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

Phase 2TerminatedNCT03041324

Sangamo Therapeutics9 enrolled

Overview

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.

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

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Mucopolysaccharidosis II MPS II

Interventions

SB-913BIOLOGICAL

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

Eligibility

Sex: ALLMin age: 5 YearsMax age: 65 Years

Medical Language ↔ Plain English

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

Locations (5)

UCSF Benioff Children's Hospital Oakland

Oakland, California, United States

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, United States

NYU School of Medicine, Neurogenetics Division

New York, New York, United States

University of North Carolina

Chapel Hill, North Carolina, United States

Outcomes

Primary Outcomes

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)

Time frame: Up to 36 months after the SB-913 infusion

Secondary Outcomes

Effect of SB-913 on IDS Activity

Change from baseline in clinical laboratory measurement of IDS activity measured in blood, at Month 33.

Time frame: 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

Time frame: 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)

Time frame: 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.

Time frame: Up to 36 months after the SB-913 infusion

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.