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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

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

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.

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

NCT ID

NCT03041324

First Posted

January 13, 2017

Last Updated

October 21, 2022

Sponsor

Sangamo Therapeutics

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

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

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

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

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

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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