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Ascending Dose Study of Genome Editing by the Zinc Finger Nuclease (ZFN) Therapeutic SB-318 in Subjects With MPS I

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: NCT02702115
Recruitment Status : Terminated (All three subjects dosed in the study have rolled over to the Long-Term Follow-up Study IVPRP-LT01 (NCT04628871))
First Posted : March 8, 2016
Results First Posted : January 26, 2023
Last Update Posted : January 26, 2023
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 of ascending doses of SB-318. SB-318 is an intravenously delivered Zinc Finger Nuclease (ZFN) Therapeutic for genome editing. It inserts a correct copy of the α-L-iduronidase (IDUA) gene into the Albumin locus in hepatocytes with the goal of lifelong therapeutic production of the IDUA enzyme.

Condition or disease Intervention/treatment Phase
MPS I Biological: SB-318 Phase 1 Phase 2

Detailed Description:
The objectives of the study are to provide long term expression of IDUA and improve the current clinical outcome of enzyme replacement therapy (ERT) or hematopoietic stem cell transplantation (HSCT) therapy in subjects with attenuated MPS I, a recessive lysosomal storage disorder that results from mutations in the gene encoding IDUA. SB-318 is a therapeutic for ZFN-mediated genome editing which will be delivered by adeno-associated virus (AAV)-derived vectors. SB-318 is intended to function by placement of the corrective copy of the IDUA 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 iduronidase for the lifetime of an MPS I patient.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 3 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-318, a rAAV2/6-based Gene Transfer in Subjects With Mucopolysaccharidosis I (MPS I)
Actual Study Start Date : May 24, 2017
Actual Primary Completion Date : November 3, 2021
Actual Study Completion Date : November 3, 2021

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Cohort 1: SB-318: Starting Dose 1.00E+13 vg/kg
A single dose of each of the three components of SB-318 [zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)] administered via intravenous (IV) infusion.
 Biological: SB-318
A single dose of each of the three components of SB-318 [zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)] administered via intravenous (IV) infusion.
Experimental: Cohort 2: SB-318 at Next Ascending Dose 5.00E+13 vg/kg
A single dose of each of the three components of SB-318 [zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)] administered via intravenous (IV) infusion.
 Biological: SB-318
A single dose of each of the three components of SB-318 [zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)] administered via intravenous (IV) infusion.
Experimental: Cohort 3: SB-318 at Next Ascending Dose 1.20E+14 vg/kg
A single dose of each of the three components of SB-318 [zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)] administered via intravenous (IV) infusion.
 Biological: SB-318
A single dose of each of the three components of SB-318 [zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)] administered via intravenous (IV) infusion.


Outcome Measures
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Primary Outcome Measures :
  1. Number of Participants With Treatment-Emergent Adverse Events [ Time Frame: Up to 36 months after the SB-318 infusion ]
    Number of Participants with Treatment-Emergent Adverse Events


Secondary Outcome Measures :
  1. Effect of SB-318 on IDUA Activity [ Time Frame: Baseline and Month 36 after the SB-318 infusion ]
    Change from baseline clinical laboratory in measurement of IDUA activity measured in leukocytes.

  2. Effect of SB-318 on Urine Glycosaminoglycans (GAG) Levels [ Time Frame: Baseline and 24 months after the SB-318 infusion ]
    Change from baseline in total GAG, Dermatan Sulfate GAG, and Heparan Sulfate GAG measured in urine at Month 24

  3. AAV2/6 Clearance in Plasma, Saliva, Urine, Stool, and Semen [ Time Frame: Up to 24 months after the SB-318 infusion ]
    Subjects with AAV2/6 clearance in plasma, saliva, urine, stool, and semen by PCR by Week 24.


Eligibility Criteria
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Ages Eligible for Study:   5 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female ≥ 5 years of age
  • Clinical diagnosis of attenuated MPS I deficiency (Hurler-Scheie, Scheie, or Hurlers status post-HSCT)

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 I)
  • Receiving antiviral therapy for hepatitis B or C, or with active hepatitis B or hepatitis C or HIV 1/2
  • Lack of tolerance to laronidase 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): NCT02702115


Locations
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United States, California
UCSF Benioff Children's Hospital Oakland
Oakland, California, United States, 94609
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] January 22, 2022

More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Sangamo Therapeutics
ClinicalTrials.gov Identifier: NCT02702115    
Other Study ID Numbers: SB-318-1502
First Posted: March 8, 2016    Key Record Dates
Results First Posted: January 26, 2023
Last Update Posted: January 26, 2023
Last Verified: December 2022

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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:
Sangamo
Mucopolysaccharidosis I
MPS I
Hurler-Scheie syndrome
Gene Therapy
Gene Editing
Zinc Finger
SB-318
 Rare
Genetic
DNA
Genome editing
Empowers
ZFN
Hurler
Gene Specific Targeted Insertion
Additional relevant MeSH terms:
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Mucopolysaccharidoses
Mucopolysaccharidosis I
Carbohydrate Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
 Lysosomal Storage Diseases
Mucinoses
Connective Tissue Diseases
Metabolic Diseases