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

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

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.

Study Overview

• Status: Terminated
• Conditions: GM1 Gangliosidosis
• Intervention / Treatment: Genetic: LYS-GM101

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 Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Paris, France, 75012
    • Hôpital Armand-Trousseau, Centre de Référence des Maladies Lysosomales (CRML), Service de Neuropédiatrie
• United Kingdom
  • Manchester, United Kingdom, M13 9WL
    • Manchester University NHS Foundation Trust
• United States
  • California
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County (CHOC)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 3 years (Child)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: LYSOGENE
• Investigators: Study Director: Clinical Operations, LYSOGENE

Study record dates

Study Major Dates

• Study Start (Actual): May 11, 2021
• Primary Completion (Actual): May 22, 2023
• Study Completion (Actual): May 22, 2023

Study Registration Dates

• First Submitted: January 21, 2020
• First Submitted That Met QC Criteria: February 13, 2020
• First Posted (Actual): February 18, 2020

Study Record Updates

• Last Update Posted (Actual): June 9, 2023
• Last Update Submitted That Met QC Criteria: June 7, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: GM1 Gangliosidosis; Lysosomal Storage Disease; Landing Disease
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lipid Metabolism, Inborn Errors; Gangliosidoses; Gangliosidosis, GM1
• Other Study ID Numbers: P1-GM-101

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No