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

GM1 Gangliosidosis Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04273269
• Other study ID #: P1-GM-101
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: May 11, 2021
• Est. completion date: May 22, 2023

Study information

• Verified date: June 2023
• Source: LYSOGENE
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 5
• Est. completion date: May 22, 2023
• Est. primary completion date: May 22, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 3 Years

Eligibility

Inclusion Criteria:

• Documented GM1 gangliosidosis diagnosis based on genotyping confirming the ß-gal gene mutations and/or documented deficiency of ß-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

Related Conditions & MeSH terms

• Gangliosidoses
• Gangliosidosis, GM1
• GM1 Gangliosidosis

Intervention

Genetic:
• LYS-GM101
LYS-GM101 is an adeno-associated viral vector serotype rh.10 (AAVrh.10) carrying the human ß-galactosidase gene, formulated as a suspension for injection

Locations

Country	Name	City	State
France	Hôpital Armand-Trousseau, Centre de Référence des Maladies Lysosomales (CRML), Service de Neuropédiatrie	Paris
United Kingdom	Manchester University NHS Foundation Trust	Manchester
United States	Children's Hospital of Orange County (CHOC)	Orange	California

Sponsors (1)

Lead Sponsor	Collaborator
LYSOGENE

Countries where clinical trial is conducted

United States,  France,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	Stage 1: Neurological examination	Neurological examination: normal/abnormal motor activity and coordination, and change from previous assessment	Up to 6 months (multiple visits)
Primary	Stage 1: Vital signs: change from baseline in heart rate	Vital signs: change from baseline in heart rate	Up to 6 months (multiple visits)
Primary	Stage 1: Vital signs: change from baseline in body temperature	Vital signs: change from baseline in body temperature	Up to 6 months (multiple visits)
Primary	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)
Primary	Stage 1: Imaging: presence of bleeding post-administration	Imaging: presence of bleeding post-administration	Up to 6 months (multiple visits)
Primary	Stage 1: Change from baseline in biochemistry laboratory parameters	Change from baseline in biochemistry laboratory parameters	Up to 6 months (multiple visits)
Primary	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)
Primary	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)
Primary	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	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)
Secondary	Brain MRI	Assess brain atrophy and brain volume	Up to 2 years (multiple visits)
Secondary	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)
Secondary	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)
Secondary	Blood and cerebrospinal fluid (CSF) biomarkers (beta-galactosidase)	Assess change in beta-galactosidase activity measured from baseline	Up to 2 years (multiple visits)
Secondary	Blood and cerebrospinal fluid (CSF) biomarkers (GM1 ganglioside)	Assess change in GM1 ganglioside level measured from baseline	Up to 2 years (multiple visits)