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

• ClinicalTrials.gov Identifier: NCT03041324
• Recruitment Status: Terminated
• First Posted: February 2, 2017
• Last Update Posted: June 8, 2021
• Sponsor: Sangamo Therapeutics
• Information provided by (Responsible Party): Sangamo Therapeutics

Study Description

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

• 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

Arms and Interventions

Arm	Intervention/treatment
Experimental: Experimental: Cohort 1: SB-913: Starting Dose; 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: Experimental: Cohort 2: SB-913 at Next Ascending Dose; 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: Experimental: Cohort 3: SB-913 at Next Ascending Dose; 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: Experimental: Cohort 4: SB-913 at Next Ascending Dose; 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

Primary Outcome Measures :

1. Incidence of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 36 months after the SB-913 infusion ]
   Incidence of 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: Up to 36 months after the SB-913 infusion ]
   Change from baseline in clinical laboratory measurement of IDS activity measured in blood.
2. Effect of SB-913 on urine glycosaminoglycans (GAG) levels [ Time Frame: Up to 36 months after the SB-913 infusion ]
   Change from baseline in total GAG, DS GAG, and HS GAG (/creatinine ratio) measured in tissues including blood, liver and cerebrospinal fluid (CSF).
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 ]
   AAV2/6 clearance by measuring vector genomes in plasma, saliva, urine, stool, and semen by PCR.

Eligibility Criteria

• 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 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

Locations

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

• Study Director: Medical Monitor; Sangamo Therapeutics

More Information

• Responsible Party: Sangamo Therapeutics
• ClinicalTrials.gov Identifier: NCT03041324
• Other Study ID Numbers: SB-913-1602
• First Posted: February 2, 2017
• Last Update Posted: June 8, 2021
• Last Verified: June 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

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