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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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GM1 Gangliosidosis

Intervention / Treatment
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* Genetic: LYS-GM101


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 3 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 8x10^12 vg/Kg LYS-GM101<br>Subjects will receive a single infusion: 8x10^12 vg/Kg LYS-GM101 | Genetic: LYS-GM101<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stage 1: Physical examination by body system | Physical examination by body system: normal/abnormal and change from previous assessment | Up to 6 months (multiple visits) | 
| Stage 1: Neurological examination | Neurological examination: normal/abnormal motor activity and coordination, and change from previous assessment | Up to 6 months (multiple visits) | 
| Stage 1: Vital signs: change from baseline in heart rate | Vital signs: change from baseline in heart rate | Up to 6 months (multiple visits) | 
| Stage 1: Vital signs: change from baseline in body temperature | Vital signs: change from baseline in body temperature | Up to 6 months (multiple visits) | 
| Stage 1: Vital signs: change from baseline in diastolic and systolic blood pressure | Vital signs: change from baseline in diastolic and systolic blood pressure | Up to 6 months (multiple visits) | 
| Stage 1: Imaging: presence of bleeding post-administration | Imaging: presence of bleeding post-administration | Up to 6 months (multiple visits) | 
| Stage 1: Change from baseline in biochemistry laboratory parameters | Change from baseline in biochemistry laboratory parameters | Up to 6 months (multiple visits) | 
| Stage 1: Change from baseline in coagulation and hematology laboratory parameters | Change from baseline in coagulation and hematology laboratory parameters | Up to 6 months (multiple visits) | 
| Stage 1: Incidence of treatment-emergent adverse event and serious adverse events | Incidence of treatment-emergent adverse event and serious adverse events | Up to 6 months (multiple visits) | 
| 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 | 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 | Up to 6 months (multiple visits) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Motor Function | Assess change from baseline in motor function using the Hammersmith Infant Neurological Evaluation (HINE) or Hammersmith Functional Motor Scale-Expanded (HFMSE) instruments | Up to 2 years (multiple visits) | 
| Brain MRI | Assess brain atrophy and brain volume | Up to 2 years (multiple visits) | 
| Developmental changes (VABS-II) | Assess developmental change from baseline in the Vineland Adaptive Behavior Scale-II-Expanded Interview (VABS-II) instrument | Up to 2 years (multiple visits) | 
| Developmental changes (BSID-III or KABC-II) | 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 | Up to 2 years (multiple visits) | 
| Blood and cerebrospinal fluid (CSF) biomarkers (beta-galactosidase) | Assess change in beta-galactosidase activity measured from baseline | Up to 2 years (multiple visits) | 
| Blood and cerebrospinal fluid (CSF) biomarkers (GM1 ganglioside) | Assess change in GM1 ganglioside level measured from baseline | Up to 2 years (multiple visits) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GM1 Gangliosidosis, Lysosomal Storage Disease, Landing Disease