A phase 1/2 study to evaluate the safety and tolerability of SB-318, a rAAV2/6-based Gene Therapy, in patients with Mucopolysaccharidosis I (MPS I)

• Register: EUCTR
• Last refreshed on: 30 April 2019
• Main ID: EUCTR2018-000206-28-GB
• Date of registration: 27/03/2018
• Prospective Registration: Yes
• Primary sponsor: Sangamo Therapeutics, Inc.
• Public title: A phase 1/2 study to evaluate the safety and tolerability of SB-318, a rAAV2/6-based Gene Therapy, in patients with Mucopolysaccharidosis I (MPS I)
• Scientific title: A Phase 1/2, 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)
• Date of first enrolment: 14/08/2018
• Target sample size: 27
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-000206-28
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

United Kingdom, United States

Contacts

• Name: SB-318-1502 Information Desk
• Affiliation: Sangamo Therapeutics, Inc.

• Name: SB-318-1502 Information Desk
• Affiliation: Sangamo Therapeutics, Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
Subjects must meet all of the following criteria to be included in the study:
1. Signed informed consent
2. =5 years of age:
a) adult cohorts 1 through 3: =18 years of age;
b) pediatric cohorts 4 and 5: 12 to 17 years of age; and
c) pediatric cohorts 6 and 7: 5 to 11 years of age.
3. Clinical diagnosis of MPS I; IDUA deficiency confirmed by gene sequencing
4. Sexually mature subjects must agree to use a barrier contraceptive method for prevention of AAV transfer as follows: for female subjects this means that the subjects’ partners must use a condom from dosing with SB-318 until at least 3 consecutive plasma samples after administration of SB-318 are negative for AAV2/6; for male subjects this means that the subjects must use a condom and must refrain from sperm donation from the time of SB-318 until at least 3 consecutive semen samples after administration of SB-318 are negative for AAV2/6. Additionally, female participants of child-bearing potential must consent to use a highly effective method of contraception.
5. Magnetic resonance imaging (MRI) negative for liver mass as read by a radiologist.

Are the trial subjects under 18? yes
Number of subjects for this age range: 16
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 9
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
Subjects who meet any of the following criteria will be excluded from participating in the study:
1. Known to be unresponsive to ERT.
2. Neutralizing antibodies in serum (immune response) to AAV2/6.
3. Serious intercurrent illness or clinically significant organic disease (unless secondary to MPS I) such as cardiovascular, hepatic, pulmonary, neurologic, or renal disease.
4. Receiving antiviral therapy for hepatitis B or C, or with active hepatitis B (HBV DNA positive or HBV surface antigen positive) or hepatitis C (HCV RNA viral load) or human immunodeficiency virus (HIV)-1/2 (HIV RNA viral load or HIV antibody positive); to be considered negative for hepatitis C after treatment of an active HCV infection, viral assays in 2 samples collected at least 6 months apart must be negative.
5. Lack of tolerance to ERT with significant infusion-associated reactions (IARs) or occurrence of anaphylaxis.
6. Polymorphisms in the ZFN-targeted region of the albumin locus.
7. Liver fibrosis score of 3 or 4 on a 0 to 4 point scale (Desmet et al. 1994) if subject has had a liver biopsy within 2 years of Screening.
8. Markers of hepatic dysfunction as evidenced by one or more of the following:
a. Platelet count <100,000/µL
b. Albumin =3.2 g/dL
c. Total bilirubin >1.5 x upper limit of normal (ULN) and direct bilirubin =0.5 mg/dL
d. Alkaline phosphatase >2.0 x ULN
e. ALT or AST >2.0 x ULN
9. Creatinine = 1.5 mg/dL.
10. Weight < 20 kg at Screening.
11. Pregnant or breastfeeding female.
12. Contraindication to the use of corticosteroids.
13. Current treatment with systemic (IV or oral) immunomodulatory agent or steroid use (topical treatment allowed, e.g., for asthma or eczema).
14. History of active malignancy in past 5 years (non-melanoma skin cancer or cervical cancer in situ permitted).
15. Participation in prior investigational drug or medical device study within the previous 3 months.
16. Prior treatment with a gene therapy product.
17. History of alcohol or substance abuse that in the opinion of the Principal Investigator may interfere with study compliance.
18. History of therapeutic non-adherence.
19. Elevated or abnormal circulating a-fetoprotein (AFP).
20. Any other reason that, in the opinion of the Principal Investigator or Medical Monitor, would render the subject unsuitable for participation in the study.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Mucopolysaccharidosis type I (MPS I)
MedDRA version: 20.1 Level: PT Classification code 10056886 Term: Mucopolysaccharidosis I System Organ Class: 10010331 - Congenital, familial and genetic disorders

Therapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]

Intervention(s)

Product Name: rAAV2/6 Left ZFN Vector
Product Code: SB-47171
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: Not yet assigned
CAS Number: 2143578-31-6
Current Sponsor code: SB-47171
Other descriptive name: Adeno-associated virus serotype 2/6 encoding Left side-zinc finger nuclease (ZFN1), SB-A6P-ZLEFT Vector
Concentration unit: vector genomes (vg)/mL
Concentration type: equal
Concentration number: 10000000000000-

Product Name: rAAV2/6 Right ZFN Vector
Product Code: SB-47898
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: Not yet assigned
CAS Number: 2143578-32-7
Current Sponsor code: SB-47898
Other descriptive name: Adeno-associated virus serotype 2/6 encoding Right side-zinc finger nuclease (ZFN2), SB-A6P-ZRIGHT Vector
Concentration unit: vector genomes (vg)/mL
Concentration type: equal
Concentration number: 10000000000000-

Product Name: SB-A6P-HRL Donor Vector
Product Code: SB-IDUA
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: Not yet assigned
CAS Number: 2143580-11-2
Current Sponsor code: SB-IDUA
Other descriptive name: Adeno-associated virus serotype 2/6 encoding human iduronidase (hIDUA) gene donor vector, SB-A6P-HRL Donor Vector
Concentration unit: vector genomes (vg)/mL
Concentration type: equal
Concentration number: 10000000000000-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: -Liver Panel: Baseline (BL), twice a week (wk) for at least the first 20 wks post infusion, then tested at wk 24, 28, 32, 36, 40, 44, 48, 52, Month 15, 18, 21, 24, 27, 30, 33, 36 & ETV
-AE assessments and concomitant medications: All time points
-Clinical Laboratory tests: All time points except day 0, Day 7, wk 28, 32, 40, 44 & 52
-vital signs & physical exam: BL, Day 0, Day 1, Day 7, wk 2, 4, 6, 8, 12, 16, 20, 24, 36, 48, Month 15, 18, 21, 24, 27, 30, 33, 36 & ETV
-ECG, Cranial nerve exam and muscle strength testing: BL, Day 7 (ECG only), wk 24, 48, Month 18, 24, 30, 36 & ETV
-ECHO: wk 48, Month 24, 36 & ETV
-chimerism assay: BL, wk 12, 48, Month 36 & ETV
-AFP: Wk 4, 8, 12, 24, 48, Month 18, 24, 30, 36 & ETV
-MRI of Liver: Wk 24, 48, Month 18, 24, 30, 36 & ETV

Secondary Objective: Secondary objectives:
• To evaluate change from Baseline over time in the following assessments:
o IDUA activity in blood
o GAG testing in urine
o Frequency of ERT administration
• To evaluate AAV2/6 clearance.

Exploratory Objectives:
• To evaluate change from Baseline over time in the following assessments:
o GAG testing in tissues (including blood, liver tissue, and cerebrospinal fluid [CSF]).
o Gene modification at the albumin locus in the liver.
o Imaging, functional, and neurocognitive testing related to MPS I.
o Immune response to AAV 2/6, ZFNs and IDUA
From consenting subjects, residual samples may be used for future research objectives.

Main Objective: To evaluate the safety and tolerability of SB-318

Primary end point(s): •Incidence of treatment-emergent AEs (including SAEs).
• Additional safety evaluations include:
o Routine hematology, chemistry and liver function laboratory tests, vital signs, physical exam, electrocardiogram (ECG), echocardiogram (ECHO), and concomitant medications.
o Monitoring of chimerism in post-HSCT subjects.
o Cranial nerve exam and muscle strength testing.
o Serial a-fetoprotein (AFP) testing and magnetic resonance imaging (MRI) of liver to evaluate for liver mass.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: -IDUA/GAG testing (blood): BL, Wk 2, 4, 6, 8, 12, 16, 20, 24, 36, 48, M 15, 18, 21, 24, 27, 30, 33, 36 & ETV
- Urine GAG levels: BL, Wk 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, M 15, 18, 21, 24, 27, 30, 33, 36 & ETV
- AAV2/6 clearance: BL, Day 7, Wk 2, 4, 8, 12, 16, 20, 24, 36 & 48
-ERT administration log: Before & after administration of SB-318 (All time points except day 1)
- Liver biopsy & Lumbar Puncture: BL, Wk 24 & 48
-PFT, 6MWT & JROM: BL, Wk 24, 48, M 18, 24, 30, 36 & ETV
-MRI of Liver: Wk 24, 48, M 18, 24, 30, 36 & ETV
-MRI of Brain : BL, Wk 48, M 24, 36 & ETV
-Neurocognitive abilities tests: BL, Wk 24, 48, M 18, 24, 30,36 & ETV
-Visual acuity test & Corneal clouding: BL, Wk 24, 48, M 24,36 & ETV
-Immunogenicity Assays: BL, Wk 4, 12, 24, 36, 48, M 18, 24

Secondary end point(s): Secondary endpoints:
• Change from Baseline in:
o IDUA activity measured in blood.
o Total GAG, DS GAG, and HS GAG levels (expressed as ratio to creatinine) measured in urine.
o Monthly and annualized frequency and dose of Aldurazyme (or equivalent ERT).
• AAV2/6 clearance measured by vector genomes in plasma, saliva, urine, stool, and semen by PCR.

Exploratory Endpoints:
• Change from Baseline in:
o Total GAG, DS GAG, and HS GAG levels measured in tissues (including blood, liver tissue, and CSF).
o Percentage and durability of gene modification at the albumin locus in liver tissue obtained at biopsy.
o Forced vital capacity measured by pulmonary function tests (PFTs).
o Distance walked measured by six-minute walk test (6MWT).
o Joint range of motion (JROM).
o MRI of liver to evaluate liver and spleen volume.
o MRI of brain and cervical spine to evaluate clinical soft tissue and/or bone.
o Neurocognitive abilities by WASI-II (Wechsler Abbreviated Scale of Intelligence, Second Edition; Shapiro et al. 2015), WPPSI-IV (Wechsler Preschool and Primary Scale of Intelligence), or BSID-III (Bayley Scales of Infant Development), and by VABS-II (Vineland Adaptive Behavior Scales).
o Eye exam for corneal clouding and vision testing.
o Histopathological exam of liver tissue.
• Immune response to AAV 2/6, ZFNs and IDUA measured in serum.

Secondary ID(s)

NCT02702115

SB-318-1502

Source(s) of Monetary Support

Sangamo Therapeutics, Inc.

Ethics review

Status: Approved
Approval date:
Contact: