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

Primary Purpose

MPS I

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
SB-318
Sponsored by
Sangamo Therapeutics
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for MPS I focused on measuring Mucopolysaccharidosis I, MPS I, Hurler-Scheie syndrome, Gene Therapy, Gene Editing, Zinc Finger, SB-318, Rare, Genetic, DNA, Sangamo, Genome editing, Empowers, ZFN, Hurler, Gene Specific Targeted Insertion

Eligibility Criteria

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

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

Sites / Locations

  • UCSF Benioff Children's Hospital Oakland

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Cohort 1: SB-318: Starting Dose 1.00E+13 vg/kg

Cohort 2: SB-318 at Next Ascending Dose 5.00E+13 vg/kg

Cohort 3: SB-318 at Next Ascending Dose 1.20E+14 vg/kg

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

Number of Participants With Treatment-Emergent Adverse Events
Number of Participants with Treatment-Emergent Adverse Events

Secondary Outcome Measures

Effect of SB-318 on IDUA Activity
Change from baseline clinical laboratory in measurement of IDUA activity measured in leukocytes.
Effect of SB-318 on Urine Glycosaminoglycans (GAG) Levels
Change from baseline in total GAG, Dermatan Sulfate GAG, and Heparan Sulfate GAG measured in urine at Month 24
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.

Full Information

First Posted
February 29, 2016
Last Updated
January 6, 2023
Sponsor
Sangamo Therapeutics
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1. Study Identification

Unique Protocol Identification Number
NCT02702115
Brief Title
Ascending Dose Study of Genome Editing by the Zinc Finger Nuclease (ZFN) Therapeutic SB-318 in Subjects With MPS I
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)
Study Type
Interventional

2. Study Status

Record Verification Date
December 2022
Overall Recruitment Status
Terminated
Why Stopped
All three subjects dosed in the study have rolled over to the Long-Term Follow-up Study IVPRP-LT01 (NCT04628871)
Study Start Date
May 24, 2017 (Actual)
Primary Completion Date
November 3, 2021 (Actual)
Study Completion Date
November 3, 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 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
MPS I
Keywords
Mucopolysaccharidosis I, MPS I, Hurler-Scheie syndrome, Gene Therapy, Gene Editing, Zinc Finger, SB-318, Rare, Genetic, DNA, Sangamo, Genome editing, Empowers, ZFN, Hurler, 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
3 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1: SB-318: Starting Dose 1.00E+13 vg/kg
Arm Type
Experimental
Arm Description
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.
Arm Title
Cohort 2: SB-318 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-318 [zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)] administered via intravenous (IV) infusion.
Arm Title
Cohort 3: SB-318 at Next Ascending Dose 1.20E+14 vg/kg
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
SB-318
Intervention Description
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.
Primary Outcome Measure Information:
Title
Number of Participants With Treatment-Emergent Adverse Events
Description
Number of Participants with Treatment-Emergent Adverse Events
Time Frame
Up to 36 months after the SB-318 infusion
Secondary Outcome Measure Information:
Title
Effect of SB-318 on IDUA Activity
Description
Change from baseline clinical laboratory in measurement of IDUA activity measured in leukocytes.
Time Frame
Baseline and Month 36 after the SB-318 infusion
Title
Effect of SB-318 on Urine Glycosaminoglycans (GAG) Levels
Description
Change from baseline in total GAG, Dermatan Sulfate GAG, and Heparan Sulfate GAG measured in urine at Month 24
Time Frame
Baseline and 24 months after the SB-318 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.
Time Frame
Up to 24 months after the SB-318 infusion

10. Eligibility

Sex
All
Minimum Age & Unit of Time
5 Years
Accepts Healthy Volunteers
No
Eligibility 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
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

12. IPD Sharing Statement

Citations:
PubMed Identifier
32278382
Citation
Ou L, Przybilla MJ, Ahlat O, Kim S, Overn P, Jarnes J, O'Sullivan MG, Whitley CB. A Highly Efficacious PS Gene Editing System Corrects Metabolic and Neurological Complications of Mucopolysaccharidosis Type I. Mol Ther. 2020 Jun 3;28(6):1442-1454. doi: 10.1016/j.ymthe.2020.03.018. Epub 2020 Apr 8.
Results Reference
derived

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

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