Study of Safety, Tolerability and Efficacy of PBGM01 in Pediatric Participants With GM1 Gangliosidosis (Imagine-1)

Phase 1/2 Open-Label, Multicenter Study to Assess the Safety, Tolerability and Efficacy of a Single Dose of PBGM01 Delivered Into the Cisterna Magna of Pediatric Type 1 (Early Onset) and Type 2a (Late Onset) Infantile GM1 Gangliosidosis

PBGM01 is a gene therapy for GM1 gangliosidosis intended to deliver a functional copy of the GLB1 gene to the brain and peripheral tissues. This study will assess in a 2 part design the safety, tolerability and efficacy of PBGM01 in patients with early onset infantile (Type 1) and late onset infantile (Type 2a) GM1 gangliosidosis

Study Overview

• Status: Active, not recruiting
• Conditions: GM1 Gangliosidosis; GM1 Gangliosidosis, Type I; GM1 Gangliosidosis, Type 2; Beta-Galactosidase-1 (GLB1) Deficiency
• Intervention / Treatment: Biological: PBGM01

Detailed Description

GM1 gangliosidosis (GM1) is an autosomal recessive disorder that results from mutations in the galactosidase beta 1 gene (GLB1), which encodes beta-galactosidase (β-gal). β-gal is a lysosomal enzyme that catalyzes the first step in the degradation of GM1 ganglioside and keratan sulfate, and GM1 patients carry GLB1 alleles that produce little or no residual β-gal activity. PBGM01 is an adeno-associated viral vector serotype hu68 carrying GLB1, the gene encoding for human beta-galactosidase, formulated as a solution for injection into the cisterna magna. This is a global interventional, multicenter, single-arm, dose escalation, adaptive design study of PBGM01 delivered as a one-time dose administered into the cisterna magna to patients with early onset infantile (Type 1) and late onset infantile (Type 2a) GM1 gangliosidosis.

In Part 1 of the study, the dose-escalation phase will assess three dose levels of PBGM01 as a one-time dose in six independent cohorts of patients with either Type 1 or Type 2a GM1 gangliosidosis. The cohorts for patients with Type 1 and Type 2a will be assessed independently from each other.

Part 2 of the study will test the safety and efficacy of PBGM01 in confirmatory cohorts for Types 1 and Type 2a GM1 gangliosidosis with a dose chosen based on the data obtained in part 1 of the study. This will be a 2-year study with a 3-year safety extension.

• Study Type: Interventional
• Enrollment (Estimated): 26
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Brazil
  • Porto Alegre, Brazil
    • Hospital de Clinicas de Porto Alegre (HCPA)
• Turkey
  • Ankara, Turkey
    • Gazi University
• United Kingdom
  • London, United Kingdom
    • Great Ormond Street Hospital
• United States
  • California
    • Oakland, California, United States, 94158
      • Benioff Children's Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Children's Hospital at St. Peter's University Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 months to 3 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• All Patients: Documented GM1 gangliosidosis diagnosis based on genotyping confirming 2 mutations in the GLB1 gene and documented deficiency of beta-galactosidase enzyme by laboratory testing.
• Early onset infantile (Type 1) must be ≥1 month and <12 months of age at enrollment and have signs and/or symptoms of GM1 gangliosidosis that started before 6 months of age with specific minimum developmental milestones remaining.
• Late onset infantile (Type 2a) must be ≥6 months and ≤24 months of age at enrollment and have signs and/or symptoms of GM1 gangliosidosis that started between 6 and 18 months of age with specific minimum developmental milestones remaining including the ability to sit independently at screening as defined by the WHO Multicenter Growth Reference Study (WHO-MGRS) criteria of being able to sit up unsupported with head erect for at least 10 seconds.

Exclusion Criteria:

1. Any clinically significant neurocognitive deficit not attributable to GM1 gangliosidosis or any other condition that may, in the opinion of the investigator, confound interpretation of study results.
2. If a 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 ventilation assisted respiratory support or a need for tracheostomy as a result of their disease. Chronic ventilatory support is defined as use of invasive or noninvasive (BiPAP) mechanical ventilation. Note: This does not exclude participants who use respiratory vests or noninvasive (BiPAP) mechanical ventilation for obstructive sleep apnea regardless of cause for less than 12 hours per day.
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. Note: This does not exclude participants who have a history of staring spells that have not been associated with EEG findings.
5. Any contraindication to the 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 a space occupying lesion causing mass effects 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 anatomy such as a large cerebellar vein or occipital sinus, or congenital anatomical abnormalities such as a Chiari malformation.
6. Any contraindication to MRI or lumbar puncture (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 is prohibited throughout the study.
10. Receipt of a vaccine within 14 days prior to dosing and/or scheduled vaccine within 30 days after dosing.
11. Estimate 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. AST or ALT > 3 times the upper limit of normal (ULN) or total bilirubin > 1.5x 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 including temperature over 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, or 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 put the subject at undue risk during the administration procedure or would interfere with evaluation of PBGM01 or interpretation of subject safety or study results.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Dose I of Dose Escalation Cohorts designed to identify the optimal dose of PBGM01; Assigned Intervention: PBGM01 Dose I: 3.3 x 10^10 GC/g estimated brain weight, single dose of PBGM01 via intra cisterna magna in Late Onset Infantile GM1 Gangliosidosis (Type 2a) and Early Onset Infantile GM1 Gangliosidosis (Type 1)	Biological: PBGM01; AAVhu68 viral vector
Experimental: Part 1: Dose II of Dose Escalation Cohorts designed to identify the optimal dose of PBGM01; Assigned Intervention: PBGM01 Dose II: 1.1 x 10^11 GC/g estimated brain weight, single dose of PBGM01 via intra cisterna magna in Late Onset Infantile GM1 Gangliosidosis (Type 2a) and Early Onset Infantile GM1 Gangliosidosis (Type 1)	Biological: PBGM01; AAVhu68 viral vector
Experimental: Part 1: Dose III of Dose Escalation Cohorts designed to identify the optimal dose of PBGM01; Assigned Intervention: PBGM01 Dose III: 2.2 x 10^11 GC/g estimated brain weight, single dose of PBGM01 via intra cisterna magna in Late Onset Infantile GM1 Gangliosidosis (Type 2a) and Early Onset Infantile GM1 Gangliosidosis (Type 1)	Biological: PBGM01; AAVhu68 viral vector
Experimental: Part 2: Expansion Cohort designed to confirm the safety and efficacy of PBGM01; Confirmatory Cohorts: Late Onset Infantile GM1 Gangliosidosis (Type 2a) and Early Onset Infantile GM1 Gangliosidosis (Type 1) Assigned Intervention: PBGM01 Single dose of PBGM01, via intra cisterna magna Dose to be determined	Biological: PBGM01; AAVhu68 viral vector

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in Developmental Milestones as Assessed by the Bayley Scale of Infant and Toddler Development, Third Edition	Assess changes in the developmental age and the total number of developmental milestones using the Bayley Scale of Infant and Toddler Development, Third Edition instrument	From baseline to 2 years (multiple visits)
Number of Participants with Treatment Related AEs and SAEs as Characterized by CTCAEv5.0	Assess the number of treatment-related adverse events (AEs) and serious adverse events (SAEs) as characterized by CTCAEv5.0	Up to 5 years (multiple visits)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in Developmental Milestones as Assessed by the Vineland Adaptive Behavior Scale-II	Assess changes in the developmental age and the total number of developmental milestones using the Vineland Adaptive Behavior Scale-II instrument	From baseline to 2 years (multiple visits)
Change in Brain Anatomy as Assessed by MRI	Assess change in disease severity, volumetric MRI measures, brain diffusivity, and white matter lesions by MRI imaging	From baseline to 2 years (multiple visits)
Change in Ventilator-Free Survival Compared with Natural History Data	Assess change compared with natural history data in ventilator-free survival and chronic ventilatory support	From baseline to 2 years (multiple visits)
Change in Baseline in Biomarkers of Beta-Galactosidase Activity in Blood and CSF	Assess change in biomarkers of beta-galactosidase activity including enzyme activity in blood and CSF	From baseline to 2 years (multiple visits)
Change in Baseline in Biomarkers of Beta-Galactosidase Substrates in Blood and CSF	Assess change in concentration of beta-galactosidase substrates including GM1 ganglioside in blood and CSF	From baseline to 2 years (multiple visits)
Change in Concentration of Biomarker of Disease Progression in Plasma and CSF	Assess change in neurofilament light chain (NfL) concentration as a marker for neurodegeneration and disease progression in plasma and CSF	From baseline to 2 years (multiple visits)
Change in Quality of Life Using Pediatric Quality of Life Scales	Assess change in quality of life as measured by Pediatric Quality of Life Scale (Peds QL) and the Pediatric Quality of Life-Infant Scale (PedsQL-IS)	From baseline to 2 years (multiple visits)

Collaborators and Investigators

• Sponsor: Gemma Biotherapeutics
• Investigators: Study Director: May Orfali, MD, Gemma Biotherapeutics

Study record dates

Study Major Dates

• Study Start (Actual): March 17, 2021
• Primary Completion (Estimated): February 1, 2026
• Study Completion (Estimated): February 1, 2029

Study Registration Dates

• First Submitted: January 4, 2021
• First Submitted That Met QC Criteria: January 14, 2021
• First Posted (Actual): January 19, 2021

Study Record Updates

• Last Update Posted (Actual): May 21, 2025
• Last Update Submitted That Met QC Criteria: May 16, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Rare disease; Infantile; Lysosomal storage disease; Late Infantile
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Lipid Metabolism Disorders; Lysosomal Storage Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases, Nervous System; Sphingolipidoses; Lipidoses; Gangliosidoses; Gangliosidosis, GM1
• Other Study ID Numbers: PBGM01-001; 2020-001109-22 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No