Sanfilippo Syndrome
Conditions
Keywords
sulfoglucosamine sulfohydrolase (SGSH), recombinant human heparan N-sulfatase (rhHNS), Hunter's Syndrome, Shire HGT, Lysosomal Storage Disease (LSD), Sanfilippo Syndrome Type A (Sanfilippo A), enzyme replacement therapy (ERT)
Brief summary
Sanfilippo syndrome Type A, or Mucopolysaccharidosis (MPS) IIIA, is a rare lysosomal storage disease caused by deficiency of the enzyme heparan N-sulfatase (sulfamidase). In the absence of this enzyme, there is an accumulation of the glycosaminoglycan, heparan sulfate, resulting in progressive neurodegeneration. Symptoms are usually first noted in the 1st or 2nd year of life, although definitive diagnosis is often delayed, with an average age of diagnosis of 4.5 years. The disease is characterized by developmental delays initially, followed by neurological developmental arrest, then regression. These developmental deficits are typically associated with severe behavioral disturbances. Patients have a significantly reduced lifespan, with few surviving beyond the 2nd or 3rd decade. The purpose of this study is to evaluate the safety and efficacy of recombinant human heparan-N-sulfatase (rhHNS) in pediatric patients with Early Stage Mucopolysaccharidosis Type III A Disease.
Detailed description
No effective, disease-modifying therapies are currently approved as treatments for this devastating and disabling disease. Shire Human Genetic Therapies (Shire HGT) is developing an enzyme replacement therapy (ERT) recombinant human heparan-N-sulfatase (rhHNS) for patients with MPS IIIA. rhHNS is being administered into the cerebrospinal fluid (CSF) via an surgically implanted intrathecal drug delivery device (IDDD), because when administered intravenously (IV) it does not cross the blood brain barrier (BBB). This study will evaluate the effect of 48 weeks of rhHNS treatment on the clinical course of MPS IIIA, using cognitive function as the primary outcome measure. The trial will evaluate 2 dosing regimens of rhHNS administered via an IDDD in comparison with a no treatment control group. Patients will be randomized 1:1:1 to either of the treatment groups or the no treatment group. Treatment will be administered in an open-label manner. The safety and tolerability profile of rhHNS will continue to be evaluated in this study.
Interventions
DRUGRecombinant human heparan N-sulfatase [rhHNS]
Recombinant human heparan N-sulfatase \[rhHNS\]
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Months to 48 Months
Healthy volunteers
No
Inclusion criteria
Each patient must meet the following criteria to be enrolled in this study. 1. Documented MPS IIIA diagnosis 2. Age ≥12 months and ≤48 months 3. The patient has a DQ score ≥60% 4. The patient is medically stable, in the opinion of the Investigator, and able to accommodate the protocol requirements, including travel, assessments, and IDDD surgery, without placing an undue burden on the patient/patient's family 5. The patient's parent(s) or legally authorized representative(s) must have voluntarily signed and dated an Independent Ethics Committee-approved informed consent form after all relevant aspects of the study have been explained and discussed with the patient's parent(s), or legally authorized representative(s). Consent of the patient's parent(s) or legally authorized representative(s) must be obtained prior to the start of any study procedures.
Exclusion criteria
Patients who meet any of the following criteria will be excluded from the study. 1. The presence of significant non-MPS IIIA related CNS impairment or behavioral disturbances that would confound the scientific integrity or interpretation of study assessments, as determined by the Investigator. 2. The presence of at least one S298P mutation in SGSH, associated with attenuated disease OR there is documentation of the S298P mutation in a sibling affected by MPS IIIA, provided parental consent is obtained to use this information. 3. The presence of relatively attenuated MPS IIIA disease in an older sibling, defined as preservation of any speech beyond the age of 10 years. 4. Visual or hearing impairment sufficient, in the clinical judgment of the investigator, to preclude cooperation with neurodevelopmental testing. Use of hearing aids is permitted. 5. In the opinion of the Investigator, the patient is assessed as having an unacceptably high risk for anesthesia due to airway compromise, drug hypersensitivity, or other conditions (such as neuroleptic malignant syndrome, malignant hyperthermia, or other anesthesia-related concerns). 6. The patient has a history of poorly controlled seizure disorder. 7. The patient is currently receiving psychotropic or other medications, which in the Investigator's opinion would be likely to substantially confound test results. 8. The patient has a history of bleeding disorder or is unable to abstain from medications that, in the opinion of the investigator, place them at risk of bleeding following surgery or LP. 9. The patient participated in a clinical trial of another investigational medicinal product, within the 30 days prior to the study (or within 5 elimination half lives of the investigational product), or is currently enrolled in another study that involves an investigational drug or device. NOTE: Nutritional supplements, including genistein are permitted if they are taken or administered outside the context of a formal investigation. 10. The patient has received a hematopoietic stem cell or bone marrow transplant, or gene therapy. 11. The patient has a condition that is contraindicated as described in the SOPH-A-PORT Mini S-IDDD 12. The patient's parent(s) or patient's legally authorized representative(s) is/are unable to understand the nature, scope, and possible consequences of the study, or do/does not agree to comply with the protocol defined schedule of assessments. 13. The patient is unable to comply with the protocol (eg, has a clinically relevant medical condition making implementation of the protocol difficult, unstable social situation, or otherwise unlikely to complete the study) or is, in the opinion of the Investigator, otherwise unsuited for the study. 14. The patient has any item (braces, tattoos, etc.) which would exclude the patient from being able to undergo MRI according to local Institutional Policy, or the patient has any other situation that would exclude the patient from undergoing any other procedure required in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Overall Response Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) | Baseline (Week 0) up to Week 48 | The BSID--III is a series of measurements to assess the motor (fine and gross), language (receptive and expressive), and cognitive development of infants and toddlers and consists of a series of developmental play tasks. The development quotient (DQ) is a means to express a neurodevelopmental/cognitive delay which was computed as a ratio and expressed as a percentage using the age equivalent score divided by the age at testing (\[age-equivalent score/chronological age\] × 100; range: 0, 100). The BSID--III DQ score is based on the cognitive domain. A positive value indicates improvement in health and cognition. Overall response was the maximum decline in the DQ of 10 points or less over 48 weeks. Number of participants with the overall response were reported here. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Baseline (Week 0) up to Week 52 | An adverse event (AE) was any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered investigational product related. This included an exacerbation of a pre-existing condition. TEAEs were defined as AE occurring on or after the time of first IDDD implantation or LP procedure to the end of study (EOS) visit (+30 days). |
| Number of Participants With Positive Anti-recombinant Human Heparan-N-Sulfatase (rhHNS) Antibody in Serum at Week 48 | Baseline (Week 0) up to Week 48 | A participant was considered positive if they had at least 1 positive result during the study. Once a participant reported antibody positive, they were considered positive for the remainder of the study. |
| Change From Baseline in Vineland Adaptive Behavior Scales Second Edition (VABS-II) Development Quotient (DQ) Score at Week 48 | Baseline (Week 0), Week 48 | The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. The DQ is a means to express a neurodevelopmental/cognitive delay. The DQ was computed as a ratio and expressed as a percentage using the age-equivalent score divided by the age at testing (\[age-equivalent score/chronological age\] × 100; range, 0, 100). The overall DQ score is calculated from the mean age-equivalent score obtained by averaging out the age-equivalent scores for the all the sub-domains except for Gross and Fine motor skills. This test measures the following 5 key domains: communication, daily living skills, socialization, motor skills, and the adaptive behavior composite (a composite of the other 4 domains). A positive value indicates improvement in health and cognition. |
| Change From Baseline in Development Quotient (DQ) Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) at Week 48 | Baseline (Week 0), Week 48 | The BSID--III is a series of measurements to assess the motor (fine and gross), language (receptive and expressive), and cognitive development of infants and toddlers and consists of a series of developmental play tasks. The DQ is a means to express a neurodevelopmental/cognitive delay which was computed as a ratio and expressed as a percentage using the age-equivalent score divided by the age at testing (\[age-equivalent score/chronological age\] × 100; range: 0, 100). The BSID--III DQ score is based on the cognitive domain. A positive value indicates improvement in health and cognition. |
| Number of Participants With Serious Adverse Events (SAE) | Baseline (Week 0) up to Week 52 | An adverse event (AE) was any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered investigational product related. This included an exacerbation of a pre-existing condition. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; lifethreatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. |
| Change From Baseline in Concentration of Glycosaminoglycan (GAG) in Cerebrospinal Fluid (CSF) at Week 48 | Baseline (Week 0), Week 48 | Change from baseline in concentration of GAG in CSF at Week 48 was reported. |
| Change From Baseline in Concentration of GAG in Urine at Week 48 | Baseline (Week 0), Week 48 | The concentration of GAG in urine was normalized to the urine creatinine value and reported as milligram (mg) GAG per millimole (mmol) creatinine. |
| Concentration of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Cerebrospinal Fluid (CSF) | Pre-dose, 4, 48 hours on Week 0 and Week 48 | Concentration of rhHNS in CSF was assessed using validated enzyme-linked immunosorbent assay (ELISA) method. |
| Maximum Observed Drug Concentration (Cmax) of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Serum | Predose, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h, and 48 h post-dose on Week 0 and Week 48 | Cmax of rhHNS in serum was evaluated using enzyme-linked immunosorbent assay (ELISA) method and liquid chromatography tandem mass spectrometry (LC-MS) method. |
| Change From Baseline in Total Cortical Grey Matter Volume at Week 48 | Baseline (Week 0), Week 48 | The change from baseline in grey matter volume at Week 48 was assessed by magnetic resonance imaging (MRI). |
Countries
Argentina, France, Germany, Italy, Netherlands, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 24 participants were screened, of them 21 participants were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| No HGT-1410 Participants received no treatment (HGT-1410). | 7 |
| HGT-1410 45 mg Q2W Participants received HGT-1410 45 mg intrathecally Q2W using surgically implanted IDDD or LP for 48 weeks. | 7 |
| HGT-1410 45 mg Q4W Participants received HGT-1410 45 mg intrathecally Q4W using surgically implanted IDDD or LP for 48 weeks. | 7 |
| Total | 21 |
Baseline characteristics
| Characteristic | No HGT-1410 | HGT-1410 45 mg Q2W | HGT-1410 45 mg Q4W | Total |
|---|---|---|---|---|
| Age, Continuous | 32.42 months STANDARD_DEVIATION 9.548 | 29.64 months STANDARD_DEVIATION 9.989 | 33.53 months STANDARD_DEVIATION 9.336 | 31.87 months STANDARD_DEVIATION 9.287 |
| Sex: Female, Male Female | 3 Participants | 5 Participants | 4 Participants | 12 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 3 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 7 | 7 / 7 | 7 / 7 |
| serious Total, serious adverse events | 3 / 7 | 5 / 7 | 6 / 7 |
Outcome results
Primary
Number of Participants With Overall Response Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III)
The BSID--III is a series of measurements to assess the motor (fine and gross), language (receptive and expressive), and cognitive development of infants and toddlers and consists of a series of developmental play tasks. The development quotient (DQ) is a means to express a neurodevelopmental/cognitive delay which was computed as a ratio and expressed as a percentage using the age equivalent score divided by the age at testing (\[age-equivalent score/chronological age\] × 100; range: 0, 100). The BSID--III DQ score is based on the cognitive domain. A positive value indicates improvement in health and cognition. Overall response was the maximum decline in the DQ of 10 points or less over 48 weeks. Number of participants with the overall response were reported here.
Time frame: Baseline (Week 0) up to Week 48
Population: ITT population included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| No HGT-1410 | Number of Participants With Overall Response Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) | 0 participants |
| HGT-1410 45 mg Q2W | Number of Participants With Overall Response Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) | 2 participants |
| HGT-1410 45 mg Q4W | Number of Participants With Overall Response Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) | 1 participants |
Comparison: 95% exact unconditional confidence interval of the difference in proportion between each of the treatment groups and the untreated control group was considered for the parameter estimation.p-value: 0.461595% CI: [-0.297, 0.745]Fisher Exact
Comparison: 95% exact unconditional confidence interval of the difference in proportion between each of the treatment groups and the untreated control group was considered for the parameter estimation.p-value: 195% CI: [-0.423, 0.647]Fisher Exact
Secondary
Change From Baseline in Concentration of GAG in Urine at Week 48
The concentration of GAG in urine was normalized to the urine creatinine value and reported as milligram (mg) GAG per millimole (mmol) creatinine.
Time frame: Baseline (Week 0), Week 48
Population: ITT population included all randomized participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| No HGT-1410 | Change From Baseline in Concentration of GAG in Urine at Week 48 | -7.18 mg GAG/mmol creatinine | Standard Deviation 39.175 |
| HGT-1410 45 mg Q2W | Change From Baseline in Concentration of GAG in Urine at Week 48 | -31.81 mg GAG/mmol creatinine | Standard Deviation 22.887 |
| HGT-1410 45 mg Q4W | Change From Baseline in Concentration of GAG in Urine at Week 48 | -42.46 mg GAG/mmol creatinine | Standard Deviation 29.861 |
Secondary
Change From Baseline in Concentration of Glycosaminoglycan (GAG) in Cerebrospinal Fluid (CSF) at Week 48
Change from baseline in concentration of GAG in CSF at Week 48 was reported.
Time frame: Baseline (Week 0), Week 48
Population: ITT population included all randomized participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| No HGT-1410 | Change From Baseline in Concentration of Glycosaminoglycan (GAG) in Cerebrospinal Fluid (CSF) at Week 48 | -0.193 micromolar | Standard Deviation 1.318 |
| HGT-1410 45 mg Q2W | Change From Baseline in Concentration of Glycosaminoglycan (GAG) in Cerebrospinal Fluid (CSF) at Week 48 | -6.888 micromolar | Standard Deviation 5.388 |
| HGT-1410 45 mg Q4W | Change From Baseline in Concentration of Glycosaminoglycan (GAG) in Cerebrospinal Fluid (CSF) at Week 48 | -5.924 micromolar | Standard Deviation 2.47 |
Secondary
Change From Baseline in Development Quotient (DQ) Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) at Week 48
The BSID--III is a series of measurements to assess the motor (fine and gross), language (receptive and expressive), and cognitive development of infants and toddlers and consists of a series of developmental play tasks. The DQ is a means to express a neurodevelopmental/cognitive delay which was computed as a ratio and expressed as a percentage using the age-equivalent score divided by the age at testing (\[age-equivalent score/chronological age\] × 100; range: 0, 100). The BSID--III DQ score is based on the cognitive domain. A positive value indicates improvement in health and cognition.
Time frame: Baseline (Week 0), Week 48
Population: ITT population included all randomized participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| No HGT-1410 | Change From Baseline in Development Quotient (DQ) Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) at Week 48 | Receptive Communication | -13.15 percentage of chronological age | Standard Deviation 13.318 |
| No HGT-1410 | Change From Baseline in Development Quotient (DQ) Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) at Week 48 | Gross Motor | -11.60 percentage of chronological age | Standard Deviation 13.668 |
| No HGT-1410 | Change From Baseline in Development Quotient (DQ) Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) at Week 48 | Expressive Communication | -14.77 percentage of chronological age | Standard Deviation 10.055 |
| No HGT-1410 | Change From Baseline in Development Quotient (DQ) Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) at Week 48 | Cognitive | -19.81 percentage of chronological age | Standard Deviation 3.974 |
| No HGT-1410 | Change From Baseline in Development Quotient (DQ) Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) at Week 48 | Fine Motor | -23.72 percentage of chronological age | Standard Deviation 14.752 |
| HGT-1410 45 mg Q2W | Change From Baseline in Development Quotient (DQ) Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) at Week 48 | Gross Motor | -12.52 percentage of chronological age | Standard Deviation 21.203 |
| HGT-1410 45 mg Q2W | Change From Baseline in Development Quotient (DQ) Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) at Week 48 | Cognitive | -23.82 percentage of chronological age | Standard Deviation 14.684 |
| HGT-1410 45 mg Q2W | Change From Baseline in Development Quotient (DQ) Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) at Week 48 | Receptive Communication | -16.33 percentage of chronological age | Standard Deviation 25.373 |
| HGT-1410 45 mg Q2W | Change From Baseline in Development Quotient (DQ) Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) at Week 48 | Expressive Communication | -19.71 percentage of chronological age | Standard Deviation 22.878 |
| HGT-1410 45 mg Q2W | Change From Baseline in Development Quotient (DQ) Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) at Week 48 | Fine Motor | -18.59 percentage of chronological age | Standard Deviation 18.879 |
| HGT-1410 45 mg Q4W | Change From Baseline in Development Quotient (DQ) Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) at Week 48 | Expressive Communication | -10.01 percentage of chronological age | Standard Deviation 15.573 |
| HGT-1410 45 mg Q4W | Change From Baseline in Development Quotient (DQ) Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) at Week 48 | Cognitive | -19.87 percentage of chronological age | Standard Deviation 12.724 |
| HGT-1410 45 mg Q4W | Change From Baseline in Development Quotient (DQ) Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) at Week 48 | Fine Motor | -18.86 percentage of chronological age | Standard Deviation 16.308 |
| HGT-1410 45 mg Q4W | Change From Baseline in Development Quotient (DQ) Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) at Week 48 | Receptive Communication | -12.41 percentage of chronological age | Standard Deviation 14.981 |
| HGT-1410 45 mg Q4W | Change From Baseline in Development Quotient (DQ) Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) at Week 48 | Gross Motor | -2.77 percentage of chronological age | Standard Deviation 18.947 |
Secondary
Change From Baseline in Total Cortical Grey Matter Volume at Week 48
The change from baseline in grey matter volume at Week 48 was assessed by magnetic resonance imaging (MRI).
Time frame: Baseline (Week 0), Week 48
Population: ITT population included all randomized participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| No HGT-1410 | Change From Baseline in Total Cortical Grey Matter Volume at Week 48 | -45.1 cubic centimeter (cc) | Standard Deviation 23.35 |
| HGT-1410 45 mg Q2W | Change From Baseline in Total Cortical Grey Matter Volume at Week 48 | -102.0 cubic centimeter (cc) | Standard Deviation 68.12 |
| HGT-1410 45 mg Q4W | Change From Baseline in Total Cortical Grey Matter Volume at Week 48 | -58.8 cubic centimeter (cc) | Standard Deviation 66.24 |
Secondary
Change From Baseline in Vineland Adaptive Behavior Scales Second Edition (VABS-II) Development Quotient (DQ) Score at Week 48
The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. The DQ is a means to express a neurodevelopmental/cognitive delay. The DQ was computed as a ratio and expressed as a percentage using the age-equivalent score divided by the age at testing (\[age-equivalent score/chronological age\] × 100; range, 0, 100). The overall DQ score is calculated from the mean age-equivalent score obtained by averaging out the age-equivalent scores for the all the sub-domains except for Gross and Fine motor skills. This test measures the following 5 key domains: communication, daily living skills, socialization, motor skills, and the adaptive behavior composite (a composite of the other 4 domains). A positive value indicates improvement in health and cognition.
Time frame: Baseline (Week 0), Week 48
Population: ITT population included all randomized participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| No HGT-1410 | Change From Baseline in Vineland Adaptive Behavior Scales Second Edition (VABS-II) Development Quotient (DQ) Score at Week 48 | Socialization Domain | -16.12 percentage of chronological age | Standard Deviation 23.32 |
| No HGT-1410 | Change From Baseline in Vineland Adaptive Behavior Scales Second Edition (VABS-II) Development Quotient (DQ) Score at Week 48 | Daily Living Skills Domain | -4.20 percentage of chronological age | Standard Deviation 29.005 |
| No HGT-1410 | Change From Baseline in Vineland Adaptive Behavior Scales Second Edition (VABS-II) Development Quotient (DQ) Score at Week 48 | Motor Skills Domain | -5.37 percentage of chronological age | Standard Deviation 24.741 |
| No HGT-1410 | Change From Baseline in Vineland Adaptive Behavior Scales Second Edition (VABS-II) Development Quotient (DQ) Score at Week 48 | Communication Domain | -5.12 percentage of chronological age | Standard Deviation 10.981 |
| HGT-1410 45 mg Q2W | Change From Baseline in Vineland Adaptive Behavior Scales Second Edition (VABS-II) Development Quotient (DQ) Score at Week 48 | Communication Domain | -20.83 percentage of chronological age | Standard Deviation 23.475 |
| HGT-1410 45 mg Q2W | Change From Baseline in Vineland Adaptive Behavior Scales Second Edition (VABS-II) Development Quotient (DQ) Score at Week 48 | Motor Skills Domain | -27.01 percentage of chronological age | Standard Deviation 20.82 |
| HGT-1410 45 mg Q2W | Change From Baseline in Vineland Adaptive Behavior Scales Second Edition (VABS-II) Development Quotient (DQ) Score at Week 48 | Daily Living Skills Domain | -27.09 percentage of chronological age | Standard Deviation 21.444 |
| HGT-1410 45 mg Q2W | Change From Baseline in Vineland Adaptive Behavior Scales Second Edition (VABS-II) Development Quotient (DQ) Score at Week 48 | Socialization Domain | -24.24 percentage of chronological age | Standard Deviation 40.617 |
| HGT-1410 45 mg Q4W | Change From Baseline in Vineland Adaptive Behavior Scales Second Edition (VABS-II) Development Quotient (DQ) Score at Week 48 | Motor Skills Domain | -17.88 percentage of chronological age | Standard Deviation 12.007 |
| HGT-1410 45 mg Q4W | Change From Baseline in Vineland Adaptive Behavior Scales Second Edition (VABS-II) Development Quotient (DQ) Score at Week 48 | Daily Living Skills Domain | -11.74 percentage of chronological age | Standard Deviation 26.713 |
| HGT-1410 45 mg Q4W | Change From Baseline in Vineland Adaptive Behavior Scales Second Edition (VABS-II) Development Quotient (DQ) Score at Week 48 | Communication Domain | -4.97 percentage of chronological age | Standard Deviation 17.253 |
| HGT-1410 45 mg Q4W | Change From Baseline in Vineland Adaptive Behavior Scales Second Edition (VABS-II) Development Quotient (DQ) Score at Week 48 | Socialization Domain | -29.34 percentage of chronological age | Standard Deviation 29.425 |
Secondary
Concentration of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Cerebrospinal Fluid (CSF)
Concentration of rhHNS in CSF was assessed using validated enzyme-linked immunosorbent assay (ELISA) method.
Time frame: Pre-dose, 4, 48 hours on Week 0 and Week 48
Population: Pharmacokinetic (PK) population included all participants who received HGT-1410, participated in the scheduled PK studies, and had sufficient samples available for analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| No HGT-1410 | Concentration of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Cerebrospinal Fluid (CSF) | Week 0: Predose | 0 nanogram per milliliter (ng/ml) | Standard Deviation 0 |
| No HGT-1410 | Concentration of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Cerebrospinal Fluid (CSF) | Week 0: 4h | 313392.49 nanogram per milliliter (ng/ml) | Standard Deviation 142748.885 |
| No HGT-1410 | Concentration of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Cerebrospinal Fluid (CSF) | Week 0: 48h | 366.05 nanogram per milliliter (ng/ml) | Standard Deviation 571.528 |
| No HGT-1410 | Concentration of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Cerebrospinal Fluid (CSF) | Week 48: Predose | 869.67 nanogram per milliliter (ng/ml) | Standard Deviation 1863.989 |
| No HGT-1410 | Concentration of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Cerebrospinal Fluid (CSF) | Week 48: 4h | 374544.38 nanogram per milliliter (ng/ml) | Standard Deviation 135047.7 |
| No HGT-1410 | Concentration of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Cerebrospinal Fluid (CSF) | Week 48: 48h | 104.49 nanogram per milliliter (ng/ml) | Standard Deviation 65.881 |
| HGT-1410 45 mg Q2W | Concentration of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Cerebrospinal Fluid (CSF) | Week 48: 4h | 335203.84 nanogram per milliliter (ng/ml) | Standard Deviation 82918.537 |
| HGT-1410 45 mg Q2W | Concentration of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Cerebrospinal Fluid (CSF) | Week 0: Predose | 0 nanogram per milliliter (ng/ml) | Standard Deviation 0 |
| HGT-1410 45 mg Q2W | Concentration of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Cerebrospinal Fluid (CSF) | Week 48: Predose | 365.04 nanogram per milliliter (ng/ml) | Standard Deviation 965.797 |
| HGT-1410 45 mg Q2W | Concentration of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Cerebrospinal Fluid (CSF) | Week 0: 4h | 266021.60 nanogram per milliliter (ng/ml) | Standard Deviation 113340.887 |
| HGT-1410 45 mg Q2W | Concentration of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Cerebrospinal Fluid (CSF) | Week 48: 48h | 8892.93 nanogram per milliliter (ng/ml) | Standard Deviation 19519.717 |
| HGT-1410 45 mg Q2W | Concentration of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Cerebrospinal Fluid (CSF) | Week 0: 48h | 2119.59 nanogram per milliliter (ng/ml) | Standard Deviation 2068.093 |
Secondary
Maximum Observed Drug Concentration (Cmax) of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Serum
Cmax of rhHNS in serum was evaluated using enzyme-linked immunosorbent assay (ELISA) method and liquid chromatography tandem mass spectrometry (LC-MS) method.
Time frame: Predose, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h, and 48 h post-dose on Week 0 and Week 48
Population: Pharmacokinetic (PK) population included all participants who received HGT-1410, participated in the scheduled PK studies, and had sufficient samples available for analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| No HGT-1410 | Maximum Observed Drug Concentration (Cmax) of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Serum | LC-MS Method: Week 0 | 102.4 ng/ml | Standard Deviation 63 |
| No HGT-1410 | Maximum Observed Drug Concentration (Cmax) of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Serum | ELISA Method: Week 0 | 120.9 ng/ml | Standard Deviation 84.77 |
| No HGT-1410 | Maximum Observed Drug Concentration (Cmax) of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Serum | LC-MS Method: Week 48 | 188.1 ng/ml | Standard Deviation 127.4 |
| No HGT-1410 | Maximum Observed Drug Concentration (Cmax) of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Serum | ELISA Method: Week 48 | 63.5 ng/ml | Standard Deviation 149.76 |
| HGT-1410 45 mg Q2W | Maximum Observed Drug Concentration (Cmax) of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Serum | LC-MS Method: Week 48 | 119.7 ng/ml | Standard Deviation 133.18 |
| HGT-1410 45 mg Q2W | Maximum Observed Drug Concentration (Cmax) of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Serum | ELISA Method: Week 0 | 237.0 ng/ml | Standard Deviation 159.68 |
| HGT-1410 45 mg Q2W | Maximum Observed Drug Concentration (Cmax) of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Serum | LC-MS Method: Week 0 | 191.0 ng/ml | Standard Deviation 125.84 |
| HGT-1410 45 mg Q2W | Maximum Observed Drug Concentration (Cmax) of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Serum | ELISA Method: Week 48 | 118.8 ng/ml | Standard Deviation 161.98 |
Secondary
Number of Participants With Positive Anti-recombinant Human Heparan-N-Sulfatase (rhHNS) Antibody in Serum at Week 48
A participant was considered positive if they had at least 1 positive result during the study. Once a participant reported antibody positive, they were considered positive for the remainder of the study.
Time frame: Baseline (Week 0) up to Week 48
Population: Safety population included all participants who received a dose of HGT-1410 using either the IDDD implantation or LP; underwent the IDDD surgical implant procedure without receiving a dose of HGT-1410; were randomly assigned to the untreated group and had any safety followup data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| No HGT-1410 | Number of Participants With Positive Anti-recombinant Human Heparan-N-Sulfatase (rhHNS) Antibody in Serum at Week 48 | 1 participants |
| HGT-1410 45 mg Q2W | Number of Participants With Positive Anti-recombinant Human Heparan-N-Sulfatase (rhHNS) Antibody in Serum at Week 48 | 7 participants |
| HGT-1410 45 mg Q4W | Number of Participants With Positive Anti-recombinant Human Heparan-N-Sulfatase (rhHNS) Antibody in Serum at Week 48 | 6 participants |
Secondary
Number of Participants With Serious Adverse Events (SAE)
An adverse event (AE) was any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered investigational product related. This included an exacerbation of a pre-existing condition. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; lifethreatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Time frame: Baseline (Week 0) up to Week 52
Population: Safety population included all participants who received a dose of HGT-1410 either using IDDD implantation or LP; underwent the IDDD surgical implant procedure without receiving a dose of HGT-1410; were randomly assigned to the untreated group and had any safety follow-up data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| No HGT-1410 | Number of Participants With Serious Adverse Events (SAE) | 3 participants |
| HGT-1410 45 mg Q2W | Number of Participants With Serious Adverse Events (SAE) | 5 participants |
| HGT-1410 45 mg Q4W | Number of Participants With Serious Adverse Events (SAE) | 6 participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
An adverse event (AE) was any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered investigational product related. This included an exacerbation of a pre-existing condition. TEAEs were defined as AE occurring on or after the time of first IDDD implantation or LP procedure to the end of study (EOS) visit (+30 days).
Time frame: Baseline (Week 0) up to Week 52
Population: Safety population included all participants who received a dose of HGT-1410 using the IDDD implantation or LP; underwent the IDDD surgical implant procedure without receiving a dose of HGT-1410; were randomly assigned to the untreated group and had any safety follow-up data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| No HGT-1410 | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 6 participants |
| HGT-1410 45 mg Q2W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 7 participants |
| HGT-1410 45 mg Q4W | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 7 participants |