Clinical trial NCT03041324: Ascending Dose Study of Genome Editing by the Zinc Finger Nuclease (ZFN) Therapeutic SB-913 in Subjects With MPS II
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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Mucopolysaccharidosis II
MPS II
Keywords: 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
Lead sponsor: Sangamo Therapeutics
Sponsor class: INDUSTRY
First posted: 2017-02-02
Enrollment: 9
Sex: ALL
Minimum age (years): 5
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 36 Months After the SB-913 Infusion
timeFrame: Up to 36 months after the SB-913 infusion
Secondary outcomes:
measure: Effect of SB-913 on IDS Activity
timeFrame: Baseline and Month 33 after the SB-913 infusion
measure: Effect of SB-913 on Urine Glycosaminoglycans (GAG) Levels
timeFrame: Baseline and 36 months after the SB-913 infusion
measure: Annualized Frequency of Idursulfase (or Equivalent ERT) Administration.
timeFrame: Up to 36 months after the SB-913 infusion
measure: AAV2/6 Clearance in Plasma, Saliva, Urine, Stool, and Semen
timeFrame: Up to 36 months after the SB-913 infusion
Other outcomes:
Locations:
city: Oakland
country: United States
facility: UCSF Benioff Children's Hospital Oakland
state: California
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: New York
country: United States
facility: NYU School of Medicine, Neurogenetics Division
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
Study officials:
affiliation: Sangamo Therapeutics
name: Medical Monitor
role: STUDY_DIRECTOR
References: