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

Mucopolysaccharidosis II Clinical Trial

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03041324
• Other study ID #: SB-913-1602
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: May 11, 2017
• Est. completion date: May 7, 2021

Study information

• Verified date: October 2022
• Source: Sangamo Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 9
• Est. completion date: May 7, 2021
• Est. primary completion date: May 7, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 5 Years to 65 Years

Eligibility

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 a-fetoprotein (AFP)
• Weight < 20 kg at Screening Visit

Related Conditions & MeSH terms

• MPS II
• Mucopolysaccharidoses
• Mucopolysaccharidosis II

Intervention

Biological:
• SB-913
Single dose of each of the 3 components of SB-913: ZFN1, ZFN2 and hIDS Donor

Locations

Country	Name	City	State
United States	University of North Carolina	Chapel Hill	North Carolina
United States	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	NYU School of Medicine, Neurogenetics Division	New York	New York
United States	UCSF Benioff Children's Hospital Oakland	Oakland	California

Sponsors (1)

Lead Sponsor	Collaborator
Sangamo Therapeutics

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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