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

• ClinicalTrials.gov Identifier: NCT04713475
• Recruitment Status: Active, not recruiting
• First Posted: January 19, 2021
• Last Update Posted: January 6, 2023
• Sponsor: Passage Bio, Inc.
• Information provided by (Responsible Party): Passage Bio, Inc.

Study Description

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-stage design the safety, tolerability and efficacy of this treatment in patients with early onset infantile (Type 1) and late onset infantile (Type 2a) GM1 gangliosidosis. Results from the Type 1 and Type 2a groups will be assessed separately.

Condition or disease	Intervention/treatment	Phase
GM1 Gangliosidosis; GM1 Gangliosidosis, Type I; GM1 Gangliosidosis, Type 2; Beta-Galactosidase-1 (GLB1) Deficiency	Biological: PBGM01	Phase 1; Phase 2

Detailed Description:

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 infantile GM1 gangliosidosis. There are two infantile subtypes of GM1 gangliosidosis: early onset infantile (Type 1) and late onset infantile (Type 2a) which are defined by the age of onset of disease symptoms.

Early Onset Infantile (Type 1):

• Onset <6 months of age
• Age at enrollment: >4 to <24 months of age

Late Onset Infantile (Type 2a):

• Onset >6 to 18 months of age
• Age at enrollment: >6 to <36 months of age (except Cohort 1 will be >12 to <36 months of age)

In Part 1 of the study, two dose levels of PBGM01 will be studied separately in patients with either Type 1 or Type 2a GM1 gangliosidosis (see table below). The cohorts for patients with Type 1 and Type 2a will be assessed independently from each other. Part 1 will enroll a total of four cohorts, enrolled sequentially with separate dose-escalation cohorts for Type 1 GM1 and Type 2a GM1. Enrollment will initiate in Cohort 1. Following completion of Cohort 1, simultaneous enrollment in Cohort 2 and Cohort 3 will occur. Cohort 4 will follow completion of cohort 3.

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 20 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Open-label, multi-center, dose escalation
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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 Subjects With Type 1 (Early Onset) and Type 2a (Late Onset) Infantile GM1 Gangliosidosis
• Actual Study Start Date: March 17, 2021
• Estimated Primary Completion Date: February 2026
• Estimated Study Completion Date: February 2029

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1: Dose Escalation Cohorts designed to identify the optimal dose of PBGM01; Cohort 1: Late Onset Infantile GM1 Gangliosidosis (Type 2a) Assigned Intervention: Drug: PBGM01 Dose 1: 3.3 x 10^10 GC/g* Single dose of PBGM01, via intra cisterna magna Cohort 2: Late Onset Infantile GM1 Gangliosidosis (Type 2a) Assigned Intervention: Drug: PBGM01 Dose 2: 1.1 x 10^11 GC/g* Single dose of PBGM01, via intra cisterna magna Cohort 3: Early Onset Infantile GM1 Gangliosidosis (Type 1) Assigned Intervention: Drug: PBGM01 Dose 1: 3.3 x 10^10 GC/g* Single dose of PBGM01, via intra cisterna magna Cohort 4: Early Onset Infantile GM1 Gangliosidosis (Type 1) Assigned Intervention: Drug: PBGM01 Dose 2: 1.1 x 10^11 GC/g* Single dose of PBGM01, via intra cisterna magna *GC/g: gene copy per gram of estimated brain weight	Biological: PBGM01; AAVhu68 viral vector
Experimental: Part 2: Expansion Cohort designed to confirm the safety and efficacy of PBGM01; Cohort 5: Late Onset Infantile GM1 Gangliosidosis (Type 2a) Assigned Intervention: Drug: PBGM01 Single dose of PBGM01, via intra cisterna magna Dose to be used for the confirmatory cohorts in Part 2 will be defined after a review of data from Part 1. Cohort 6: Early Onset Infantile GM1 Gangliosidosis (Type 1) Assigned Intervention: Drug: PBGM01 Single dose of PBGM01, via intra cisterna magna Dose to be used for the confirmatory cohorts in Part 2 will be defined after a review of data from Part 1.	Biological: PBGM01; AAVhu68 viral vector

Outcome Measures

Primary Outcome Measures :

1. Number of Participants with Treatment Related AEs and SAEs as Characterized by CTCAEv5.0 [ Time Frame: Up to 5 years (multiple visits) ]
   Assess the number of treatment-related adverse events (AEs) and serious adverse events (SAEs) as characterized by CTCAEv5.0
2. Change in Nerve Conduction Velocity and Amplitude from Baseline on Nerve Conduction Studies [ Time Frame: From baseline to 5 years (multiple visits) ]
   Assess changes in nerve conduction velocity and amplitude in the distal segments of the sural, radial, and medial sensory nerves and peroneal motor nerve as measured on conventional nerve conduction studies
3. Number of Participants with Clinically Significant Laboratory Abnormalities as Measured Using Hematology, Chemistry and Coagulation Tests [ Time Frame: Up to 5 years (multiple visits) ]
   Assess the number of participants with clinically significant laboratory changes including hematology, serum chemistry, and coagulation tests
4. Assess Humoral Response Against the Vector and Transgene in Serum [ Time Frame: Up to 5 years (multiple visits) ]
   Assess serum antibody titers against AAVhu68 and against beta-galactosidase following ICM administration of PBGM01
5. Assess Humoral Response Against the Vector and Transgene in CSF [ Time Frame: Up to 5 years (multiple visits) ]
   Assess antibody titers in the cerebrospinal fluid against AAVhu68 and against beta-galactosidase following ICM administration of PBGM01

Secondary Outcome Measures :

1. Change from Baseline in Developmental Milestones as Assessed by the Vineland Adaptive Behavior Scale-II [ Time Frame: From baseline to 2 years (multiple visits) ]
   Assess changes in the developmental age and the total number of developmental milestones using the Vineland Adaptive Behavior Scale-II instrument
2. Change from Baseline in Developmental Milestones as Assessed by the Bayley Scale of Infant and Toddler Development, Third Edition [ Time Frame: From baseline to 2 years (multiple visits) ]
   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
3. Change in Biomarkers of Beta-Galactosidase Activity in Blood [ Time Frame: From baseline to 2 years (multiple visits) ]
   Assess change in biomarkers of beta-galactosidase activity including enzyme activity and hexosaminidase activity in blood when compared with baseline
4. Change in Biomarkers of Beta-Galactosidase Activity in CSF [ Time Frame: From baseline to 2 years (multiple visits) ]
   Assess change in biomarkers of beta-galactosidase activity including enzyme activity and hexosaminidase activity in CSF when compared with baseline
5. Change in Biomarkers of Beta-Galactosidase Substrates in Blood [ Time Frame: From baseline to 2 years (multiple visits) ]
   Assess change in concentration of beta-galactosidase substrates including GM1 ganglioside and keratan sulfate in blood
6. Change in Biomarkers of Beta-Galactosidase Substrates in CSF [ Time Frame: From baseline to 2 years (multiple visits) ]
   Assess change in concentration of GM1 ganglioside in CSF when compared with baseline
7. Change in Concentration of Biomarker of Disease Progression in Plasma [ Time Frame: From baseline to 2 years (multiple visits) ]
   Assess change in neurofilament light chain (NfL) concentration as a marker for neurodegeneration and disease progression in plasma
8. Change in Concentration of Biomarker of Disease Progression in CSF [ Time Frame: From baseline to 2 years (multiple visits) ]
   Assess change in neurofilament light chain concentration (NfL) as a marker for neurodegeneration and disease progression in CSF
9. Change in Brain Anatomy as Assessed by MRI [ Time Frame: From baseline to 2 years (multiple visits) ]
   Assess change in disease severity, volumetric MRI measures, brain diffusivity, and white matter lesions by MRI imaging
10. Change in Quality of Life Using Pediatric Quality of Life Scales [ Time Frame: From baseline to 2 years (multiple visits) ]
    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)
11. Change in Ventilator-Free Survival Compared with Natural History Data [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change compared with natural history data in ventilator-free survival and chronic ventilatory support

Eligibility Criteria

• Ages Eligible for Study: 4 Months to 36 Months (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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
• Age: 4 to 36 months (first cohort will be 12-36 months)

Subjects:

• Early onset infantile (Type 1): Subjects who have signs and/or symptoms of GM1 gangliosidosis that started at or before 6 months of age and have specific developmental milestones remaining
• Late onset infantile (Type 2a): Subjects who have signs and/or symptoms of GM1 gangliosidosis that started between 6 and 18 months of age and have specific developmental milestones remaining

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.
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 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 of 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.

Contacts and Locations

Locations

United States, California

Benioff Children's Hospital

Oakland, California, United States, 94158

United States, Minnesota

University of Minnesota

Minneapolis, Minnesota, United States, 55455

United States, New Jersey

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

New Brunswick, New Jersey, United States, 08901

United States, Pennsylvania

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

Brazil

Hospital de Clínicas de Porto Alegre (HCPA)

Porto Alegre, Brazil

Canada

Montreal Children's Hospital

Montréal, Canada

The Hospital for Sick Children

Toronto, Canada

Turkey

Gazi University

Ankara, Turkey

United Kingdom

Great Ormond Street Hospital

London, United Kingdom

Sponsors and Collaborators

Passage Bio, Inc.

Investigators

• Study Director: Samiah Al-Zaidy, MD; Passage Bio, Inc.

More Information

• Responsible Party: Passage Bio, Inc.
• ClinicalTrials.gov Identifier: NCT04713475
• Other Study ID Numbers: PBGM01-001; 2020-001109-22 ( EudraCT Number )
• First Posted: January 19, 2021
• Last Update Posted: January 6, 2023
• Last Verified: January 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Passage Bio, Inc.:

Infantile; Late Infantile; Rare disease; Lysosomal storage disease

Additional relevant MeSH terms:

Gangliosidoses; Gangliosidosis, GM1; 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; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Lipid Metabolism Disorders