MPS I
Conditions
Keywords
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
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.
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.
Interventions
BIOLOGICALSB-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.
Sponsors
Sangamo Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events | Up to 36 months after the SB-318 infusion | Number of Participants with Treatment-Emergent Adverse Events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of SB-318 on IDUA Activity | Baseline and Month 36 after the SB-318 infusion | Change from baseline clinical laboratory in measurement of IDUA activity measured in leukocytes. |
| Effect of SB-318 on Urine Glycosaminoglycans (GAG) Levels | Baseline and 24 months after the SB-318 infusion | Change from baseline in total GAG, Dermatan Sulfate GAG, and Heparan Sulfate GAG measured in urine at Month 24 |
| AAV2/6 Clearance in Plasma, Saliva, Urine, Stool, and Semen | Up to 24 months after the SB-318 infusion | Subjects with AAV2/6 clearance in plasma, saliva, urine, stool, and semen by PCR by Week 24. |
Countries
United States
Participant flow
Recruitment details
The original protocol anticipated 9-12 subjects in 3 cohorts at ascending doses. However, enrollment ended after 3 subjects were enrolled in 2 cohorts. (No subjects were enrolled in cohort 3). After interim data analysis, the sponsor decided to stop enrollment in this study at 3 subjects enrolled, all adults, in 2 cohorts. (No subjects were enrolled in cohort 3) The sponsor continues to monitor the subjects in a 10-year,follow-up study ST-IVPRP-LT01 (NCT04628871).
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: SB-318: Starting Dose_1.00E+13 vg/kg 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. | 1 |
| Cohort 2: SB-318 at Next Ascending Dose_5.00E+13 vg/kg 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. | 2 |
| Cohort 3: SB-318 at Next Ascending Dose_1.20E+14 vg/kg 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. | 0 |
| Total | 3 |
Baseline characteristics
| Characteristic | Cohort 1: SB-318: Starting Dose_1.00E+13 vg/kg | Cohort 2: SB-318 at Next Ascending Dose_5.00E+13 vg/kg | Cohort 3: SB-318 at Next Ascending Dose_1.20E+14 vg/kg | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Baseline Iduronidase (IDUA) Activity | 1.200 nmol/hr/mg | 9.955 nmol/hr/mg STANDARD_DEVIATION 2.7789 | — | 7.037 nmol/hr/mg STANDARD_DEVIATION 5.4232 |
| Baseline Urine Glycosaminoglycans (GAG Levels) Dermatan Sulfate, Urine | 129.3500 g/mol creatinine | 15.6680 g/mol creatinine STANDARD_DEVIATION 6.37527 | — | 53.5620 g/mol creatinine STANDARD_DEVIATION 65.78896 |
| Baseline Urine Glycosaminoglycans (GAG Levels) Heparan Sulfate Urine | 109.4200 g/mol creatinine | 12.3345 g/mol creatinine STANDARD_DEVIATION 3.72575 | — | 44.6963 g/mol creatinine STANDARD_DEVIATION 56.11422 |
| Baseline Urine Glycosaminoglycans (GAG Levels) Total GAG | 11.360 g/mol creatinine | 3.620 g/mol creatinine STANDARD_DEVIATION 0.8485 | — | 6.200 g/mol creatinine STANDARD_DEVIATION 4.5088 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 1 participants | 2 participants | — | 3 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 2 | 0 / 0 |
| other Total, other adverse events | 1 / 1 | 2 / 2 | 0 / 0 |
| serious Total, serious adverse events | 0 / 1 | 2 / 2 | 0 / 0 |
Outcome results
Primary
Number of Participants With Treatment-Emergent Adverse Events
Number of Participants with Treatment-Emergent Adverse Events
Time frame: Up to 36 months after the SB-318 infusion
Population: No subjects were enrolled in Cohort 3
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: SB-318: Starting Dose_1.00E+13 vg/kg | Number of Participants With Treatment-Emergent Adverse Events | 1 Participants |
| Cohort 2: SB-318 at Next Ascending Dose_5.00E+13 vg/kg | Number of Participants With Treatment-Emergent Adverse Events | 2 Participants |
| Cohort 3: SB-318 at Next Ascending Dose_1.20E+14 vg/kg | Number of Participants With Treatment-Emergent Adverse Events | 0 Participants |
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.
Time frame: Up to 24 months after the SB-318 infusion
Population: No subjects were enrolled in Cohort 3
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: SB-318: Starting Dose_1.00E+13 vg/kg | AAV2/6 Clearance in Plasma, Saliva, Urine, Stool, and Semen | 1 Participants |
| Cohort 2: SB-318 at Next Ascending Dose_5.00E+13 vg/kg | AAV2/6 Clearance in Plasma, Saliva, Urine, Stool, and Semen | 2 Participants |
| Cohort 3: SB-318 at Next Ascending Dose_1.20E+14 vg/kg | AAV2/6 Clearance in Plasma, Saliva, Urine, Stool, and Semen | 0 Participants |
Secondary
Effect of SB-318 on IDUA Activity
Change from baseline clinical laboratory in measurement of IDUA activity measured in leukocytes.
Time frame: Baseline and Month 36 after the SB-318 infusion
Population: No subjects were enrolled in Cohort 3
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: SB-318: Starting Dose_1.00E+13 vg/kg | Effect of SB-318 on IDUA Activity | -1.200 nmol/hr/mg | — |
| Cohort 2: SB-318 at Next Ascending Dose_5.00E+13 vg/kg | Effect of SB-318 on IDUA Activity | -2.515 nmol/hr/mg | Standard Deviation 5.9185 |
Secondary
Effect of SB-318 on Urine Glycosaminoglycans (GAG) Levels
Change from baseline in total GAG, Dermatan Sulfate GAG, and Heparan Sulfate GAG measured in urine at Month 24
Time frame: Baseline and 24 months after the SB-318 infusion
Population: No subjects were enrolled in Cohort 3
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: SB-318: Starting Dose_1.00E+13 vg/kg | Effect of SB-318 on Urine Glycosaminoglycans (GAG) Levels | Dermatan Sulfate | 0.510 g/mol creatinine | — |
| Cohort 1: SB-318: Starting Dose_1.00E+13 vg/kg | Effect of SB-318 on Urine Glycosaminoglycans (GAG) Levels | Heparan Sulfate | 30.2000 g/mol creatinine | — |
| Cohort 1: SB-318: Starting Dose_1.00E+13 vg/kg | Effect of SB-318 on Urine Glycosaminoglycans (GAG) Levels | Total GAG | 0.940 g/mol creatinine | — |
| Cohort 2: SB-318 at Next Ascending Dose_5.00E+13 vg/kg | Effect of SB-318 on Urine Glycosaminoglycans (GAG) Levels | Dermatan Sulfate | -0.090 g/mol creatinine | Standard Deviation 0.396 |
| Cohort 2: SB-318 at Next Ascending Dose_5.00E+13 vg/kg | Effect of SB-318 on Urine Glycosaminoglycans (GAG) Levels | Heparan Sulfate | 3.6005 g/mol creatinine | Standard Deviation 8.22436 |
| Cohort 2: SB-318 at Next Ascending Dose_5.00E+13 vg/kg | Effect of SB-318 on Urine Glycosaminoglycans (GAG) Levels | Total GAG | 0.240 g/mol creatinine | Standard Deviation 0.0424 |