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

Sponsor

Sangamo Therapeutics (Industry)

Overall Status

Terminated

CT.gov ID

NCT03041324

Collaborator

(none)

Enrollment

Locations

Arms

47.9

Actual Duration (Months)

1.8

Patients Per Site

Patients Per Site Per Month

Study Details

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

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

Incidence of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [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

Effect of SB-913 on IDS activity [Up to 36 months after the SB-913 infusion]
Change from baseline in clinical laboratory measurement of IDS activity measured in blood.
Effect of SB-913 on urine glycosaminoglycans (GAG) levels [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).
Annualized frequency of idursulfase (or equivalent ERT) administration. [Up to 36 months after the SB-913 infusion]
Change from baseline in annualized frequency of idursulfase (or equivalent ERT)
AAV2/6 clearance in plasma, saliva, urine, stool, and semen [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

Criteria

Ages Eligible for Study:

5 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

	Site	City	State	Country	Postal Code
1	UCSF Benioff Children's Hospital Oakland	Oakland	California	United States	94609
2	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611
3	NYU School of Medicine, Neurogenetics Division	New York	New York	United States	10016
4	University of North Carolina	Chapel Hill	North Carolina	United States	27514
5	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229