| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| GM1 gangliosidosis (GM1) is an autosomal recessive disorder that results from mutations in the human galactosidase beta 1 gene (GLB1), which encodes beta-galactosidase (β-gal). |
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| E.1.1.1 | Medical condition in easily understood language |
| When people have GM1, the gene (GLB1) that carries instructions to make a specific protein, called an enzyme, does not work properly. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- To assess the safety and tolerability of PBGM01 following administration of a single dose into the cisterna magna
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| E.2.2 | Secondary objectives of the trial |
- To assess the efficacy of PBGM01 following administration of a single dose into the cisterna magna
- To assess the pharmacodynamic effects of PBGM01 following administration of a single dose into the cisterna magna
- To assess the effects of PBGM01 following administration of a single dose into the cisterna magna on disease progression
- To assess the effects of PBGM01 following administration of a single dose into the cisterna magna on quality of life and healthcare resource utilization |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
This study will include infants who have confirmed biallelic pathological GLB1 mutations AND β-gal activity below the lower bound of the normal range. Subjects will be >4 months to <24 months of age at enrollment, with either symptoms of Type 1 (Early Onset Infantile) GM1 characterized by early onset (<6 months of age), predictive of rapid progression; or subjects aged >6 months to <24 months of age with symptoms of Type 2a (Late Onset Infantile) GM1 characterized by later onset presentation (>6 to 18 months of age), predictive of slower progression.
Inclusion Criteria
Subjects who are homozygous or compound heterozygous for GLB1 gene deletion or pathological mutation.
Type 1 (Early Onset Infantile) GM1
Subjects with medical record documentation of onset of signs or symptoms of GM1 before 6 months of age, with hypotonia and/or developmental delay and/or other signs consistent with GM1 (e.g., hepatosplenomegaly, skeletal dysplasia, cherry-red maculae, cardiomyopathy, and coarse facial features) AND must have at least two of the following remaining developmental skills within the past week confirmed/observed by the site examiner at the time of screening:
• Shows ability to move arms and legs intentionally.
• Looks at an object of interest for at least 3 continuous seconds.
• When held upright against a caregiver’s chest, can roll their head from one side to the other (e.g., if the child is lying with their left ear on the caregiver’s shoulder, they can switch to lying with their right ear on the caregiver’s shoulder without assistance or repositioning).
• Vocalizes a specific mood such as pleasure during activity with toys, free play, or social interaction; or displeasure when play is interrupted, toys removed, or child restrained.
• Throaty, gurgling or nasal sounds elicited by interaction with caregiver.
• Child’s eyes track a moving person through midline to the left and right.
Type 2a (Late Onset Infantile) GM1
Subjects with medical record documentation of onset of signs or symptoms of GM1 at age >6 months to 18 months of age, with hypotonia and/or plateauing or delay in achieving further developmental milestones and/or any other documented signs consistent with GM1 (e.g., hepatosplenomegaly, skeletal dysplasia, cherry-red maculae, cardiomyopathy, and coarse facial features) AND must meet age-dependent developmental criteria for symptomatic Late Onset Infantile GM1 subjects below:
Symptomatic subjects ≤ 12 months of age are required to have at least 1 of the 4 age appropriate gross motor, fine motor, language/cognitive or social developmental milestones listed for their age in the table below within the past week confirmed/observed by the site examiner at the time of screening.
Symptomatic subjects >12 and <24 months are required to have at least 2 of the 4 developmental milestones for a child 50% of their age (see table on page 67 of the protocol) within the past week confirmed/observed by the site examiner at the time of screening. For example, a 16-month-old child would need to have at least 2 of the 4 developmental milestones of an 8-month old child.
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| E.4 | Principal exclusion criteria |
Subjects should be reevaluated throughout the course of the study to ensure that they have not acquired any condition that might qualify them for exclusion from study procedures. If they develop any condition (s) that would exclude them from the study prior to receiving PBGM01, they should be withdrawn from the study. If after receiving PBGM01, a subject develops a contraindication to a procedure (e.g. MRI), investigators should refrain from performing such procedures (which could potentially cause harm) for the duration of the study (all other study procedures and data collection will continue).
1. Any clinically significant neurocognitive deficit not attributable to GM1 or any other condition that may, in the opinion of the investigator, confound interpretation of study results.
2. If any subject had an acute illness requiring hospitalization within 30 days of enrollment, the history must be discussed with the sponsor’s medical monitor before allowing the subject to be enrolled.
3. History of chronic ventilation-assisted respiratory support or a need for tracheostomy as a result of their disease.
4. Intractable seizure or uncontrolled epilepsy defined as having had an episode of status epilepticus, or seizures requiring hospitalization within 30 days prior to dosing of PBGM01.
5. Any contraindication to ICM administration procedure, including contraindications to fluoroscopic imaging and anesthesia or any condition that would increase the risk of adverse outcomes from the ICM procedure, including but not limited to the presence of space occupying lesion causing mass effect or signs of increased intracranial pressure, space-occupying lesion in the posterior fossa or foramen magnum, aberrant vascular anatomy such as a large midline posterior inferior cerebellar artery, aberrant venous anomaly such as a large midline cerebellar vein or occipital sinus, congenital anatomical abnormalities such as Chiari malformation.
6. Any contraindication to MRI or LP.
7. Prior gene therapy.
8. Use of miglustat within 48 hours prior to dosing of PBGM01. The use of miglustat is prohibited throughout the study.
9. Use of enzyme replacement therapy or other investigational therapy within 5 half-lives prior to dosing of PBGM01. The use of enzyme replacement therapy is prohibited throughout the study.
10. Receipt of a vaccine within 14 days of dosing
11. Estimated glomerular filtration rate (eGFR) <30 mL/minute based on creatinine
12. Coagulopathy (INR > 1.5 or activated partial thromboplastin time [aPTT] > 40 seconds)
13. Thrombocytopenia (Platelet count < 100,000 per µL)
14. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 x upper limit of normal (ULN) or total bilirubin >1.5 x ULN.
15. Cardiomyopathy (screening troponin level above the ULN)
16. Peripheral neuropathy
17. Medical conditions or laboratory or vital sign abnormalities that would increase risk of complications from intra-cisterna magna injection, anesthesia, fluoroscopy, LP, and/or MRI (Temperature > 38°C, oxygen saturation below 95% on room air or baseline oxygen requirement, heart rate or respiratory rate abnormal for age of the subject, abnormal blood pressure for age, evidence of infection)
18. Any condition (e.g., history of any disease, evidence of any current disease, any finding upon physical examination, or any laboratory abnormality) that, in the opinion of the investigator, would interfere with evaluation of PBGM01 or interpretation of subject safety or study results. This includes:
a. Abnormal laboratory values considered clinically significant by the investigator
b. Failure to thrive, defined as: Falling 20 percentiles (20/100) in body weight in the 3 months preceding Screening/Baseline
c. Underlying defect in immune function
d. History of multiple and severe life-threatening infections.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Adverse events, neurological examination, nerve conduction studies, Total Neuropathy Score-Nurse, hematology, serum chemistry, liver tests, coagulation (PT, aPTT, INR), CSF anti-AAVhu68 NAbs, vector shedding, urinalysis, physical examination, vital signs, ECG, brain MRI, and CSF cytology and chemistry (cell counts, protein, glucose) will be assessed over 5 years. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Key Secondary Endpoint will be assessed at 2 years and over 5 years:
• Vineland Adaptive Behavior Scales, Second Edition
Other Secondary Endpoints will be assessed at 2 years and over 5 years:
• Bayley Scale of Infant and Toddler Development, Third Edition (up to 42 months of age); Kaufman Assessment Battery for Children, Second Edition (>42 months of age)
• WHO Multicenter Growth Reference Study Motor Development Milestones Assessment
• Hammersmith Infant Neurodevelopment Examination
• Clinician and Caregiver Global Impression of Severity and Change
• Peabody Developmental Motor Scales, Second Edition (starting at 3 years of age)
• β-galactosidase activity, hexosaminidase activity, and neurofilament light chain levels in CSF and serum
• β-galactosidase substrates, which may include GM1 ganglioside, dp5, A2G2’, and keratan sulfate in CSF and/or serum and/or urine
All will be assessed over 5 years.
• Total brain volume, brain substructure volume, and ventricle volume and T1/T2 signal intensity as measured by MRI
• Skeletal abnormalities as measured by lateral spinal x-rays
• Cardiomyopathy measured by cardiac echocardiogram
• Hepatosplenomegaly measured by abdominal ultrasound
• Changes in EEG background features as measured by serial EEG
• Assessment of mechanical ventilation-free survival
• Assessment of nutrition status by need of placement and use of feeding tubes
• Seizure diary
• Hearing and vision testing
All will be assessed at pre-specified time points over 5 years
• Quality of life: Pediatric Quality of Life Inventory/ Pediatric Quality of Life Inventory-Infant Scale, version 4.0
• Healthcare resource utilization: chart review for hospital days, ER visits, ICU admissions, surgeries, need for hearing and visual aids
All will be assessed at pre-specified time points over 5 years
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| at 2 years and over 5 years |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 1 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Brazil |
| Canada |
| Turkey |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
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