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

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)

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.

Study Overview

• Status: Terminated
• Conditions: Mucopolysaccharidosis II; MPS II
• Intervention / Treatment: Biological: SB-913

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 Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Oakland, California, United States, 94609
      • UCSF Benioff Children's Hospital Oakland
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H. Lurie Children's Hospital of Chicago
  • New York
    • New York, New York, United States, 10016
      • NYU School of Medicine, Neurogenetics Division
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • University of North Carolina
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 63 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	Up to 36 months after the SB-913 infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of SB-913 on IDS Activity	Change from baseline in clinical laboratory measurement of IDS activity measured in blood, at Month 33.	Baseline and Month 33 after the SB-913 infusion
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	Baseline and 36 months after the SB-913 infusion
Annualized Frequency of Idursulfase (or Equivalent ERT) Administration.	Change from baseline in annualized frequency of idursulfase (or equivalent ERT)	Up to 36 months after the SB-913 infusion
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.	Up to 36 months after the SB-913 infusion

Collaborators and Investigators

• Sponsor: Sangamo Therapeutics
• Investigators: Study Director: Medical Monitor, Sangamo Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): May 11, 2017
• Primary Completion (Actual): May 7, 2021
• Study Completion (Actual): May 7, 2021

Study Registration Dates

• First Submitted: January 13, 2017
• First Submitted That Met QC Criteria: January 31, 2017
• First Posted (Estimate): February 2, 2017

Study Record Updates

• Last Update Posted (Actual): October 25, 2022
• Last Update Submitted That Met QC Criteria: October 21, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Mucopolysaccharidosis II; Gene Editing; Zinc Finger; SB-913; Rare; Genetic; DNA; Sangamo; ZFN; Gene therapy; Hunter syndrome; Hunter; MPS ll; Genome editing; Champions; Gene Specific Targeted Insertion
• Additional Relevant MeSH Terms: Metabolic Diseases; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Connective Tissue Diseases; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Mental Retardation, X-Linked; Intellectual Disability; Heredodegenerative Disorders, Nervous System; Mucopolysaccharidosis II; Mucopolysaccharidoses
• Other Study ID Numbers: SB-913-1602

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No