Study of Safety, Tolerability and Efficacy of PBGM01 in Pediatric Participants With GM1 Gangliosidosis

NCT04713475 | Active Not Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: PBGM01-0012020-001109-22
• Study Type: interventional
• Target: 26
• Locations: 4 countries
• Sites: 7

Brief Summary

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

Conditions

GM1 Gangliosidosis; GM1 Gangliosidosis, Type I; GM1 Gangliosidosis, Type 2; Beta-Galactosidase-1 (GLB1) Deficiency

Keywords

Infantile; Late Infantile; Rare disease; Lysosomal storage disease

Outcome Measures

Primary Outcomes (2)

• 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)

• 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)

Secondary Outcomes (7)

• Change from Baseline in Developmental Milestones as Assessed by the Vineland Adaptive Behavior Scale-II

  From baseline to 2 years (multiple visits)

• Change in Baseline in Biomarkers of Beta-Galactosidase 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

  From baseline to 2 years (multiple visits)

• Change in Concentration of Biomarker of Disease Progression in Plasma and CSF

  From baseline to 2 years (multiple visits)

• Change in Brain Anatomy as Assessed by MRI

  From baseline to 2 years (multiple visits)

Study Arms (4)

Part 1: Dose I of Dose Escalation Cohorts designed to identify the optimal dose of PBGM01

EXPERIMENTAL

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

Part 1: Dose II of Dose Escalation Cohorts designed to identify the optimal dose of PBGM01

EXPERIMENTAL

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

Part 1: Dose III of Dose Escalation Cohorts designed to identify the optimal dose of PBGM01

EXPERIMENTAL

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

Part 2: Expansion Cohort designed to confirm the safety and efficacy of PBGM01

EXPERIMENTAL

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

Interventions

PBGM01 BIOLOGICAL

AAVhu68 viral vector

Part 1: Dose I of Dose Escalation Cohorts designed to identify the optimal dose of PBGM01; Part 1: Dose II of Dose Escalation Cohorts designed to identify the optimal dose of PBGM01; Part 1: Dose III of Dose Escalation Cohorts designed to identify the optimal dose of PBGM01; Part 2: Expansion Cohort designed to confirm the safety and efficacy of PBGM01

Eligibility Criteria

• Age: 1 Month - 24 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.
• 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.
• 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.
• 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.
• Any contraindication to MRI or lumbar puncture (LP).
• Prior gene therapy.
• Use of miglustat within 48 hours prior to dosing of PBGM01. The use of miglustat is prohibited throughout the study.
• 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.
• Receipt of a vaccine within 14 days prior to dosing and/or scheduled vaccine within 30 days after dosing.
• Estimate glomerular filtration rate (eGFR) \<30 mL/minute based on creatinine
• Coagulopathy (INR \> 1.5) or activated partial thromboplastin time \[aPTT\] \> 40 seconds
• Thrombocytopenia (platelet count \< 100,000 per μL.
• AST or ALT \> 3 times the upper limit of normal (ULN) or total bilirubin \> 1.5x ULN
• Cardiomyopathy (screening troponin level above the ULN).

Sponsors & Collaborators

• Gemma Biotherapeutics: lead

Study Sites (7)

Benioff Children's Hospital

Oakland, California, 94158, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Children's Hospital at St. Peter's University Hospital

New Brunswick, New Jersey, 08901, United States

Location

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Hospital de Clínicas de Porto Alegre (HCPA)

Porto Alegre, Brazil

Location

Gazi University

Ankara, Turkey (Türkiye)

Location

Great Ormond Street Hospital

London, United Kingdom

Location

Related Publications (1)

• Zhang X, Brind'Amour K, King KE, Hartmaier S, Harris K, Weinstein DA, Girman CJ. Strategy for Generating Blinded Evidence for Single-Arm Trials with External Controls Using Expert Review of Home Video. Ther Innov Regul Sci. 2023 Nov;57(6):1304-1313. doi: 10.1007/s43441-023-00568-4. Epub 2023 Aug 17.

  PMID: 37592153 DERIVED

MeSH Terms

Conditions

Gangliosidosis, GM1; Rare Diseases; Lysosomal Storage Diseases

Condition Hierarchy (Ancestors)

Gangliosidoses; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipidoses; Lipid Metabolism, Inborn Errors; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• May Orfali, MD

  Gemma Biotherapeutics

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Open-label, multi-center, dose escalation

Study Record Dates

• First Submitted: January 4, 2021
• First Posted: January 19, 2021
• Study Start: March 17, 2021
• Primary Completion: February 1, 2026
• Study Completion (Estimated): February 1, 2029
• Last Updated: May 21, 2025

Record last verified: 2025-05

Locations

US (4); GB (1); TU (1); BR (1)