Ascending Dose Study of Genome Editing by the Zinc Finger Nuclease (ZFN) Therapeutic SB-318 in Subjects With MPS I

• Sponsor: Sangamo Therapeutics (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02702115
• Collaborator: (none)
• Enrollment: 3
• Location: 1
• Arms: 3
• Actual Duration (Months): 53.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of the study is to evaluate the safety, tolerability of ascending doses of SB-318. SB-318 is an intravenously delivered Zinc Finger Nuclease (ZFN) Therapeutic for genome editing. It inserts a correct copy of the α-L-iduronidase (IDUA) gene into the Albumin locus in hepatocytes with the goal of lifelong therapeutic production of the IDUA enzyme.

Condition or Disease	Intervention/Treatment	Phase
MPS I	Biological: SB-318	Phase 1/Phase 2

Detailed Description

The objectives of the study are to provide long term expression of IDUA and improve the current clinical outcome of enzyme replacement therapy (ERT) or hematopoietic stem cell transplantation (HSCT) therapy in subjects with attenuated MPS I, a recessive lysosomal storage disorder that results from mutations in the gene encoding IDUA. SB-318 is a therapeutic for ZFN-mediated genome editing which will be delivered by adeno-associated virus (AAV)-derived vectors. SB-318 is intended to function by placement of the corrective copy of the IDUA 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 iduronidase for the lifetime of an MPS I patient.

Study Design

• Study Type: Interventional
• Actual Enrollment: 3 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-318, a rAAV2/6-based Gene Transfer in Subjects With Mucopolysaccharidosis I (MPS I)
• Actual Study Start Date: May 24, 2017
• Actual Primary Completion Date: Nov 3, 2021
• Actual Study Completion Date: Nov 3, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1: SB-318: Starting Dose A single dose of each of the three components of SB-318 [zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)] administered via intravenous (IV) infusion.	Biological: SB-318; A single dose of each of the three components of SB-318 [zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)] administered via intravenous (IV) infusion.
Experimental: Cohort 2: SB-318 at Next Ascending Dose A single dose of each of the three components of SB-318 [zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)] administered via intravenous (IV) infusion.	Biological: SB-318; A single dose of each of the three components of SB-318 [zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)] administered via intravenous (IV) infusion.
Experimental: Cohort 3: SB-318 at Next Ascending Dose A single dose of each of the three components of SB-318 [zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)] administered via intravenous (IV) infusion.	Biological: SB-318; A single dose of each of the three components of SB-318 [zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)] administered via intravenous (IV) infusion.

Outcome Measures

Primary Outcome Measures

1. Incidence of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [Up to 36 months after the SB-318 infusion]

   Incidence of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) in subjects who receive SB-318 as assessed by Common Terminology Criteria for Adverse Events (CTCAE)

Secondary Outcome Measures

1. Effect of SB-318 on IDUA activity [Up to 36 months after the SB-318 infusion]

   Change from baseline clinical laboratory in measurement of IDUA activity measured in blood.

2. Effect of SB-318 on urine glycosaminoglycans (GAG) levels [Up to 36 months after the SB-318 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. AAV2/6 clearance in plasma, saliva, urine, stool, and semen [Up to 36 months after the SB-318 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: No

Inclusion Criteria:

• Male or female ≥ 5 years of age

• Clinical diagnosis of attenuated MPS I deficiency (Hurler-Scheie, Scheie, or Hurlers status post-HSCT)

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 I)

• Receiving antiviral therapy for hepatitis B or C, or with active hepatitis B or hepatitis C or HIV 1/2

• Lack of tolerance to laronidase 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

Sponsors and Collaborators

• Sangamo Therapeutics

Investigators

• Study Director: Medical Monitor, Sangamo Therapeutics

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sangamo Therapeutics
• ClinicalTrials.gov Identifier: NCT02702115
• Other Study ID Numbers: SB-318-1502
• First Posted: Mar 8, 2016
• Last Update Posted: Dec 16, 2021
• Last Verified: Oct 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Sangamo Therapeutics: Mucopolysaccharidosis I; MPS I; Hurler-Scheie syndrome; Gene Therapy; Gene Editing; Zinc Finger; SB-318; Rare; Genetic; DNA; Sangamo; Genome editing; Empowers; ZFN; Hurler; Gene Specific Targeted Insertion
• Additional relevant MeSH terms: Mucopolysaccharidoses; Mucopolysaccharidosis I

Study Results

No Results Posted as of Dec 16, 2021