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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

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

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.

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

NCT ID

NCT02702115

First Posted

February 29, 2016

Last Updated

January 6, 2023

Sponsor

Sangamo Therapeutics

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

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

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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