MPS II, Mucopolysaccharidosis II
Conditions
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
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.
Interventions
BIOLOGICALSB-913
Single dose of each of the 3 components of SB-913: ZFN1, ZFN2 and hIDS Donor
Sponsors
Sangamo Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 36 Months After the SB-913 Infusion | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of SB-913 on IDS Activity | Baseline and Month 33 after the SB-913 infusion | Change from baseline in clinical laboratory measurement of IDS activity measured in blood, at Month 33. |
| Effect of SB-913 on Urine Glycosaminoglycans (GAG) Levels | Baseline and 36 months after the SB-913 infusion | Change from baseline in total GAG, Dermatan Sulfate GAG, and Heparan Sulfate GAG measured in urine at Month 36 |
| Annualized Frequency of Idursulfase (or Equivalent ERT) Administration. | Up to 36 months after the SB-913 infusion | Change from baseline in annualized frequency of idursulfase (or equivalent ERT) |
| AAV2/6 Clearance in Plasma, Saliva, Urine, Stool, and Semen | Up to 36 months after the SB-913 infusion | 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. |
Countries
United States
Participant flow
Recruitment details
The original enrollment goal was 32 subjects: Subjects with MPS II disease sequentially enrolled in age cohorts: age \>18 (adult cohorts 1 through 4), age 12-17 (pediatric cohorts 5 and 6), and age 5-11 (pediatric cohorts 7 and 8). Due to the lack of observed clinical benefit, Sangamo Therapeutics, Inc. decided to stop enrollment in this study at 9 subjects, all adults in 3 cohorts. We continue to monitor the subjects in a 10-year, long-term follow-up study ST-IVPRP-LT01 (NCT04628871).
Participants by arm
| Arm | Count |
|---|---|
| Experimental: Cohort 1 SB-913 Starting Dose 5.00E+12 vg/kg A single dose of each of the three components of SB-913 \[zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)\] administered via intravenous (IV) infusion. | 2 |
| Experimental: Cohort 2 SB-913 at Next Ascending Dose 1.00E+13 vg/kg A single dose of each of the three components of SB-913 \[zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)\] administered via intravenous (IV) infusion. | 2 |
| Experimental: Cohort 3 SB-913 at Next Ascending Dose 5.00E+13 vg/kg A single dose of each of the three components of SB-913 \[zinc finger nucleases (ZFN1, ZFN2, and hIDUA Donor)\] administered via intravenous (IV) infusion. | 5 |
| Total | 9 |
Baseline characteristics
| Characteristic | Experimental: Cohort 3 SB-913 at Next Ascending Dose 5.00E+13 vg/kg | Total | Experimental: Cohort 1 SB-913 Starting Dose 5.00E+12 vg/kg | Experimental: Cohort 2 SB-913 at Next Ascending Dose 1.00E+13 vg/kg |
|---|---|---|---|---|
| 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 | 5 Participants | 9 Participants | 2 Participants | 2 Participants |
| Baseline Iduronate 2 Sulfatase (IDS) Results | 7.054 nmol/mL/hr STANDARD_DEVIATION 3.74949 | 5.2833 nmol/mL/hr STANDARD_DEVIATION 3.68909 | 4.93 nmol/mL/hr STANDARD_DEVIATION 1.79605 | 1.21 nmol/mL/hr STANDARD_DEVIATION 0.55154 |
| Baseline Urine Glycosaminoglycans (GAG) Levels Dermatan Sulfate, Urine (g/mol creatinine) | 4.094 (g/mol creatinine) STANDARD_DEVIATION 0.79563 | 4.3678 (g/mol creatinine) STANDARD_DEVIATION 1.14354 | 4.255 (g/mol creatinine) STANDARD_DEVIATION 1.70413 | 5.165 (g/mol creatinine) STANDARD_DEVIATION 1.83141 |
| Baseline Urine Glycosaminoglycans (GAG) Levels Heparan Sulfate, Urine (g/mol creatinine) | 5.074 (g/mol creatinine) STANDARD_DEVIATION 0.76843 | 6.0967 (g/mol creatinine) STANDARD_DEVIATION 2.62108 | 4.955 (g/mol creatinine) STANDARD_DEVIATION 0.24749 | 9.795 (g/mol creatinine) STANDARD_DEVIATION 4.16486 |
| Baseline Urine Glycosaminoglycans (GAG) Levels Total GAG (g/mol creatinine) | 4.816 (g/mol creatinine) STANDARD_DEVIATION 2.96001 | 5.2678 (g/mol creatinine) STANDARD_DEVIATION 2.36252 | 4.785 (g/mol creatinine) STANDARD_DEVIATION 1.44957 | 6.88 (g/mol creatinine) STANDARD_DEVIATION 0.9051 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 0 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 | 5 Participants | 8 Participants | 1 Participants | 2 Participants |
| Region of Enrollment United States | 5 participants | 9 participants | 2 participants | 2 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 5 Participants | 9 Participants | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 2 | 0 / 5 |
| other Total, other adverse events | 2 / 2 | 2 / 2 | 5 / 5 |
| serious Total, serious adverse events | 1 / 2 | 1 / 2 | 3 / 5 |
Outcome results
Primary
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
Population: All subjects in this study who received any portion of the SB-913 infusion
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Experimental: Cohort 1 SB-913 Starting Dose 5.00E+12 vg/kg | Number of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 36 Months After the SB-913 Infusion | 2 participants |
| Experimental: Cohort 2 SB-913 at Next Ascending Dose 1.00E+13 vg/kg | Number of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 36 Months After the SB-913 Infusion | 2 participants |
| Experimental: Cohort 3 SB-913 at Next Ascending Dose 5.00E+13 vg/kg | Number of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 36 Months After the SB-913 Infusion | 5 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. 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
Population: All subjects in this study who received any portion of the SB-913 infusion
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Cohort 1 SB-913 Starting Dose 5.00E+12 vg/kg | AAV2/6 Clearance in Plasma, Saliva, Urine, Stool, and Semen | 2 Participants |
| Experimental: Cohort 2 SB-913 at Next Ascending Dose 1.00E+13 vg/kg | AAV2/6 Clearance in Plasma, Saliva, Urine, Stool, and Semen | 2 Participants |
| Experimental: Cohort 3 SB-913 at Next Ascending Dose 5.00E+13 vg/kg | AAV2/6 Clearance in Plasma, Saliva, Urine, Stool, and Semen | 5 Participants |
Secondary
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
Population: All subjects in this study who received any dose of the SB-913 infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental: Cohort 1 SB-913 Starting Dose 5.00E+12 vg/kg | Annualized Frequency of Idursulfase (or Equivalent ERT) Administration. | -2.8 Number of Infusions | — |
| Experimental: Cohort 2 SB-913 at Next Ascending Dose 1.00E+13 vg/kg | Annualized Frequency of Idursulfase (or Equivalent ERT) Administration. | 9.9 Number of Infusions | Standard Deviation 25.5 |
| Experimental: Cohort 3 SB-913 at Next Ascending Dose 5.00E+13 vg/kg | Annualized Frequency of Idursulfase (or Equivalent ERT) Administration. | -0.5 Number of Infusions | Standard Deviation 6.13 |
Secondary
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
Population: All subjects in this study who received any dose of the SB-913 infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental: Cohort 1 SB-913 Starting Dose 5.00E+12 vg/kg | Effect of SB-913 on IDS Activity | -2.6600 nmol/mL/hr | Standard Deviation 3.5213 |
Secondary
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
Population: All subjects in this study who received any dose of the SB-913 infusion
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental: Cohort 1 SB-913 Starting Dose 5.00E+12 vg/kg | Effect of SB-913 on Urine Glycosaminoglycans (GAG) Levels | Dermatan Sulfate Urine | -0.025 g/mol creatinine | Standard Deviation 1.18087 |
| Experimental: Cohort 1 SB-913 Starting Dose 5.00E+12 vg/kg | Effect of SB-913 on Urine Glycosaminoglycans (GAG) Levels | Total GAG | 1.035 g/mol creatinine | Standard Deviation 0.03536 |
| Experimental: Cohort 1 SB-913 Starting Dose 5.00E+12 vg/kg | Effect of SB-913 on Urine Glycosaminoglycans (GAG) Levels | Heparan Sulfate Urine | 1.895 g/mol creatinine | Standard Deviation 2.39709 |
| Experimental: Cohort 2 SB-913 at Next Ascending Dose 1.00E+13 vg/kg | Effect of SB-913 on Urine Glycosaminoglycans (GAG) Levels | Dermatan Sulfate Urine | -3.39 g/mol creatinine | — |
| Experimental: Cohort 2 SB-913 at Next Ascending Dose 1.00E+13 vg/kg | Effect of SB-913 on Urine Glycosaminoglycans (GAG) Levels | Total GAG | -2.6 g/mol creatinine | — |
| Experimental: Cohort 2 SB-913 at Next Ascending Dose 1.00E+13 vg/kg | Effect of SB-913 on Urine Glycosaminoglycans (GAG) Levels | Heparan Sulfate Urine | -7.6 g/mol creatinine | — |
| Experimental: Cohort 3 SB-913 at Next Ascending Dose 5.00E+13 vg/kg | Effect of SB-913 on Urine Glycosaminoglycans (GAG) Levels | Total GAG | 1.734 g/mol creatinine | Standard Deviation 1.58357 |
| Experimental: Cohort 3 SB-913 at Next Ascending Dose 5.00E+13 vg/kg | Effect of SB-913 on Urine Glycosaminoglycans (GAG) Levels | Heparan Sulfate Urine | 2.880 g/mol creatinine | Standard Deviation 2.91261 |
| Experimental: Cohort 3 SB-913 at Next Ascending Dose 5.00E+13 vg/kg | Effect of SB-913 on Urine Glycosaminoglycans (GAG) Levels | Dermatan Sulfate Urine | 0.262 g/mol creatinine | Standard Deviation 0.6985 |