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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03041324
Recruitment Status : Terminated (All nine subjects dosed in the study have rolled over to the Long-Term Follow-up Study IVPRP-LT01 [NCT04628871])
First Posted : February 2, 2017
Results First Posted : September 27, 2022
Last Update Posted : October 25, 2022
Sponsor:
Information provided by (Responsible Party):
Sangamo Therapeutics

Study Description
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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.

Condition or disease Intervention/treatment Phase
Mucopolysaccharidosis II MPS II Biological: SB-913 Phase 1 Phase 2

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.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 9 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : May 11, 2017
Actual Primary Completion Date : May 7, 2021
Actual Study Completion Date : May 7, 2021

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Cohort 1 SB-913 Starting Dose 5.00E+12 vg/kg
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.
 Biological: SB-913
Single dose of each of the 3 components of SB-913: ZFN1, ZFN2 and hIDS Donor
Experimental: Cohort 2 SB-913 at Next Ascending Dose 1.00E+13 vg/kg
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.
 Biological: SB-913
Single dose of each of the 3 components of SB-913: ZFN1, ZFN2 and hIDS Donor
Experimental: Cohort 3 SB-913 at Next Ascending Dose 5.00E+13 vg/kg
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.
 Biological: SB-913
Single dose of each of the 3 components of SB-913: ZFN1, ZFN2 and hIDS Donor


Outcome Measures
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Primary Outcome Measures :
  1. Number of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 36 Months After the SB-913 Infusion [ 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 :
  1. Effect of SB-913 on IDS Activity [ Time Frame: Baseline and Month 33 after the SB-913 infusion ]
    Change from baseline in clinical laboratory measurement of IDS activity measured in blood, at Month 33.

  2. Effect of SB-913 on Urine Glycosaminoglycans (GAG) Levels [ Time Frame: Baseline and 36 months after the SB-913 infusion ]
    Change from baseline in total GAG, Dermatan Sulfate GAG, and Heparan Sulfate GAG measured in urine at Month 36

  3. Annualized Frequency of Idursulfase (or Equivalent ERT) Administration. [ Time Frame: Up to 36 months after the SB-913 infusion ]
    Change from baseline in annualized frequency of idursulfase (or equivalent ERT)

  4. AAV2/6 Clearance in Plasma, Saliva, Urine, Stool, and Semen [ Time Frame: Up to 36 months after the SB-913 infusion ]

    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.



Eligibility Criteria
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Ages Eligible for Study:   5 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03041324


Locations
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United States, California
UCSF Benioff Children's Hospital Oakland
Oakland, California, United States, 94609
United States, Illinois
Ann & Robert H. Lurie Children's Hospital of Chicago
Chicago, Illinois, United States, 60611
United States, New York
NYU School of Medicine, Neurogenetics Division
New York, New York, United States, 10016
United States, North Carolina
University of North Carolina
Chapel Hill, North Carolina, United States, 27514
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
Sponsors and Collaborators
Sangamo Therapeutics
Investigators
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Study Director: Medical Monitor Sangamo Therapeutics
  Study Documents (Full-Text)

Documents provided by Sangamo Therapeutics:
Study Protocol  [PDF] December 12, 2019
Statistical Analysis Plan  [PDF] October 30, 2020

More Information
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Responsible Party: Sangamo Therapeutics
ClinicalTrials.gov Identifier: NCT03041324    
Other Study ID Numbers: SB-913-1602
First Posted: February 2, 2017    Key Record Dates
Results First Posted: September 27, 2022
Last Update Posted: October 25, 2022
Last Verified: October 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Sangamo Therapeutics:
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
Additional relevant MeSH terms:
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Mucopolysaccharidosis II
Mucopolysaccharidoses
Carbohydrate Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lysosomal Storage Diseases
Mucinoses
Connective Tissue Diseases
 Metabolic Diseases
Mental Retardation, X-Linked
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Genetic Diseases, X-Linked
Heredodegenerative Disorders, Nervous System