A Safety and Efficacy Study of LYS-GM101 Gene Therapy in Patients With GM1 Gangliosidosis

• ClinicalTrials.gov Identifier: NCT04273269
• Recruitment Status: Terminated
• First Posted: February 18, 2020
• Last Update Posted: June 9, 2023
• Sponsor: LYSOGENE
• Information provided by (Responsible Party): LYSOGENE

Study Description

Brief Summary:

LYS-GM101 is a gene therapy for GM1 gangliosidosis intended to deliver a functional copy of the GLB1 gene to the central nervous system. This study will assess, in a 2-stage adaptive-design, the safety and efficacy of treatment in subjects with infantile GM1 gangliosidosis.

Condition or disease	Intervention/treatment	Phase
GM1 Gangliosidosis	Genetic: LYS-GM101	Phase 1; Phase 2

Detailed Description:

GM1 gangliosidosis is a fatal autosomal recessive disease caused by mutations in the GLB1 gene leading to accumulation of GM1 ganglioside in neurons and progressive neurodegeneration. There are three pediatric subtypes: early infantile, late infantile and juvenile. This is an interventional, multicenter, single-arm, 2-stage adaptive design study of LYS-GM101 for which the first stage (Stage 1) is for safety evaluation (FIH) and the second stage (Stage 2) will establish efficacy as compared to the natural history of the disease. The participants with infantile GM1 gangliosidosis will receive a single dose of LYS-GM101 by intracisternal injection. After a two-year evaluation period (main part of the study), each participant will be followed for an additional three-year long-term follow-up period.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 5 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label Adaptive-Design Study of Intracisternal Adenoassociated Viral Vector Serotype rh.10 Carrying the Human β-Galactosidase cDNA for Treatment of GM1 Gangliosidosis
• Actual Study Start Date: May 11, 2021
• Actual Primary Completion Date: May 22, 2023
• Actual Study Completion Date: May 22, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: 8x10^12 vg/Kg LYS-GM101; Subjects will receive a single infusion: 8x10^12 vg/Kg LYS-GM101	Genetic: LYS-GM101; LYS-GM101 is an adeno-associated viral vector serotype rh.10 (AAVrh.10) carrying the human β-galactosidase gene, formulated as a suspension for injection

Outcome Measures

Primary Outcome Measures :

1. Stage 1: Physical examination by body system [ Time Frame: Up to 6 months (multiple visits) ]
   Physical examination by body system: normal/abnormal and change from previous assessment
2. Stage 1: Neurological examination [ Time Frame: Up to 6 months (multiple visits) ]
   Neurological examination: normal/abnormal motor activity and coordination, and change from previous assessment
3. Stage 1: Vital signs: change from baseline in heart rate [ Time Frame: Up to 6 months (multiple visits) ]
   Vital signs: change from baseline in heart rate
4. Stage 1: Vital signs: change from baseline in body temperature [ Time Frame: Up to 6 months (multiple visits) ]
   Vital signs: change from baseline in body temperature
5. Stage 1: Vital signs: change from baseline in diastolic and systolic blood pressure [ Time Frame: Up to 6 months (multiple visits) ]
   Vital signs: change from baseline in diastolic and systolic blood pressure
6. Stage 1: Imaging: presence of bleeding post-administration [ Time Frame: Up to 6 months (multiple visits) ]
   Imaging: presence of bleeding post-administration
7. Stage 1: Change from baseline in biochemistry laboratory parameters [ Time Frame: Up to 6 months (multiple visits) ]
   Change from baseline in biochemistry laboratory parameters
8. Stage 1: Change from baseline in coagulation and hematology laboratory parameters [ Time Frame: Up to 6 months (multiple visits) ]
   Change from baseline in coagulation and hematology laboratory parameters
9. Stage 1: Incidence of treatment-emergent adverse event and serious adverse events [ Time Frame: Up to 6 months (multiple visits) ]
   Incidence of treatment-emergent adverse event and serious adverse events
10. Stage 1: Assessment of humoral immune response by measurement of antibodies anti-AAV and anti-beta-galactosidase (ELISA) and cellular immune response by beta-galactosidase-specific T-cell proliferation assay [ Time Frame: Up to 6 months (multiple visits) ]
    Assessment of humoral immune response by measurement of antibodies anti-AAV and anti-beta-galactosidase (ELISA) and cellular immune response by beta-galactosidase-specific T-cell proliferation assay

Secondary Outcome Measures :

1. Motor Function [ Time Frame: Up to 2 years (multiple visits) ]
   Assess change from baseline in motor function using the Hammersmith Infant Neurological Evaluation (HINE) or Hammersmith Functional Motor Scale-Expanded (HFMSE) instruments
2. Brain MRI [ Time Frame: Up to 2 years (multiple visits) ]
   Assess brain atrophy and brain volume
3. Developmental changes (VABS-II) [ Time Frame: Up to 2 years (multiple visits) ]
   Assess developmental change from baseline in the Vineland Adaptive Behavior Scale-II-Expanded Interview (VABS-II) instrument
4. Developmental changes (BSID-III or KABC-II) [ Time Frame: Up to 2 years (multiple visits) ]
   Assess developmental change from baseline in the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III) or the Kaufman Assessment Battery for Children, 2nd Edition (KABC-II) instruments
5. Blood and cerebrospinal fluid (CSF) biomarkers (beta-galactosidase) [ Time Frame: Up to 2 years (multiple visits) ]
   Assess change in beta-galactosidase activity measured from baseline
6. Blood and cerebrospinal fluid (CSF) biomarkers (GM1 ganglioside) [ Time Frame: Up to 2 years (multiple visits) ]
   Assess change in GM1 ganglioside level measured from baseline

Eligibility Criteria

• Ages Eligible for Study: up to 3 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Documented GM1 gangliosidosis diagnosis based on genotyping confirming the β-gal gene mutations and/or documented deficiency of β-gal enzyme by laboratory testing
• Children with early infantile GM1 gangliosidosis less than 12 months of age with ability to swallow
• Children with late infantile GM1 gangliosidosis less than 3 years of age with ability to sit

Exclusion Criteria:

• Uncontrolled seizure disorder. Patients who are stable on anti-convulsive medications may be included
• More than 40% brain atrophy as measured by MRI total brain volume at screening
• Current participation in a clinical trial of another investigational medicinal product
• Past participation in a gene therapy trial
• History of hematopoietic stem cell transplantation
• Any condition that would contraindicate treatment with immunosuppressant therapy
• Presence of concomitant medical condition or anatomical abnormality precluding lumbar puncture or intracisternal injection
• Presence of any permanent items (e.g., metal braces) precluding undergoing MRI
• History of non-GM1 gangliosidosis medical condition that would confound scientific rigor or interpretation of results
• Rare and unrelated serious comorbidities, e.g., Down syndrome, intraventricular hemorrhage in the new-born period, extreme low birth weight (<1500 grams) or known bleeding disorders
• Any vaccination 1 month prior to the planned immunosuppressant treatment
• Serology consistent with HIV exposure or consistent with active hepatitis B or C infection
• Grade 2 or higher lab abnormalities for Liver function tests (LFT), bilirubin, creatinine, hemoglobin, white blood cell (WBC) count, platelet count, prothrombin time (PT), and partial thromboplastin time (PTT), according to CTCAE v5.0

Contacts and Locations

Locations

United States, California

Children's Hospital of Orange County (CHOC)

Orange, California, United States, 92868

France

Hôpital Armand-Trousseau, Centre de Référence des Maladies Lysosomales (CRML), Service de Neuropédiatrie

Paris, France, 75012

United Kingdom

Manchester University NHS Foundation Trust

Manchester, United Kingdom, M13 9WL

Sponsors and Collaborators

LYSOGENE

Investigators

• Study Director: Clinical Operations; LYSOGENE

More Information

• Responsible Party: LYSOGENE
• ClinicalTrials.gov Identifier: NCT04273269
• Other Study ID Numbers: P1-GM-101
• First Posted: February 18, 2020
• Last Update Posted: June 9, 2023
• Last Verified: June 2023

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

Keywords provided by LYSOGENE:

GM1 Gangliosidosis; Lysosomal Storage Disease; Landing 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