Sangamo, Genome editing, Champions, Hunter, Gene Specific Targeted Insertion

Eligibility Criteria

5 Years - 65 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Male or female 5 years to 65 years of age.
  • Clinical diagnosis of MPS II (based on evidence of hepatosplenomegaly, dysostosis multiplex by X-ray, valvular heart disease, or obstructive airway disease) IDS deficiency confirmed by gene sequencing.

Exclusion Criteria:

  • Known to be unresponsive to ERT
  • Neutralizing antibodies to AAV 2/6
  • Serious intercurrent illness or clinically significant organic disease (unless secondary to MPS II)
  • Receiving antiviral therapy for hepatitis B or C, or with active hepatitis B or hepatitis C or HIV 1/2
  • Lack of tolerance to idursulfase treatment with significant IARs or occurrence of anaphylaxis
  • Markers of hepatic dysfunction
  • Creatinine ≥ 1.5 mg/dL
  • Contraindication to the use of corticosteroids for immunosuppression
  • Current treatment with systemic (IV or oral) immunomodulatory agent or steroid use (topical treatment allowed)
  • Participation in prior investigational drug or medical device study within the previous 3 months
  • Prior treatment with a gene therapy product
  • Elevated or abnormal circulating α-fetoprotein (AFP)
  • Weight < 20 kg at Screening Visit

Sites / Locations

  • UCSF Benioff Children's Hospital Oakland
  • Ann & Robert H. Lurie Children's Hospital of Chicago
  • NYU School of Medicine, Neurogenetics Division
  • University of North Carolina
  • Cincinnati Children's Hospital Medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Cohort 1 SB-913 Starting Dose 5.00E+12 vg/kg

Cohort 2 SB-913 at Next Ascending Dose 1.00E+13 vg/kg

Cohort 3 SB-913 at Next Ascending Dose 5.00E+13 vg/kg

Arm Description

A single dose of each of the three components of SB-913 [zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)] administered via intravenous (IV) infusion.

A single dose of each of the three components of SB-913 [zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)] administered via intravenous (IV) infusion.

A single dose of each of the three components of SB-913 [zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)] administered via intravenous (IV) infusion.

Outcomes

Primary Outcome Measures

Number of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 36 Months After the SB-913 Infusion
Number of participants with Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) in subjects who receive SB-913 as assessed by Common Terminology Criteria for Adverse Events (CTCAE)

Secondary Outcome Measures

Effect of SB-913 on IDS Activity
Change from baseline in clinical laboratory measurement of IDS activity measured in blood, at Month 33.
Effect of SB-913 on Urine Glycosaminoglycans (GAG) Levels
Change from baseline in total GAG, Dermatan Sulfate GAG, and Heparan Sulfate GAG measured in urine at Month 36
Annualized Frequency of Idursulfase (or Equivalent ERT) Administration.
Change from baseline in annualized frequency of idursulfase (or equivalent ERT)
AAV2/6 Clearance in Plasma, Saliva, Urine, Stool, and Semen
Subjects with AAV2/6 clearance in plasma, saliva, urine, stool, and semen by PCR by Week 24. All the subjects had AAV2/6 clearance in all the samples assessed (i.e., plasma, saliva, urine, stool, and semen) by week 24. Subjects were only tested until Week 24 because, by that time, they all had 3 consecutive negative tests in all body fluids.

Full Information

First Posted
January 13, 2017
Last Updated
October 21, 2022
Sponsor
Sangamo Therapeutics
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1. Study Identification

Unique Protocol Identification Number
NCT03041324
Brief Title
Ascending Dose Study of Genome Editing by the Zinc Finger Nuclease (ZFN) Therapeutic SB-913 in Subjects With MPS II
Official Title
A Phase I / 2, Multicenter, Open-label, Single-dose, Dose-ranging Study to Assess the Safety and Tolerability of SB-913, a rAAV2/6-based Gene Transfer in Subjects With Mucopolysaccharidosis II (MPS II)
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Terminated
Why Stopped
All nine subjects dosed in the study have rolled over to the Long-Term Follow-up Study IVPRP-LT01 [NCT04628871]
Study Start Date
May 11, 2017 (Actual)
Primary Completion Date
May 7, 2021 (Actual)
Study Completion Date
May 7, 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 Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of the study is to evaluate the safety, tolerability and effect on leukocyte and plasma Iduronate 2-Sulfatase (IDS) enzyme activity of ascending doses of SB-913. SB-913 is an intravenously delivered Zinc Finger Nuclease (ZFN) Therapeutic for genome editing. It inserts a correct copy of the IDS gene into the Albumin locus in hepatocytes with the goal of lifelong therapeutic production of the IDS enzyme.
Detailed Description
The objectives of the study are to provide long term expression of IDS and improve the current clinical outcome of enzyme replacement therapy (ERT) in subjects with MPS II, a recessive lysosomal storage disorder that results from mutations in the gene encoding IDS. SB-913 is a therapeutic for ZFN-mediated genome editing which will be delivered by adeno-associated virus (AAV)-derived vectors. SB-913 is intended to function by placement of the corrective copy of IDS 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 Iduronate 2-Sulfatase for the lifetime of an MPS II patient.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Mucopolysaccharidosis II, MPS II
Keywords
MPS ll, Mucopolysaccharidosis II, Hunter syndrome, Gene Editing, Gene therapy, Zinc Finger, ZFN, SB-913, Rare, Genetic, DNA, Sangamo, Genome editing, Champions, Hunter, Gene Specific Targeted Insertion

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
9 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1 SB-913 Starting Dose 5.00E+12 vg/kg
Arm Type
Experimental
Arm Description
A single dose of each of the three components of SB-913 [zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)] administered via intravenous (IV) infusion.
Arm Title
Cohort 2 SB-913 at Next Ascending Dose 1.00E+13 vg/kg
Arm Type
Experimental
Arm Description
A single dose of each of the three components of SB-913 [zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)] administered via intravenous (IV) infusion.
Arm Title
Cohort 3 SB-913 at Next Ascending Dose 5.00E+13 vg/kg
Arm Type
Experimental
Arm Description
A single dose of each of the three components of SB-913 [zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)] administered via intravenous (IV) infusion.
Intervention Type
Biological
Intervention Name(s)
SB-913
Intervention Description
Single dose of each of the 3 components of SB-913: ZFN1, ZFN2 and hIDS Donor
Primary Outcome Measure Information:
Title
Number of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 36 Months After the SB-913 Infusion
Description
Number of participants with Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) in subjects who receive SB-913 as assessed by Common Terminology Criteria for Adverse Events (CTCAE)
Time Frame
Up to 36 months after the SB-913 infusion
Secondary Outcome Measure Information:
Title
Effect of SB-913 on IDS Activity
Description
Change from baseline in clinical laboratory measurement of IDS activity measured in blood, at Month 33.
Time Frame
Baseline and Month 33 after the SB-913 infusion
Title
Effect of SB-913 on Urine Glycosaminoglycans (GAG) Levels
Description
Change from baseline in total GAG, Dermatan Sulfate GAG, and Heparan Sulfate GAG measured in urine at Month 36
Time Frame
Baseline and 36 months after the SB-913 infusion
Title
Annualized Frequency of Idursulfase (or Equivalent ERT) Administration.
Description
Change from baseline in annualized frequency of idursulfase (or equivalent ERT)
Time Frame
Up to 36 months after the SB-913 infusion
Title
AAV2/6 Clearance in Plasma, Saliva, Urine, Stool, and Semen
Description
Subjects with AAV2/6 clearance in plasma, saliva, urine, stool, and semen by PCR by Week 24. All the subjects had AAV2/6 clearance in all the samples assessed (i.e., plasma, saliva, urine, stool, and semen) by week 24. Subjects were only tested until Week 24 because, by that time, they all had 3 consecutive negative tests in all body fluids.
Time Frame
Up to 36 months after the SB-913 infusion

10. Eligibility

Sex
All
Minimum Age & Unit of Time
5 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female 5 years to 65 years of age. Clinical diagnosis of MPS II (based on evidence of hepatosplenomegaly, dysostosis multiplex by X-ray, valvular heart disease, or obstructive airway disease) IDS deficiency confirmed by gene sequencing. Exclusion Criteria: Known to be unresponsive to ERT Neutralizing antibodies to AAV 2/6 Serious intercurrent illness or clinically significant organic disease (unless secondary to MPS II) Receiving antiviral therapy for hepatitis B or C, or with active hepatitis B or hepatitis C or HIV 1/2 Lack of tolerance to idursulfase treatment with significant IARs or occurrence of anaphylaxis Markers of hepatic dysfunction Creatinine ≥ 1.5 mg/dL Contraindication to the use of corticosteroids for immunosuppression Current treatment with systemic (IV or oral) immunomodulatory agent or steroid use (topical treatment allowed) Participation in prior investigational drug or medical device study within the previous 3 months Prior treatment with a gene therapy product Elevated or abnormal circulating α-fetoprotein (AFP) Weight < 20 kg at Screening Visit
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Monitor
Organizational Affiliation
Sangamo Therapeutics
Official's Role
Study Director
Facility Information:
Facility Name
UCSF Benioff Children's Hospital Oakland
City
Oakland
State/Province
California
ZIP/Postal Code
94609
Country
United States
Facility Name
Ann & Robert H. Lurie Children's Hospital of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
NYU School of Medicine, Neurogenetics Division
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
University of North Carolina
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27514
Country
United States
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Ascending Dose Study of Genome Editing by the Zinc Finger Nuclease (ZFN) Therapeutic SB-913 in Subjects With MPS II

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